Methods of enhancing the pharmacokinetics or increasing the plasma concentration of 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylic acid methyl ester or a salt thereof using inhibitors of cytochrome P450

Abstract

Described herein are compositions and uses thereof comprising (a) methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate or a salt thereof; and (b) an agent for reducing metabolism of (a).

Description

[0001] Cross Reference to Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 62 / 959,514, filed January 10, 2020, the entirety of which is incorporated by reference herein in its entirety. BACKGROUND

[0003] Orexins (OXs) are neuropeptides that regulate sleep / wakefulness and are involved in energy homeostasis, mood, stress, and reward by activating two G protein-coupled receptors, OX1R and OX2R. OX2R agonists directly target the underlying pathophysiology of narcolepsy type 1 (NT1) by restoring OX2R receptor signaling in these patients who lack intrinsic OXs. Methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate shows significant effects on improving wakefulness and reducing cataplexy-like symptoms in rodent models of narcolepsy and improves wakefulness in healthy mice and non-human primates.

[0004] Methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate is the first OX2R agonist to enter human studies and has proven to be safe and well-tolerated when administered intravenously (IV) in single-dose studies in healthy volunteers and NT1 patients. SUMMARY

[0005] One embodiment is a combination therapy comprising (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing the metabolism of the OX2R agonist, compositions and kits comprising the combination therapy, and methods of using the combination therapy.

[0006] Another embodiment is a method for enhancing the pharmacokinetics of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate or a salt thereof comprising administering to a subject (a) methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate or a salt thereof; and (b) an agent for reducing the metabolism of (a).

[0007] Another embodiment is a method for increasing the plasma concentration of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate or a salt thereof comprising administering to a subject (a) methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate or a salt thereof; and (b) an agent for reducing the metabolism of (a).

[0008] Another embodiment is a method for increasing wakefulness or reducing excessive sleepiness in a subject in need thereof comprising administering to the subject (a) 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-l- carboxylic acid methyl ester, or a salt thereof; and (b) an agent for reducing metabolism of (a).

[0009] Another embodiment is a pharmaceutical composition comprising (a) 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylic acid methyl ester, or a salt thereof; and (b) an agent for reducing metabolism of (a). BRIEF DESCRIPTION OF DRAWINGS

[0010] Figure 1 A study schematic for Example 1 is shown.

[0011] Figure 2 A plot of arithmetic mean dose-normalized (to the 112 mg Compound A dose) plasma Compound A concentration versus time is shown for healthy subjects following a single intravenous dose of 14 mg of Compound A alone over 9 hours on Day 2, a single oral dose of 112 mg of Compound A alone on Day 3, and a single oral dose of 14 mg of Compound A coadministered with multiple once-daily oral doses of 150 mg of cobicistat on Days 5-13 on Day 12.

[0012] Figure 3 A plot of arithmetic mean plasma Compound A concentration versus time is shown for healthy subjects following a single intravenous dose of 14 mg of Compound A alone over 9 hours on Day 2, a single oral dose of 112 mg of Compound A alone on Day 3, and a single oral dose of 14 mg of Compound A coadministered with multiple once-daily oral doses of 150 mg of cobicistat on Days 5-13 on Day 12. DETAILED DESCRIPTION

[0013] Disclosed herein are combination therapies comprising (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing metabolism of the OX2R agonist, compositions and kits comprising the combination therapies, and methods of using the combination therapies. Suitable OX2R agonists include, but are not limited to, those disclosed in WO2017 / 135306, the contents of which are hereby incorporated by reference.

[0014] Disclosed herein are combination therapies comprising (a) methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate or a salt thereof (hereinafter referred to as "Compound (I)"); and (b) an agent for reducing the metabolism of Compound (I), compositions and kits comprising the combination therapies, and methods of using the combination therapies. The present invention can improve the bioavailability of methyl 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate, in particular, which has extensive first-pass metabolism.

[0015] The methods, compositions, and uses disclosed herein include treating a disease or disorder or a symptom associated with excessive sleepiness in a subject in need thereof, as well as treating a subject suffering from excessive sleepiness but who has not yet been diagnosed with any disease or disorder. There are many causes of excessive sleepiness, including but not limited to abnormalities in sleep quantity or sleep quality, as well as neurological, psychological, cardiac, and pulmonary disorders.

[0016] In one embodiment, the methods, compositions, and uses of the present disclosure can involve treating excessive sleepiness caused by a deficiency in the orexin neuropeptide that regulates arousal, wakefulness, and appetite. Excessive sleepiness can also occur in individuals who are not deficient in orexin. The present disclosure also relates to treating diseases, disorders, and / or symptoms of excessive sleepiness that are not associated with a decrease in orexin levels.

[0017] Disclosed herein are methods for enhancing the pharmacokinetics of Compound (I), comprising administering to a subject (a) Compound (I); and (b) an agent for reducing the metabolism of Compound (I).

[0018] Also disclosed herein is a combination therapy for use in enhancing the pharmacokinetics of Compound (I), comprising (a) Compound (I); and (b) an agent for reducing the metabolism of Compound (I).

[0019] Also disclosed herein is the use of (a) Compound (I); and (b) an agent for reducing the metabolism of Compound (I) in the manufacture of a medicament for enhancing the pharmacokinetics of Compound (I).

[0020] Also disclosed herein is an agent for reducing the metabolism of Compound (I) for use in enhancing the pharmacokinetics of Compound (I).

[0021] Also disclosed herein is the use of an agent for reducing the metabolism of Compound (I) in the manufacture of a medicament for enhancing the pharmacokinetics of Compound (I).

[0022] Disclosed herein are methods for increasing the plasma concentration of Compound (I), comprising administering to a subject (a) Compound (I); and (b) an agent for reducing the metabolism of Compound (I).

[0023] Also disclosed herein is a combination therapy for use in increasing the plasma concentration of Compound (I), comprising (a) Compound (I); and (b) an agent for reducing the metabolism of Compound (I).

[0024] Also disclosed herein is the use of (a) Compound (I); and (b) an agent for reducing the metabolism of Compound (I), in the manufacture of a medicament for increasing the plasma concentration of Compound (I).

[0025] Also disclosed herein is an agent for reducing the metabolism of Compound (I) for use in increasing the plasma concentration of Compound (I).

[0026] Also disclosed herein is the use of an agent for reducing the metabolism of Compound (I), in the manufacture of a medicament for increasing the plasma concentration of Compound (I).

[0027] Disclosed herein is a method for maintaining the medicinal effect of Compound (I), comprising administering to a subject (a) Compound (I); and (b) an agent for reducing the metabolism of Compound (I).

[0028] Also disclosed herein is a combination therapy for use in maintaining the medicinal effect of Compound (I), comprising (a) Compound (I); and (b) an agent for reducing the metabolism of Compound (I).

[0029] Also disclosed herein is the use of (a) Compound (I); and (b) an agent for reducing the metabolism of Compound (I), in the manufacture of a medicament for maintaining the medicinal effect of Compound (I).

[0030] Disclosed herein is a method for maintaining a therapeutically effective plasma concentration of Compound (I), comprising administering to a subject (a) Compound (I); and (b) an agent for reducing the metabolism of Compound (I).

[0031] Also disclosed herein is a combination therapy for use in maintaining a therapeutically effective plasma concentration of Compound (I), comprising (a) Compound (I); and (b) an agent for reducing the metabolism of Compound (I).

[0032] Also disclosed herein is the use of (a) Compound (I); and (b) an agent for reducing the metabolism of Compound (I), in the manufacture of a medicament for maintaining a therapeutically effective plasma concentration of Compound (I).

[0033] Disclosed herein is a method for reducing the metabolism of Compound (I), comprising administering to a subject (a) Compound (I); and (b) a CYP3A inhibitor.

[0034] Also disclosed herein is a combination therapy for use in reducing the metabolism of Compound (I), comprising (a) Compound (I); and (b) a CYP3A inhibitor.

[0035] Also disclosed herein is the use of (a) Compound (I); and (b) a CYP3A inhibitor in the manufacture of a medicament for reducing the metabolic clearance of Compound (I).

[0036] Disclosed herein is a method for reducing the time-dependent decrease in plasma concentration of Compound (I) comprising administering to a subject (a) Compound (I); and (b) a CYP3A inhibitor.

[0037] Also disclosed herein is a combination therapy for use in reducing the time-dependent decrease in plasma concentration of Compound (I) comprising (a) Compound (I); and (b) a CYP3A inhibitor.

[0038] Also disclosed herein is the use of (a) Compound (I); and (b) a CYP3A inhibitor in the manufacture of a medicament for reducing the time-dependent decrease in plasma concentration of Compound (I).

[0039] Disclosed herein is a method for reducing the metabolic clearance of Compound (I) comprising administering to a subject (a) Compound (I); and (b) a CYP3A4 inhibitor.

[0040] Also disclosed herein is a combination therapy for use in reducing the metabolic clearance of Compound (I) comprising (a) Compound (I); and (b) a CYP3A4 inhibitor.

[0041] Also disclosed herein is the use of (a) Compound (I); and (b) a CYP3A4 inhibitor in the manufacture of a medicament for reducing the metabolic clearance of Compound (I).

[0042] Disclosed herein is a method for reducing the time-dependent decrease in plasma concentration of Compound (I) comprising administering to a subject (a) Compound (I); and (b) a CYP3A4 inhibitor.

[0043] Also disclosed herein is a combination therapy for use in reducing the time-dependent decrease in plasma concentration of Compound (I) comprising (a) Compound (I); and (b) a CYP3A4 inhibitor.

[0044] Also disclosed herein is the use of (a) Compound (I); and (b) a CYP3A4 inhibitor in the manufacture of a medicament for reducing the time-dependent decrease in plasma concentration of Compound (I).

[0045] Disclosed herein is a method for increasing wakefulness in a subject in need thereof comprising administering to the subject (a) Compound (I); and (b) an agent for reducing the metabolic clearance of Compound (I).

[0046] Also disclosed herein is a combination therapy for use in increasing wakefulness in a subject, comprising (a) Compound (I); and (b) an agent for reducing metabolism of Compound (I).

[0047] Also disclosed herein is the use of (a) methyl 3-((methylsulfonyl)amino)-2-(((4- phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylate (Compound (I)), or a salt thereof; and (b) an agent for reducing metabolism of Compound (I) in the manufacture of a medicament for increasing wakefulness.

[0048] Disclosed herein is a method for reducing excessive sleepiness in a subject in need thereof, comprising administering to the subject (a) Compound (I); and (b) an agent for reducing metabolism of Compound (I).

[0049] Also disclosed herein is a combination therapy for use in reducing excessive sleepiness in a subject, comprising (a) Compound (I); and (b) an agent for reducing metabolism of Compound (I).

[0050] Also disclosed herein is the use of (a) Compound (I); and (b) an agent for reducing metabolism of Compound (I) in the manufacture of a medicament for reducing excessive sleepiness in a subject.

[0051] Disclosed herein is a method for treating excessive sleepiness in a subject in need thereof, comprising administering to the subject (a) Compound (I); and (b) an agent for reducing metabolism of Compound (I).

[0052] Also disclosed herein is a combination therapy for use in treating excessive sleepiness in a subject, comprising (a) Compound (I); and (b) an agent for reducing metabolism of Compound (I).

[0053] Also disclosed herein is the use of (a) Compound (I); and (b) an agent for reducing metabolism of Compound (I) in the manufacture of a medicament for treating excessive sleepiness.

[0054] Disclosed herein is a method for treating type 1 narcolepsy in a subject in need thereof, comprising administering to the subject (a) Compound (I); and (b) an agent for reducing metabolism of Compound (I).

[0055] Also disclosed herein is a combination therapy for use in treating type 1 narcolepsy in a subject in need thereof, comprising (a) Compound (I); and (b) an agent for reducing metabolism of Compound (I).

[0056] Disclosed herein is the use of (a) Compound (I); and (b) an agent for reducing metabolism of Compound (I) in the manufacture of a medicament for treating type 1 narcolepsy in a subject in need thereof.

[0057] Alternatively, disclosed herein is a method for reducing cataplexy-like events (e.g., cataplexy) in a subject in need thereof, comprising administering to the subject (a) Compound (I); and (b) an agent for reducing metabolism of Compound (I). In some embodiments, the subject is afflicted with or diagnosed with narcolepsy type 1. In some embodiments, the cataplexy-like event is cataplexy.

[0058] Also disclosed herein is a combination therapy for use in reducing cataplexy-like events (e.g., cataplexy) in a subject in need thereof, comprising (a) Compound (I); and (b) an agent for reducing metabolism of Compound (I). In some embodiments, the subject is afflicted with or diagnosed with narcolepsy type 1. In some embodiments, the cataplexy-like event is cataplexy.

[0059] Disclosed herein is the use of (a) Compound (I); and (b) an agent for reducing metabolism of Compound (I) in the manufacture of a medicament for reducing cataplexy-like events (e.g., cataplexy) in a subject in need thereof. In some embodiments, the subject is afflicted with or diagnosed with narcolepsy type 1. In some embodiments, the cataplexy-like event is cataplexy.

[0060] Disclosed herein is a method for treating shift work disorder, shift work sleep disorder, or jet lag in a subject in need thereof, comprising administering to the subject (a) Compound (I); and (b) an agent for reducing metabolism of Compound (I).

[0061] Also disclosed herein is a combination therapy for use in treating shift work disorder, shift work sleep disorder, or jet lag in a subject in need thereof, comprising (a) Compound (I); and (b) an agent for reducing metabolism of Compound (I).

[0062] Disclosed herein is the use of (a) Compound (I); and (b) an agent for reducing metabolism of Compound (I) in the manufacture of a medicament for treating shift work disorder, shift work sleep disorder, or jet lag in a subject in need thereof.

[0063] Disclosed herein is a method for enhancing the pharmacokinetics of an orexin 2 receptor (OX2R) agonist, comprising administering to the subject (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing metabolism of the OX2R agonist.

[0064] Also disclosed herein is a combination therapy for use in enhancing the pharmacokinetics of an OX2R agonist, comprising (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing metabolism of the OX2R agonist.

[0065] Also disclosed herein is the use of (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing the metabolism of the OX2R agonist in the manufacture of a medicament for enhancing the pharmacokinetics of the OX2R agonist.

[0066] Also disclosed herein is an agent for reducing the metabolism of an orexin 2 receptor (OX2R) agonist for use in enhancing the pharmacokinetics of the OX2R agonist.

[0067] Also disclosed herein is the use of an agent for reducing the metabolism of an orexin 2 receptor (OX2R) agonist in the manufacture of a medicament for enhancing the pharmacokinetics of the OX2R agonist.

[0068] Disclosed herein is a method for increasing the plasma concentration of an orexin 2 receptor (OX2R) agonist comprising administering to a subject (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing the metabolism of the OX2R agonist.

[0069] Also disclosed herein is a combination therapy for use in increasing the plasma concentration of an orexin 2 receptor (OX2R) agonist comprising (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing the metabolism of the OX2R agonist.

[0070] Also disclosed herein is the use of (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing the metabolism of the OX2R agonist in the manufacture of a medicament for increasing the plasma concentration of the OX2R agonist.

[0071] Also disclosed herein is an agent for reducing the metabolism of an orexin 2 receptor (OX2R) agonist for use in increasing the plasma concentration of the OX2R agonist.

[0072] Also disclosed herein is the use of an agent for reducing the metabolism of an orexin 2 receptor (OX2R) agonist in the manufacture of a medicament for increasing the plasma concentration of the OX2R agonist.

[0073] Disclosed herein is a method for maintaining the medicinal effect of an orexin 2 receptor (OX2R) agonist comprising administering to a subject (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing the metabolism of the OX2R agonist.

[0074] Also disclosed herein is a combination therapy for use in maintaining the medicinal effect of an orexin 2 receptor (OX2R) agonist comprising (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing the metabolism of the OX2R agonist.

[0075] Also disclosed herein is the use of (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing the metabolism of the OX2R agonist in the manufacture of a medicament for maintaining the medicinal effect of the OX2R agonist.

[0076] Disclosed herein are methods for maintaining a pharmaceutically effective plasma concentration of an orexin 2 receptor (OX2R) agonist comprising administering to a subject (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing metabolism of the OX2R agonist.

[0077] Also disclosed herein is a combination therapy for use in maintaining a pharmaceutically effective plasma concentration of an OX2R agonist comprising (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing metabolism of the OX2R agonist.

[0078] Also disclosed herein is the use of (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing metabolism of the OX2R agonist in the manufacture of a medicament for maintaining a pharmaceutically effective plasma concentration of an OX2R agonist.

[0079] Disclosed herein are methods for reducing metabolism of an orexin 2 receptor (OX2R) agonist comprising administering to a subject (a) an orexin 2 receptor (OX2R) agonist; and (b) a CYP3A4 inhibitor.

[0080] Also disclosed herein is a combination therapy for use in reducing metabolism of an OX2R agonist comprising (a) an orexin 2 receptor (OX2R) agonist; and (b) a CYP3A4 inhibitor.

[0081] Also disclosed herein is the use of (a) an orexin 2 receptor (OX2R) agonist; and (b) a CYP3A4 inhibitor in the manufacture of a medicament for reducing metabolism of an OX2R agonist.

[0082] Disclosed herein are methods for reducing time-dependent reduction in plasma concentration of an orexin 2 receptor (OX2R) agonist comprising administering to a subject (a) an orexin 2 receptor (OX2R) agonist; and (b) a CYP3A4 inhibitor.

[0083] Also disclosed herein is a combination therapy for use in reducing time-dependent reduction in plasma concentration of an OX2R agonist comprising (a) an orexin 2 receptor (OX2R) agonist; and (b) a CYP3A4 inhibitor.

[0084] Also disclosed herein is the use of (a) an orexin 2 receptor (OX2R) agonist; and (b) a CYP3A4 inhibitor in the manufacture of a medicament for reducing time-dependent reduction in plasma concentration of an OX2R agonist.

[0085] Disclosed herein are methods for increasing wakefulness in a subject in need thereof comprising administering to the subject (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing metabolism of the OX2R agonist.

[0086] Also disclosed herein is a combination therapy for use in increasing wakefulness in a subject, comprising (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing metabolism of the OX2R agonist.

[0087] Also disclosed herein is the use of (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing metabolism of the OX2R agonist in the manufacture of a medicament for increasing wakefulness.

[0088] Disclosed herein is a method for reducing excessive sleepiness in a subject in need thereof, comprising administering to the subject (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing metabolism of the OX2R agonist.

[0089] Also disclosed herein is a combination therapy for use in reducing excessive sleepiness in a subject, comprising (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing metabolism of the OX2R agonist.

[0090] Also disclosed herein is the use of (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing metabolism of the OX2R agonist in the manufacture of a medicament for reducing excessive sleepiness in a subject.

[0091] Disclosed herein is a method for treating excessive sleepiness in a subject in need thereof, comprising administering to the subject (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing metabolism of the OX2R agonist.

[0092] Also disclosed herein is a combination therapy for use in treating excessive sleepiness in a subject, comprising (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing metabolism of the OX2R agonist.

[0093] Also disclosed herein is the use of (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing metabolism of the OX2R agonist in the manufacture of a medicament for treating excessive sleepiness.

[0094] Disclosed herein is a method for treating type 1 narcolepsy in a subject in need thereof, comprising administering to the subject (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing metabolism of the OX2R agonist.

[0095] Also disclosed herein is a combination therapy for use in treating type 1 narcolepsy in a subject in need thereof, comprising (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing metabolism of the OX2R agonist.

[0096] Disclosed herein is the use of (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing metabolism of the OX2R agonist in the manufacture of a medicament for treating type 1 narcolepsy in a subject in need thereof.

[0097] Alternatively, disclosed herein is a method for reducing cataplexy-like events (e.g., cataplexy) in a subject in need thereof, comprising administering to the subject (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing metabolism of the OX2R agonist. In some embodiments, the subject is afflicted with or diagnosed with type 1 narcolepsy. In some embodiments, the cataplexy-like event is cataplexy.

[0098] Also disclosed herein is a combination therapy for use in treating shift work disorder, shift work sleep disorder, or jet lag in a subject in need thereof, comprising (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing metabolism of the OX2R agonist.

[0099] Also disclosed herein is a combination therapy for use in treating shift work disorder, shift work sleep disorder, or jet lag in a subject in need thereof, comprising (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing metabolism of the OX2R agonist.

[0100] Also disclosed herein is a combination therapy for use in treating shift work disorder, shift work sleep disorder, or jet lag in a subject in need thereof, comprising (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing metabolism of the OX2R agonist.

[0101] Also disclosed herein is a combination therapy for use in treating shift work disorder, shift work sleep disorder, or jet lag in a subject in need thereof, comprising (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing metabolism of the OX2R agonist.

[0102] Also disclosed herein is a combination therapy for use in treating shift work disorder, shift work sleep disorder, or jet lag in a subject in need thereof, comprising (a) an orexin 2 receptor (OX2R) agonist; and (b) an agent for reducing metabolism of the OX2R agonist.

[0103] In some embodiments, the OX2R agonist is Compound (I).

[0104] The methods and uses disclosed herein can treat narcolepsy type 1 in a subject in need thereof. In some embodiments, treating narcolepsy type 1 can include reducing or alleviating one or more symptoms of narcolepsy type 1. The one or more symptoms of narcolepsy type 1 can be selected from the group consisting of excessive daytime sleepiness (EDS) and cataplexy. In some embodiments, the one or more symptoms of narcolepsy type 1 are selected from the group consisting of excessive daytime sleepiness (EDS) and cataplexy. Narcolepsy can be diagnosed by diagnostic criteria commonly used in the art, such as the International Classification of Sleep Disorders, Third Edition (ICSD-3) and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).

[0105] The methods and uses disclosed herein can increase wakefulness and / or reduce and / or treat excessive sleepiness in a subject in need thereof. In some embodiments, the reduction and / or treatment of wakefulness and / or excessive sleepiness is determined by electroencephalogram (EEG) and / or electromyogram (EMG). In some embodiments, the reduction of wakefulness and / or sleepiness is determined by using the Maintenance of Wakefulness Test (MWT). The MWT can be quantified by EEG. EEG is a test that detects brain electrical activity using small metal discs or electrodes that are attached to the scalp. In some embodiments, the reduction of wakefulness and / or sleepiness is determined by using the Multiple Sleep Latency Test (MSLT) or the Oxford Sleep Resistance (OSLER) test. In some embodiments, the test is the Karolinska Sleepiness Scale (KSS), the Epworth Sleepiness Scale (ESS), or the Stanford Sleepiness Scale. In some embodiments, the subject with excessive sleepiness can have or be diagnosed with narcolepsy type 1, narcolepsy type 2, idiopathic hypersomnia, hypersomnia, somnolence, sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea with continuous positive airway pressure), or a disturbance of consciousness such as coma, etc., or narcolepsy syndrome with symptoms of narcolepsy; hypersomnia or hypersomnia syndrome with excessive daytime sleepiness (e.g., Parkinson’s disease, Guillain-barre syndrome, and Kleine Levin syndrome); Parkinson’s disease, Alzheimer’s Disease, DLB (dementia with Lewy bodies), Prader-Willi Syndrome, depression (depression, atypical depression, major depressive disorder, treatment-resistant depression), attention-deficit / hyperactivity disorder (ADHD), sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea with continuous positive airway pressure), or excessive daytime sleepiness in other vigilance disorders; or residual excessive daytime sleepiness in sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea with continuous positive airway pressure); etc.In some embodiments, the excessive sleepiness of the subject can be caused by or associated with narcolepsy type 1, narcolepsy type 2, idiopathic hypersomnia, hypersomnia, somnolence, sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea with continuous positive airway pressure), or a disturbance of consciousness such as coma, etc.; or narcolepsy with symptoms of cataplexy; hypersomnia or hypersomnia syndrome with excessive daytime sleepiness (e.g., Parkinson’s disease, Guillain-Barre syndrome, and Kleine-Levin syndrome); Parkinson’s disease, Alzheimer’s disease, DLB (dementia with Lewy bodies), Prader-Willi syndrome, depression (depressive disorder, atypical depression, major depressive disorder, treatment-resistant depression), ADHD, sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea with continuous positive airway pressure), or other vigilance disorders; etc.

[0106] The methods and uses disclosed herein can increase wakefulness and / or reduce and / or treat excessive sleepiness in a subject in need thereof. In some embodiments, the excessive sleepiness is excessive daytime sleepiness.

[0107] The methods and uses disclosed herein can increase the plasma concentration of Compound (I) in a subject; or can maintain a pharmaceutically effective plasma concentration of Compound (I) in a subject; or can reduce the time-dependent decrease in plasma concentration of Compound (I) in a subject. In some embodiments, the plasma concentration of Compound (I) is increased by at least 5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 200-fold, 500-fold, 1000-fold or more after administration of Compound (I) and an agent for reducing the metabolism of Compound (I), wherein the increase is compared to the plasma concentration of Compound (I) after administration of Compound (I) alone. In some embodiments, the plasma concentration of Compound (I) in a subject can be measured at least 4, 6, 9, 12, 24, 36, or 48 hours or more after administration of Compound (I) to the subject.

[0108] The methods and uses disclosed herein can maintain a pharmaceutically effective plasma concentration of Compound (I) in a subject. In some embodiments, the pharmaceutically effective plasma concentration of Compound (I) can be at least 5, 10, 25, 50, 75, 100, 150, 200, 250, or 300 ng / mL or more. In some embodiments, the pharmaceutically effective plasma concentration of Compound (I) in a subject can be measured at least 4, 6, 9, 12, 24, 36, or 48 hours or more after administration of Compound (I) to the subject.

[0109] The methods and uses disclosed herein can increase the Cmax of Compound (I) in a subject. In some embodiments, the Cmax of Compound (I) is increased by at least 5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 200-fold, or more after administration of Compound (I) and an agent for reducing the metabolism of Compound (I), wherein the increase is compared to the Cmax of Compound (I) after administration of Compound (I) alone.

[0110] The methods and uses disclosed herein can increase the AUCinf of Compound (I) in a subject. In some embodiments, the AUCinf of Compound (I) is increased by at least 5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 200-fold, 500-fold, or more after administration of Compound (I) and an agent for reducing the metabolism of Compound (I), wherein the increase is compared to the AUCinf of Compound (I) after administration of Compound (I) alone.

[0111] The methods and uses disclosed herein can increase the AUClast of Compound (I) in a subject. In some embodiments, the AUClast of Compound (I) is increased by at least 5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 200-fold, 500-fold, or more after administration of Compound (I) and an agent for reducing the metabolism of Compound (I), wherein the increase is compared to the AUClast of Compound (I) after administration of Compound (I) alone.

[0112] AUClast and AUCinf can be calculated as follows: AUClast: Area under the concentration-time curve from time 0 to the last quantifiable concentration, as calculated by the linear-log trapezoidal method. AUCinf: Area under the concentration-time curve from time 0 extrapolated to infinity. AUC ∞ calculated as AUC last plus the ratio of the last measurable blood concentration to the elimination rate constant.

[0113] The methods and uses disclosed herein can reduce the number of cataplexy-like events (e.g., cataplexy) in a subject in need thereof. In some embodiments, the number of cataplexy-like events is reduced by between 1 and 20, or by more cataplexy-like events. In some embodiments, the number of cataplexy-like events is reduced by between 1 and 8, or by more events, during a 24 hour period. In some embodiments, the number of cataplexy-like events is reduced by between 50% and 95%, or by more cataplexy-like events, as compared to if Compound (I) is not administered to the subject. In some embodiments, the number of cataplexy-like events is reduced by between 1 and 20, or by more events, in a period of between 1 and 15 days. Cataplexy-like events include cataplexy.

[0114] The methods and uses disclosed herein can treat a disease selected from the group consisting of: narcolepsy type 1, narcolepsy type 2, idiopathic hypersomnia, excessive daytime sleepiness, sleepiness, sleepiness disorder, sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea with continuous positive airway pressure), and disorders of consciousness such as coma and the like, and narcolepsy syndrome with cataplexy, sleepiness disorder with excessive daytime sleepiness or hypersomnia syndrome (e.g., Parkinson’s disease, Guillain-Barre syndrome, and Kleine-Levin syndrome), Parkinson’s disease, Alzheimer’s disease, DLB (dementia with Lewy bodies), Prader-Willi syndrome, depression (depression, atypical depression, major depressive disorder, treatment-resistant depression), ADHD, excessive daytime sleepiness in sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea with continuous positive airway pressure), sleep apnea syndrome (e.g., obstructive sleep apnea, obstructive sleep apnea with continuous positive airway pressure) and other vigilance disorders, obesity, diabetes, residual excessive daytime sleepiness in obesity, and the like.

[0115] The methods and uses disclosed herein can include performing one or more tests to quantify sleepiness in a subject. In some embodiments, the test is selected from the group consisting of MSLT, MWT, and OSLER test. In some embodiments, the test is MWT. In some embodiments, the test is KSS, ESS, or Stanford Sleepiness Scale.

[0116] The methods and uses disclosed herein include administering Compound (I) to a subject in need thereof. In some embodiments, Compound (I) is administered orally. In some embodiments, Compound (I) is administered non-orally. In some embodiments, the non-oral administration is intravenous, subcutaneous, transdermal, intradermal, or transmucosal administration.

[0117] Compound (I) can be administered orally and non-orally in suitable unit dosage forms, such as intramuscular, intraperitoneal, intravenous, intra-arterial, intraventricular, intracisternal injection or infusion; subcutaneous injection; or implant; or inhalation spray, intratracheal, nasal, vaginal, rectal, subcutaneous, transdermal, intradermal, epidural, ocular insertion, or ocular instillation administration, containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles appropriate for each route of administration.

[0118] Alternatively or additionally, administering Compound (I) can include administering an effective amount of Compound (I). In some embodiments, administering Compound (I) can include administering a therapeutically effective amount of Compound (I). An effective amount of Compound (I) can be between about 3 mg and about 500 mg. An effective amount of Compound (I) can be between about 3 mg and about 400 mg. An effective amount of Compound (I) can be between about 3 mg and about 300 mg. An effective amount of Compound (I) can be between about 3 mg and about 200 mg. An effective amount of Compound (I) can be between about 3 mg and 100 mg. An effective amount of Compound (I) can be between about 3 mg and 50 mg. In some embodiments, an effective amount is the same as a therapeutically effective amount. An effective amount of Compound (I) can be between 5 and 300 mg. An effective amount of Compound (I) can be between 5 and 250 mg. An effective amount of Compound (I) can be between 5 and 200 mg. An effective amount of Compound (I) can be between 5 and 150 mg. An effective amount of Compound (I) can be between 5 and 100 mg. An effective amount of Compound (I) or a salt thereof can be between 5 and 50 mg. An effective amount of Compound (I) can be between 10 and 300 mg. An effective amount of Compound (I) can be between 10 and 250 mg. An effective amount of Compound (I) can be between 10 and 200 mg. An effective amount of Compound (I) can be between 10 and 150 mg. An effective amount of Compound (I) can be between 10 and 100 mg. An effective amount of Compound (I) can be between 10 and 50 mg. In some embodiments, an effective amount is the same as a therapeutically effective amount.

[0119] Compound (I) can be administered between 1 and 3 times or more per day. In some embodiments, Compound (I) is administered at least once per day. In some embodiments, Compound (I) is administered at least twice per day.

[0120] Compound (I) can be administered between 1 and 7 times or more per week. In some embodiments, Compound (I) is administered at least once per week. In some embodiments, Compound (I) is administered at least twice per week. In some embodiments, Compound (I) is administered at least 3 times per week.

[0121] The compositions, methods, and uses disclosed herein can include an agent for reducing metabolism of the OX2R agonist. The agent for reducing metabolism of the OX2R agonist can increase bioavailability of the OX2R agonist or systemic exposure of the OX2R agonist. The agent for reducing metabolism of the OX2R agonist can reduce first-pass metabolism or systemic clearance of the OX2R agonist. The agent for reducing metabolism of the OX2R agonist can enhance pharmacokinetics of the OX2R agonist. The agent for reducing metabolism of the OX2R agonist can increase plasma concentration of the OX2R agonist. In some embodiments, the OX2R agonist is Compound (I). In some embodiments, Compound (I) is (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate (hereinafter “Compound A”) or a salt thereof. In some embodiments, the agent for reducing metabolism of the OX2R agonist is an inhibitor of one or more enzymes of the cytochrome P450 enzyme system. In some embodiments, the agent for reducing metabolism of the OX2R agonist is a CYP3A inhibitor. In some embodiments, the agent for reducing metabolism of the OX2R agonist is a CYP3A4 inhibitor.In some implementation schemes, the CYP3A4 inhibitor is selected from the group consisting of: atazanavir, boceprevir, clarithromycin, cobistat, conivaptan, curcumin, danazol, danoprevir, darunavir, delavirdine, diltiazem, ditiocarb, econazole, efavirenz, elvitegravir, ergotamine, edalalisib, indinavir, itraconazole, and ketoconazole. The drugs include onazole, loperamide, lopinavir, methimazole, midostaurin, naloxone, nefazodone, nelfinavir, nilotinib, posaconazole, ribociclib, ritonavir, saquinavir, stiripentol, telaprevir, telithromycin, terfenadine, tipranavir, troleandomycin, and voriconazole. In some embodiments, the CYP3A4 inhibitor is selected from the group consisting of ritonavir and cobistat. In some embodiments, the CYP3A4 inhibitor is cobistat.

[0122] The agent for reducing the metabolism of the OX2R agonist may be administered concurrently with compound (I). The agent for reducing the metabolism of the OX2R agonist may be administered after administration of the OX2R agonist. The agent for reducing the metabolism of the OX2R agonist may be administered before administration of the OX2R agonist. In some embodiments, the agent for reducing the metabolism of the OX2R agonist is administered daily (single daily dose or multiple daily doses). In some embodiments, the agent for reducing the metabolism of the OX2R agonist is administered once daily. In some embodiments, the agent for reducing the metabolism of the OX2R agonist is administered at least twice daily.

[0123] The agent for reducing metabolism of an OX2R agonist can be administered orally and non-orally, such as intramuscularly, intraperitoneally, intravenously, intra-arterially, intraventricularly, intracisternally, subcutaneously, or by implant; or by inhalation spray, intratracheally, nasally, vaginally, rectally, subcutaneously, transdermally, intradermally, epidurally, ocularly, or ocularly instilled, in suitable unit dosage formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. The agent for reducing metabolism of an OX2R agonist can be administered orally.

[0124] The agent for reducing metabolism of an OX2R agonist can be formulated with the OX2R agonist. The agent for reducing metabolism of an OX2R agonist can be formulated separately from the OX2R agonist. The compositions or combination therapies disclosed herein can comprise a single container comprising the OX2R agonist and the agent for reducing metabolism of an OX2R agonist. Alternatively, the compositions or combination therapies disclosed herein can comprise a first container comprising the OX2R agonist and a second container comprising the agent for reducing metabolism of an OX2R agonist.

[0125] The agent for reducing metabolism of an OX2R agonist can be administered between 1 and 3 or more times per day. In some embodiments, the agent for reducing metabolism of an OX2R agonist is administered at least once per day. In some embodiments, the agent for reducing metabolism of an OX2R agonist is administered at least twice per day.

[0126] The agent for reducing metabolism of an OX2R agonist can be administered between 1 and 7 or more times per week. In some embodiments, the agent for reducing metabolism of an OX2R agonist is administered at least once per week. In some embodiments, the agent for reducing metabolism of an OX2R agonist is administered at least twice per week. In some embodiments, the agent for reducing metabolism of an OX2R agonist is administered at least 3 times per week.

[0127] The agent for reducing metabolism of an OX2R agonist can be cobicistat. Administering cobicistat can comprise administering an effective amount of cobicistat. In some embodiments, administering cobicistat can comprise administering a therapeutically effective amount of cobicistat. The effective amount of cobicistat can be between 5 mg and 500 mg, between 10 mg and 400 mg, between 50 mg and 300 mg, between 75 mg and 250 mg, or between 100 mg and 200 mg. In some embodiments, the effective amount of cobicistat can be 150 mg.

[0128] The agent for reducing metabolism of an OX2R agonist can be ritonavir. Administering ritonavir can include administering an effective amount of ritonavir. In some embodiments, administering ritonavir can include administering a therapeutically effective amount of ritonavir. An effective amount of ritonavir can be between 5 mg and 500 mg, between 10 mg and 400 mg, between 15 mg and 300 mg, between 20 mg and 200 mg, or between 25 mg and 100 mg. In some embodiments, an effective amount of ritonavir can be 25 mg, 50 mg, or 100 mg.

[0129] The compositions, methods, and uses disclosed herein can include an agent for reducing metabolism of Compound (I). An agent for reducing metabolism of Compound (I) can increase bioavailability of Compound (I) or systemic exposure of Compound (I). An agent for reducing metabolism of Compound (I) can reduce first-pass metabolism or systemic clearance of Compound (I). An agent for reducing metabolism of Compound (I) can enhance the pharmacokinetics of Compound (I). An agent for reducing metabolism of Compound (I) can increase the plasma concentration of Compound (I). In some embodiments, an agent for reducing metabolism of Compound (I) is an inhibitor of one or more enzymes of the cytochrome P450 enzyme system. In some embodiments, an agent for reducing metabolism of Compound (I) is a CYP3A inhibitor. In some embodiments, an agent for reducing metabolism of Compound (I) is a CYP3A4 inhibitor. In some embodiments, the CYP3A4 inhibitor is selected from the group consisting of atazanavir, boceprevir, clarithromycin, cobicistat, conivaptan, curcumin, danazol, danoprevir, darunavir, delavirdine, diltiazem, disulfiram, enilconazole, efavirenz, elvitegravir, ergotamine, elacridar, indinavir, itraconazole, ketoconazole, loperamide, lopinavir, methimazole, mifepristone, naloxone, nefazodone, nelfinavir, nilotinib, posaconazole, ribociclib, ritonavir, saquinavir, stiripentol, telaprevir, telithromycin, terfenadine, tipranavir, tolnaftate, and voriconazole. In some embodiments, the CYP3A4 inhibitor is selected from the group consisting of ritonavir and cobicistat. In some embodiments, the CYP3A4 inhibitor is cobicistat.

[0130] An agent for reducing metabolism of Compound (I) can be administered concurrently with Compound (I). An agent for reducing metabolism of Compound (I) can be administered after administration of Compound (I). An agent for reducing metabolism of Compound (I) can be administered before administration of Compound (I). In some embodiments, an agent for reducing metabolism of Compound (I) is administered daily (single daily dose or multiple daily doses). In some embodiments, an agent for reducing metabolism of Compound (I) is administered once daily. In some embodiments, an agent for reducing metabolism of Compound (I) is administered at least twice daily.

[0131] The agent for reducing metabolism of Compound (I) can be administered orally and non-orally, such as intramuscularly, intraperitoneally, intravenously, intra-arterially, intraventricularly, intracisternally, subcutaneously, or by implant; or by inhalation spray, intratracheally, nasally, vaginally, rectally, subcutaneously, transdermally, intradermally, epidurally, ocularly, or ocularly by instillation, in suitable unit dosage formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. The agent for reducing metabolism of Compound (I) can be administered orally.

[0132] The agent for reducing metabolism of Compound (I) can be formulated with Compound (I). The agent for reducing metabolism of Compound (I) can be formulated separately from Compound (I). The compositions or combination therapies disclosed herein can comprise a single container comprising Compound (I) and an agent for reducing metabolism of Compound (I). Alternatively, the compositions or combination therapies disclosed herein can comprise a first container comprising Compound (I) and a second container comprising an agent for reducing metabolism of Compound (I).

[0133] The agent for reducing metabolism of Compound (I) can be administered between 1 and 3 or more times per day. In some embodiments, the agent for reducing metabolism of Compound (I) is administered at least once per day. In some embodiments, the agent for reducing metabolism of Compound (I) is administered at least twice per day.

[0134] The agent for reducing metabolism of Compound (I) can be administered between 1 and 7 or more times per week. In some embodiments, the agent for reducing metabolism of Compound (I) is administered at least once per week. In some embodiments, the agent for reducing metabolism of Compound (I) is administered at least twice per week. In some embodiments, the agent for reducing metabolism of Compound (I) is administered at least 3 times per week.

[0135] The agent for reducing metabolism of Compound (I) can be combretastatin. Administering combretastatin can include administering an effective amount of combretastatin. In some embodiments, administering combretastatin can include administering a therapeutically effective amount of combretastatin. The effective amount of combretastatin can be between 5 mg and 500 mg, between 10 mg and 400 mg, between 50 mg and 300 mg, between 75 mg and 250 mg, or between 100 mg and 200 mg. In some embodiments, the effective amount of combretastatin can be 150 mg.

[0136] The agent for reducing metabolism of Compound (I) can be ritonavir. Administering ritonavir can include administering an effective amount of ritonavir. In some embodiments, administering ritonavir can include administering a therapeutically effective amount of ritonavir. The effective amount of ritonavir can be between 5 mg and 500 mg, between 10 mg and 400 mg, between 15 mg and 300 mg, between 20 mg and 200 mg, or between 25 mg and 100 mg. In some embodiments, the effective amount of ritonavir can be 25 mg, 50 mg, or 100 mg.

[0137] The methods disclosed herein can further include administering one or more additional therapies. The kits and compositions disclosed herein can further include one or more additional therapies. The one or more additional therapies can be selected from stimulants, antidepressants, central nervous system depressants, histamine 3 (H3) receptor antagonists, and any other concomitant medications described herein. In some embodiments, the stimulant is modafinil. In some embodiments, the antidepressant is clomipramine. In some embodiments, the central nervous system depressant is sodium oxybate. In some embodiments, the H3 receptor antagonist is pitolisant.

[0138] Two or more of the above concomitant medications can be used in appropriate proportions.

[0139] The methods disclosed herein can not further include administering one or more additional agents for reducing metabolism of Compound (I). The kits and compositions disclosed herein can not further include one or more additional agents for reducing metabolism of Compound (I).

[0140] Also disclosed herein are pharmaceutical compositions comprising (a) 3-((methylsulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-l-carboxylic acid methyl ester (Compound (I)), or a salt thereof; (b) an agent for reducing metabolism of Compound (I); and (c) a pharmaceutically acceptable carrier thereof.

[0141] Also disclosed herein are pharmaceutical compositions comprising (a) an OX2R agonist; (b) an agent for reducing metabolism of the OX2R agonist; and (c) a pharmaceutically acceptable carrier thereof.

[0142] The pharmaceutically acceptable carrier can be a cyclodextrin. The cyclodextrin can be betadex sulfobutyl ether sodium.

[0143] In some embodiments, various organic or inorganic carrier substances conventionally used for the preparation of materials are used as pharmaceutically acceptable carriers. These are incorporated as excipients, lubricants, binders, and disintegrants for solid preparations; or as solvents, solubilizers, suspending agents, isotonic agents, buffers, and soothing agents for liquid preparations; and the like; and formulation additives such as preservatives, antioxidants, colorants, sweeteners, and the like can be added as needed.

[0144] Examples of dosage forms of the aforementioned pharmaceutical compositions include tablets (including sugar-coated tablets, film-coated tablets, oral disintegrating tablets), capsules (including soft capsules, microcapsules), granules, powders, troches, syrups, emulsions, suspensions, films (e.g., oral disintegrating films), injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip infusions), external preparations (e.g., skin preparations, ointments), suppositories (e.g., rectal suppositories, vaginal suppositories), pills, nasal preparations, pulmonary preparations (inhalants), eye drops, and the like, which can each be safely administered orally or non-orally (e.g., topically, rectally, intravenously). These preparations can be controlled-release preparations (e.g., sustained-release microcapsules), such as immediate-release preparations, sustained-release preparations, and the like.

[0145] In some embodiments, 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.

[0146] In some embodiments, the OX2R agonist is Compound (I). In some embodiments, Compound (I) is an optically active compound. In some embodiments, Compound (I) is (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate (Compound A). Compound (I), including optically active compounds thereof, can be produced as disclosed in WO2017 / 135306, which is incorporated by reference in its entirety.

[0147] Also disclosed herein are kits comprising Compound (I). In some embodiments, the kit comprises (a) a container comprising Compound (I); (b) a container comprising an agent for reducing the metabolism of Compound (I); and (c) instructions for administering Compound (I) and the agent.

[0148] Also disclosed herein are kits comprising an OX2R agonist. In some embodiments, the kit comprises (a) an OX2R agonist; (b) a container comprising an agent for reducing metabolism of the OX2R agonist; and (c) instructions for administering (a) and (b).

[0149] The kits disclosed herein can also include an additional container comprising saline.

[0150] The container can be a glass vial. Alternatively, the container can be a syringe.

[0151] The present disclosure is not limited to the particular embodiments described in this application, which are intended as single illustrations of individual aspects of the present disclosure. All of the various embodiments of the present disclosure will not be described here. Many modifications and variations of this disclosure can be made without departing from its spirit and scope, which will be apparent to those skilled in the art. Functionally equivalent methods and devices within the scope of the present disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is limited only by the terms of the appended claims and the full scope of equivalents for which such claims are entitled.

[0152] It should be understood that the present disclosure is not limited to particular uses, methods, reagents, compounds, compositions, or biological systems, which of course can vary. It will also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0153] Additionally, where a feature or aspect of the present disclosure is described according to a Markush group, it is understood that any individual member or subgroup member of the Markush group is also described by the present disclosure.

[0154] As those skilled in the art will understand, for any and all purposes, particularly for the purpose of providing a written description, all scopes disclosed herein also encompass any and all possible subscopes and combinations thereof. Any listed scope can be readily identified as sufficiently descriptive and such that the same scope can be decomposed into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each scope discussed herein can be readily decomposed into a lower third, a middle third, and an upper third, etc. As those skilled in the art will also understand, all language such as “at most,” “at least,” “greater than,” “less than,” etc., includes the listed numbers and refers to a scope that can subsequently be decomposed into subscopes as discussed above. Finally, as those skilled in the art will understand, a scope includes each individual member. Thus, for example, a group having 1-3 units means a group having 1, 2, or 3 units. Similarly, a group having 1-5 units means a group having 1, 2, 3, 4, or 5 units, and so on.

[0155] definition

[0156] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this disclosure pertains. The following references provide general definitions for many of the terms used in this invention: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd edition, 1994); The Cambridge Dictionary of Science and Technology (Walker, ed., 1988); The Glossary of Genetics, 5th edition, R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, unless otherwise indicated, the following terms have the meanings attributed to them. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit this disclosure.

[0157] As used herein, the singular forms “a (kind)” and “the” are intended to also include the plural forms unless the context clearly indicates otherwise.

[0158] As used herein, the term "about" or "approximately," otherwise used in connection with a particular quantity, means that the quantity is within an acceptable error range for the particular measurement as determined by one of ordinary skill in the art, which will depend in part on how the quantity is measured or assayed, limitations of the measurement system, and the like. For example, "about" can mean within 3 or more than 3 standard deviations, per the practice in the art. Or, "about" can mean ranges approximately 20%, preferably approximately 10%, more preferably approximately 5%, and still more preferably approximately 1% of a given value. Or, particularly with respect to biological systems or processes, the terms can mean within an order of magnitude, preferably within 5-fold and more preferably within 2-fold of a certain value.

[0159] As used herein, the term "administering" a dose to a subject includes any route by which the dose is introduced or delivered to the subject to perform its intended function. Administration can be by oral routes or any suitable non-oral route, including but not limited to intravenous, intramuscular, intraperitoneal, subcutaneous, and other suitable routes as described herein. Administration includes self-administration and administration by another.

[0160] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of Compound (I) (or OX2R agonist) sufficient to effect a desired result or a desired therapeutic effect. In the case of therapeutic applications, the amount of Compound (I) (or OX2R agonist) administered to a subject can depend on the type and severity of the disease (e.g., narcolepsy, narcolepsy type 1) or symptoms and 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.

[0161] As used herein, the term "modulate" means to change, either positively or negatively. Exemplary modulation includes a change of about 1%, about 2%, about 5%, about 10%, about 25%, about 50%, about 75%, or about 100%.

[0162] As used herein, the term "increase" means a positive change of at least about 5%, including but not limited to a positive change of about 5%, about 10%, about 25%, about 30%, about 50%, about 75%, or about 100%.

[0163] As used herein, the term "decrease" means a negative change of at least about 5%, including but not limited to a negative change of about 5%, about 10%, about 25%, about 30%, about 50%, about 75%, or about 100%.

[0164] As used herein, the term "OX2R agonist" refers to an orexin neuropeptide agonist that acts on the orexin 2 receptor. In some embodiments, the OX2R agonist is Compound (I). In some embodiments, Compound (I) is (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylic acid methyl ester (hereinafter "Compound A") or a salt thereof.

[0165] Examples

[0166] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the compositions of the application, and the assay, screening, and treatment methods, and are not intended to limit the scope of what the inventors regard as their application.

[0167] Example 1 : Phase 1 open-label study to evaluate the effect of cobicistat on single-dose pharmacokinetics of Compound A orally administered to healthy subjects

[0168] The objective of this study is to evaluate the effect of cobicistat on Compound A. The primary objective is to evaluate whether cobicistat can increase the plasma concentration of Compound A in humans following oral administration of Compound A, and thus can be used in combination with Compound A as part of an oral dosing regimen. The magnitude of this intended drug-drug interaction (DDI) is also quantified.

[0169] Another objective of this study is to assess the time course of cobicistat inactivation of CYP3A to characterize the onset of CYP3A inhibition and the attainment of steady-state inhibition levels. Midazolam is a benzodiazepine derivative that is metabolized exclusively via the CYP3A enzymatic pathway and is therefore used as an in vivo probe of human CYP3A activity.

[0170] Study Objectives

[0171] 1. Primary Objective:

[0172] • Evaluate the effect of steady-state cobicistat on single-dose pharmacokinetics of Compound A administered orally

[0173] 2. Secondary Objectives:

[0174] • Evaluate the safety and tolerability of a single oral dose of Compound A with and without cobicistat.

[0175] Study Endpoints

[0176] 1. Primary Endpoint

[0177] • Plasma PK parameters (AUC0-t, AUC0-∞, Cmax, Tmax) of Compound A following oral administration with and without cobicistat​∞ AUC last C max )

[0178] 2. Secondary endpoints

[0179] • Adverse events

[0180] Overview of Study Design

[0181] This was a non-randomized, open-label, fixed-sequence study in healthy men and women (women of non-childbearing potential [WONCBP]) subjects.

[0182] On Day 1, subjects orally received 1 mg midazolam and pharmacokinetic (PK) blood samples for midazolam (and its metabolite, 1-hydroxy (1-OH) midazolam) were collected prior to and up to 24 hours post-dose to determine baseline cytochrome P450 (CYP) 3A activity. On Day 2, subjects received 14 mg Compound A in a 9-hour intravenous (IV) infusion and PK blood samples for Compound A were collected prior to and up to 15 hours post-infusion. On Day 3, subjects orally received 112 mg Compound A and PK blood samples and urine samples for Compound A were collected prior to and up to 48 hours post-dose.

[0183] From Day 5 to Day 13, subjects orally received 150 mg cobitolimod once daily (QD) and PK blood samples for cobitolimod were collected prior to and up to 24 hours post-dose on Day 5. Pre-dose blood samples for cobitolimod PK were also collected on Days 7, 9, 10, and 11.

[0184] On Days 7 and 10, 0.5 mg midazolam was orally administered (30 minutes after cobitolimod dose) and PK blood for midazolam and 1-OH midazolam was collected daily on each of these days prior to and up to 24 hours post midazolam dose.

[0185] On Day 12, 14 mg Compound A was orally administered (30 minutes after cobitolimod dose) and PK blood samples and urine samples for Compound A were collected prior to and up to 48 hours post Compound A dose; PK blood samples for cobitolimod were collected prior to and up to 24 hours post cobitolimod dose on Day 12 and 24 hours post cobitolimod dose on Day 13.

[0186] Safety was assessed by monitoring adverse events (AEs), vital signs, safety 12-lead electrocardiograms (ECGs), safety laboratory assessments, pulse oximetry, C-SSRS (Columbia-Suicide Severity Rating Scale), and physical examinations throughout the study.

[0187] A summary of the overall study design is depicted in Figure 1 .

[0188]

[0189]

[0190] Study Population

[0191] Healthy male and female participants aged 19 to 55 years (inclusive) were selected. Their body mass index (BMI) at the time of selection was 18.0-32.0 kg / m². 2 (inclusive).

[0192] Key inclusion criteria:

[0193] • Healthy adult males or females (non-fertile) aged 19-55 years (inclusive) at the time of screening.

[0194] • Continuous nonsmokers who have not used nicotine-containing products for at least 90 days prior to the first dose and throughout the study period.

[0195] • At the time of screening, the body mass index (BMI) should be ≥18.0 and ≤32.0 kg / m². 2 (inclusive).

[0196] • Medically healthy, with no significant clinical medical history, physical examination, laboratory data, vital signs, or electrocardiogram, as determined by researchers or designated personnel.

[0197] Key exclusion criteria:

[0198] • Individuals who are expected to be mentally or legally incapacitated or have serious emotional problems during the screening visit or during the study.

[0199] • A history or presence of clinically significant medical or psychotic symptoms or diseases, as determined by researchers or designated personnel.

[0200] • Any medical history that the researchers or designated personnel believe may confound the study results or pose an additional risk to the subjects due to their participation in the study.

[0201] • A history of alcohol or substance abuse or its presence within the past 2 years prior to the first dose, according to the Diagnostic and Statistical Manual of Mental Disorders-V criteria.

[0202] • Unavoidable or anticipated use:

[0203] o Any drugs known to be significant inducers or inhibitors of CYP3A4 enzyme and / or P-gp, including St. John's wort, within 28 days prior to the first dose, throughout the study period, and up to follow-up. Consult appropriate sources (e.g., Flockhart Tables). TM) to confirm lack of PK / pharmacodynamic interaction with study drug.

[0204] o Any medications, including prescription and over-the-counter medications, herbal remedies, antacids, or vitamin supplements within 28 days prior to first dose and throughout the study and until the follow-up visit. Product labels were reviewed to confirm no serious drug interactions 2018]. Acetaminophen (up to 2 g every 24 hours) can have been self-administered by the study personnel or designee after the first dose. If the subject has been taking the same stable dose of thyroid hormone replacement medication for 3 months immediately prior to the first dose, use of the thyroid hormone replacement medication can be permitted.

[0205] Primary Criteria for Evaluation and Analysis

[0206] Primary endpoints of the study:

[0207] The plasma pharmacokinetic parameters following oral administration of Compound A with and without cobicistat were as follows

[0208] • Maximum observed concentration (Cmax).

[0209] • Area under the concentration-time curve from time 0 to infinity, calculated using the observed value for the last quantifiable concentration (AUCinf).

[0210] • Area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUClast).

[0211] Blood PK sampling for Compound A:

[0212] • Study Day 2: Pre-dose (prior to start of Compound A IV infusion), 1, 2, 4, 9, 9.17, 10, and 13 hours post-infusion start

[0213] • Study Day 3: 24 hours post-dose Day 2 (pre-dose (prior to oral administration of Compound A)) and 0.17, 0.33, 0.5, 1, 2, 4, 6, 9, and 12 hours post-dose

[0214] • Study Day 4: 24 and 36 hours post-dose Day 3

[0215] • Study Day 5: 48 hours post-dose Day 3 and prior to cobicistat administration

[0216] • Study Days 12-14: Pre-dose (prior to oral administration of cobicistat and Compound A) and 0.17, 0.33, 0.5, 1, 2, 4, 6, 9, 12, 24, 36, and 48 hours post-dose oral administration of Compound A

[0217] Blood PK sampling for cobicistat:

[0218] • Study Day 5: Pre-dose (prior to cobicistat administration) and 0.5, 1, 2, 4, 6, 9, and 12 hours post-dose

[0219] • Study Day 6: 24 hours post-dose Day 5 and prior to cobicistat administration

[0220] • Study Day 7: Pre-dose (prior to cobicistat and midazolam administration)

[0221] • Study Day 9: Pre-dose (prior to cobicistat administration)

[0222] • Study Day 10: Pre-dose (prior to cobicistat and midazolam administration)

[0223] • Study Day 11: Pre-dose (prior to cobicistat administration)

[0224] • Study Day 12: Pre-dose (prior to cobicistat and Compound A oral administration) and 0.5, 1, 2, 4, 6, 9, and 12 hours post-dose cobicistat

[0225] • Study Day 13: 24 hours post-dose Day 12 and prior to cobicistat administration

[0226] • Study Day 14: 24 hours post-dose Day 13

[0227] Blood PK sampling for midazolam and its metabolite (1-hydroxymidazolam):

[0228] • Study Day 1: Pre-dose (prior to midazolam administration), 0.5, 1, 1.5, 2, 4, 6, 8, 12 hours post-dose

[0229] • Study Day 2: 24 hours post-dose Day 1 and prior to start of Compound A IV infusion

[0230] • Study Day 7: Pre-dose (prior to cobicistat and midazolam administration), 0.5, 1, 1.5, 2, 4, 6, 8, 12 hours post-dose midazolam

[0231] • Study Day 8: 24 hours post-dose midazolam Day 7 and prior to cobicistat administration

[0232] • Study Day 10: Pre-dose (prior to cobicistat and midazolam administration), 0.5, 1, 1.5, 2, 4, 6, 8, 12 hours post-dose midazolam

[0233] • Study Day 11: 24 hours post-dose midazolam Day 10 and prior to cobicistat administration

[0234] PK parameter analysis:

[0235] The plasma pharmacokinetic parameters (Cmax, AUCinf and AUClast) of Compound A following oral administration with and without cobicistat were calculated.

[0236] The statistical comparison of the dose-normalized plasma Compound A PK following oral administration of 112 mg Compound A alone on Day 3 and 14 mg Compound A + MD 150 mg cobicistat on Day 12 in healthy subjects is presented in Table 2.

[0237]

[0238] The results show that following oral administration of 14 mg Compound A + MD 150 mg cobicistat on Day 12, the dose-normalized Cmax, AUCinf and AUClast of plasma Compound A are much higher than following oral administration of 112 mg Compound A alone on Day 3.

[0239] The arithmetic mean plasma concentration-time curves of Compound A following IV administration of 14 mg Compound A alone on Day 2, oral administration of 112 mg Compound A alone on Day 3 and oral administration of 14 mg Compound A + MD 150 mg cobicistat on Day 12 in healthy subjects are presented on a semi-log scale, normalized to a 112 mg Compound A dose in Figure 2 and not normalized in Figure 3 .

[0240] Pharmacokinetic results

[0241] Plasma Compound A

[0242] • Co-administration of oral 14 mg Compound A + QD 150 mg cobicistat increased the geometric LSM (least squares mean) Cmax and AUC (AUClast and AUC∞) of Compound A to approximately 50-fold and 109-fold, respectively, of the corresponding values following oral administration of 112 mg Compound A alone, after dose normalization to 112 mg.

[0243] • Oral administration of 112 mg Compound A alone compared to IV administration of 14 mg Compound A alone, the geometric mean dose-normalized Cmax and AUC∞ of Compound A were reduced by approximately 84% and 97%, respectively.

[0244] • Following oral administration of 14 mg Compound A + QD 150 mg cobicistat, the geometric mean dose-normalized Cmax and AUC∞ of Compound A were increased to 7.9-fold and 2.8-fold, respectively, compared to IV administration of 14 mg Compound A alone (9-hour IV infusion).

[0245] • Co-administration of 14 mg Compound A PO + QD 150 mg cobicistat extended the mean t1 / 2z of Compound A to about 8 hours compared to 4.9 hours after 112 mg Compound A PO alone and 3.7 hours after 14 mg Compound A IV alone.

[0246] Plasma midazolam

[0247] • Cobicistat increased midazolam Cmax to the same extent on Days 7 and 10 and approximately 5-fold compared to the corresponding value obtained after 1 mg midazolam alone on Day 5.

[0248] • Cobicistat increased midazolam AUC∞ to the same extent on Days 7 and 10 and approximately 25 to 27-fold compared to the corresponding value obtained after 1 mg midazolam alone on Day 5.

[0249] Conclusions

[0250] Cobicistat significantly increased systemic exposure of orally administered Compound A in healthy adult subjects via potent CYP3A inhibition. In this study, a single oral dose of Compound A in the presence of steady-state cobicistat appeared to be generally safe and well tolerated by healthy adult subjects.

Claims

1. Use of (a) methyl 3-(((methanesulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate or a salt thereof; and (b) a combination of CYP3A4 inhibitors in the preparation of a medicament for enhancing the pharmacokinetics of methyl 3-((methanesulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate or a salt thereof.

2. The use of (a) methyl 3-(((methanesulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate or a salt thereof; and (b) a combination of CYP3A4 inhibitors in the preparation of a medicament for enhancing the plasma concentration of methyl 3-((methanesulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate or a salt thereof.

3. The use of (a) methyl 3-((methanesulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylic acid or a salt thereof; and (b) a combination of CYP3A4 inhibitors in the preparation of a medicament for increasing the alertness of a subject in need or reducing excessive drowsiness.

4. The use as described in any one of claims 1-3, wherein the CYP3A4 inhibitor is selected from the group consisting of ritonavir and cobistat.

5. The use as described in claim 4, wherein the CYP3A4 inhibitor is cobistat.

6. The use as claimed in any one of claims 1-3, wherein (a) it is administered orally.

7. The use as described in any one of claims 1-3, wherein (a) it is applied daily.

8. The use as claimed in claim 7, wherein (a) it is administered in a single daily dose or multiple daily doses.

9. The use as described in any one of claims 1-3, wherein the CYP3A4 inhibitor is administered daily.

10. The use as described in claim 9, wherein the CYP3A4 inhibitor is administered in a single daily dose or multiple daily doses.

11. The use as described in any one of claims 1-3, wherein the CYP3A4 inhibitor is administered after the administration of (a).

12. The use as described in any one of claims 1-3, wherein the CYP3A4 inhibitor is administered prior to the administration of (a).

13. The use as described in any one of claims 1-3, wherein the CYP3A4 inhibitor is administered simultaneously with (a).

14. The use as claimed in any one of claims 1-3, wherein (a) is an optically active compound.

15. The use as described in claim 14, wherein (a) is (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylic acid methyl ester or a salt thereof.

16. A composition comprising (a) methyl 3-((methanesulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylic acid or a salt thereof; and (b) a CYP3A4 inhibitor.

17. The composition of claim 16, wherein the CYP3A4 inhibitor is selected from the group consisting of ritonavir and cobistat.

18. The composition of claim 16, wherein the CYP3A4 inhibitor is cobistat.

19. The composition according to any one of claims 16-18, wherein (a) is an optically active compound.

20. The composition of claim 19, wherein (a) is (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylic acid methyl ester or a salt thereof.

21. The use according to any one of claims 1-3, wherein the amount of methyl 3-((methanesulfonyl)amino)-2-(((4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylic acid or a salt thereof administered is from 5 mg to 50 mg.

22. The use as described in claim 5, wherein the dosage of cobistat is 100 mg to 200 mg.

23. The use as described in any one of claims 1-3, wherein the CYP3A4 inhibitor is ritonavir, and the dosage of ritonavir is from 25 mg to 100 mg.

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