Methods and Compositions for Treating Sleep Apnea - Patent application

Abstract

Described herein are methods for treating pharyngeal airway obstruction (e.g., sleep apnea) by administering a norepinephrine reuptake inhibitor (NRI) in combination with mandibular advancement device (MAD) therapy, which treatment may further include administration of a muscarinic receptor antagonist (MRA) and / or a hypnotic agent.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 239,064, filed August 31, 2021, the entire contents of which are incorporated herein by reference.

[0002] The present invention provides a method of treating pharyngeal airway collapse (eg, sleep apnea) by administering a norepinephrine reuptake inhibitor (NRI) in combination with mandibular advancement device (MAD) therapy. [Background technology]

[0003] Obstructive sleep apnea (OSA) is a common disorder caused by blockage of the pharyngeal airway during sleep. OSA can lead to significant health problems. Summary of the Invention

[0004] One aspect of the present invention provides a method of treating a subject having a condition associated with pharyngeal airway obstruction, the method comprising administering to a subject in need thereof an effective amount of a norepinephrine reuptake inhibitor (NRI) in combination with mandibular advancement device (MAD) therapy.

[0005] Embodiments of this aspect of the invention may include one or more of the following optional features: In some embodiments, the NRI is a norepinephrine selective reuptake inhibitor (NSRI). In some embodiments, the NSRI is selected from the group consisting of amidaline, atomoxetine, CP-39,332, daredalin, edivoxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, and viloxazine, or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is a non-selective norepinephrine reuptake inhibitor (NNRI) selected from the group consisting of amitriptyline, amoxapine, bupropion, ciclazindol, desipramine, desvenlafaxine, dexmethilphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxine, maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetrazine, phenmetrazine, protryptyline, radafaxine, tapentadol, teniloxazine, and venlafaxine, or a pharma- ceutically acceptable salt thereof. In some embodiments, the NRI is selected from the group consisting of atomoxetine or a pharma- ceutically acceptable salt thereof and reboxetine or a pharma- ceutically acceptable salt thereof. In some embodiments, the NRI is atomoxetine or a pharma- ceutically acceptable salt thereof. In some embodiments, the NRI is reboxetine or a pharma- ceutically acceptable salt thereof. In some embodiments, the method further comprises administering to the subject a muscarinic receptor antagonist (MRA). In some embodiments, the MRA is selected from the group consisting of atropine, propantheline, bethanechol, solifenacin, darifenacin, tolterodine, fesoterodine, trospium, and oxybutynin, or a pharma- ceutically acceptable salt thereof.In some embodiments, the MRA is selected from the group consisting of anisotropine, benztropine, biperiden, clidinium, cyclimine, dicyclomine, diphemanil, diphenidol, ethopropazine, glycopyrrolate, hexocyclium, isopropamide, mepenzolate, methixene, methscopolamine, oxyphencyclimine, oxyphenonium, procyclidine, scopolamine, tridihexetyl, and trihexyphenidyl, or a pharmaceutically acceptable salt thereof. In some embodiments, the MRA is oxybutynin or a pharmaceutically acceptable salt thereof. In some embodiments, the MRA is (R)-oxybutynin or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises administering a hypnotic agent to the subject. In some embodiments, the hypnotic agent is selected from the group consisting of trazodone, zolpidem, eszopiclone, benzodiazepines, gabapentin, tiagabine, and xyrem. In some embodiments, the hypnotic agent is trazodone. In some embodiments, the hypnotic agent is zolpidem. In some embodiments, atomoxetine or a pharma- ceutically acceptable salt thereof is administered in a dose of about 20 to about 150 mg. In some embodiments, atomoxetine or a pharma- ceutically acceptable salt thereof is administered in a dose of about 25 to about 100 mg. In some embodiments, oxybutynin or a pharma- ceutically acceptable salt thereof is administered in a dose of about 1 to about 15 mg. In some embodiments, oxybutynin or a pharma- ceutically acceptable salt thereof is administered in a dose of about 2 mg to about 10 mg. In some embodiments, (R)-oxybutynin or a pharma- ceutically acceptable salt thereof is administered in a dose of about 0.5 to about 10 mg. In some embodiments, (R)-oxybutynin or a pharma- ceutically acceptable salt thereof is administered in a dose of about 1 mg to about 5 mg. In some embodiments, the NRI, MRA, and / or hypnotic agent are administered in a single composition. In some embodiments, the single composition is an oral dosage form. In some embodiments, the oral dosage form is a syrup, pill, tablet, lozenge, capsule, or patch. In some embodiments, the single composition is in an immediate release formulation.In some embodiments, the single composition is in an immediate release formulation, the NRI is administered in a dose of about 20 to about 150 mg, and the MRA is administered in a dose of about 1 to about 15 mg. In some embodiments, the single composition is in an immediate release formulation, the NRI is administered in a dose of about 25 to about 100 mg, and the MRA is administered in a dose of about 2 to about 10 mg. In some embodiments, the single composition is in an immediate release formulation, the NRI is administered in a dose of about 20 to about 50 mg, and the MRA is administered in a dose of about 2 to about 10 mg. In some embodiments, the single composition is in an immediate release formulation, the NRI is administered in a dose of about 40 to about 80 mg, and the MRA is administered in a dose of about 2 to about 10 mg. In some embodiments, the single composition is in a controlled release formulation. In some embodiments, the single composition is in a controlled release formulation, the NRI is administered in a dose of about 20 to about 150 mg, and the MRA is administered in a dose of about 0.5 to about 10 mg. In some embodiments, the single composition is in a controlled release formulation, the NRI is administered in a dose of about 25 to about 100 mg, and the MRA is administered in a dose of about 2 to about 6 mg. In some embodiments, the single composition is in a controlled release formulation, the NRI is administered in a dose of about 20 to about 50 mg, and the MRA is administered in a dose of about 2 to about 6 mg. In some embodiments, the single composition is in a controlled release formulation, the NRI is administered in a dose of about 40 to about 80 mg, and the MRA is administered in a dose of about 2 to about 6 mg. In some embodiments, the single composition further comprises a pharma- ceutically acceptable carrier. In some embodiments, the single composition is administered prior to the initiation of mandibular advancement device (MAD) therapy. In some embodiments, the single composition is administered simultaneously with mandibular advancement device (MAD) therapy. In some embodiments, the condition associated with pharyngeal airway obstruction is sleep apnea. In some embodiments, the condition associated with pharyngeal airway obstruction is obstructive sleep apnea (OSA). In some embodiments, the condition associated with pharyngeal airway obstruction is snoring. In some embodiments, the condition associated with pharyngeal airway obstruction is simple snoring. In some embodiments, the subject is in a state where consciousness is not fully conscious. In some embodiments, the state where consciousness is not fully conscious is sleep.

[0006] Another aspect of the invention provides a norepinephrine reuptake inhibitor (NRI) and a mandibular advancement device (MAD) for use in treating a subject having a condition associated with pharyngeal airway obstruction. Some embodiments further comprise a muscarinic receptor antagonist (MRA) and / or a hypnotic agent.

[0007] Another aspect of the invention provides a therapeutic combination comprising: (a) a pharmaceutical composition comprising a norepinephrine reuptake inhibitor (NRI) and a pharma- ceutically acceptable carrier, and (b) a mandibular advancement device (MAD), for use in treating a subject having a condition associated with pharyngeal airway obstruction. In some embodiments, the pharmaceutical composition further comprises a muscarinic receptor antagonist (MRA) and / or a hypnotic agent.

[0008] Another aspect of the invention provides atomoxetine, or a pharma- ceutically acceptable salt thereof, oxybutynin (e.g., (R)-oxybutynin) or a pharma- ceutically acceptable salt thereof, and a mandibular advancement device (MAD), for use in treating a subject having a condition associated with pharyngeal airway obstruction.

[0009] Another aspect of the present invention provides atomoxetine, or a pharma- ceutically acceptable salt thereof, a hypnotic agent (e.g., trazodone or zolpidem, or a pharma- ceutically acceptable salt thereof), and a mandibular advancement device (MAD), for use in treating a subject having a condition associated with pharyngeal airway obstruction.

[0010] Another aspect of the present invention provides atomoxetine, or a pharma- ceutically acceptable salt thereof, oxybutynin (e.g., (R)-oxybutynin) or a pharma- ceutically acceptable salt thereof, and a mandibular advancement device (MAD), for use in the treatment of sleep apnea.

[0011] Another aspect of the present invention provides atomoxetine, or a pharma- ceutically acceptable salt thereof, oxybutynin (e.g., (R)-oxybutynin) or a pharma- ceutically acceptable salt thereof, and a mandibular advancement device (MAD), for use in the treatment of snoring.

[0012] Another aspect of the present invention provides atomoxetine, or a pharma- ceutically acceptable salt thereof, a hypnotic agent (e.g., trazodone or zolpidem, or a pharma- ceutically acceptable salt thereof), and a mandibular advancement device (MAD), for use in the treatment of sleep apnea.

[0013] Another aspect of the present invention provides atomoxetine, or a pharma- ceutically acceptable salt thereof, a hypnotic agent (e.g., trazodone or zolpidem, or a pharma- ceutically acceptable salt thereof), and a mandibular advancement device (MAD), for use in the treatment of snoring.

[0014] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials used in the present invention are described herein, but other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification (including definitions) will control.

[0015] Other features and advantages of the invention will be apparent from the following detailed description and drawings, and from the claims.

[0016] The following figures are illustrative and do not limit the claimed scope of the invention. [Brief description of the drawings]

[0017] [Figure 1] Graphic illustration of obstructive apnea. The top channel shows the electroencephalogram (EEG) pattern during sleep. The next channel represents airflow. The next three channels show ventilatory effort due to rib and abdominal movement and changes in esophageal pressure, all of which reflect the effort of breathing into an obstructed upper airway. The final channel shows oxyhemoglobin saturation. [Diagram 2] 1 is an overview of the MandADO study design described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] In humans, the pharyngeal airway region has no bony or cartilage support and is held open by muscles. When these muscles relax during sleep, the pharynx can become obstructed and airflow ceases. Ventilatory efforts continue and increase as seen by the increasing changes in esophageal pressure in an attempt to overcome the obstruction, as shown in Figure 1. Rib and abdominal movement is in the opposite direction as a result of the diaphragm contracting against the obstructed airway, thereby causing the abdominal wall to bulge outwards and the chest wall to dent inwards.

[0019] The increased effort to breathe leads to arousal from sleep, which can be visualized by electroencephalography (see Figure 1), resulting in the opening of the airway and the resumption of normal breathing. The lack of airflow during apnea also causes hypoxia, indicated by a drop in oxyhemoglobin saturation (see Figure 1). Severity is commonly measured using the Apnea-Hypopnea Index (AHI), which is the sum of the average number of apneas (cessation of breathing lasting at least 10 seconds) and hypopneas (drop in airflow and oxygen saturation) per hour of sleep (Ruehland, WR. et al., The new AASM criteria for scoring hypopneas: Impact on the apnea hypopnea index. SLEEP 2009;32(2):150-157).

[0020] Figure 1 is a graphic illustration of obstructive apnea. The top channel shows the electroencephalogram (EEG) pattern during sleep. The next channel represents airflow. The next three channels show ventilatory effort due to rib and abdominal movement and changes in esophageal pressure, all of which reflect the effort of breathing against an obstructed upper airway. The final channel shows oxyhemoglobin saturation.

[0021] When a strict definition of OSA is used (AHI ≥ 15 events per hour or AHI ≥ 5 events per hour with daytime sleepiness), the estimated prevalence is approximately 15% in men and 5% in women. In the United States, approximately 30 million people have OSA, of which approximately 6 million are diagnosed. The prevalence of OSA in the United States is thought to be increasing due to an aging population and increasing rates of obesity. OSA is associated with major comorbidities and economic costs, such as hypertension, diabetes, cardiovascular disease, motor vehicle accidents, workplace accidents, and fatigue / loss of productivity. (Young, T. et al., WMJ 2009;108:246; Peppard, PE. et al., Am J Epidemiol 2013;177:1006.).

[0022] The current primary treatment is continuous positive airway pressure (CPAP). Although CPAP is effective for nearly all patients, and approximately 85% of diagnosed patients are prescribed CPAP, compliance is low. Patients find CPAP uncomfortable and often intolerable. At least 30% of patients (up to 80%) are regularly non-compliant and therefore go untreated (Weaver, TE. Proc Am Thorac Soc. 2008 Feb 15;5(2):173-178). Other treatments with varying success rates include oral appliances (10%) and surgery (5%), but neither are likely to be effective across the population.

[0023] Attempts to find drugs that activate pharyngeal muscles in humans during sleep have been disappointing: drugs such as serotonin reuptake inhibitors, tricyclic antidepressants, and sedatives have all been tested in humans and shown to be ineffective in reducing the severity of OSA. For example, Hudgel, DA. et al.,Chest.1991 Aug;100(2):416-21;Brownell LG.et al.,N Engl J Med 1982,307:1037-1042;Sangal RB.et al.,Sleep Med.2008 Jul;9(5):506-10.Epub 2007 Sep 27; Marshall, NS. et al. Sleep 2008 Jun; 31 (6): 824-31; Eckert, DJ.

[0024] Recent studies have shown that a combination of atomoxetine and oxybutynin (called "ato-oxy") administered before bedtime reduces OSA in patients with varying severity. The ato-oxy combination administered overnight reduced the number of obstructive events, improved overnight oxygen desaturation, and enhanced genioglossus activity in an unselected group of patients with OSA. Data collected in a proof-of-concept study showed that it was possible to improve or reverse OSA using drugs with specific neurotransmitter profiles administered systemically. See Taranto-Montemurro, L. et al., The Combination of Atomoxetine and Oxybutynin Greatly Reduces Obstructive Sleep Apnea Severity. A Randomized, Placebo-controlled, Double-Blind Crossover Trial. Am J Respir Crit Care Med 2019 May 15;199(10):1267-1276.

[0025] There remains a need for additional therapies to treat conditions associated with pharyngeal airway obstruction, such as sleep apnea.

[0026] Treatment method The methods described herein include treating disorders associated with muscular obstruction of the pharyngeal airway during sleep. In some embodiments, the disorder is sleep apnea (e.g., obstructive sleep apnea (OSA)) or snoring (e.g., simple snoring). In general, the methods include administering to a subject in need of, or determined to be in need of, such treatment a therapeutically effective amount of a norepinephrine reuptake inhibitor (NRI) in combination with mandibular advancement device (MAD) therapy. In some embodiments, the treatment further includes administering a muscarinic receptor antagonist (MRA) and / or a hypnotic agent. In certain embodiments, the methods include administering to a subject in need of, or determined to be in need of, such treatment a therapeutically effective amount of (i) atomoxetine or a pharma- ceutical acceptable salt thereof, and (ii) oxybutynin (e.g., (R)-oxybutynin) or a pharma-ceutical acceptable salt thereof in combination with mandibular advancement device (MAD) therapy. In certain embodiments, the methods include administering to a subject in need of, or determined to be in need of, such treatment, therapeutically effective amounts of (i) atomoxetine, or a pharma- ceutical acceptable salt thereof, and (ii) a hypnotic agent (e.g., trazodone or zolpidem, or a pharma- ceutical acceptable salt thereof), in combination with mandibular advancement device (MAD) therapy.

[0027] As used in this context, "treat" means to improve at least one symptom of a disorder associated with pharyngeal airway obstruction. Often, pharyngeal airway obstruction during sleep causes snoring and / or breathing interruptions (apnea or hypopnea), arousals from sleep, and reduced oxygenation (hypoxemia). Thus, treatment can result in a reduction in snoring, apnea / hypopnea, sleep fragmentation, and hypoxemia. Administering a therapeutically effective amount of a compound described herein to a subject with OSA can result in a reduction in AHI. Measurement of OSA disease and symptoms can be performed, for example, by polysomnography (PSG).

[0028] In general, the "effective amount" of a compound refers to an amount sufficient to induce a desired biological response, for example, to treat a condition associated with pharyngeal airway obstruction, for example, to treat sleep apnea or snoring. Those of ordinary skill in the art will understand that the effective amount of the compound of the present invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the method of administration, and the age, weight, health status, and condition of the subject. The effective amount includes treatment and prophylactic treatment.

[0029] An effective amount can be administered in one or more administrations, applications, or dosages. The NRI, MRA, and / or hypnotic agent can be administered from one or more times per day to one or more times per week. This includes administering once every other day. In some embodiments, the NRI, MRA, and / or hypnotic agent are administered daily. In some embodiments, the NRI, MRA, and / or hypnotic agent are administered daily before bedtime, e.g., immediately before bedtime or 15-60 minutes before bedtime. In some embodiments, the NRI, MRA, and / or hypnotic agent are administered daily before attachment of the MAD to the subject, e.g., immediately before attachment of the MAD or 15-60 minutes before attachment of the MAD. In some embodiments, the NRI, MRA, and / or hypnotic agent are administered daily simultaneously with the MAD already attached to the subject. In some embodiments, the NRI, MRA, and / or hypnotic agent are administered as a single composition. In some embodiments, the composition is administered orally. One of ordinary skill in the art will appreciate that certain factors, including, but not limited to, the severity of the disease or disorder, previous treatments, the overall health and / or age of the subject, other existing diseases, etc., can affect the dosage and timing required to effectively treat a subject. Moreover, treatment of a subject with a therapeutically effective amount of a therapeutic compound described herein can include a single treatment or a series of treatments.

[0030] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic effect in the treatment of a disease, disorder, or condition, or an amount sufficient to delay or minimize the onset of one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent that alone or in combination with other therapies provides a therapeutic effect in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids the causes or symptoms of a disease or condition, or improves the therapeutic effect of another therapeutic agent.

[0031] As used herein, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "patient" refer to animals (e.g., birds (chickens, quails, turkeys, etc.), or mammals), with "mammals" including non-primates (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), and more particularly humans. In one embodiment, the subject is a non-human animal, such as a farm animal (e.g., horses, cows, pigs, or sheep) or a pet (e.g., dog, cat, guinea pig, or rabbit). In a preferred embodiment, the subject is a human.

[0032] As used herein, "pharmaceutical acceptable" means approved or approvable by a regulatory agency of the Federal or state government, or a corresponding agency in a country other than the United States, for use in animals, or more specifically in humans, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias.

[0033] "Pharmaceutically acceptable salts" includes "pharmaceutically acceptable acid addition salts" and "pharmaceutically acceptable base addition salts." "Pharmaceutically acceptable acid addition salts" refers to salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids, such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, which retain the biological effectiveness of the free base and which are not biologically or otherwise undesirable.

[0034] "Pharmaceutically acceptable base addition salts" include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Exemplary salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine (see, e.g., Berge, SM. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19, incorporated herein by reference).

[0035] As used herein, the term "unit dosage form" is defined to refer to the form in which a compound is administered to a subject. Specifically, the unit dosage form can be, for example, a pill, a capsule, or a tablet. In some embodiments, the unit dosage form is a capsule. In some embodiments, the unit dosage form is a tablet.

[0036] As used herein, "solid dosage form" means a solid pharmaceutical dose(s), such as tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers, and chewables.

[0037] For the compounds disclosed herein, single stereochemical isomers as well as enantiomers, diastereomers, cis / trans conformational isomers, and rotamers, as well as racemic and non-racemic mixtures thereof, are within the scope of the invention. Unless otherwise specified, all tautomeric forms of the compounds disclosed herein are within the scope of the invention.

[0038] Norepinephrine reuptake inhibitors (NRIs), muscarinic receptor antagonists (MRAs), and hypnotics Exemplary norepinephrine reuptake inhibitors (NRIs) include selective NRIs, such as amidaburin (UK-3540-1), atomoxetine (Strattera), CP-39,332, daredalin (UK-3557-15), edivoxetine (LY-2216684), esreboxetine, lortalamine (LM-1404), nisoxetine (LY-94,939), reboxetine (Edronax, Vestra), talopram (Lu 3-010), talsupram (Lu 5-005), tandamine (AY-23,946), viloxazine (Vivalan), and non-selective NRIs such as amitriptyline, amoxapine, bupropion, cyclazindol, desipramine, desvenlafaxine, dexmethylphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxine (GW-320,659), maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetrazine, phenmetrazine, protriptyline, radafaxine (GW-353,162), tapentadol (Nucynta), teniloxazine (Lucelan, Metatone), and venlafaxine, and pharmaceutically acceptable salts thereof.

[0039] In some embodiments, the NRI is atomoxetine or a pharma- ceutically acceptable salt thereof. In some embodiments, the NRI is reboxetine or a pharma- ceutically acceptable salt thereof.

[0040] Atomoxetine is the generic name for the pharmaceutical agent having the chemical name (-)-N-methyl-3-phenyl-3-(o-tolyloxy)-propylamine, and its pharmaceutical salts. Atomoxetine is the R(-)-isomer as determined by X-ray diffraction. In some embodiments, atomoxetine may be atomoxetine hydrochloride.

[0041] In some embodiments, the method includes administering a dose of atomoxetine or a pharma- ceutically acceptable salt thereof (or a dose equivalent of another NRI) of about 20 mg to about 150 mg. In some embodiments, the dose of atomoxetine or a pharma- ceutically acceptable salt thereof is about 25 mg to about 100 mg. In some embodiments, the dose of atomoxetine or a pharma- ceutically acceptable salt thereof is about 40 mg to about 80 mg. In some embodiments, the dose of atomoxetine or a pharma- ceutically acceptable salt thereof is about 20 mg to about 50 mg. In some embodiments, the dose of atomoxetine or a pharma- ceutically acceptable salt thereof is about 50 mg to about 100 mg. In some embodiments, the dose of atomoxetine or a pharma- ceutically acceptable salt thereof is about 40 mg. In some embodiments, the dose of atomoxetine or a pharma- ceutically acceptable salt thereof is about 80 mg.

[0042] Exemplary muscarinic receptor antagonists (MRAs) include atropine, propantheline, bethanechol, solifenacin, darifenacin, tolterodine, fesoterodine, trospium, and oxybutynin, and pharmaceutically acceptable salts thereof, which have activity against the M2 receptor. Other exemplary antimuscarinic agents include anisotropine, benztropine, biperiden, clidinium, cyclimine, dicyclomine, diphemanil, diphenidol, ethopropazine, glycopyrrolate, hexocyclium, isopropamide, mepenzolate, methixene, methscopolamine, oxyphencyclimine, oxyphenonium, procyclidine, scopolamine, tridihexethyl, and trihexyphenidyl, and pharmaceutically acceptable salts thereof.

[0043] In some embodiments, the muscarinic receptor antagonist is oxybutynin or (R)-oxybutynin, or a pharmaceutically acceptable salt thereof.As used herein, "(R)-oxybutynin" refers to the (R)-oxybutynin stereoisomer that is substantially free of other stereoisomers of oxybutynin.In some embodiments, the muscarinic receptor antagonist is fesoterodine.

[0044] Oxybutynin is the generic name of the pharmaceutical substance with the chemical name 4-diethylamino-2-butynylphenylcyclohexyl glycolate or 4-(diethylamino)but-2-ynyl 2-cyclohexyl-2-hydroxy-2-phenyl acetate, and its pharma- ceutically acceptable salts. In various embodiments, oxybutynin can be a racemic mixture of R- and S-enantiomers, or an isolated enantiomer, such as the R-enantiomer. In various embodiments, oxybutynin can be oxybutynin chloride or (R)-oxybutynin chloride.

[0045] In methods comprising administering oxybutynin or (R)-oxybutynin or a pharma- ceutically acceptable salt thereof (or another MRA), the dose of oxybutynin or (R)-oxybutynin or a pharma- ceutically acceptable salt thereof may be about 0.5 mg to about 25 mg (or its dose equivalent of another MRA), or in some embodiments, about 2 mg to about 15 mg. In some embodiments, the dose of oxybutynin or a pharma- ceutically acceptable salt thereof is about 2.5 mg to about 10 mg, for example, 5 mg. In some embodiments, the dose of (R)-oxybutynin or a pharma- ceutically acceptable salt thereof is about 0.5 mg to about 5 mg, for example, 2.5 mg. In some embodiments, the dose of oxybutynin or (R)-oxybutynin or a pharma- ceutically acceptable salt thereof is about 1 mg to about 5 mg.

[0046] Exemplary hypnotics include benzodiazepines such as temazepam, brotizolam, flurazepam, nitrazepam, and triazolam, cyclopyrrolone hypnotics such as zolpidem, zopiclone, and eszopiclone, gabapentin, trazodone, diphenhydramine, suvorexant, tasimelteon, ramelteon, agomelatine, doxepin, zaleplon, doxylamine, sodium oxybate, and tiagabine, and pharmaceutically acceptable salts thereof.

[0047] In some embodiments, the hypnotic agent is trazodone or a pharma- ceutically acceptable salt thereof.In some embodiments, the hypnotic agent is zolpidem or a pharma- ceutically acceptable salt thereof.

[0048] Mandibular advancement device (MAD) Mandibular advancement devices (MADs), including mandibular advancement splints (MASs) or mandibular repositioning appliances (MRAs), prevent upper airway obstruction by thrusting the mandible forward, thus repositioning the jaw and tongue. Both videoendoscopic and magnetic resonance imaging (MRI)-based studies have determined that these devices increase airway volume primarily at the level of the velopharynx. Airway space is enlarged primarily laterally, which is believed to be due to traction forces on the soft tissue connection between the pharynx and the mandibular ramus. MADs also improve airway strength and stiffness by increasing muscle activity of the tongue and other muscles of the airway.

[0049] MADs vary widely in design and sophistication. Variables include adjustability, the nature or degree of customization, and the materials used, which are not mutually exclusive.

[0050] In some embodiments, the MAD is a boil and bite MAD, a one-piece custom MAD, or a two-piece custom MAD.

[0051] In some embodiments, the MAD is a boil-and-bite MAD. Non-adjustable "boil-and-bite" MADs are available from pharmacies and various websites. They are constructed of a thermoplastic material that becomes moldable when warmed by immersion in hot water. The user takes an impression of their teeth by biting into the softened material, which is then allowed to cool.

[0052] In some embodiments, the MAD is a custom-made MAD. A custom-made MAD is constructed in a laboratory using a dental impression. A custom-made MAD can be a one-piece or an adjustable two-piece appliance.

[0053] In some embodiments, the MAD is a one-piece custom MAD. The upper and lower dental splints are fused together in a one-piece device (monolithic casting). While most of these appliances are custom dental manufactured appliances, there are "semi-custom" MADs that do not require specialist dental input.

[0054] In some embodiments, the MAD is a two-piece custom MAD. The adjustable two-piece appliance is provided in the form of separate upper and lower plates. The construction requires additional specialized jaw articulation and is more expensive. The serially titrated mandibular protrusion is believed to increase the success of treatment by allowing for gradual adaptation to the optimal protrusion. The ability to titrate the protrusion according to efficacy and tolerance is an advantage of the adjustable MAD (aMAD). Existing studies comparing so-called fixed MADs (fMADs) with aMADs have had methodological limitations and inconsistent findings. For example, one study comparing the two appliances sets different protrusions for fMADs and aMADs, thus essentially comparing the protrusions and not the appliances. Thus, the MADs used in the methods of the present invention can vary depending on the needs of the subject and the body / mouth / teeth structure.

[0055] Pharmaceutical Compositions Also provided herein is a pharmaceutical composition comprising a norepinephrine reuptake inhibitor (NRI), a muscarinic receptor antagonist (MRA), and / or a hypnotic agent as active ingredients. The active ingredients may be in a single composition or in separate compositions. In certain embodiments, the pharmaceutical composition comprises (i) atomoxetine or a pharma- ceutically acceptable salt thereof and (ii) oxybutynin (e.g., (R)-oxybutynin) or a pharma- ceutically acceptable salt thereof as active ingredients.

[0056] Pharmaceutical compositions typically include a pharma- ceutically acceptable carrier. As used herein, the term "pharma- ceutically acceptable carrier" includes saline, solvents, dispersion media, diluents, fillers, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration.

[0057] The active ingredient for use in the present invention can be provided as a pharma- ceutically acceptable salt.For example, in some embodiments, oxybutynin is oxybutynin chloride.In some embodiments, (R)-oxybutynin is (R)-oxybutynin chloride.In some embodiments, atomoxetine is atomoxetine hydrochloride.

[0058] A pharmaceutical composition is typically formulated to be compatible with its intended route of administration, examples of which include systemic oral or transdermal administration, and sublingual administration, e.g., via tablet or spray.

[0059] Methods for formulating suitable pharmaceutical compositions are known in the art, see, for example, Remington: The Science and Practice of Pharmacy, 21st ed., 2005; and the books in the series Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs (Dekker, NY). For example, oral compositions generally include an inert diluent or an edible carrier. For the purpose of oral administration, the active compound(s) can be formulated with an excipient and used in the form of pills, tablets, lozenges, or capsules (e.g., gelatin capsules). Oral compositions can also be prepared using liquid carriers. In some embodiments, the composition according to the present invention can be in unit dosage form. In some embodiments, the composition according to the present invention can be in solid dosage form, for example, tablets or capsules.

[0060] Pharmaceutically compatible binders and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain the following ingredients, or compounds of a similar nature: microcrystalline cellulose, gum tragacanth or gelatin as a binder; starch or lactose as an excipient; alginic acid, primogel or corn starch as a disintegrating agent; magnesium stearate or sterols as a lubricant; colloidal silicon dioxide as a lubricant; sucrose or saccharin as a sweetening agent; or peppermint, methyl salicylate, or orange flavoring as a flavoring agent.

[0061] Systemic administration of the compounds described herein can also be performed by transdermal administration, for example, by applying a patch, gel, or lotion to the skin. For transdermal administration, a penetrant suitable for penetrating the epidermal barrier can be used in the formulation. Such penetrants are generally known in the art. For example, for transdermal administration, the active compound can be formulated into an ointment, salve, gel, or cream, as is generally known in the art. Gels and / or lotions can be provided via individual sachets or metered pumps that are applied once a day. See, for example, Cohn et al., Ther Adv Urol. 2016 Apr; 8(2): 83-90.

[0062] In one embodiment, the therapeutic compound is prepared with a carrier that prevents the therapeutic compound from being rapidly eliminated from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable and biocompatible polymers can be used, including, for example, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Such formulations can be prepared using standard techniques, and are commercially available, for example, from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions can also be used as pharma-ceutically acceptable carriers. These can be prepared by methods known to those skilled in the art, for example, according to the methods described in U.S. Pat. No. 4,522,811.

[0063] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration or use in the methods described herein.

[0064] In some embodiments, the pharmaceutical composition is for use in treating a condition associated with pharyngeal airway obstruction. In some embodiments, the condition is sleep apnea (e.g., OSA) or snoring (e.g., simple snoring). In certain embodiments, provided herein is a pharmaceutical composition comprising atomoxetine or a pharma- ceutically acceptable salt thereof, and cannabidiol or a pharma- ceutically acceptable salt thereof, and optionally oxybutynin (e.g., (R)-oxybutynin) or a pharma- ceutically acceptable salt thereof, for use in treating sleep apnea (e.g., OSA) or snoring (e.g., simple snoring).

[0065] combination Also provided herein is a norepinephrine reuptake inhibitor (NRI) and a mandibular advancement device (MAD) for use in treating a subject having a condition associated with pharyngeal airway obstruction. In some embodiments, the combination for use further comprises a muscarinic receptor antagonist (MRA). In some embodiments, the combination for use further comprises a hypnotic agent. Further provided herein is a therapeutic combination comprising (a) a pharmaceutical composition comprising a norepinephrine reuptake inhibitor (NRI) and a pharma- ceutically acceptable carrier, and (b) a mandibular advancement device (MAD) for use in treating a subject having a condition associated with pharyngeal airway obstruction. In some embodiments, the combination for use further comprises a muscarinic receptor antagonist (MRA). In some embodiments, the combination for use further comprises a hypnotic agent. Various embodiments of the combination and therapeutic combination will be apparent from the detailed description provided herein, including the compositions and methods described herein. In certain embodiments of the combination of the present invention, the NRI is atomoxetine or a pharma- ceutically acceptable salt thereof and the MRA is oxybutynin (eg, (R)-oxybutynin) or a pharma- ceutically acceptable salt thereof. EXAMPLES

[0066] The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

[0067] Example 1. A randomized, double-blind, multiple-dose, two-period crossover study to evaluate the efficacy and safety of AD036 (atomoxetine + oxybutynin) + mandibular advancement device versus AD036 alone in OSA patients with a suboptimal response to a mandibular advancement device (MandADO)

[0068] basis AD036, a combination of atomoxetine and oxybutynin, is a drug combination in development for the treatment of obstructive sleep apnea (OSA). The primary mechanism of action of AD036 is thought to be an increase in pharyngeal muscle stiffness and responsiveness.

[0069] Mandibular advancement device (MAD) therapy ameliorates OSA by mechanically increasing the retropalatal and lingual spaces. Improvement in OSA severity with MAD therapy, as measured by the apnea-hypopnea index (AHI), is typically about 50%, although in some patients improvement may be less or may be considered inadequate due to, for example, elevated residual AHI or subjective reports of continued excessive daytime sleepiness (EDS) or snoring.

[0070] The MandADO trial is designed to evaluate the safety and efficacy of combination treatment with AD036 and MAD for OSA in patients with an inadequate response to MAD alone.

[0071] obstructive sleep apnea The National Commission on Sleep Disorders Research has identified sleep disorders as a major public health burden. OSA is the most common and severe of these sleep disorders, affecting approximately 20 million people in the United States, with approximately 13% of men and 6% of women affected (1). OSA is characterized by recurrent collapse or "obstruction" of the pharyngeal airway during sleep, manifesting as recurrent episodes of hypopnea (i.e., shallow breathing) or apnea (i.e., cessation of breathing). These hypopnea or apnea episodes can cause arousals from sleep, sleep fragmentation, excessive daytime sleepiness, and / or neuropsychological impairment.

[0072] Studies have shown that many pathogenic factors or traits contribute to the development of OSA (2-5). The most important factors are the presence of an anatomically small and obstructive upper airway and the loss of pharyngeal muscle tone or responsiveness during sleep.

[0073] Long-term OSA is associated with increased mortality and a number of adverse cardiovascular, neurocognitive, metabolic, and daytime functional outcomes (6-15).

[0074] Unmet medical need The most common treatment for OSA is currently positive airway pressure, typically continuous positive airway pressure (CPAP), delivered by a device that mechanically maintains an open airway. Although the efficacy of CPAP is often good when the device is used, many, perhaps most, patients find these devices uncomfortable or intolerable, and most estimates indicate that fewer than 50% of patients prescribed CPAP use it for more than 4 hours each night, if at all (16). Mandibular advancement devices offer an alternative to CPAP, but patients may have a suboptimal treatment response. Current pharmacological therapy is limited to treating excessive daytime sleepiness resulting from OSA.

[0075] The study endpoints are shown in Table 1 below. [Table 1]

[0076] Overall study design Figure 2 provides an overview of the study design.

[0077] The MandADO study is a randomized, double-blind, placebo-controlled, two-period crossover study in patients with an inadequate response to MAD alone. Patients with subjective reports of increased residual AHI EDS or snoring on current custom MAD therapy provided by a dental or maxillofacial specialist are eligible for screening if there is clinical suspicion or evidence of elevated residual AHI. Participants undergo an initial pre-screening to determine potential study eligibility or exclusion factors, followed by a Screening Visit 1 for patients who remain eligible. Subsequently, only participants who meet all non-PSG enrollment criteria at Visit 1 are eligible for a Screening PSG at Visit 2. The Screening PSG is performed with the MAD in place. Patients are eligible to enroll in the study if their residual AHI (4%) with MAD is >10 and all other enrollment criteria are met.

[0078] Enrolled patients will be randomized to receive one of two study treatments, each for one week: - Period 1: A run-in period of low doses of AD036 on days 1-3 consisting of 40 mg atomoxetine and 5 mg oxybutynin, followed by a full dose period of AD036 on days 4-7 consisting of 80 mg atomoxetine and 5 mg oxybutynin (all doses overencapsulated) in combination with nocturnal MAD use. - Period 2: MAD used nightly all night in combination with two matching placebo capsules.

[0079] Study medication for Period 1 is dispensed at Visit 2 prior to patient discharge. Study medication consists of two different tablets, one of each to be taken each night at the patient's usual bedtime. After 6 days (maximum 8 days) of home medication, patients return for PSG at Visit 3 with the remainder of the dispensed study medication, which is dispensed from their medication supply at lights out. A symptom questionnaire is administered the morning after each PSG, and study medication for the second crossover period is dispensed. Patients are instructed not to begin taking study medication for the second period until after a 1-week washout period. At the end of the 1-week washout period, the site contacts the patient by phone to begin dosing for the second crossover period. As with Period 1, after 6 days (maximum 8 days) of home medication, patients return for PSG at Visit 4 with the remainder of the dispensed study medication, and study medication for Visit 4 is from the patient's Period 2 supply.

[0080] Adverse events and concomitant medication information will be collected at each study site visit and during the End-of-Study debriefing 2 weeks after Visit 4. End-of-Study debriefing with patients will occur 2 weeks after completion of study medication.

[0081] Participants who discontinue the study will not be replaced. No subsequent open-label extension is planned following this study.

[0082] Inclusion criteria 1. Current use of MADs for OSA. Patients who have discontinued MADs within 6 months are eligible if MAD use is resumed at least 2 weeks prior to V2. 2. Age between 25 and 65 years (inclusive) at the time of the screening visit. 3. AHI >10 at V2 baseline using MAD (4%). If the initial PSG shows an AHI(4%) between 8 and 9, it may be repeated and the mean AHI(4%) will be used. 4. ≤25% of apneas are central or mixed apneas on V2 baseline PSG. 5. 18.5-40.0 kg / m at the pre-PSG screening visit 2 BMI (inclusive) 6. If the male is sexually active with a female partner(s) of childbearing potential, the participant must agree to practice protocol-specified contraception methods from study day 1 through 1 week after the final dose of study drug. 7. If women of childbearing potential (WOCBP), participants must agree to practice protocol-specified contraception from Study Day 1 through 1 week after the last dose of study drug (see Appendix 4: Contraception Instructions and Pregnancy Information Collection). All WOCBP must have a negative serum pregnancy test performed at screening. 8. For women of childbearing ability, participants must be either postmenopausal (defined as age 55 years or older with no menstrual period for 12 months or more without another medical cause) or permanently surgically infertile (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy). 9. Participants will voluntarily agree to participate in this study and sign an Institutional Review Board (IRB)-approved informed consent prior to conducting any of the screening visit procedures. 10. Participants must be able to understand the nature of the study and have the opportunity to answer any questions.

[0083] Exclusion criteria Participants will be excluded from the study if they meet any of the following criteria: 1. History of clinically significant sleep disorder other than OSA. 2. Clinically significant craniofacial malformations. 3. Clinically significant cardiac disease (e.g., rhythm disorders, coronary artery disease, or heart failure) or hypertension requiring more than two medications for control (combination medications are considered one medication for this purpose). 4. Clinically significant neurological disorder, including epilepsy / convulsions. 5. History of schizophrenia, schizoaffective disorder, or bipolar disorder according to the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) or the International Classification of Diseases, 10th edition. 6. History of suicide attempt within 1 year prior to screening or current suicidal ideation. 7. Medically unresolved positive screen for a history of DSM-V defined substance abuse or substance use disorder within 24 months prior to the screening visit. 8. Significant illness or infection requiring medical treatment within the past 30 days. 9. Clinically significant cognitive impairment as determined by the investigator. 10. Pregnant or lactating women. 11. The use of positional devices is permitted but should be kept constant for 2 weeks prior to V2 and throughout the course of the study. 12. CPAP use must be discontinued at least 2 weeks prior to V2 and throughout the course of the study. 13. History of long-term oxygen therapy. 14. Use of drugs from the list of prohibited concomitant medications. 15. Treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor, a strong cytochrome P450 2D6 (CYP2D6) inhibitor, or a monoamine oxidase inhibitor (MAOI) within 14 days of initiating treatment or concomitantly with treatment. 16. Use of another investigational drug within 30 days or 5 half-lives prior to dosing, whichever is longer. 17. Hepatic transaminases: >2x upper limit of normal (ULN), total bilirubin: >1.5x ULN (except in cases with confirmed Gilbert's syndrome), estimated glomerular filtration rate: <60ml / min. 18. PLM Arousal Index:>15 19. Typical sleep duration of <5 hours. 20. ESS:>18 21. Night or shift sleep schedules in which the primary sleep period is during the day. 22. Occupation as a professional driver or operator of heavy or hazardous equipment. 23. Typically smoking more than 10 cigarettes or more than 2 cigars per day or inability to refrain from smoking during an overnight PSG visit. 24. Not intending to use the specified contraceptive method. 25. History of regular alcohol consumption of more than 14 standard units per week (men) or more than 7 standard units per week (women) or an inability to limit alcohol consumption to less than 2 units per day (men) or 1 unit per day (women) and not consume within 3 hours of bedtime or on the night of PSG. 26. Willing to limit intake of caffeine-containing beverages (e.g., coffee, cola, tea) to 400 mg caffeine / day or less during the study period and not use within 3 hours of bedtime. 27. Any condition that the investigator determines would present an unreasonable risk to the participant or would interfere with participation in the study or confound interpretation of the study. 28.Candidate who, for any reason, the Investigator believes is not suitable for receiving atomoxetine and / or dronabinol or is unable or unlikely to understand or comply with the dosing schedule or study assessments. Food and dietary restrictions 1. Participants should refrain from consuming any nutrients known to modulate CYP enzyme activity (e.g., grapefruit or grapefruit juice, pomelo juice, starfruit, pomegranate, and bitter orange or moro (blood) orange products) within 72 hours prior to and during the study after the first dose of study drug. 2. Diet should generally remain stable during the study, e.g., no new dietary programs should be initiated. Caffeine, alcohol, and tobacco 1. During the outpatient portion of the study, participants should refrain from drinking more than 2 standard units of alcohol per day for men or 1 unit / day for women, and should not consume within 3 hours before bedtime. Alcohol should not be consumed on the night of PSG. 2. Moderate consumption of caffeinated beverages containing up to a total of 400 mg of caffeine per day will be permitted during the study, not to be consumed within 3 hours prior to bedtime.

[0084] Study Drugs AD036 or placebo will be taken in combination with MAD during each crossover period. AD036 will consist of one overencapsulated atomoxetine (40 mg on days 1-3 and 80 mg on days 4-7) and one overencapsulated oxybutynin 5 mg. Table 2 shows the dosing formulations and routes of administration. [Table 2]

[0085] Combination therapy Concomitant therapy with the following medications, as listed below, is prohibited: For medications typically used as needed for symptomatic conditions (e.g., occasional use of sleep aids), the medication should not be used for at least 1 week prior to the first study PSG and for the duration of the study.

[0086] Prohibited medications include MAOIs or other drugs that affect monoamine concentrations (e.g., rasagiline) (MAOIs are contraindicated in combination with: atomoxetine, lithium, cannabinoids, selective serotonin reuptake inhibitors (e.g., paroxetine), selective norepinephrine reuptake inhibitors (e.g., duloxetine), norepinephrine reuptake inhibitors (e.g., reboxetine), alpha-1 antagonists (e.g., tamsulosin), tricyclic antidepressants (e.g., desipramine), CYP2D6 inhibitors, strong CYP3A4 inhibitors (e.g., ketoconazole), benzodiazepines and other anxiolytics, opioids. , sedatives and sedative-hypnotics (including non-benzodiazepine "Z drugs" (zolpidem, zaleplon, eszopiclone)), muscle relaxants, vasopressors, drugs with a clinically significant cardiac QT interval prolonging effect, drugs known to lower the seizure threshold (e.g., chloroquine), amphetamines, antiepileptics, antiemetics, modafinil or armodafinil, beta 2 agonists (e.g., albuterol), antipsychotics, sedating antihistamines, pseudoephedrine, phenylephrine, oxymetazoline, nicotine replacement products, most drugs for Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, or drugs for other neurodegenerative diseases.

[0087] Medications that do not have a substantial effect on the central nervous system (CNS), respiration, or muscle activity are generally permitted, including, but not limited to, the following drugs and drug classes: antihypertensives (angiotensin-converting enzyme (ACE) / angiotensin II receptor blocker (ARB) inhibitors, calcium channel blockers, hydrochlorothiazide, etc.), statins, proton pump inhibitors and histamine h2-receptor blockers, over-the-counter (OTC) antacids, non-sedating antihistamines (e.g., cetirizine, loratadine), acetaminophen, laxatives, erectile dysfunction medications, inhaled corticosteroids (e.g., fluticasone), antidiabetic drugs, ocular hypotensives and other ophthalmic agents (e.g., timolol), hormone therapy (e.g., estrogen replacement or antiestrogens), and hormonal contraceptives, thyroid medications, anticoagulants, osteoporosis medications.

[0088] Study Assessment and Procedures The study procedures and their timing are summarized in the SoA table shown in Table 3 below.

[0089] Polysomnography Methods: Standard overnight PSG recording and data interpretation will be performed according to the American Academy of Sleep Medicine (AASM) scoring manual. Participants will be fitted with standard PSG electrodes. Lights-off time will be established according to the participant's habitual schedule and will remain constant throughout the PSG study night. Participants will be allowed 8 hours of sleep time.

[0090] Participants should be actively encouraged to spend at least 1 / 3 of the night in the supine position and at least 1 / 3 of the night in the lateral position on each night of the study.

[0091] Safety assessment The planned time points for all safety evaluations are shown in SoA Table 3.

[0092] Safety monitoring will be guided by the established safety profiles of atomoxetine and oxybutynin and the MAD. Safety assessments will include physical examination, measurement of vital signs, monitoring and recording of AEs, SAEs, and pregnancy, and recording of study or treatment discontinuation. Effects on OSA and sleep parameters (e.g., sleep time and sleep stages) will also be monitored by PSG. [Table 3-1] [Table 3-2]

[0093] Other embodiments It is understood that the invention has been described in conjunction with its detailed description, which illustrates and does not limit the scope of the invention, which is defined in the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. A norepinephrine reuptake inhibitor (NRI), a muscarinic receptor antagonist (MRA), and a mandibular advancement device (MAD) for use in treating a subject having a condition associated with pharyngeal airway collapse.

2. A norepinephrine reuptake inhibitor (NRI), a hypnotic agent, and a mandibular advancement device (MAD) for use in treating a subject having a condition associated with pharyngeal airway collapse.

3. A therapeutic combination comprising: (a) a pharmaceutical composition comprising a norepinephrine reuptake inhibitor (NRI) and a pharmaceutically acceptable carrier; and (b) a mandibular advancement device (MAD) for use in treating a subject having a condition associated with pharyngeal airway collapse.

4. 4. The therapeutic combination of claim 3, further comprising a muscarinic receptor antagonist (MRA) and / or a hypnotic agent in said pharmaceutical composition.

5. Atomoxetine or a pharmaceutically acceptable salt thereof, oxybutynin or a pharmaceutically acceptable salt thereof, and a mandibular advancement device (MAD) for use in treating a subject having a condition associated with pharyngeal airway collapse.

6. Atomoxetine or a pharmaceutically acceptable salt thereof, oxybutynin or a pharmaceutically acceptable salt thereof, and a mandibular advancement device (MAD) for use in the treatment of sleep apnea.

7. Atomoxetine or a pharmaceutically acceptable salt thereof, oxybutynin or a pharmaceutically acceptable salt thereof, and a mandibular advancement device (MAD) for use in the treatment of snoring.

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