Methods and compositions for treating sleep apnea with a combination of a GLP-1 agonist and a second active agent

Abstract

Methods of treating obstructive sleep apnea using a GLP-1 receptor agonist and a second active agent are described herein, as well as related pharmaceutical compositions and therapeutic combinations. The second active agent is selected from the group consisting of atomoxetine, reboxetine, viloxazine, edivoxetine, oxybutynin, and trazodone, and stereoisomers thereof, and pharmaceutically acceptable salts thereof.

Description

METHODS AND COMPOSITIONS FOR TREATING SLEEP APNEAWITH A COMBINATION OF A GLP-1 RECEPTOR AGONIST AND ASECOND ACTIVE AGENTCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and benefit of United States Provisional Patent Application Nos. 63 / 600,103, filed November 17, 2023, and 63 / 680,273, filed August 7, 2024, each of which are incorporated herein by reference in their entirety.TECHNICAL FIELD

[0002] The present invention relates to methods of treating sleep apnea using a combination of a GLP-1 receptor agonist and a second active agent, wherein the second active agent may be atomoxetine, reboxetine, viloxazine, edivoxetine, oxybutynin, or trazodone, as well as related pharmaceutical compositions and therapeutic combinations.BACKGROUND

[0003] Obstructive Sleep Apnea (OSA) is a common disorder caused by collapse of the pharyngeal airway during sleep. OSA can have serious health consequences.SUMMARY

[0004] One aspect of the present invention provides a method of treating a subject having a condition associated with pharyngeal airway collapse, the method comprising administering to a subject in need thereof an effective amount of a GLP-1 receptor agonist and a second active agent, wherein the second active agent may be atomoxetine, reboxetine, viloxazine, edivoxetine, oxybutynin, or trazodone, including stereoisomers thereof and pharmaceutically acceptable salts thereof.

[0005] Embodiments of this aspect of the invention may include one or more of the following optional features. In some embodiments, the second active agent is atomoxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the second active agent is reboxetine or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. In some embodiments, the second active agent is viloxazine or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. In some embodiments, the second active agent is edivoxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the second active agent is oxybutynin or a stereoisomer thereof or a pharmaceutically acceptable saltthereof. In some embodiments, the second active agent is racemic oxybutynin or a pharmaceutically acceptable salt thereof. In some embodiments, the second active agent is (R)-oxybutynin or a pharmaceutically acceptable salt thereof. In some embodiments, the second active agent is trazodone or a pharmaceutically acceptable salt thereof.

[0006] In some embodiments, the GLP-1 receptor agonist is selected from the group consisting of semaglutide, tirzepatide, retatrutide, dulaglutide, exenatide, PEGylated exenatide, survodutide, efpeglenatide, liraglutide, lixisenatide, cotadutide, noiiglutide, mazdutide, albiglutide, beinaglutide, PEG-1 oxenati de, pemvidutide, taspoglutide, efocipegtrutide, orforglipron, and danuglipron, including stereoisomers thereof and pharmaceutically acceptable salts thereof. In some embodiments, the GLP-1 receptor agonist is selected from the group consisting of semaglutide, tirzepatide, liraglutide, and retatrutide, including stereoisomers thereof and pharmaceutically acceptable salts thereof. In some embodiments, the GLP-1 receptor agonist is semaglutide or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is tirzepatide or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is liraglutide or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is retatrutide or a pharmaceutically acceptable salt thereof.

[0007] In some embodiments, the atomoxetine or pharmaceutically acceptable salt thereof is administered at a dose of from about 20 to about 200 mg. In some embodiments, the atomoxetine or pharmaceutically acceptable salt thereof is administered at a dose of from about 25 to about 100 mg. In some embodiments, the oxybutynin or pharmaceutically acceptable salt thereof is administered at a dose of from about 1 to about 15 mg. In some embodiments, the oxybutynin or pharmaceutically acceptable salt thereof is administered at a dose of from about 2 mg to about 10 mg. In some embodiments, the (R)-oxybutynin or pharmaceutically acceptable salt thereof is administered at a dose of from about 0.5 to about 10 mg. In some embodiments, the (R)-oxybutynin or pharmaceutically acceptable salt thereof is administered at a dose of from about 1 mg to about 5 mg. In some embodiments, the trazodone or pharmaceutically acceptable salt thereof is administered at a dose of from about 12.5 mg to about 200 mg. In some embodiments, the GLP-1 receptor agonist and second active agent are administered in a single composition. In some embodiments, the single composition is an oral administration form. In some embodiments, the oral administration form is a syrup, pill, tablet, troche, or capsule. In some embodiments, the GLP-1 receptor agonist and second active agent are administered as separate compositions. In some embodiments, the condition associated with pharyngeal airway collapse is sleepapnea. In some embodiments, the condition associated with pharyngeal airway collapse is obstructive sleep apnea (OSA). In some embodiments, the OSA is severe OSA. In some embodiments, the OSA is moderate OSA. In some embodiments, the OSA is mild OSA. In some embodiments, the condition associated with pharyngeal airway collapse is snoring. In some embodiments, the condition associated with pharyngeal airway collapse is simple snoring. In some embodiments, the subject is obese. In some embodiments, the subject suffers from severe OSA. In some embodiments, the subject suffers from moderate OSA. In some embodiments, the subject suffers from mild OSA.

[0008] Also provided herein is a GLP-1 receptor agonist and a second active agent for use in treating obstructive sleep apnea, wherein the second active agent may be atomoxetine, reboxetine, viloxazine, edivoxetine, oxybutynin, or trazodone, including stereoisomers thereof and pharmaceutically acceptable salts thereof.

[0009] Also provided herein is a therapeutic combination of a GLP-1 receptor agonist and a second active agent, for use in treating obstructive sleep apnea, wherein the second active agent may be atomoxetine, reboxetine, viloxazine, edivoxetine, oxybutynin, or trazodone, including stereoisomers thereof and pharmaceutically acceptable salts thereof.

[0010] Another aspect of the invention provides a pharmaceutical composition comprising a GLP-1 receptor agonist and a second active agent, and a pharmaceutically acceptable carrier or excipient, wherein the second active agent may be atomoxetine, reboxetine, viloxazine, edivoxetine, oxybutynin, or trazodone, including stereoisomers thereof and pharmaceutically acceptable salts thereof.

[0011] Embodiments of this aspect of the invention may include one or more of the following optional features of the pharmaceutical composition. In some embodiments, the second active agent is atomoxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the second active agent is reboxetine or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. In some embodiments, the second active agent is viloxazine or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. In some embodiments, the second active agent is edivoxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the second active agent is oxybutynin or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. In some embodiments, the second active agent is racemic oxybutynin or a pharmaceutically acceptable salt thereof. In some embodiments, the second active agent is (R)-oxybutynin or a pharmaceutically acceptable salt thereof. In some embodiments, the second active agent is trazodone or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is selected fromthe group consisting of semaglutide, tirzepatide, retatrutide, dulaglutide, exenatide, PEGylated exenatide, survodutide, efpeglenatide, liraglutide, lixisenatide, cotadutide, noiiglutide, mazdutide, albiglutide, beinaglutide, PEG-loxenatide, pemvidutide, taspoglutide, efocipegtrutide, orforglipron, and danuglipron, including stereoisomers thereof and pharmaceutically acceptable salts thereof. In some embodiments, the GLP-1 receptor agonist is selected from the group consisting of semaglutide, tirzepatide, liraglutide, and retatrutide, including stereoisomers thereof and pharmaceutically acceptable salts thereof.

[0012] 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 are described herein for use in the present invention; other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and 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.

[0013] Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The following figures are provided by way of example and are not intended to limit the scope of the claimed invention.

[0015] FIG. 1 is a graphic illustration of an obstructive apnea. The top channel shows the electroencephalogram (EEG) pattern of sleep. The next channel represents airflow. The next three channels show ventilator effort by movements of the rib cage and abdomen and changes in esophageal pressure, all of which reflect a respiratory effort against an occluded upper airway. The last channel indicates oxyhemoglobin saturation.

[0016] FIG. 2 is a diagram showing the overview of the study designDETAILED DESCRIPTION

[0017] In humans, the pharyngeal airway region has no bone or cartilage support, and it is held open by muscles. When these muscles relax during sleep, the pharynx can collapse resulting in cessation of airflow. As shown in Fig. 1, ventilatory effort continues and increases in an attempt to overcome the obstruction, shown by an increase in esophageal pressure change. Rib cage and abdominal movements are in the opposite direction as a resultof the diaphragm contracting against an occluded airway, forcing the abdominal wall to distend out and the chest wall to cave inward.

[0018] Increasing efforts to breathe lead to an arousal from sleep, visualisable on an EEG (Fig. 1), and result in opening of the airway and a resumption of normal breathing. The lack of airflow during the apnea also causes hypoxia, shown by a drop in oxyhemoglobin saturation (Fig. 1). Severity is generally measured using the apnea-hypopnea index (AHI), which is the combined average number of apneas (cessation of breathing for at least ten seconds) and hypopneas (reduced airflow and oxygen saturation) that occur per hour of sleep (Ruehland et al., The new AASM criteria for scoring hypopneas: Impact on the apnea hypopnea index. SLEEP 2009; 32(2): 150-157).

[0019] The National Commission on Sleep Disorders Research identified sleep disorders as a major public health burden. Obstructive sleep apnea (OSA) is the most common of the more serious sleep disorders and affects approximately 30-50 million people in the United States (US), with approximately 13% of men and 6% of women affected (Peppard et al, 2013). OSA is characterized by repetitive collapse or obstruction of the pharyngeal airway during sleep, manifestingas repetitive episodes of hypopnea (i.e., shallow breathing) or apnea (i.e., paused breathing). These episodes of hypopnea or apnea and falls in oxygenation may lead to arousal from sleep, sleep fragmentation, excessive daytime sleepiness, and / or neuropsychological impairment.

[0020] Research has shown that a number of pathogenic factors, or traits, contribute to the development of OSA (Eckert et al, 2013; Wellman et al, 2011; Wellman et al, 2013;Younes, 2003). The most important factors are the presence of an anatomically small, collapsible upper airway and a loss of pharyngeal muscle tone or responsiveness during sleep.

[0021] Fig. 1 is a graphic illustration of an obstructive sleep apnea. The top channel shows the electroencephalogram (EEG) pattern of sleep. The next channel represents airflow. The next three channels show ventilatory effort by movements of the rib cage and abdomen and changes in esophageal pressure, all of which reflect a respiratory effort against an occluded upper airway. The last channel indicates oxyhemoglobin saturation.

[0022] When a stringent definition of OSA is used (an AHI of >15 events per hour or AHI >5 events per hour with daytime sleepiness), the estimated prevalence is approximately 15 percent in males and 5 percent in females. An estimated 30 million individuals in the United States have OSA, of which approximately 6 million have been diagnosed. The prevalence of OSA in the United States appears to be increasing due to aging and increasing rates of obesity. OSA is associated with major comorbidities and economic costs, including:hypertension, diabetes, cardiovascular disease, motor vehicle accidents, workplace accidents, and fatigue / lost productivity. (Young et al., WMJ 2009; 108:246; Peppard et al., Am J Epidemiol 2013; 177:1006.)

[0023] The present leading treatment is continuous positive airway pressure (CPAP). CPAP is effective in virtually all patients, and approximately 85% of diagnosed patients are prescribed CPAP, but compliance is low. Patients find CPAP uncomfortable and often intolerable; at least 30% of patients (up to 80%) are regularly non-adherent and thus untreated (Weaver, Proc Am Thorac Soc. 2008 Feb 15; 5(2): 173-178). Other treatment modalities with variable rates of success include oral appliances (10%) and surgery (5%), but neither is likely to be effective across the general population.

[0024] The search for medicines to activate pharyngeal muscles in sleeping humans has been discouraging; agents such as serotonin reuptake inhibitors, tricyclic antidepressants, and sedatives have all been tested in humans and shown to be ineffective at reducing OSA severity. See, e.g., Proia and Hudgel, Chest. 1991 Aug;100(2):416-21; Brownell et al., N Engl J Med 1982, 307:1037-1042; Sangal et al., Sleep Med. 2008 Jul;9(5):506-10. Epub 2007 Sep 27; Marshall et al. p. 2008 Jun;31(6):824-31; Eckert et al., Clin Sci (Lond). 2011 Jun;120(12);505-14; Taranto-Montemurro et al., Sleep. 2017 Feb l;40(2). In view of the low compliance and disappointing results of pharmaceutical therapies, there remains a need for further therapies for treating conditions associated with pharyngeal airway collapse such as sleep apnea.

[0025] In a recent study, a combination of atomoxetine and oxybutynin, referred to as “ato- oxy,” administered before bedtime has been shown to reduce OSA in patients with a wide range of severity. The ato-oxy combination, which was administered for one night, reduced the number of obstructive events, improved the overnight oxygen desaturation, and enhanced the genioglossus muscle activity in a group of unselected patients with OSA. The data collected in the proof-of-concept trial showed that it was possible to improve or abolish OSA using drugs with specific neurotransmitter profiles administered systemically. See Taranto- Montemurro, Luigi et al. “The Combination of Atomoxetine and Oxybutynin Greatly Reduces Obstructive Sleep Apnea Severity. A Randomized, Placebo-controlled, DoubleBlind Crossover Trial.” American journal of respiratory and critical care medicine vol. 199,10 (2019): 1267-1276.

[0026] The promising “ato-oxy” study results has lead to developing AD 109, a new fixed dose drug combination of aroxybutynin and atomoxetine for treating OSA. Aroxybutynin has never been marketed, but racemic oxybutynin is approved as an antispasmodic drug thatinhibits the muscarinic action of acetylcholine on smooth muscle and is indicated for the treatment of symptoms of bladder instability associated with voiding in patients with uninhibited neurogenic or reflex neurogenic bladder such as urgency, frequency, urinary leakage, urge incontinence and dysuria. Atomoxetine is a pre-synaptic norepinephrine reuptake inhibitor indicated for the treatment of attention deficit hyperactivity disorder in children and adults. AD 109 targets two neurochemical pathways at the hypoglossal nucleus which control the upper airway musculature during sleep: excitatory signaling (atomoxetine) and blockade of inhibitory signaling (aroxybutynin). Aroxybutynin also mitigates disruption of sleep caused by atomoxetine.

[0027] For example, Phase 2 studies of increasing duration were conducted to test the safety and efficacy of AD 109. The MARIPOSA Study (APC-005) was a parallel-arm study that established the efficacy and safety of AD 109 over a 1 -month period of dosing. Currently, two phase 3 studies, APC-APN-304 and 305, are underway to examine the efficacy and safety of AD 109 vs placebo at 6-months and 1-year of dosing in participants who are intolerant to, or currently refuse, continuous positive airway pressure (CPAP).

[0028] In various aspects, the present disclosure provides compositions and methods of treatment to enhance the efficacy of AD 109 with incretin-based therapy. Incretins are a group of hormones that are released in the gut after eating and stimulate the body to secrete insulin in response to nutrients.

[0029] Glucagon-Like Peptide-1 (GLP-1) receptor agonist drugs are members of a recently developed class of incretins used in the treatment of obesity, conditions that are common in the OSA population. Incretin-based therapy for obesity represents a promising development in the treatment of these conditions. These compounds can be incretin mimetics or enhancers that serve to regulate blood glucose levels by stimulating the pancreas and delaying gastric emptying. It is recognized that obesity is a common comorbidity and risk factor for the development of OSA in some people. Considering the high prevalence of OSA in a population of obese patients, it is likely that this class of medications will be considered for co-administration with AD109 in some patients. Incretins delay gastric emptying when dosing is initiated, and have the potential to impact the absorption of concomitantly administered orally administered medications; however, the delay is largest with the first dose and this effect diminishes over time, such that at steady state no dose adjustments for drug-drug interactions are recommended for either tirzepatide, semaglutide, or liraglutide. This phase 3 study is thus conducted on participants who have been on a stable dose of tirzepatide, semaglutide or liraglutide for at least 4 weeks.

[0030] The Example disclosed herein describes the clinical trial protocol testing the safety, efficacy, and tolerability of AD 109 combined with an incretin-based therapy in patients with OSA, including obese individuals.Definitions

[0031] As used in this context, to “treat” means to ameliorate at least one symptom of the disorder associated with pharyngeal airway collapse. Often, pharyngeal airway collapse during sleep results in snoring and / or an interruption in breathing (apnea or hypopnea), arousal from sleep, and reduced oxygenation (hypoxemia); thus, a treatment can result in a reduction in snoring, apneas / hypopneas, sleep fragmentation, and hypoxemia. Administration of a therapeutically effective amount of a compound described herein for the treatment of a subject with OSA may result in decreased AHI. Measurement of OSA disease and symptoms may be, for example, by polysomnography (PSG).

[0032] In general, an “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response, e.g., to treat a condition associated with pharyngeal airway collapse, e.g., to treat sleep apnea or snoring. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment.

[0033] An effective amount can be administered in one or more administrations, applications or dosages. The compositions can be administered from one or more times per day to one or more times per week; including once every other day. In some embodiments, the compositions are administered daily. In some embodiments, the compositions are administered daily before sleep time, e.g., immediately before sleep time or 15-60 minutes before sleep time. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and / or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of the therapeutic compounds described herein can include a single treatment or a series of treatments.

[0034] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0035] As used herein, the terms “subject” and “patient” are used interchangeably. The terms “subject” and “patient” refer to an animal (e.g., a bird such as a chicken, quail or turkey, or a mammal), specifically a "mammal" including a non-primate (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate (e.g., a monkey, chimpanzee and a human), and more specifically a human. In one embodiment, the subject is a non-human animal such as a farm animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat, guinea pig or rabbit). In a preferred embodiment, the subject is a human.

[0036] As used herein, “pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0037] “Pharmaceutically acceptable salts” includes “pharmaceutically acceptable acid addition salts” and “pharmaceutically acceptable base addition salts.” “Pharmaceutically acceptable acid addition salts” refers to those salts that retain the biological effectiveness of the free bases and that are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic 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.

[0038] “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 the 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, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, for example, S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19 which is incorporated herein by reference.)

[0039] For the compounds disclosed herein, single stereochemical isomers, as well as enantiomers, diastereomers, cis / trans conformation isomers, and rotational isomers, and racemic and non-racemic mixtures thereof, are within the scope of the invention. Unless otherwise indicated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention.

[0040] As used herein, the term “unit dosage form” is defined to refer to the form in which the compound is administered to a subject. Specifically, the unit dosage form can be, for example, a pill, capsule, or tablet. In some embodiments, the unit dosage form is a capsule.

[0041] As used herein, “solid dosage form” means a pharmaceutical dose(s) in solid form, e.g. tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers and chewables.

[0042] An adverse event (AE) is defined as any untoward medical occurrence in a clinical study subject, temporally associated with the use of a study treatment, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment.

[0043] A severe adverse event (SAE) is defined as an untoward medical occurrence that, at any dose is life threatening. The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe.

[0044] As used herein the term “mild” adverse event is one that is easily tolerated by the subject, causing minimal discomfort and not interfering with everyday activities. As used herein the term “moderate” adverse event causes sufficient discomfort and interferes with subject’s normal everyday activities. As used herein the term “severe” adverse event preventsthe subject’s normal everyday activities. An AE that is assessed as severe should not be confused with an SAE. Severe is a category utilized for rating the intensity of an event; and both AE and SAE can be assessed as severe. An event is defined as ‘serious’ when it meets at least one of the predefined outcomes as described in the definition of an SAE, not when it is rated as severe.

[0045] The following abbreviations are used throughout this disclosure.Listing of AbbreviationsMethods of Treatment

[0046] The methods described herein include methods for the treatment of disorders associated with pharyngeal airway muscle collapse during sleep. In some embodiments, the disorder is sleep apnea (e.g., obstructive sleep apnea (OSA)) or snoring (e.g., simple snoring). Generally, the methods include administering a therapeutically effective amount of a GLP-1 receptor agonist with a second active agent, to a subject who is in need of, or who has been determined to be in need of, such treatment. The second active agent may be atomoxetine, reboxetine, viloxazine, edivoxetine, oxybutynin, or trazodone, including stereoisomers thereof and pharmaceutically acceptable salts thereof. In some embodiments, the OSA is severe OSA. In some embodiments, the OSA is moderate OSA. In some embodiments, the OSA is mild OSA. In some embodiments, the subject is obese. In some embodiments the OSA is severe OSA and the subject is obese.

[0047] For the compounds disclosed herein, single stereochemical isomers, as well as enantiomers, diastereomers, cis / trans conformation isomers, and rotational isomers, and racemic and non-racemic mixtures thereof, are within the scope of the invention. Unless otherwise indicated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention.

[0048] GLP-1 receptor agonists are known in the art. For example, semaglutide and methods of making are described in WO 2006 / 097537 and tirzepatide and methods of making are described in U.S. patent no. 9,474,780, each of which are incorporated herein by reference.

[0049] The therapeutically effective amount of the GLP-1 receptor agonist compounds described herein for use in the methods described herein may be from about 0.01 pg to about 50 mg; about 0.1 pg to about 25 mg; or about 1 pg to about 15 mg. These therapeutically effective doses may be administered once / day, twice / day, thrice / day, once / week, biweekly, or once / month, depending on the formulation. The exact dose to be administered is determined, for example, by the formulation, such as an immediate release formulation or an extended release formulation. For transdermal, nasal or oral dosage forms, the dosage may be increased, e.g., by about 5-fold, about 10-fold, or greater.

[0050] In some embodiments, the GLP-1 receptor agonist is administered orally. In alternative embodiments, the GLP-1 receptor agonist may be administered by injection, e.g., subcutaneous injection. In some embodiments, the GLP-1 receptor agonist is administered once per day, e.g., before bed. In some embodiments, the GLP-1 receptor agonist is administered twice per day. In some embodiments, the GLP-1 receptor agonist is administered once per week.

[0051] In some embodiments, the GLP-1 receptor agonist is semaglutide or a pharmaceutically acceptable salt thereof, and semaglutide is administered orally. In some embodiments, the dose of semaglutide orally administered to the patient is from about 0.1 mg to about 100 mg. In some embodiments, the dose of semaglutide orally administered to the patient is from about 1 mg to about 25 mg. In some embodiments, the dose of semaglutide orally administered to the patient is from about 3 mg to about 14 mg. In some embodiments, semaglutide is administered orally once daily, e g., before bedtime.

[0052] In some embodiments, the GLP-1 receptor agonist is semaglutide or a pharmaceutically acceptable sal thereof, and semaglutide is administered by injfection, e.g., subcutaneously. In some embodiments, the dose of semaglutide administered to the patientby subcutaneous injection is from about 0.1 to about 5 mg, e.g., from about 0.25 to about 2.4 mg. In some embodiments, the semaglutide is administered once weekly.

[0053] In some embodiments, the GLP-1 receptor agonist is tirzepatide or a pharmaceutically acceptable salt thereof, and tirzepatide is administered by injection, e.g., subcutaneously. In some embodiments, the dose of tirzepatide administered to the patient by subcutaneous injection is from about 0.5 mg to about 50 mg. In some embodiments, the dose of tirzepatide administered to the patient by subcutaneous injection is from about from about 1 mg to about 25 mg. In some embodiments, the dose of tirzepatide administered to the patient by subcutaneous injection is from about from about 2.5 mg to about 15 mg. In some embodiments, tirzepatide is administered once weekly.

[0054] In some embodiments, the GLP-1 receptor agonist is retatrutide or a pharmaceutically acceptable salt thereof, and retatrutide is administered by injection, e.g., subcutaneously. In some embodiments, the dose of retatrutide administered to the patient by subcutaneous injection is from about from about 0.1 mg to about 50 mg. In some embodiments, the dose of tirzepatide administered to the patient by subcutaneous injection is from about from about 0.5 mg to about 25 mg. In some embodiments, the dose of tirzepatide administered to the patient by subcutaneous injection is from about from about 1 mg to about 12 mg. In some embodiments, tirzepatide is administered once weekly.

[0055] In some embodiments, the GLP-1 receptor agonist is liraglutide or a pharmaceutically acceptable salt thereof and liraglutide is administered by injection, e.g., subcutaneously. In some embodiments, the dose of liraglutide administered to the patient by subcutaneous injection is from about 0.1 to about 5 mg. In some embodiments, the dose of liraglutide administered to the patient by subcutaneous injection is from about from about 0.2 mg to about 3 mg. In some embodiments, the dose of liraglutide administered to the patient by subcutaneous injection is from about from about 0.6 mg to about 1.8 mg. In some embodiments, liraglutide is administered once daily.

[0056] Atomoxetine is the generic name of the pharmaceutical substance with 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.

[0057] Oxybutynin is the generic name for the pharmaceutical substance with the chemical name 4-diethylamino-2-butynylphenylcyclohexylglycolate or 4-(diethylamino)but-2-ynyl 2- cyclohexyl-2-hydroxy-2-phenylacetate, and its pharmaceutically acceptable salts. In various embodiments, oxybutynin may be a racemic mixture of R- and S- enantiomers, or an isolatedenantiomer, e.g., the R-enantiomer. In various embodiments, oxybutynin may be oxybutynin chloride or (R)-oxybutynin chloride.

[0058] Viloxazine is the generic name of the pharmaceutical substance with the chemical name of 2-[(2-ethoxyphenoxy)methyl]morpholine, and its pharmaceutically acceptable salts. In various embodiments, viloxazine may be a racemic mixture of R- and S- enantiomers, or an isolated enantiomer, e.g., the S-enantiomer. In various embodiments, viloxazine may be viloxazine hydrochloride or S-viloxazine hydrochloride.

[0059] Reboxetine is the generic name of the pharmaceutical substance with the chemical name of 2-((2-ethoxyphenoxy)(phenyl)methyl)morpholine or 2-[a-(2- ethoxyphenoxy)benzyl]-morpholine, and its pharmaceutically acceptable salts. In various embodiments, reboxetine may be a racemic mixture of R,R- and S,S-enanti omers, or an isolated enantiomer, e.g., the S, S-enantiomer. In some embodiments, reboxetine may be reboxetine hydrochloride. In some embodiments, reboxetine may be reboxetine mesylate.

[0060] Edivoxetine is the generic name of the pharmaceutical substance with the chemical name of (lR)-2-(5-fluoro-2-methoxyphenyl)-l-[(2S)-morpholin-2-yl]-l-(oxan-4-yl)ethanol, and its pharmaceutically acceptable salts.

[0061] Trazodone is the generic name of the pharmaceutical substance with the chemical name 2-[3-[4-(3-chlorophenyl)piperazin-l-yl]propyl]-[l,2,4]triazolo[4,3-a]pyridin-3-one, and its pharmaceutical salts, including its hydrochloride salt. Trazodone is available as a generic medication as well as sold under the trade names Desyrel and Oleptro.

[0062] In some embodiments, the present methods include administering a dose of from about 20 mg to about 200 mg of atomoxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the dose of atomoxetine or a pharmaceutically acceptable salt thereof is from about 25 mg to about 100 mg. In some embodiments, the dose of atomoxetine or pharmaceutically acceptable salt thereof is from about 40 mg to about 80 mg. In some embodiments, the dose of atomoxetine or pharmaceutically acceptable salt thereof is from about 20 mg to about 50 mg. In some embodiments, the dose of atomoxetine or a pharmaceutically acceptable salt thereof is from about 50 mg to about 100 mg. In some embodiments, the dose of atomoxetine or pharmaceutically acceptable salt thereof is about 40 mg. In some embodiments, the dose of atomoxetine or pharmaceutically acceptable salt thereof is about 80 mg. In some embodiments, the dose of atomoxetine or pharmaceutically acceptable salt thereof is about 75 mg.

[0063] In methods comprising administration of oxybutynin or (R)-oxybutynin or a pharmaceutically acceptable salt thereof, the dose of oxybutynin or (R)-oxybutynin orpharmaceutically acceptable salt thereof may be from about 1 mg to about 25 mg, or in some embodiments, from about 2 mg to about 15 mg. In some embodiments, the dose of oxybutynin or (R)-oxybutynin or pharmaceutically acceptable salt thereof is from about 0 5 mg to about 10 mg. In some embodiments, the dose of oxybutynin or (R)-oxybutynin or pharmaceutically acceptable salt thereof is from about 1 mg to about 10 mg. In some embodiments, the dose of racemic oxybutynin or pharmaceutically acceptable salt thereof is from about 2.5 mg to about 10 mg, e g., 5 mg. In some embodiments, the dose of (R)- oxybutynin or pharmaceutically acceptable salt thereof is from about 1 mg to about 5 mg, e.g., 2.5 mg.

[0064] In methods comprising administration of edivoxetine or a pharmaceutically acceptable salt thereof, the dose of edivoxetine or the pharmaceutically acceptable salt thereof may be from about 5 mg to about 50 mg. In some embodiments, the edivoxetine or pharmaceutically acceptable salt thereof is administered at a dosage of from about 6 mg to about 36 mg. In some embodiments, the dose of edivoxetine or a pharmaceutically acceptable salt thereof is from about 6 mg to about 20 mg. In some embodiments, the dose of edivoxetine or a pharmaceutically acceptable salt thereof is from about 20 mg to about 36 mg. In some embodiments, the dose of edivoxetine or a pharmaceutically acceptable salt thereof is from about 10 mg to about 25 mg.

[0065] In methods comprising administration of viloxazine or a pharmaceutically acceptable salt thereof, the dose of viloxazine or the pharmaceutically acceptable salt thereof may be from about 50 mg to about 800 mg. In some embodiments, the dose of viloxazine or a pharmaceutically acceptable salt thereof is from about 50 mg to about 300 mg. In some embodiments, the dose of viloxazine or pharmaceutically acceptable salt thereof is from about 300 mg to about 800 mg. In some embodiments, the dose of viloxazine or pharmaceutically acceptable salt thereof is from about 100 mg to about 500 mg.

[0066] In some embodiments, the methods include administering a dose of from about 0.2 mg to about 12 mg of reboxetine or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. In some embodiments, the dose of reboxetine or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is from about 1 mg to about 8 mg. In some embodiments, the dose of reboxetine or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is from about 0.5 mg to about 6 mg. In some embodiments, the dose of reboxetine or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is from about 2 mg to about 6 mg. In some embodiments, the dose of reboxetine or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is about 4 mg. In some embodiments,the dose of reboxetine or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is about 6 mg. In some embodiments, the dose of reboxetine or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is about 2 mg. In some embodiments, the dose of reboxetine or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is about 3 mg.

[0067] In some embodiments, the trazodone or a pharmaceutically acceptable salt thereof is administered at a dose of from about 12.5 to about 200 mg. In some embodiments, the trazodone or a pharmaceutically acceptable salt thereof is administered at a dose of from about 12.5 to about 50 mg. In some embodiments, the trazodone or a pharmaceutically acceptable salt thereof is administered at a dose of from about 50 to about 200 mg. In some embodiments, the trazodone or a pharmaceutically acceptable salt thereof is administered at a dose of from about 25 to about 100 mg.

[0068] In some embodiments, the methods include administration of a third active agent selected from among atomoxetine, reboxetine, viloxazine, edivoxetine, oxybutynin, or trazodone, including stereoisomers thereof and pharmaceutically acceptable salts thereof. For example, the second active agent may be selected from atomoxetine, reboxetine, viloxazine, and edivoxetine, or a stereoisomer thereof or pharmaceutically acceptable salt thereof, and the third active agent may be selected from oxybutynin or trazodone, or a stereoisomer thereof or pharmaceutically acceptable salt thereof. In some embodiments, the second active agent is atomoxetine and the third active agent is oxybutynin or a pharmaceutically acceptable salt thereof. In some embodiments, the second active agent is atomoxetine and the third active agent is (R)-oxybutynin or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, the second active agent is administered orally. In some embodiments, the third active agent is administered orally.

[0070] In some embodiments, the GLP-1 receptor agonist is semaglutide or a pharmaceutically acceptable salt thereof and the second active agent is atomoxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is semaglutide or a pharmaceutically acceptable salt thereof and the second active agent is viloxazine or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is semaglutide or a pharmaceutically acceptable salt thereof and the second active agent is oxybutynin or a stereoisomer thereof (e g., racemic oxybutynin or (R)-oxybutynin) or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is semaglutide or a pharmaceutically acceptable salt thereof and the second active agent is trazodone or a pharmaceutically acceptable saltthereof. In some embodiments, the GLP-1 receptor agonist is semaglutide or a pharmaceutically acceptable salt thereof, the second active agent is atomoxetine or a pharmaceutically acceptable salt thereof, and the third active agent is oxybutynin or a stereoisomer thereof (e.g., racemic oxybutynin or (R)-oxybutynin) or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is semaglutide or a pharmaceutically acceptable salt thereof, the second active agent is atomoxetine or a pharmaceutically acceptable salt thereof, and the third active agent is trazodone or a pharmaceutically acceptable salt thereof.

[0071] In some embodiments, the GLP-1 receptor agonist is tirzepatide or a pharmaceutically acceptable salt thereof and the second active agent is atomoxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is tirzepatide or a pharmaceutically acceptable salt thereof and the second active agent is viloxazine or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is tirzepatide or a pharmaceutically acceptable salt thereof and the second active agent is oxybutynin or a stereoisomer thereof (e g., racemic oxybutynin or (R)-oxybutynin) or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is tirzepatide or a pharmaceutically acceptable salt thereof and the second active agent is trazodone or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is tirzepatide or a pharmaceutically acceptable salt thereof, the second active agent is atomoxetine or a pharmaceutically acceptable salt thereof, and the third active agent is oxybutynin or a stereoisomer thereof (e.g., racemic oxybutynin or (R)-oxybutynin) or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is tirzepatide or a pharmaceutically acceptable salt thereof, the second active agent is atomoxetine or a pharmaceutically acceptable salt thereof, and the third active agent is trazodone or a pharmaceutically acceptable salt thereof.

[0072] In some embodiments, the GLP-1 receptor agonist is retatrutide or a pharmaceutically acceptable salt thereof and the second active agent is atomoxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is retatrutide or a pharmaceutically acceptable salt thereof and the second active agent is viloxazine or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is retatrutide or a pharmaceutically acceptable salt thereof and the second active agent is oxybutynin or a stereoisomer thereof (e.g., racemic oxybutynin or (R)-oxybutynin) or a pharmaceutically acceptable salt thereof. In someembodiments, the GLP-1 receptor agonist is retatrutide or a pharmaceutically acceptable salt thereof and the second active agent is trazodone or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is retatrutide or a pharmaceutically acceptable salt thereof, the second active agent is atomoxetine or a pharmaceutically acceptable salt thereof, and the third active agent is oxybutynin or a stereoisomer thereof (e.g., racemic oxybutynin or (R)-oxybutynin) or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is retatrutide or a pharmaceutically acceptable salt thereof, the second active agent is atomoxetine or a pharmaceutically acceptable salt thereof, and the third active agent is trazodone or a pharmaceutically acceptable salt thereof.

[0073] In some embodiments, the GLP-1 receptor agonist is liraglutide or a pharmaceutically acceptable salt thereof and the second active agent is atomoxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is liraglutide or a pharmaceutically acceptable salt thereof and the second active agent is viloxazine or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is liraglutide or a pharmaceutically acceptable salt thereof and the second active agent is oxybutynin or a stereoisomer thereof (e g., racemic oxybutynin or (R)-oxybutynin) or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is liraglutide or a pharmaceutically acceptable salt thereof and the second active agent is trazodone or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is liraglutide or a pharmaceutically acceptable salt thereof, the second active agent is atomoxetine or a pharmaceutically acceptable salt thereof, and the third active agent is oxybutynin or a stereoisomer thereof (e.g., racemic oxybutynin or (R)-oxybutynin) or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor agonist is liraglutide or a pharmaceutically acceptable salt thereof, the second active agent is atomoxetine or a pharmaceutically acceptable salt thereof, and the third active agent is trazodone or a pharmaceutically acceptable salt thereof.Pharmaceutical Compositions

[0074] The combination drug composed of aroxybutynin and atomoxetine, designated AD 109, is being developed by Apnimed in Phase 3 for the treatment of obstructive sleep apnea (OSA). Also provided herein are pharmaceutical compositions comprising a GLP-1 receptor agonist and a second active agent, as active ingredients. The second active agentmay be atomoxetine, reboxetine, viloxazine, edivoxetine, oxybutynin, or trazodone, including stereoisomers thereof and pharmaceutically acceptable salts thereof.

[0075] Exemplary GLP-1 receptor agonists include semaglutide, tirzepatide, retatrutide, dulaglutide, exenatide, PEGylated exenatide, survodutide, efpeglenatide, liraglutide, lixisenatide, cotadutide, noiiglutide, mazdutide, albiglutide, beinaglutide, PEG-loxenatide, pemvidutide, taspoglutide, efocipegtrutide, orforglipron, and danuglipron, stereoisomers thereof, and pharmaceutically acceptable salts thereof.

[0076] In some embodiments, the pharmaceutical composition further includes a third active agent selected from among atomoxetine, reboxetine, viloxazine, edivoxetine, oxybutynin, and trazodone, including stereoisomers thereof and pharmaceutically acceptable salts thereof. For example, the second active agent may atomoxetine, reboxetine, viloxazine, or edivoxetine, or a stereoisomer thereof or pharmaceutically acceptable salt thereof, and the third active agent may be oxybutynin or trazodone, or a stereoisomer thereof or pharmaceutically acceptable salt thereof. In some embodiments, the second active agent is atomoxetine and the third active agent is oxybutynin or a pharmaceutically acceptable salt thereof. In some embodiments, the second active agent is atomoxetine and the third active agent is (R)-oxybutynin or a pharmaceutically acceptable salt thereof.

[0077] Pharmaceutical compositions typically include a pharmaceutically acceptable carrier. As used herein the language “pharmaceutically acceptable carrier” includes saline, solvents, dispersion media, diluents, fillers, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.

[0078] The active ingredients for use in the present invention may be provided as a free base or as pharmaceutically acceptable salts. For example, in some embodiments, oxybutynin is oxybutynin chloride. In some embodiments, (R)-oxybutynin is (R)-oxybutynin chloride. In some embodiments, racemic oxybutynin is racemic oxybutynin chloride. In some embodiments, atomoxetine is atomoxetine hydrochloride.

[0079] Pharmaceutical compositions are typically formulated to be compatible with its intended route of administration. Examples of routes of administration include systemic oral or transdermal administration.

[0080] Methods of formulating suitable pharmaceutical compositions are known in the art, see, e.g., 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 ediblecarrier. For the purpose of oral therapeutic administration, the active compound(s) can be incorporated with excipients and used in the form of pills, tablets, troches, or capsules, e.g., gelatin capsules. Oral compositions can also be prepared using a fluid carrier. In some embodiments, a composition according to the present invention may be a unit dosage form. In some embodiments, a composition according to the present invention may be a solid dosage form, e.g., a tablet or capsule.

[0081] Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0082] Systemic administration of the compounds as described herein can also be by transdermal means, e.g., using a patch, gel, or lotion, to be applied to the skin. For transdermal administration, penetrants appropriate to the permeation of the epidermal barrier can be used in the formulation. Such penetrants are generally known in the art. For example, for transdermal administration, the active compounds can formulated into ointments, salves, gels, or creams as generally known in the art. The gel and / or lotion can be provided in individual sachets, or via a metered-dose pump that is applied daily; see, e.g., Cohn et al., Ther Adv Urol. 2016 Apr; 8(2): 83-90.

[0083] In one embodiment, the therapeutic compounds are prepared with carriers that will protect the therapeutic compounds against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Such formulations can be prepared using standard techniques, or obtained commercially, e.g., from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0084] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration or use in a method described herein.

[0085] Pharmaceutical compositions containing the GLP- 1 receptor agonist compounds described herein may be provided for peripheral administration, such as parenteral (e.g., subcutaneous, intravenous, intramuscular), a continuous infusion (e g., intravenous drip, intravenous bolus, intravenous infusion), topical, nasal, or oral administration. Suitable pharmaceutically acceptable carriers and their formulation are described in standard formulation treatises, such as Remington's Pharmaceutical Sciences by Martin; and Wang et al, Journal of Parenteral Science and Technology, Technical Report No. 10, Supp. 42:2S (1988). The GLP-1 receptor agonist compounds can also be formulated as pharmaceutically acceptable salts (e.g., acid addition salts) and / or complexes thereof.

[0086] In some embodiments, the pharmaceutical composition is for use in treating a condition associated with pharyngeal airway collapse. In some embodiments, the condition is sleep apnea (e.g., OSA) or snoring (e.g., simple snoring).Kits and Combinations

[0087] Also provided herein is a kit comprising a GLP-1 receptor agonist and a second active agent, which may be atomoxetine, reboxetine, viloxazine, edivoxetine, oxybutynin, or trazodone, including stereoisomers thereof and pharmaceutically acceptable salts thereof. For example, the kit may comprise separate pharmaceutical compositions with each composition having a single active ingredient. The kits can be used for treating a subject having a condition associated with pharyngeal airway collapse. Various embodiments of kits will be apparent from the detailed description provided herein.

[0088] Also provided herein is a GLP-1 receptor agonist and a second active agent, which may be atomoxetine, reboxetine, viloxazine, edivoxetine, oxybutynin, or trazodone, including stereoisomers thereof and pharmaceutically acceptable salts thereof, for use in treating a subject having a condition associated with pharyngeal airway collapse. Further provided herein is a therapeutic combination of a GLP-1 receptor agonist and a second active agent, which may be atomoxetine, reboxetine, viloxazine, edivoxetine, oxybutynin, or trazodone, including stereoisomers thereof and pharmaceutically acceptable salts thereof, for use in treating a subject having a condition associated with pharyngeal airway collapse. Various embodiments of combinations and therapeutic combinations will be apparent from the detailed description provided herein.EXAMPLE

[0089] The invention is further described in the following example, which does not limit the scope of the invention described in the claims.A Phase 2 Safety, Efficacy, and Tolerability of Fixed Dose Combination of Aroxybutynin / Atomoxetine (AD109) in Obstructive Sleep Apnea Patients Taking Tirzepatide, Semaglutide or Liraglutide

[0090] The primary objective of this study is to evaluate the safety, efficacy, and tolerability of treatment with AD 109 in OSA patients in the presence of concomitant incretin-based therapy, e.g., tirzepatide, semaglutide or liraglutide, three GLP-1 receptor agonist drugs associated with substantial weight loss.Overall design

[0091] The study design is an open-label, parallel-arm, 6 weeks study of AD 109 in participants with OSA and obesity. The overview of the study is shown in Fig. 2. One arm consists of patients concomitantly taking tirzepatide, semaglutide or liraglutide, and a second comparator arm consists of patients not taking any GLP-1 receptor agonist but who otherwise would meet the criteria for prescribing a GLP-1 receptor agonist (i.e., BMI>27). Each arm is composed of approximately 20 participants. The participants on a GLP-1 receptor agonist must be on a stable maintenance dose that has remained unchanged for at least four weeks prior to enrollment. All study procedures, including open-label dosing of AD 109, are the same for both arms; the arms differ only in concomitant GLP-1 receptor agonist use.

[0092] The study drug administration will occur in 2 sequential study periods:1. Fasting Pharmacokinetic (PK) Period: Subjects will be instructed to complete an overnight fast prior to arrival at the research site. A single dose of AD 109 (2.5mg Aroxybutynin / 75mg Atomoxetine) will be administered in the morning with PK sampling done at pre-dose, 0.5, 1, 2, 4, 6, 8 hours before they are allowed to leave. Subjects will return the following day for a final PK sample during the 24-30 post dose window and then transition to the treatment period.2. Treatment Period: Beginning the second day after the PK period, subjects will begin dosing AD 109 each night before bed. Subjects will initiate AD 109 with 7 days of a lower run-in dose (aroxybutynin 2.5mg / atomoxetine 37.5mg) followed by the full dose of AD109 (aroxybutynin 2.5 mg / atomoxetine 75 mg) for the subsequent 30 days. In the final week of AD109 treatment, all subjects will undergo 2 nights of HSAT. Participants who discontinue dosing of AD 109 are encouraged to continue all other study activities for the full duration of the study.

[0093] Approximately 40 subjects will be enrolled in the study. The subjects will be divided into two arms; the first arm will include approximately 20 subjects administered tirzepatide,semaglutide or liraglutide + AD 109; and the second arm will include approximately 20 subjects administered AD 109 without any GLP-1 receptor agonist therapy.

[0094] The overall study duration for each subject will be up to 10 weeks, as follows:• Screening, up to 4 weeks• PK period, 2 days• Run-in Dose, 1 week• Dosing period, up to 5 weeks

[0095] Study procedures and scheduled assessment events are summarized in the schedule of Assessments (SoA) in Table 2. Adherence to the study design requirements, including those specified in the SoA, is essential and required for study conductStudy Participants

[0096] Participants will be recruited both from the existing clinic population at the study sites, including databases of individuals who participated in other studies, and through direct advertising and outreach to the community. The participant must voluntarily agree to participate in this study and sign an Institutional Review Board (IRB)-approved informed consent prior to performing any of the Screening Visit procedures. Participants must be able to understand the nature of the study and must have the opportunity to have any questions answered.Inclusion Criteria

[0097] Participates must be using an acceptable GLP-1 receptor agonist prescribed by a physician at a stable dose maintained for 4 weeks or more. Sites will need to verify and record the incretin-based therapy, e.g., name of drug. Prospective participants will undergo initial pre-screening for enrollment by evaluation of the study site’s database or through an initial online screening questionnaire or similar methods are contacted by telephone for additional pre-screening to confirm initial eligibility. These screening answers are used to determine a history of OSA or considered at high risk for the condition (e.g., as assessed by STOP -BANG Questionnaire score >4. Only participants who qualify based on pre-screening questions will be screened. Participants who meet the eligibility criteria assessed at Visit 1 will undergo two nights of home sleep apnea test (HSAT) to determine an average Respiratory Event Index (REM). The HSAT will be dispensed by and returned after use to the sites, and the collected data will subsequently be transmitted by the site to a central repository for centralized scoring by certified technicians who are independent and blinded to the treatment arm. A qualifying study (REM >5) will allow patients to enroll in the study toreceive AD 109. Participants with a qualifying REI will be enrolled in the study. Participants must also meet other inclusion criteria including:• Age and Sex o Are between the ages of 18-75 years at the time of informed consent.• BMI o BMI between 27 and 43 kg / m2 for men, or 45 kg / m2 for women, inclusive.• OSA History and Measures o HSAT criteria■ Mean REI4 (Hypopneas defined by 4% oxygen desaturation) of >5 and <45. REI is determined as a mean number collected across 2 nights of testing initiated at Visit 2■ < 25% central or mixed apneas (as proportion of total apneas and hypopneas) o Participants with a history of using devices for OSA treatment, including CPAP, oral or nasal devices, or positional devices, may enroll as long as the devices have not been used for at least 2 weeks prior to first HSAT and are not used during participation in the study.• Weight o For the subjects in the incretin arm the following criteria must be met■ Patients must have an identified prescriber and adhere to drug labelling considerations.■ A patient’ s individual dose is stable over the past 4 weeks without intention to increase to decrease dosing based on side effects or efficacy.■ Willingness to maintain a medication administration diary during the study. o The following agents and doses are acceptable to meet inclusion criteria:■ Tirzepatide (Mounjaro®, Zepbound®): doses of 2.5mg, 5mg, 7.5mg, lOmg, 12.5mg, 15mg can be given once weekly by subcutaneous injection■ Semaglutide (Ozempic®, Wegovy®): doses of 0.25mg, 0.5mg, Img, 1.7mg, 2.0mg or 2.4mg can be given once weekly by subcutaneous injection■ Liraglutide (Saxenda®): doses of 0.6mg, 1.2mg, 1.8mg, 2.4mg, 3.0mg can be given once weekly by subcutaneous injection.

[0098] Female participants of childbearing potential are eligible to participate if they agree to use a highly effective method of contraception that is user dependent with a failure rate of <1% per year when consistently and correctly as described in the definitions section. Female participants on HRT, or whose menopausal status is in doubt, will be required to use one of the non-estrogen hormonal highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status before study enrollment.

[0099] Pregnancy testing will be performed whenever a menstrual cycle is missed or when pregnancy is otherwise suspected. The Investigator will collect pregnancy information on any female participant who becomes pregnant while participating in this study. Information will be recorded on the appropriate form and submitted to the Sponsor within 24 hours of learning of a participant’s pregnancy. The participant will be followed to determine the outcome of the pregnancy. The Investigator will collect any follow up information on the participant and the neonate and the information will be forwarded to the Sponsor. Generally, follow up will not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of the pregnancy will be reported, regardless of fetal state (presence or absence of anomalies) or indication for the procedure.

[0100] Any female participant who becomes pregnant while participating in the study will be withdrawn from IMP treatment.

[0101] Contraception guidance for male participants with female partners of childbearing potential are eligible to participate if they agree to one of the following during the protocol- defined time frame:

[0102] • Male participants are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent.• Male participants agree to use a contraceptive method with a failure rate of <1% per year as described in the table below when having penile-vaginal intercourse with a WOCBP who is not currently pregnant.• Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or to use a male condom during each episode of penile penetration during the protocol -defined period.

[0103] In addition, male participants must refrain from donating sperm for the duration of the study and for 3 months after the last dose of study treatment.

[0104] Participants must also pass a physical examination. The physical examination at screening includes an assessment of general appearance, with attention to the following physical features: dermatologic, head, eyes, ears, nose, mouth / throat / neck, thyroid, lymph nodes, respiratory, cardiovascular, gastrointestinal, extremities, musculoskeletal, neurologic, and psychiatric systems. Height and weight will also be measured and recorded (with shoes removed and wearing light indoor clothing). Vital signs will be measured at each visit listed in the SoA and will include seated blood pressure, pulse rate, body temperature, and respiratory rate. Measurements should be made in the same arm of the participant at each visit. Systolic and diastolic blood pressure will be repeated for a total of 3 measurements, each at least 2 minutes apart, with patient seated with arm on table or similar support at the level of chest. The method used to measure body temperature at screening should be maintained throughout the study for each participant, and should be recorded (e.g., ear, mouth, or armpit). Investigators should pay special attention to clinical signs related to previous serious illnesses or surgery.

[0105] The physical examination includes obtaining a 12-lead electrocardiogram (ECG) using an ECG machine that automatically calculates the heart rate and measures the PR, QRS, and QT intervals. The ECG will be recorded in the supine position after the participant has rested in this position for at least 1 minute.

[0106] Participants must meet the laboratory assessment criteria for inclusion in the study. A list of clinical laboratory tests to be performed is shown in Table 1 and the timing and frequency of tests are presented in the schedule of assessments (SoA), Table 2. All protocol- required laboratory assessments must be conducted in accordance with the laboratory manual and the SoA and the laboratory reports must be reviewed by the Investigator and filed with the source documents. If laboratory values from laboratory assessments not specified in the protocol result in the need for a change in participant management or are considered clinically relevant by the Investigator (e.g., are considered to be an SAE or an AE or require dose modification), then the results must be recorded in the eCRF.Exclusion Criteria

[0107] Exclusion criteria for participating in the study includes the following medical conditions or history:• Narcolepsy, restless leg syndrome requiring medication, REM sleep behavior disorder• Current bothersome symptoms of insomnia (difficulty initiating or maintaining sleep, as distinct from unrefreshing sleep or other symptoms attributable to OSA).Participants being treated for insomnia can be enrolled only if the condition is stable and generally controlled.• Pierre Robin, Treacher Collins, or other craniofacial malformation syndrome, or grade >3 tonsillar hypertrophy.• Clinically significant or medically uncontrolled cardiovascular disease, e g., ventricular arrhythmia requiring medical or device therapy, unstable atrial fibrillation (including cardioversion, ablation, or change in anti arrhythmic regimen within past 3 months [patients in whom anti coagulation is indicated must be on such treatment for enrollment], or resting heart rate >100), untreated or unstable coronary artery disease (including revascularization within 3 months), cardiac failure, cerebrovascular event or transient ischemic attack or revascularization within 3 months.Table 1. Clinical Laboratory TestsAbbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; FSH = follicle stimulating hormone; HbAlc = hemoglobin Ale (glycated hemoglobin); hCG = human chorionic gonadotropin; RBC = red blood cell count; WBC= white blood cell; WOCBP = women of childbearing potential.• Neuromuscular disorder (e.g., motor neuron disease, muscular dystrophy, or myopathy, myasthenic syndrome); epilepsy; Parkinson, Alzheimer, or other neurodegenerative disease.• Schizophrenia, schizoaffective disorder, generalized anxiety disorder or bipolar disorder according to Diagnostic and Statistical Manual of Mental Disorders-5 (DSM 5) or International Classification of Disease tenth edition criteria.• Attempted suicide within 1 year prior to screening, or current suicidal ideation.• Severe or frequent constipation considered currently bothersome by the patient, or symptomatic gastric motility disorder.• Current bothersome symptoms of bladder outlet obstruction including difficulty initiating or maintaining urinary flow, straining, or sensation of incomplete bladder emptying; participants being treated with alpha-1 adrenergic antagonist for benignprostatic hypertrophy can be enrolled only if the condition is stable and generally controlled.• Active substance use disorder as defined in DSM-5, or other substance use that in the Investigator’s opinion would present an unreasonable risk to the participant, or which would interfere with their participation in the study or confound study interpretation. Positive screen for drugs with abuse liability is an important but not sole determinant of substance use disorder and study eligibility. Participants who use marijuana daily will be excluded.• A serious illness or infection in the past 30 days as determined by Investigator.• Clinically significant cognitive dysfunction as determined by Investigator.• Narrow angle glaucoma.• Women who are pregnant or nursing.• Prior use of mandibular advancement devices, nasal devices, or sleeping position devices for the treatment of OSA may enroll as long as the devices are not used during in the study.• A history of chronic oxygen therapy.• Having implanted device for the treatment of OSA are excluded (e g., hypoglossal nerve stimulator, or investigational devices).• Use of another investigational agent within 30 days or 5 half-lives, whichever is longer, prior to dosing.• MADRS - Suicidal Thoughts question response of thinking of or planning suicide.• Systolic blood pressure up to 140 mm Hg or diastolic blood pressure up to 90 mm Hg is allowed in participants not currently treated with antihypertensives. If the participant is under the care of a healthcare provider managing blood pressure and on stable (at least 1 month) antihypertensive therapy, systolic blood pressure up to 145 / 90 is allowed at enrollment. If initial blood pressure (measured in triplicate, use average of final two readings) is above this enrollment threshold, it may be repeated up to a total of 3 times (each in triplicate) to confirm that the reading was not due to measurement technique or transient factors, with selection of the lowest repeated measure. The determination that blood pressure meets enrollment criteria involves the clinical judgment of the investigator interpreting blood pressure readings.• Unexplained or new identification of hepatic transaminases (AST or ALT) >2X the upper limit of normal (ULN) generally is exclusionary. However, elevation between2-2.5 may be allowed with prior consent of the sponsor if evidence suggests it is due to nonalcoholic fatty liver disease (NAFLD) or other condition that would not be expected to acutely worsen or require medical intervention during the course of the study.• Total bilirubin >1 ,5X ULN (unless confirmed Gilbert syndrome).• Estimated glomerular filtration rate < 50 ml / min.• ECG abnormality indicative of clinically significant cardiac disease that may be adversely affected by AD 109• Other Exclusions• Night- or shift- work sleep schedule which causes the major sleep period to be during the day, including on a rotating basis.• Frequent travel or jet lag is likely to interfere with study procedures or evaluations.• Employment as a commercial driver or other vehicle operator (includes independent contractors and ride-share services).• History of sleepiness-related MVA.• Unwilling to use specified contraception.• Any condition that in the investigator’s opinion would present an unreasonable risk to the participant, including nature or severity of OSA symptoms, or which would interfere with their participation in the study or confound study interpretation.• Participant considered by the investigator, for any reason, an unsuitable candidate to receive AD 109 or unable or unlikely to understand or comply with the dosing schedule or study evaluations.• Subjects with a history of gastric weight loss surgery (e.g. sleeve gastrectomy, gastric bypass, adjustable gastric banding, biliopancreatic diversion).

[0108] Sites should be aware that patients in the community may be using non-FDA approved versions of tirzepatide or, semaglutide, or liraglutide. Patients participating in the current trial must only use GLP-1 receptor agonist drugs obtained with a prescription from a licensed health care provider, and only obtain the medicines from state-licensed pharmacies or outsourcing facilities registered with FDA. Patients using compounded GLP-1 drugs that are not FDA-approved or evaluated for safety and effectiveness and are prohibited from study enrollment.Meals and Dietary Restrictions

[0109] Participants should refrain from consumption of any nutrients known to modulate CYP enzyme activity (e.g., grapefruit or grapefruit juice, pomelo juice, star fruit, pomegranate, and Seville or Moro [blood] orange products) within 72 hours before the first administration of study drug and during the study. Diet should be generally stable during the study, e.g., new diet programs should not be initiated.Caffeine, Alcohol, and Tobacco

[0110] Moderate consumption of caffeinated beverages, containing up to a total of 400 mg caffeine per day (e g., two medium coffees), is permitted during the study period, consumed no less than 3 hours prior to bedtime.

[0111] Participants should refrain from more than 2 standard units per day for men or 1 unit / day for women of alcohol. Alcohol should not be consumed on evenings with HST use.

[0112] Smoking more than 10 cigarettes or 2 cigars per day (or equivalent Vaping), or inability to abstain from smoking during overnight PSG visits is exclusionary

[0113] Screen failures are defined as participants who consent to participate in the clinical study but are not subsequently randomized to study treatment / entered in the study. A minimal set of screen failure information is required to ensure transparent reporting of screen failure participants that meets the Consolidated Standards of Reporting Trials publishing requirements and to respond to queries from regulatory authorities. Minimal information includes demography and reason for screen failure.Safety Monitoring

[0114] Safety monitoring will be guided by the established safety profiles of aroxybutynin and atomoxetine, and by Phase 1 and 2 safety data for the combination drug AD 109. Safety assessments will include physical examinations, measurement of vital signs, monitoring and recording of an adverse events (AE), severe adverse event (SAE), and pregnancies, and recording of study or treatment discontinuations. Effects on OSA and sleep parameters (e.g., sleep time, heart rate, body position and blood oxygen saturation level) will also be monitored by HSAT.

[0115] Standard overnight HSAT recording and data interpretation will be performed in accordance with the American Academy of Sleep Medicine (AASM) scoring manual. Participants will be provided and trained to perform HSAT in a standardized fashion. Time of lights out will be established according to the participant’s approximate habitual schedule and kept similar across the HSAT study nights.

[0116] Subjects will be given 8 hours of time-in bed. 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 study.

[0117] HSAT studies will be scored by a centralized HSAT center, blinded to treatment assignment. Scoring will determine an average REI across two individual nights of recording (> 4 hours of recording per night minimum).Adverse Events

[0118] All AEs and SAEs will be collected from time of consent until the end of the study at the timepoints specified in the SoA. All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated in Appendix 3. The Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being available.

[0119] Investigators are not obligated to actively seek AEs or SAEs after the conclusion of study participation. However, if the Investigator learns of any SAE, including a death, at any time after a participant has been discharged from the study, and he / she considers the event to be reasonably related to the study drug or study participation, the Investigator must promptly notify the Sponsor. The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures for completing and transmitting SAE reports are provided in Appendix 3. Care will be taken not to introduce bias when detecting AEs and / or SAEs. Open-ended and non leading verbal questioning of the participant is the preferred method to inquire about AE occurrence. Once an AE / SAE is reported, questioning should be directed at characterizing and documenting the event, including specific signs or symptoms not volunteered by the participant (e.g., pertinent negatives).

[0120] Events that meet the definition of an adverse event include the following:• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs measurements), including those that worsen from baseline, considered clinically significant in the medical and scientific judgment of the Investigator (i.e., not related to progression of underlying disease).• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and / or intensity of the condition.• New conditions detected or diagnosed after study treatment administration even though it may have been present before the start of the study.• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a concomitant medication. Overdose per se will not be reported as an AE / SAE unless it is an intentional overdose taken with possible suicidal / self-harming intent. Such overdoses should be reported regardless of sequelae.• "Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as an AE or SAE. Such instances will be captured in the efficacy assessments. However, the signs, symptoms, and / or clinical sequelae resulting from a lack of efficacy will be reported as an AE or SAE if they fulfill the definition of an AE or SAE.

[0121] Events the do not meet the definition of an AD include the following:• Any clinically significant abnormal laboratory findings or other abnormal safety assessments which are associated with the underlying disease, unless judged by the Investigator to be more severe than expected for the participant’s condition.• The disease / disorder being studied or expected progression, signs, or symptoms of the disease / disorder being studied, unless more severe than expected for the participant’s condition.• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the procedure is the AE.• Situations in which an untoward medical occurrence did not occur (social and / or convenience admission to a hospital).• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen

[0122] If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions are met (e.g., hospitalization for signs / symptoms of the disease under study, death due to progression of disease).Severe Adverse Event

[0123] Events that meet the definition of a SAE include events that require inpatient hospitalization or prolongation of existing hospitalization. In general, hospitalization signifies that the participant has been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and / or treatment that would not have been appropriate in the physician’s office or outpatient setting. Complications that occur during hospitalization are AE. If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or wasnecessary, the AE should be considered serious. Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE.

[0124] An adverse event is severe if it results in persistent disability or incapacity. The term disability means a substantial disruption of a person’s ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) which may interfere with or prevent everyday life functions but do not constitute a substantial disruption.

[0125] Participants will be prescreened on visits 1 and 2 as described below and eligible participants will be enrolled the study on Visit 3. All screening evaluations must be reviewed to confirm that participants met all eligibility criteria. The Investigator will maintain a screening log to record details of all participants screened and to confirm eligibility or record reasons for screening failure, as applicable.

[0126] Rescreening, or repeating specific screening tests or steps at a time not otherwise specified in the protocol, is permitted with prior consent of the sponsor if initial results were missing or uninterpretable or represented a transient or reversible status that has resolved or stabilized, including with acute or ongoing treatment (e.g., poorly controlled hypertension or diabetes that has been adequately addressed to meet enrollment criteria), or if confirming earlier eligibility is necessary because of concern of a change in the participant’s status, or if protocol enrollment criteria are changed through protocol amendment. Repeat testing for drugs of abuse is permitted based on the judgment of the investigator. The duration of the screening period can be extended with prior agreement of sponsor if necessary to protect patient safety or ensure appropriateness of participation in the study.

[0127] During the study, a monitor will make site visits to review protocol compliance, compare EDC / eCRF entries and individual participant’s medical records, assess drug accountability, and ensure that the study is being conducted according to pertinent regulatory requirements. The EDC / eCRF entries will be verified with source documentation. The review of medical records will be performed in a manner to ensure that participant confidentiality is maintained.

[0128] Checking of the EDC / eCRF entries for completeness and clarity, and cross-checking with source documents, will be required to monitor the progress of the study. Moreover, regulatory authorities of certain countries, IRBs, FECs, and / or the Sponsor’s Clinical Quality Assurance Group may wish to carry out such source data checks and / or on-site audit inspections.Visit 1 Screening

[0129] Individuals who remain eligible for the study following pre-screening attend Visit 1. Study eligibility for non-HSAT based enrollment criteria are determined at Visit 1. Only individuals who are found to be eligible at Visit 1, including results of clinical laboratory testing, and HSAT results, which are not available until several days post-visit, continue further screening. The following activities occur at Visit 1 :• Informed consent• Demographics and medical history, including medications and history of PAP use or other treatments for OSA, will be gathered.• Confirmation that the subject will temporarily cease the use of PAP therapy, mandibular advancement devices, nasal devices, or sleeping position devices for the treatment of OSA will be covered.• Physical examination, height, weight, vital signs, AEs / SAEs, conmeds, clinical laboratory testing, urine drugs of abuse test, pregnancy test, 12-lead ECG• Sites will need to verify the incretin-based therapy: o Type / name of drug. Sites should be aware that patients in the community may be using non-FDA approved versions of tirzepatide, semaglutide, or liraglutide. Patients participating in the current trial must only use GLP-1 drugs obtained with a prescription from a licensed health care provider, and only obtain the medicines from state-licensed pharmacies or outsourcing facilities registered with FDA. Compounded GLP-1 drugs are not FDA- approved or evaluated for safety and effectiveness and are prohibited. Dosing: scheduling and stability of current dose >4 weeks without plans for additional dose escalation during trial period• Subjects will complete the following questionnaires: o MADRS - Suicidal Thoughts question that indicate thinking of or planning suicide are exclusionary at VI, and should be clinically addressed as indicated)Attorney Docket No. 263947-558411Table 2. Schedule of Activities1Clinical lab testing conducted locally.2AE / SAE collection begins at Visit 158152115.2 37Attorney Docket No. 263947-55841158152115.2 38Attorney Docket No. 263947-5584113Vital signs will be completed at pre-IP dispense and after the last blood draw.4V3 PK sampling will require samples: Predose, 0.5, 1, 2, 4, 6, 8 hours post dose. V4 PK sample will be a single sample taken 24-30 hours after the V3 dose (ideally). V7 Pk sample will be a spot sample5Prior to dosing at V3; Additional pregnancy testing may be done at other times when clinically indicated, e.g. if a menstrual cycle is missed or when pregnancy is otherwise suspected.6Home Sleep Testing device will be provided by site at VI and V6. Data collection will be for 2 nights at home for both visits.7Study drug will be dispensed at V4 as a 7 day run-in dose blister pack and a 33 day bottle. Subjects will be instructed to take drug ~30 minute before bedtime.58152115.2 39o PROMIS Fatigue o PROMIS Sleep Impairment o ESS o CSSA

[0130] The HSAT device will be provided by the site to the participant with instructions for use and application. The participant will use the device ideally across two consecutive nights, and the average REI4 score across 2 technically adequate nights of study (each with a minimum recording time of 4 hours) will serve as baseline for calculation of efficacy outcomes. The devices will be returned to the site and the data will be sent to a centralized scoring service. The service will ensure minimum study quality to determine the REI4 and provide the result to the site typically within 72 hours for continued eligibility assessment. HSAT testing may be repeated under certain circumstances, as described in the HSAT scoring guide, if deemed inadequate to determine participant eligibility.Visit 2 Screening

[0131] Participants will return to the site for Visit 2 to complete the following activities:• Medical and concomitant therapy (medication or device) monitoring• Vital signs (triplicate blood pressure, heart rate, respiratory rate, body temperature, weight) are measured during the day.• The site will obtain the HSAT devices and will verify data acquisition and confirm data upload for third party scoring. If data acquisition was incomplete, the site will dispense another HSAT device to the participant.Visit 3 - Day 1

[0132] Individuals who are found to be eligible on all enrollment criteria after visits 1 and 2 will be contacted by phone to schedule Visit 3. Participants will be advised to arrive the morning of Visit 3 in an overnight fasted state (>8hrs). They will be permitted to drink water during this time as needed. The following activities occur at Visit 3 :• AE / SAE and concomitant therapy monitoring.• Vital signs (triplicate blood pressure, heart rate, respiratory rate, body temperature, weight) are measured before and after PK collection. Weight will only be measured before PK collection.• Urine pregnancy test in WOCBA.• PK blood sampling will be conducted according to the laboratory manual and site operating procedure, preferably using an intravenous catheter typically inserted in aforearm vein for multiple samples. Blood samples will be collected into labeled tubes containing the appropriate reagents as specified by the bioanalytical facility.• Pharmacokinetic protocol includes the following sequence of events: o Obtain pre-dose blood sample for PK. o Single dose administration of AD109 (2.5mg / 75mg) with at least 8 oz of water. o Obtain blood sample for PK at times 0.5, 1,2, 4, 6, and 8 hours post dose (actual time recorded in relation to dose). o 2 hours post dosing, subject can resume eating and drinking ad-libitum. o Subject can depart from the site after the 8 hour sample is obtained and venous catheter is removed. o AE / SAE monitoring conducted for the duration of this visit.Visit 4 - Day 2

[0133] Participants return the next day to complete a single blood sample for PK analysis between 24-30 hours (non-fasting) after the single dose administered at V3. The following activities will occur at site visit 3:• The subject’s vitals are assessed for AE / SAE and concomitant therapy.• The subj ect’ s weight will be recorded.• Participants are instructed on IMP dosing and IMP is dispensed. o IMP is dispensed as:■ One blister package of 7 tablets of the run-in dose (2.5mg Aroxybutynin / 37.5mg Atomoxetine).■ One bottle of 33 tablets of the full dose (2.5mg Aroxybutynin / 75mg Atomoxetine).• The site will instruct participants on study procedures, including the following, and address scheduling of future study visits. o IMP is taken nightly at home within 30 minutes of bedtime. o Participant will be instructed to retain empty blister pack for drug accountability.Phone Call; Day 4-5

[0134] Subjects will be called to assess any AE / SAE with concomitant therapy and review (medication or device) monitoring information. The assistant will review the study procedures and schedule of future visits to the study site with the subject.Visit 5; Day 9-11

[0135] Participants must return for visit 5 with all IMP so that drug accountability can be conducted. The following activities occur at Visit 5:• AE / SAE and concomitant therapy (medication or device) monitoring• Vital signs (triplicate blood pressure, heart rate, respiratory rate, body temperature and weight)• Review of study procedures and future study visits• Drug accountability will be conducted for the blister package and the bottle of study drug• Participant will be re-instructed on IMP dosing and IMP is dispensed. o IMP is taken nightly at home within 30 minutes of bedtime (and at lights out at PSG visits). o Participants are re-dispensed the bottle of study drug to be use for the remainder of the study.Phone Call; Day 12-13

[0136] Subjects will be called to assess any AE / SAE with concomitant therapy and review (medication or device) monitoring information. The assistant will review the study procedures and schedule of future site visits with the subject.Phone Call; Day 24-25

[0137] Subjects will be called to assess any AE / SAE with concomitant therapy and review (medication or device) monitoring information. The assistant will review the study procedures and schedule of future site visits with the subject.Visit 6; Day 31-38

[0138] Participants return to the site on Visit 6 with remaining IMP for drug accountability and to obtain HSAT equipment for home recording over 2 nights. In addition, the following efficacy and safety assessments:

[0139] • AE / SAE and concomitant therapy (medication or device) monitoring.• Vital signs (triplicate blood pressure, heart rate, respiratory rate, body temperature and weight).• Site verifies that the subject has sufficient IMP available for the home administration during HSAT. HSAT is conducted without the use of PAP or other therapies for OSA, and with IMP dosing (if dosing not otherwise discontinued).Drug accountability is conducted and the bottle of study drug is re-dispensed to the participant for use for the remainder of the study.Review of study procedures and future study visits

[0140] HSAT device is returned to site at Visit 7, and results do not affect subsequent study activities.Visit 7: Day 39-41, End of Study

[0141] Participants return to the site on Visit 7 to have the following efficacy and safety assessments:• AE / SAE and concomitant therapy (medication or device) monitoring.• Vital signs (triplicate blood pressure, heart rate, respiratory rate, body temperature and weight). Conducted prior to blood draw for clinical lab and PK.• HSAT apparatus is returned and data capture transfer verified by site (> 4 hours / night recording) for central scoring.• Blood collection for clinical lab testing and final spot PK sample (non-fasting).• Participants return with the bottle of study drug for drug accountability.• Subjects will complete the following questionnaires: o MADRS (responses that indicate thinking or planning suicide should be clinically addressed as indicated) o PROMIS Sleep Impairment o PROMIS Fatigue o ESS o CSSA• For any ongoing AE / SAE, participants will be called weekly for 2 weeks or until AE / SAE resolution, whichever comes first.• Subjects that withdraw / early terminate from the study (either Sponsor or subject driven) should be encouraged to complete an EOS visit completing all activities of the V7 / EOS as described by the protocol’s Schedule of Activities. This would mean skipping any remaining calls / visits including the V6 HSAT but otherwise capturing the other activities outlined in V7 / EOS schedule of activities. For any ongoing AE / SAE, participants will be called weekly for 2 weeks or until AE / SAE resolution, whichever comes first.Study Drug(s) Administered

[0142] AD 109 is a tablet containing both aroxybutynin and atomoxetine as described below. During the treatment portion of the study, a 7 day run-in period will use a lower dose (2.5mg / 37.5mg) given nightly, followed by the full dose (2.5mg / 75mg) used for the remainder of the study. During the treatment portion, study drug is taken at home within 30 minutes of lights out, including on HSAT nights, and consists of one tablet. The following formulations are used in this study are shown in Table 3.Table 3. Study Drug Formulations

[0143] Nightly dosing in the fully fasted state is not recommended; participants should avoid going to bed feeling hungry. A meal or snack no more than 3 hours prior to dosing is recommended. IMP is initially dispensed as 1 blister strip of 7 doses of the run-in dose of AD109 (aroxybutynin 2.5 mg and atomoxetine 37.5 mg) and 1 bottle of 33 doses of the target dose of AD 109 (aroxybutynin 2.5 mg and atomoxetine 75 mg).

[0144] The objectives and endpoints of the study are shown below in Table 4.Table 4. Objectives and Endpoints of the Study

[0145] Statistical analysis of the study will be based on a more technical and detailed elaboration of statistical procedures, including planned analyses, population definitions and methodology presented in a Statistical Analysis Plan (SAP) that takes precedence over such descriptions in the protocol. For the purpose of population analyses, the following sets are defined in Table 5 below.Table 5. Population Sets for AnalysisConcomitant Therapy

[0146] Concomitant therapy with the medications listed below generally is disallowed. However, if the medication is used at a sufficiently low dose or short duration, it may be permitted with prior approval of the sponsor. A period of one month typically should pass between discontinuing a prohibited medication and screening, to allow determination that the patient’s medical condition was stable, but this period can be shorter if appropriate in the clinical judgement of the investigator and with prior approval of the sponsor. Te Sponsor may approve on a case-by-case basis a medication that is typically disallowed can be used to treat an intercurrent illness or condition that arises during the course of the study; consideration will be given to whether IMP dosing and / or other study activities will be temporarily paused in such circumstance. The sponsor must approve any such plans for temporary interruption.• MAOIs or other drugs that affect monoamine concentrations (e.g., rasagiline, isocarboxazid, phenelzine, selegiline, tranylcypromine, linezolid, methylene blue, procarbazine) [MAOIs are contraindicated for use with atomoxetine)• Norepinephrine Reuptake Inhibitors (e.g., atomoxetine, reboxetine, viloxazine)• Tricyclic antidepressants (e.g., amitriptyline, clomipramine, amoxapine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine)• Strong CYP2D6 inhibitors (e.g., bupropion, fluoxetine, paroxetine, quinidine)• Strong CYP3A4 inhibitors (e.g., oral ketoconazole, ceritinib, clarithromycin, idelalisib, indinavir, oral itraconazole, mibefradil, nefazodone, nelfinavir, ribociclib, ritonavir, saquinavir, telithromycin, tucatinib, voriconazole)• St John’s Wort• Barbiturates (e.g., phenobarbital, amobarbital, butalbital, methohexital, primidone, secobarbital)• Buspirone• Opioids (e.g., hydrocodone, oxycodone, oxymorphone, morphine, codeine, fentanyl, hydromorphone, methadone, meperidine, tramadol, carfentanil, buprenorphine) o Includes combination drugs (e.g., oxycodone + acetaminophen, hydrocodone + acetaminophen, tramadol + acetaminophen)• Muscle relaxants in participants >65 years of age (e.g., baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, dantrolene, metaxolone, methocarbamol, orphenadrine, tizanidine)• Pressor agents (e.g., midodrine, droxidopa)• Central agonist antihypertensives (alpha methyldopa, clonidine, guanabenz, guanfacine)• Amphetamines (including dextroamphetamine, methylphenidate, dexmethylphenidate, methamphetamine, lisdexamfetamine) and other sympathomimetic amines (e.g., phentermine)• Other drugs when used primarily or exclusively for weight loss (e.g., bupropionnaltrexone, orlistat, phentermine-topiramate).• Dopaminergic or antihistaminergic antiemetics (e.g., dimenhydrinate, meclizine, prochlorperazine, domperidone, olanzapine, metoclopramide, promethazine)• Modafinil, armodafinil, solriamfetol, pitolisant• Esketamine• Antipsychotics (e.g., risperidone, quetiapine, olanzapine, ziprasidone, paliperidone, aripiprazole, clozapine, asenapine, chlorpromazine, haloperidol)• Oral anticholinergics (e.g., benztropine, tolterodine, darifenacin, trospium, solifenacin, oxybutynin)• Cholinesterase inhibitors (e g., donepezil, galantamine, rivastigmine, tacrine)• More than occasional use or brief course of first-generation sedating antihistamines (e.g., diphenhydramine, chlorphenamine, doxylamine, brompheniramine, hydroxyzine) o Includes combination drugs (e.g., ibuprofen + diphenhydramine, acetaminophen + diphenhydramine, naproxen + diphenhydramine)

[0147] Allowed medications include but are not limited to those listed below. Medications that do not have substantial effects on the central nervous system (CNS), respiration, or muscle activity are typically allowed even if not listed below.• Benzodiazepines (e.g., alprazolam, chlordiazepoxide, clorazepate, diazepam, lorazepam, oxazepam, prazepam, quazepam, clonazepam, estazolam, temazepam, triazolam)• Nonbenzodiazepine “Z-drugs” (zolpidem, zaleplon, eszopiclone) and orexin antagonists (e g., suvorexant, daridorexant, lemborexant).• Trazodone• Most commonly used antihypertensives (angiotensin-converting-enzyme / angiotensin II receptor blocker inhibitors, calcium channel blockers, spironolactone, hydrochlorothiazide, beta-blockers, etc.) [note that central agonist antihypertensives are prohibited, as listed under prohibited medications]• Statins• Gabapentin, pregabalin• Selective Serotonin Reuptake Inhibitors that do not strongly inhibit CYP 2D6 or 3A4 are allowed (e.g., citalopram, escital opram, duloxetine, fluvoxamine, mirtazapine, sertraline, venlafaxine)• Proton pump inhibitors and histamine H2 receptor blockers• Antacids, proton pump inhibitors• Non-sedating antihistamines (e.g., cetirizine, desloratadine, loratadine, fexofenadine, levocetirizine)• Melatonin• Non-steroidal anti-inflammatory drugs and acetaminophen• Anti-asthmatics• Antibiotics, topical antifungals• Laxatives• Immunomodulators• Erectile dysfunction drugs• Inhaled corticosteroids (e.g., fluticasone)• Antidiabetics• Ocular hypotensives and other ophthalmics (e.g., timolol)• Hormonal therapy (e.g., estrogen replacement or anti-estrogens) and hormonal contraceptives• Thyroid medications• Anticoagulants• Gout medications• OTC topicals (e g., topical pain relievers)• Osteoporosis drugsIndividual Participant IMP Stopping Criteria

[0148] If a clinically significant finding is identified, the Investigator or qualified designee will determine if IMP dosing can continue and whether any change in participant management is needed. IMP dosing, and / or other associated study activities, can be temporarily stopped and restarted to assess relationship of clinical findings to IMP, with prior agreement of Sponsor. IMP dosing can continue if PAP is initiated and no IMP stopping criteria have been met.

[0149] The following measures were factored into a decision to discontinue the IMP:• Blood pressure or pulse increase that, in the judgement of the investigator, may be related to IMP and presents a safety risk to the individual participant considering baseline factors and comorbidities. The following values should be factored into a decision to discontinue IMP: o Pulse increase of greater than 15 bpm that results in an overall bpm to over 90; or pulse greater than 100 bpm o Blood pressure >160 systolic and / or >100 diastolic• Abuse, diversion, or misuse of IMP.• Clinically significant hallucinations (excluding sleep-related hallucinations), amnesia, delusional thinking, delirium, manic symptoms, aggressive behavior, suicidality, homicidally, agitation, confusion, or convulsions / seizures.• SAE considered related to study drug.• Acute urinary obstruction.• Sleepiness-related MVAAny other AE or change in participant status that in the judgment of the Investigator necessitates the participant stopping IMP to protect participant safety or the safety of others.

[0150] Note that new or increased antihypertensive therapy is not itself a criterion for stopping IMP. Compliance with antihypertensive therapy can be encouraged and factored into clinical decisions about IMP continuation.Participant Withdraw from Study

[0151] Participants who discontinue from dosing IMP will be encouraged to continue all other study procedures through the end of the study. Unless the subject specifically withdraws consent for such further follow up, all participants who withdraw from the study with an ongoing AE must be followed until the event is resolved or deemed stable.

[0152] A participant may withdraw from the study at any time at his / her own request. An Investigator may ask a subject whether the subject wishes to provide continued follow-up and further data collection separately from interventional aspects of the study. Under this circumstance, the discussion with the subject would distinguish between study-related interventions and continued follow-up of associated clinical outcome information.Participants who withdraw from the study are requested to return for Visit 7 / EOS activities approximately 2 weeks following cessation of IMP dosing.

[0153] Any other AE or change in participant status that in the judgment of the Investigator necessitates the participant stopping IMP to protect participant safety or the safety of others. Participants who discontinue from dosing IMP will be encouraged to continue all other study procedures through the end of the study.End of Study Definition

[0154] A participant is considered to have completed the study if he / she has completed all phases of the study through the last scheduled procedure shown in the Schedule of Activities (SoA) in Table 2. The end of the study is defined as the date of the last visit of the last participant in the study or last scheduled procedure shown in the SoA for the last participant in the study.Safety and Efficacy Scales and Tests

[0155] The Epworth Sleepiness Scale (ESS) is a self-administered questionnaire with 8 questions. Participants are asked to rate, on a 4-point scale (0-3), their usual chances of dozing off or falling asleep while engaged in 8 different activities in recent times. The ESSscore (the sum of 8 item scores, 0-3) can range from 0 to 24. The higher the ESS score, the higher that person’s average sleep propensity in daily life, or their ‘daytime sleepiness’. The questionnaire takes approximately 2 or 3 minutes to answer. PROMIS (Patient-Reported Outcomes Measurement Information System) sleep impairment and fatigue measures were developed with modem psychometric techniques including item response theory to assess various self-reported aspects of sleep and daytime impairment. Items are based on 5-point scales, either frequency or intensity, with higher scores corresponding to more severe or worse symptoms.

[0156] MADRS (Montgomery-Asberg depression rating scale) is a ten-item diagnostic questionnaire typically used to measure the severity of depressive symptoms. Each item is based on a 6-point scale, with the overall score ranging from 0-60. Higher scores can indicate more severe depression or, in the context of this study, symptoms of OSA or effects of study drug.

[0157] The Cocaine Selective Severity Assessment (CSSA) was originally designed to measure the signs and symptoms of cocaine withdrawal. The CSSA is used in this study as a safety measure for withdrawal symptoms that might be caused by AD 109, particularly the atomoxetine component, which affects the norepinephrine system, a system also affected by cocaine. The CSSA is interview-based and administered by study site personnel. Special training or equipment is not needed, and the assessment is administered according to brief written guidelines.Pharmacokinetic analysis

[0158] A non-compartmental analysis (with Phoenix® WinNonlin® version 8, or higher) will be used to derive the pharmacokinetic parameters of atomoxetine and R-oxybutynin listed in Table 6. Reason for exclusion of AUC: In the case where less than 3 consecutive measurable concentrations are observed, the AUC parameters will not be estimated. Subjects will be excluded from the PK parameters requiring U estimation if the terminal phase cannot be reliably estimated (R2of at least 80% and using minimum of three data points not including C max).

[0159] One dose of the 75mg / 2.5mg formulation is taken at approximately 0800 while the subject is awake. Blood samples for PK analysis will be collected into a labeled tube containing the appropriate anticoagulant as specified by the bioanalytical facility. As an option to the subject or if judged necessary by the clinical staff, blood samples may be collected from an indwelling cannula (stylet catheter that requires no flushing), which will beplaced in the forearm vein of the subject. Samples will be collected prior to dosing (pre-dose) and at 0.5, 1, 2, 4, 6, 8, and between 24-30 hours (non-fasting) post dose. A final PK sample will be taken at the end of the study as a spot measurement. The time of PK blood sample collection will be calculated relative to the time of study drug administration. The actual time of all PK blood draws will be recorded and reported for all subjects. Atomoxetine and R- oxybutynin concentrations and major metabolites for PK assessments will be obtained through bioanalysis of plasma derived from the blood samples drawn during this study, using a validated bioanalytical method.Table 6. Pharmacokinetic Parameters

[0160] Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in other situations such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical treatment to prevent one of the other outcomes listed in the above definition. These events should usually be considered serious. Examplesof such events include invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization, or development of drug dependency or drug abuse.Assessment of Causality

[0161] The Investigator is obligated to assess the relationship between study treatment and each occurrence of an AE or SAE. A "reasonable possibility" of a relationship conveys that there are facts, evidence, and / or arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. The Investigator will use clinical judgment to determine the relationship. Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as the temporal relationship of the event to study treatment administration will be considered and investigated. The Investigator will also consult the Investigator’ s Brochure and / or Product Information, for marketed products, in his / her assessment. For each AE / SAE, the Investigator must document in the medical notes that he / she has reviewed the AE / SAE and has provided an assessment of causality. There may be situations in which an SAE has occurred and the Investigator has minimal information to include in the initial report to the CRO. However, it is very important that the Investigator always make an assessment of causality for every event before the initial transmission of the SAE data to the eCRF.

[0162] The Investigator may change his / her opinion of causality based on subsequent information and send an SAE follow-up report with the updated causality assessment. The causality assessment is one of the criteria used when determining regulatory reporting requirements. The Investigator is obligated to perform or arrange for the conduct of supplemental measurements and / or evaluations as medically indicated or as requested by the CRO to elucidate the nature and / or causality of the AE or SAE as fully as possible. This may include additional laboratory tests or investigations, histopathological examinations, or consultation with other health care professionals.Follow-up of AE and SAE

[0163] It is the responsibility of the Investigator to record and follow-up on an AE or SAE. Investigators should document information related to the AE or SAE event, e.g., diagnosis, hospital progress, laboratory, diagnostic reports, and intensity (mild, moderate, or severe) in the eCRF. Any personal identifiers are blinded in reports to the CRO. The Investigator is required to proactively follow each participant after the initial AE / SAE report at subsequent visits / contacts. Participants must be proactively questioned about changes in ongoingAEs / SAEs at intervals and with a precision that is clinically appropriate for the specific AE / SAE, including documentation of duration, time, or date of resolution, or change in severity or seriousness or related events. All AE / SAEs will be followed until resolution, stabilization, until the event is otherwise explained, or the participant is lost to follow-up.Reporting a SAE

[0164] While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous abortion is always considered to be an SAE and will be reported as such. Any post-study pregnancy-related SAE considered reasonably related to the study treatment by the Investigator will be reported to the Sponsor. While the Investigator is not obligated to actively seek this information in former study participants, he or she may learn of an SAE through spontaneous reporting.

[0165] Any AE that is serious, associated with the use of the study treatment, and unexpected (SUSAR) has additional reporting requirements, as described below. If the SUSAR is fatal or life-threatening, associated with study treatment, and unexpected, regulatory authorities and IRBs / IECs will be notified within 7 calendar days after the Sponsor learns of the event. Additional follow-up (cause of death, autopsy report, and hospital report) information should be reported within an additional 8 days (15 days total). If the SUSAR is not fatal or life-threatening but is otherwise serious, associated with study treatment, and unexpected, regulatory authorities and IRBs / IECs will be notified within 15 calendar days after the Sponsor learns of the event. The Sponsor will notify the Investigators in a timely fashion of relevant information about SUSARs that could adversely affect the safety of participants. The Sponsor will provide follow-up information if necessary and annual safety updates to the regulatory authorities and lECs responsible for the study. These updates will include information on SUSARs and other relevant safety findings.

[0166] If a participant dies during participation in the study, the Investigator will provide the CRO with a copy of any post-mortem findings including histopathology. New or updated information will be recorded in the originally completed eCRF. The Investigator will submit any updated SAE data to the CRO via eCRF completion within 24 hours of receipt of the information.

[0167] Prompt notification (within 24 hours,) by the Investigator to the Sponsor and the CRO via eCRF of an SAE is essential so that legal obligations and ethical responsibilities towards the safety of participants and the safety of a study treatment under clinicalinvestigation are met. In the event that the EDC is unavailable for entry, the Investigator must call or email the CRO within the 24 hours. When calling or emailing to report an SAE, state that you are reporting an SAE and give the Investigator’s name, your name, the telephone number where you can be reached, and the protocol number and title.

[0168] The Investigator and the Sponsor (or Sponsor’s designated agent) will review each SAE report and the Sponsor / CRO will evaluate the seriousness and the causal relationship of the event to study treatment. In addition, the Sponsor (or Sponsor’s designated agent) will evaluate the expectedness according to the reference documents (Investigator’s Brochure or US product labeling for atomoxetine or aroxybutynin). Based on the Investigator and Sponsor’s assessment of the event, a decision will be made concerning the need for further action. After the study is completed at a given site, the electronic data collection tool will be taken off-line to prevent the entry of new data or changes to existing data.

[0169] If a site receives a report of a new SAE from a study participant or receives updated data on a previously reported SAE after the electronic data collection tool has been taken offline, then the site can report this information on a paper SAE form or by telephone. The Sponsor has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a study treatment under clinical investigation. The Sponsor will comply with country-specific regulatory requirements relating to safety reporting to the regulatory authority, IRB / Independent Ethics Committees (IEC), and Investigators. Investigator safety reports must be prepared for suspected unexpected serious adverse reactions (SUSAR) according to local regulatory requirements and Sponsor policy and forwarded to Investigators as necessary. An Investigator who receives a safety report describing an SAE or other specific safety information (e.g., summary or listing of SAE) from the Sponsor will file it along with the Investigator’s Brochure and will notify the IRB / IEC, if appropriate according to local requirements.

[0170] All SAEs will be recorded from randomization until the end of the study. Serious adverse events occurring after the end of the study and coming to the attention of the Investigator must be reported only if they are considered (in the opinion of the Investigator) causally-related to the study treatment.

[0171] Details of all pregnancies in female participants after the start of study treatment and until at least 5 terminal half-lives after the last dose will be collected. If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of learning of the pregnancy and should follow the procedures outlined in Appendix 4. Abnormal pregnancyoutcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered to be SAEs.

[0172] In the event of an overdose, the Investigator should refer to the investigator brochure for sivopixant and to approved product label for acetazolamide for advice on overdose and:• Contact the Medical Monitor immediately;• closely monitor the participant for AE / SAE and laboratory abnormalities; and• document the quantity of the excess dose as well as the duration of the overdosing in the eCRF.

[0173] Decisions regarding dose interruptions or modifications will be made by the Investigator in consultation with the Medical Monitor based on the clinical evaluation of the participant.Other Embodiments

[0174] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method of treating a subject having a condition associated with pharyngeal airway collapse, the method comprising administering to a subject in need thereof an effective amount a GLP-1 receptor agonist and a second active agent selected from the group consisting of atomoxetine, reboxetine, viloxazine, edivoxetine, oxybutynin, and trazodone, and stereoisomers thereof and pharmaceutically acceptable salts thereof.

2. The method of claim 1, wherein the second active agent is atomoxetine or a pharmaceutically acceptable salt thereof.

3. The method of claim 1, wherein the second active agent is reboxetine or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

4. The method of claim 1, wherein the second active agent is viloxazine or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

5. The method of claim 1, wherein the second active agent is edivoxetine or a pharmaceutically acceptable salt thereof.

6. The method of claim 1, wherein the second active agent is oxybutynin or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

7. The method of claim 6, wherein the oxybutynin is (R)-oxybutynin or a pharmaceutically acceptable salt thereof.

8. The method of claim 6, wherein the oxybutynin is racemic oxybutynin or a pharmaceutically acceptable salt thereof.

9. The method of claim 1, wherein the second active agent is trazodone or a pharmaceutically acceptable salt thereof.

10. The method of any one of claims 1-9, wherein the GLP-1 receptor agonist is selected from the group consisting of semaglutide, tirzepatide, retatrutide, dulaglutide, exenatide, PEGylated exenatide, survodutide, efpeglenatide, liraglutide, lixisenatide, cotadutide, noiiglutide, mazdutide, albiglutide, beinaglutide, PEG-loxenatide, pemvidutide, taspoglutide, efocipegtrutide, orforglipron, and danuglipron, and stereoisomers thereof, and pharmaceutically acceptable salts thereof.

11. The method of claim 10, wherein the GLP-1 receptor agonist is selected from the group consisting of semaglutide, tirzepatide, liraglutide, and retatrutide, and stereoisomers thereof, and pharmaceutically acceptable salts thereof.

12. The method of claim 11, wherein the GLP-1 receptor agonist is semaglutide or a pharmaceutically acceptable salt thereof.

13. The method of claim 11, wherein the GLP-1 receptor agonist is tirzepatide or a pharmaceutically acceptable salt thereof.

14. The method of claim 11, wherein the GLP-1 receptor agonist is retatrutide or a pharmaceutically acceptable salt thereof.

15. The method of claim 12, wherein semaglutide is orally administered at a dose of from about 1 mg to about 25 mg per day.

16. The method of any preceding claim, wherein the atomoxetine or pharmaceutically acceptable salt thereof is administered at a dose of from about 20 to about 200 mg.

17. The method of any preceding claim, wherein the atomoxetine or pharmaceutically acceptable salt thereof is administered at a dose of from about 25 to about 100 mg.

18. The method of any preceding claim, wherein the oxybutynin or pharmaceutically acceptable salt thereof is administered at a dose of from about 1 to about 15 mg.

19. The method of any preceding claim, wherein the oxybutynin or pharmaceutically acceptable salt thereof is administered at a dose of from about 2 mg to about 10 mg.

20. The method of any preceding claim, wherein the (R)-oxybutynin or pharmaceutically acceptable salt thereof is administered at a dose of from about 0.5 to about 10 mg.

21. The method of any preceding claim, wherein the (R)-oxybutynin or pharmaceutically acceptable salt thereof is administered at a dose of from about 1 mg to about 5 mg.

22. The method of any preceding claim, wherein the trazodone or pharmaceutically acceptable salt thereof is administered at a dose of from about 12.5 mg to about 200 mg.

23. The method of any preceding claim, wherein edivoxetine or a pharmaceutically acceptable salt thereof is administered at a dose of from about 6 mg to about 36 mg.

24. The method of any preceding wherein viloxazine or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is administered at a dose of from about 50 mg to about 800 mg.

25. The method of any preceding claim, wherein the GLP-1 receptor agonist and the second active agent are administered in a single composition.

26. The method of claim 25, wherein the single composition is an oral administration form, such as a syrup, pill, tablet, troche, or capsule.

27. The method of any preceding claim, further comprising administering a third active agent selected from the group consisting of atomoxetine, reboxetine, viloxazine, edivoxetine, oxybutynin, and trazodone, and stereoisomers thereof, and pharmaceutically acceptable salts thereof.

28. The method of claim 28, wherein the second active agent is selected from the group consisting of atomoxetine, reboxetine, viloxazine, and edivoxetine, and stereoisomers thereof and pharmaceutically acceptable salts thereof, and the third active agent is selected from the group consisting of oxybutynin and trazodone, and stereoisomers thereof, and pharmaceutically acceptable salts thereof.

29. The method of claim 28, wherein the second active agent is atomoxetine or a pharmaceutically acceptable salt thereof and the third active agent is (R)-oxybutynin or a pharmaceutically acceptable salt thereof.

30. The method of any preceding claim, wherein the condition associated with pharyngeal airway collapse is sleep apnea.

31. The method of claim 30, wherein the condition associated with pharyngeal airway collapse is obstructive sleep apnea (OSA).

32. The method of any preceding claim, wherein the condition associated with pharyngeal airway collapse is snoring.

33. The method of claim 32, wherein the condition associated with pharyngeal airway collapse is simple snoring.

34. The method of any preceding claim, wherein the subject is in a non-fully conscious state, such as sleep.

35. A GLP-1 receptor agonist and a second active agent selected from the group consisting of selected from the group consisting of atomoxetine, reboxetine, viloxazine, edivoxetine, oxybutynin, and trazodone, and stereoisomers thereof, and pharmaceutically acceptable salts thereof, for use in treating obstructive sleep apnea.

36. A therapeutic combination of a GLP-1 receptor agonist and a second active agent selected from the group consisting of atomoxetine, reboxetine, viloxazine, edivoxetine, oxybutynin, and trazodone, and stereoisomers thereof, and pharmaceutically acceptable salts thereof, for use in treating obstructive sleep apnea.

37. A pharmaceutical composition comprising a GLP-1 receptor agonist and a second active agent selected from the group consisting of atomoxetine, reboxetine, viloxazine, edivoxetine, oxybutynin, and trazodone, and stereoisomers thereof and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier or excipient.

38. The pharmaceutical composition of claim 37, wherein the second active agent is atomoxetine or a pharmaceutically acceptable salt thereof.

39. The pharmaceutical composition of claim 37, wherein the second active agent is reboxetine or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

40. The pharmaceutical composition of claim 37, wherein the second active agent is viloxazine or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

41. The pharmaceutical composition of claim 37, wherein the second active agent is edivoxetine or a pharmaceutically acceptable salt thereof.

42. The pharmaceutical composition of claim 37, wherein the second active agent is oxybutynin or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

43. The pharmaceutical composition of claim 37, wherein the second active agent is trazodone or a pharmaceutically acceptable salt thereof.

44. The pharmaceutical composition of claim 42, wherein the oxybutynin is (R)-oxybutynin or a pharmaceutically acceptable salt thereof.

45. The pharmaceutical composition of claim 42, wherein the oxybutynin is racemic oxybutynin or a pharmaceutically acceptable salt thereof.

46. The pharmaceutical composition of any one of claims 37-45, wherein the GLP-1 receptor agonist is selected from the group consisting of semaglutide, tirzepatide, retatrutide, dulaglutide, exenatide, PEGylated exenatide, survodutide, efpeglenatide, liraglutide, lixisenatide, cotadutide, noiiglutide, mazdutide, albiglutide, beinaglutide, PEG-loxenatide, pemvidutide, orforglipron, and danuglipron, and a stereoisomers thereof, and pharmaceutically acceptable salts thereof.

47. The pharmaceutical composition of claim 46, wherein the GLP-1 receptor agonist is selected from the group consisting of semaglutide, tirzepatide, liraglutide, and retatrutide, and stereoisomers thereof, and pharmaceutically acceptable salts thereof.

48. The pharmaceutical composition of claim 47, wherein the GLP-1 receptor agonist is semaglutide or a pharmaceutically acceptable salt thereof.

49. The pharmaceutical composition of claim 47, wherein the GLP-1 receptor agonist is tirzepatide or a pharmaceutically acceptable salt thereof.

50. The pharmaceutical composition of claim 47, wherein the GLP-1 receptor agonist is retatrutide or a pharmaceutically acceptable salt thereof.

51. The pharmaceutical composition of any preceding claim, further comprising a third active agent selected from the group consisting of atomoxetine, reboxetine, viloxazine, edivoxetine, oxybutynin, and trazodone, and stereoisomers thereof, and pharmaceutically acceptable salts thereof.

52. The pharmaceutical composition of claim 51, wherein the second active agent is selected from the group consisting of atomoxetine, reboxetine, viloxazine, and edivoxetine, and stereoisomers thereof, and pharmaceutically acceptable salts thereof, and the third active agent is selected from the group consisting of oxybutynin and trazodone, and stereoisomers thereof, and pharmaceutically acceptable salts thereof.

53. The pharmaceutical composition of claim 52, wherein the second active agent is atomoxetine or a pharmaceutically acceptable salt thereof and the third active agent is (R)- oxybutynin or a pharmaceutically acceptable salt thereof.

54. The method of any one of claims 1 to 34, wherein treatment with a GLP-1 receptor agonist in combination with the second or third agents reduces OSA, snoring, or depressive symptoms compared to treatment with no GLP-1 receptor agonist55. The method of any one of claims 1 to 34 or 54, wherein the subject is obese.

56. The method of any one of claims 1 to 34 or 54 to 55, wherein the subject suffers from severe OSA.

57. The method of any one of claims 1 to 34 or 54 to 55, wherein the subject suffers from moderate OSA.

58. The method of any one of claims 1 to 34 or 54 to 55, wherein the subject suffers from mild OSA.

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