Methods and compositions for treating sleep apnea

Abstract

Methods and compositions for the treatment of conditions associated with pharyngeal airway muscle collapse while the subject is in a non-fully conscious state, e.g., sleep apnea and snoring, comprising administration of (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a non myorelaxing hypnotic and / or 5-HT2A inverse agonist or antagonist.

Description

(19) *EP004635514A2* (11) EP 4 635 514 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: 22.10.2025 Bulletin 2025 / 43 (21) Application number: 25200289.4 (22) Date of filing: 07.02.2020 (51) International Patent Classification (IPC): A61K 45 / 06 (2006.01) (52) Cooperative Patent Classification (CPC): (C-Sets available) A61K 45 / 06; A61K 31 / 138; A61K 31 / 437; A61K 31 / 4468; A61P 25 / 00 (Cont.) (84) Designated Contracting States: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR (30) Priority: 08.02.2019 US 201962803223 P (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: 20752195.6 / 3 920 898 (71) Applicant: The Brigham & Women’s Hospital, Inc. Boston, Massachusetts 02115 (US) (72) Inventors: • MONTEMURRO, Luigi Taranto Brookline, MA 02445 (US) • WELLMAN, D. Andrew Wayland, MA 01778 (US) (74) Representative: Forresters IP LLP Skygarden Erika-Mann-Straße 11 80636 München (DE) Remarks: This application was filed on 04‑09‑2025 as a divisional application to the application mentioned under INID code 62. (54) METHODS AND COMPOSITIONS FOR TREATING SLEEP APNEA (57) Methods and compositions for the treatment of conditions associated with pharyngeal airway muscle collapse while the subject is in a non-fully conscious state, e.g., sleep apnea and snoring, comprising admin- istration of (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a non myorelaxing hypnotic and / or 5-HT2A in- verse agonist or antagonist. EP 4 63 5 51 4 A 2 Processed by Luminess, 75001 PARIS (FR) (Cont. next page) (52) Cooperative Patent Classification (CPC): (Cont.) C-Sets A61K 31 / 138, A61K 2300 / 00; A61K 31 / 437, A61K 2300 / 00; A61K 31 / 4468, A61K 2300 / 00 2 EP 4 635 514 A2 3 1 EP 4 635 514 A2 2 Description CLAIM OF PRIORITY

[0001] This application claims the benefit of U.S. Pro- visional Patent Application Serial No. 62 / 803,223, filed on February 8, 2019. The entire contents of the foregoing are hereby incorporated by reference. FEDERALLY SPONSORED RESEARCH OR DEVEL- OPMENT

[0002] This invention was made with Government sup- port under Grant Nos. HL102321 and HL095491 awarded by the National Institutes of Health. The Gov- ernment has certain rights in the invention. TECHNICAL FIELD

[0003] The present invention is based, at least in part, on the discovery of methods and compositions for the treatment of conditions associated with pharyngeal air- way collapse while the subject is in a non-fully conscious state, e.g., snoring and sleep apnea, comprising admin- istration of a norepinephrine reuptake inhibitor (NRI) and a non myorelaxing hypnotic or 5-HT2A inverse agonist or antagonist. BACKGROUND

[0004] Obstructive Sleep Apnea (OSA) is a common disorder (Young et al., Am J Respir Crit Care Med 2002;165:1217‑39) caused by collapse of the pharyn- geal airway during sleep. OSA can have serious health consequences. SUMMARY

[0005] The present disclosure is based upon the ad- ministration of noradrenergic and non-myorelaxing hyp- notic drugs to increase pharyngeal muscle activity in sleeping humans and reduce snoring and sleep apnea severity, e.g., in OSA patients.

[0006] Thus, provided herein are methods for treating a subject having a condition associated with pharyngeal airway collapse while the subject is in a non-fully con- scious state. The methods include administering to a subject in need thereof an effective amount of (i) a nor- epinephrine reuptake inhibitor (NRI) and (ii) a non myor- elaxing hypnotic and / or 5-HT2A inverse agonist or an- tagonist.

[0007] In some embodiments, the NRI is a norepi- nephrine selective reuptake inhibitor (NSRI), e.g., an NSRI selected from the group consisting of Amedalin, Atomoxetine, CP‑39,332, Daledalin, Edivoxetine, Esre- boxetine, Lortalamine, Nisoxetine, Reboxetine, Talo- pram, Talsupram, Tandamine, and Viloxazine.

[0008] In some embodiments, the NRI is a norepi- nephrine non-selective reuptake inhibitor (NNRI), e.g., an NNRI selected from the group consisting of Amitripti- line, Amoxapine, Bupropion, Ciclazindol, Desipramine, Desvenlafaxine, Dexmethilphenidate, Diethylpropion, Doxepin, Duloxetine, Imipramine, Levomilnacipran, Manifaxine, Maprotiline, Methylphenidate, Milnacipran, Nefazodone, Nortriptyline, Phendimetrazine, Phenme- trazine, Protryptyline, Radafaxine, Tapentadol, Tenilox- azine, and Venlafaxine.

[0009] In some embodiments, the NRI is selected from the group consisting of Atomoxetine and Reboxetine.

[0010] In some embodiments, the NRI is Atomoxetine, and in specific embodiments, the dosage of Atomoxetine is 20 - 100 mg, e.g., 25‑75 mg.

[0011] In some embodiments, the non myorelaxing hypnotic is a benzodiazepinehypnotic, e.g., temazepam, brotizolam, flurazepam, nitrazepam, or triazolam; or a non-benzodiazepine hypnotic, e.g., a cyclopyrrolone hypnotic, e.g., zolpidem, zopiclone or eszopiclone, a stereoisomer of zopiclone; gabapentin; trazodone; di- phenhydramine; suvorexant; tasimelteon; ramelteon; agomelatine; doxepin; zaleplon; doxylamine; sodium oxybate; or tiagabine.

[0012] In some embodiments, the 5-HT2A inverse agonist is AC‑90179, ketanserin, nelotanserin, eplivan- serin, pimavanserin, or volinanserin; or the 5-HT2A an- tagonist is trazodone, mirtazapine, ketanserin, cloza- pine, olanzapine, quetiapine, risperidone, iloperidone, perospirone, asenapine, nefazodone, MDL‑100,907, cy- proheptadine, pizotifen, LY‑367,265, 2-alkyl‑4-aryl-tetra- hydro-pyrimido-azepines, haloperidol, chlorpromazine, hydroxyzine (Atarax), 5-MeO-NBpBrT, or Niaprazine. In some embodiments, the 5-HT2A antagonist is ketan- serin, iloperidone, perospirone, risperdone or nefazo- done.

[0013] In some embodiments, the 5-HT2A inverse agonist or antagonist is pimvanserin, preferably adminis- tered at a dose of 20‑40 mg, preferably 34 mg.

[0014] In some embodiments, the non my orelaxing hypnotic or 5-HT2A inverse agonist or antagonist is in an immediate release formulation.

[0015] In some embodiments, the non myorelaxing hypnotic or 5-HT2A inverse agonist or antagonist is in an extended release formulation.

[0016] In some embodiments, the non myorelaxing hypnotic is zolpidem, and in specific embodiments, the dosage of zolpidem is 2‑12.5 mg.

[0017] In some embodiments, the zolpidem is in an immediate release formulation, e.g., with a dose of 2‑10 mg.

[0018] In some embodiments, the zolpidem is in an extended release formulation, e.g., with a dose of 5‑12.5 mg.

[0019] In some embodiments, the disease or disorder is Obstructive Sleep Apnea (e.g., AHI of ≥ 10 events per hour) or Simple Snoring.

[0020] In some embodiments, the non-fully conscious state is sleep. 5 10 15 20 25 30 35 40 45 50 55 4 3 EP 4 635 514 A2 4

[0021] In some embodiments, the NRI and the non myorelaxing hypnotic are administered in a single com- position.

[0022] In some embodiments, the NRI and 5-HT2A inverse agonist or antagonist are administered in a single composition.

[0023] In some embodiments, the single composition is an oral administration form.

[0024] In some embodiments, the oral administration form is a syrup, pill, tablet, troche, or capsule.

[0025] In some embodiments, the single composition is a transdermal administration form, e.g., a patch.

[0026] Also provided herein are pharmaceutical com- positions comprising (i) a norepinephrine reuptake inhi- bitor (NRI) (ii) a non myorelaxing hypnotic and / or 5-HT2A inverseagonist or antagonist, and (iii) a pharmaceutically acceptable carrier.

[0027] In some embodiments, the NRI is a norepi- nephrine selective reuptake inhibitor (NSRI), e.g., se- lected from the group consisting of Amedalin, Atomox- etine, CP‑39,332, Daledalin, Edivoxetine, Esreboxetine, Lortalamine, Nisoxetine, Reboxetine, Talopram, Talsu- pram, Tandamine, and Viloxazine. In some embodi- ments, the NRI is a norepinephrine non-selective reup- take inhibitor (NNRI) selected from the group consisting of Amitriptiline, Amoxapine, Bupropion, Ciclazindol, De- sipramine, Desvenlafaxine, Dexmethilphenidate, Diethylpropion, Doxepin, Duloxetine, Imipramine, Levo- milnacipran, Manifaxine, Maprotiline, Methylphenidate, Milnacipran, Nefazodone, Nortriptyline, Phendimetra- zine, Phenmetrazine, Protryptyline, Radafaxine, Tapen- tadol (Nucynta), Teniloxazine (Lucelan, Metatone) and Venlafaxine.

[0028] In some embodiments, the NRI is selected from the group consisting of Atomoxetine and Reboxetine.

[0029] In some embodiments, the NRI is Atomoxetine, and in specific embodiments, the dosage of Atomoxetine is 20 - 100 mg.

[0030] In some embodiments, the non myorelaxing hypnotic is a benzodiazepinehypnotic, e.g., temazepam, brotizolam, flurazepam, nitrazepam, or triazolam; or a non-benzodiazepine hypnotic, e.g., a cyclopyrrolone hypnotic, preferably selected from the group consisting of zolpidem, zopiclone, and eszopiclone; gabapentin; trazodone; diphenhydramine; suvorexant; tasimelteon; ramelteon; agomelatine; doxepin; zaleplon; doxylamine; sodium oxybate; or tiagabine, In some embodiments, the non myorelaxing hypnotic is in an immediate release formulation. In some embodiments, the non myorelaxing hypnotic is in an extended release formulation.

[0031] In some embodiments, the non myorelaxing hypnotic is zolpidem. In some embodiments, the zolpi- dem is in an immediate release formulation, e.g., with a dose of 2‑10 mg. In some embodiments, the zolpidem is in an extended release formulation, e.g., with a dose of 5‑12.5 mg.

[0032] In some embodiments, the 5-HT2A inverse agonist is AC‑90179, ketanserin, nelotanserin, eplivan- serin, pimavanserin, or volinanserin; or the 5-HT2A an- tagonist is trazodone, mirtazapine, ketanserin, cloza- pine, olanzapine, quetiapine, risperidone, iloperidone, perospirone, asenapine, nefazodone, MDL‑100,907, cy- proheptadine, pizotifen, LY‑367,265, 2-alkyl‑4-aryl-tetra- hydro-pyrimido-azepines, haloperidol, chlorpromazine, hydroxyzine (Atarax), 5-MeO-NBpBrT, or Niaprazine. In some embodiments, the 5-HT2A antagonist is ketan- serin, iloperidone, perospirone, risperdone or nefazo- done.

[0033] In some embodiments, the 5-HT2A inverse agonist or antagonist is pimvanserin, present in a dose of 20‑40 mg or 30‑40 mg, preferably 34 mg.

[0034] Also provided are the compositions described herein for use in treating a subject having a condition associated with pharyngeal airway collapse while the subject is in a non-fully conscious state. In some embodi- ments, the disease or disorder is sleep apnea or Simple Snoring. In some embodiments, the disease or disorder is Obstructive Sleep Apnea.

[0035] In some embodiments, the non-fully conscious state is sleep.

[0036] In some embodiments, the NRI and the non myorelaxing hypnotic are administered in a single com- position.

[0037] In some embodiments, the single composition is an oral administration form.

[0038] In some embodiments, the oral administration form is a pill, tablet, troche, or capsule.

[0039] Also provided herein are a norepinephrine re- uptake inhibitor (NRI) and a non my orelaxing hypnotic and / or 5-HT2A inverse agonist or antagonist, for use in treating a subject having a condition associated with pharyngeal airway collapse while the subject is in a non-fully conscious state.

[0040] Further, providedherein are kits comprising (i) a norepinephrine reuptake inhibitor (NRI) and (ii) a non myorelaxing hypnotic and / or 5-HT2A inverse agonist or antagonist, e.g., for use in method described herein, e.g., for treating a subject having a condition associated with pharyngeal airway collapse while the subject is in a non-fully conscious state. The kit can comprise, e.g., separate pharmaceutical compositions of any of the in- dividual active drugs claimed herein with a pharmaceu- tically acceptable salt or carrier wherein said kit may contain (a) separate or common bottles or packets allow- ing potentially separate dosaging and (b) optionally a set of kit instructions.

[0041] 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 materi- als are described herein for use in the present invention; other, suitable methods and materials known in the art canalso beused. Thematerials,methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, databaseentries, andother referencesmentionedherein 5 10 15 20 25 30 35 40 45 50 55 5 5 EP 4 635 514 A2 6 are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0042] Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims. DESCRIPTION OF DRAWINGS

[0043] FIG. 1. 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 ventilatory effort by movements of the rib cage and abdomen and changes in esophageal pressure, all of which reflect contraction of respiratory muscles. The last channel indicates oxyhemoglobin saturation. FIG. 2. Atomoxetine alone (Ato) and oxybutynin alone (Oxy) did not systematically reduce OSA se- verity (apnea hypopnea index, AHI). In contrast, there was a potent effect of these agents when administered together. White lines indicate means, boxes indicate 95% CI. FIG. 3A‑3B. Atomoxetine is responsible for most of the ventilatory improvement. Ventilation was mea- sured during ’passive’ condition (when ventilatory drive is close to eupneic level and the upper airway dilator muscles are relatively relaxed, 3A) and during ’active conditions’ (when ventilatory drive is close to the arousal threshold and the upper airway muscles are close to the maximal activation possible during sleep, 3B). Vpassive is generally considered a mea- sure of collapsibility of the upper airway. The in- crease in Vactive from atomoxetine to ato-oxy was likely due to an increase in arousal threshold (more time was allowed during sleep for muscle recruit- ment) rather than to the effect of oxybutynin. FIG. 4. Arousal threshold change from placebo to atomoxetine (ato), oxybutynin (oxy) and the drug combination (ato-oxy). *p=0.03 vs placebo and oxy. FIGs. 5A-B. After inducing a reflex activation of the genioglossus muscle with a transient obstruction of the upper airway during sleep, the time during which the activity of the genioglossus remained elevated above baseline after the obstructive stimulus was removed was 2-fold longer during slow wave sleep (SWS) compared to NREM 2 (N2) sleep. FIG. 6. Theeffect of the combinationof Atomoxetine- Pimavanserin (Ato-Pima) on OSA severity (apnea hypopnea index, AHI), on the arousal index, the upper airway collapsibility (ventilation at low ventila- tory drive, Vpassive) and the arousal threshold. DETAILED DESCRIPTION

[0044] Inhumans, thepharyngeal airway regionhasno 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 the amplitude of esophageal pressure swings. Rib cage and abdominal movements are in the opposite direction as a result of the diaphragm contracting against an occluded airway, forcing the abdominal wall to distend out and the chest wall to cave inward.

[0045] Increasing efforts to breathe lead to an arousal from sleep, visualizable on an EEG (Fig. 1), and result in opening of the airway and a resumption of normal breath- ing. 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 hourof sleep.See, for example, Ruehland et al., The new AASM criteria for scoring hypopneas: Impact on the apnea hypopnea index. SLEEP 2009;32(2):150‑157.

[0046] When a stringent definition of OSA is used (an AHIof≥15eventsperhourorAHI≥5eventsperhourwith daytime sleepiness), the estimated prevalence is ap- proximately15percent inmalesand5percent 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 comorbid- ities and economic costs, including: hypertension, dia- betes, cardiovascular disease, motor vehicle accidents, workplace accidents, and fatigue / lost productivity. See, for example, Young et al., WMJ 2009; 108:246; Peppard et al., Am J Epidemiol 2013; 177:1006.

[0047] The present leading treatment (Engleman and Wild, Sleep Med Rev 2003;7:81‑99; Kribbs et al., The American review of respiratory disease 1993;147:887‑95) is continuouspositive airwaypressure (CPAP). CPAP is effective in virtually all patients, and approximately85%ofdiagnosedpatientsare treated, but compliance is low.Patients findCPAPuncomfortableand 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 in- clude oral appliances (10%) and surgery (5%), but neither is likely to be effective across the general popula- tion. No pharmacologic treatments have been shown to be effective to date.

[0048] The search for medicines to activate pharyn- gealmuscles insleepinghumanshasbeendiscouraging; 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.When takenalone, noradrenergic drugs suchas 5 10 15 20 25 30 35 40 45 50 55 6 7 EP 4 635 514 A2 8 norepinephrine reuptake inhibitors only mildly reduce OSA severity, and only in selected patients. 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., Sleep. 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 1;40(2).

[0049] The tricyclic antidepressants protriptyline (Brownell et al. N Engl J Med 1982; 307:1037‑1042; Smith et al. Am Rev Respir Dis 1983; 127:8‑139) and desipramine (Taranto-Montemurro et al. Eur Respir J 2016; 48:1340‑135), as well as the selective norepi- nephrine reuptake inhibitor atomoxetine (Bart Sangal et al. Sleep Med 2008; 9:506‑510), have all been tested inpatientswithOSA,withmodest success in reducing the severity of the disorder. Three randomized controlled trials (Brownell et al. 1982, supra; Whyte et al. Sleep 1988; 11:463‑472; Hanzel et al. Chest 1991; 100:416‑421) and several observational studies (Smith et al. supra; Conway et al. Thorax 1982; 37:49‑53; Clark et al. Neurology 1979; 29:1287‑1292) assessed the ef- fects of protriptyline on OSA severity. Brownell and co- workers (Brownell et al. 1982, supra) found no change in AHI during NREM sleep after 4 weeks of therapy with protriptyline 20 mg in a group of 5 obese men with severe OSA.However, thepatientshad improvements inoxygen saturation and daytime sleepiness, suggesting at least some positive impact of the drug on respiration during sleep. In another double-blind trial,Whyte and coworkers (Whyte et al. 1988, supra) found that administration of protriptyline 20 mg for 14 days in 10 moderate-to-severe OSA patients did not change NREM AHI as a group, but the inter-individual variability in response was substan- tial. Lastly, in an open label, 4-week crossover trial on 9 patients,Hanzel et al (Chest 1991; 100:416‑421) showed a statistically significant reduction in AHI by 42% from baseline. These results, taken together, suggest that protriptylinemaybehelpful in asubgroupofOSApatients that still needs to be identified.

[0050] Similar to protriptyline, another tricyclic drug, desipramine, was tested in a placebo-controlled, double blind crossover trial lasting 1 night. However, variable results were obtained in terms of AHI reduction in the 14 patients studied (Taranto-Montemurro et al. 2016, su- pra). Although the effect on OSA severity was not sig- nificant as a group, patients exhibited a less collapsible airway on desipramine compared to placebo. Moreover, a post-hoc analysis identified the subgroup of patients withminimalmuscle compensationas thephenotype that responded best to the treatment. Additionally, in a trial performed on normal controls, desipramine increased genioglossus activity and reduced upper airway collap- sibility during sleep.

[0051] The selective norepinephrine reuptake inhibitor atomoxetine was tested by Bart-Sangal et al (2008, supra) in a prospective observational study of 15 patients with mild OSA. The drug did not improve AHI but did significantly improve daytime sleepiness. As shown herein, atomoxetine administered alone did not improve OSA severity in a sample of 9 moderate-to-severe OSA patients (Taranto-Montemurro et al. Am J Respir Crit Care Med 2019; 199:1267‑1276).

[0052] In the last decade, animal1, 2 and human3 re- search has shown that noradrenergic withdrawal in the central nervous system plays a primary role in determin- ing the upper airway dilator muscles hypotonia during sleep. Translational work performed recently in our la- boratory showed that drugs with noradrenergic proper- ties such as desipramine can increase genioglossus muscle activity3 and can reduce upper airway collapsi- bility during sleep in humans4. However, our team and others have shown that noradrenergic drugs taken alone cannot reduce OSA severity. Protriptyline5, 6, desipra- mine4 and atomoxetine7 have been tested in patients with OSA without success in reducing the AHI. Never- theless,whenatomoxetinewasgiven in combinationwith the antimuscarinic oxybutynin, OSA severity was re- duced by 63% compared to placebo in 20 unselected patients during a randomized double blinded crossover trial of a single night conducted in our lab8. Originally, the reason for combining oxybutynin to atomoxetine was to contrast the inhibitory mechanism mediated by muscari- nic receptors that, according to Richard Homer’s group9, is responsible for the episodes of major suppression of genioglossus activity during REM sleep. Yet, the inhibi- tory role of muscarinic receptor is not supported by all animal research: for example Kubin et al. showed that in the anesthetized rat model the REM sleep-related de- pression of genioglossus activity can be fully explained by the combined withdrawal of two excitatory inputs: noradrenergic and serotonergic10, 11.

[0053] A second possible mechanism at work in the combination of atomoxetine and oxybutynin is that oxy- butynin could act as a hypnotic by increasing the arousal threshold and consolidating sleep, thus contrasting the wake-promoting effects of atomoxetine. Previous litera- ture reported that antimuscarinics administered at low doses have mild sedative effects12 and induce sleepi- ness13. Moreover, and consistently with this hypothesis, it has been also recently shown that oxybutynin can improve sleep quality by reducing symptoms of noctur- ia14.

[0054] A low respiratory arousal threshold (wake up easily in response to upper airway obstruction) can limit neuromuscular compensation of the upper airway and contribute to the development of sleep-related hypop- neas and apneas in many individuals. A reduction in ventilation during sleep during an obstructive apnea / hy- popnea, leads to a buildup in CO2 that increases venti- latory drive that can activate the pharyngeal muscles and reduce upper airway resistance by making the upper airway stiffer. A low respiratory arousal threshold, how- ever, can preempt this important compensatory mechan- ism. Therefore, while for people with high arousal thresh- 5 10 15 20 25 30 35 40 45 50 55 7 9 EP 4 635 514 A2 10 old thearousal is a life-savingmechanism toprotect them from asphyxia during sleep, it may be destabilizing for patients with a low arousal threshold, because the pre- mature awakening can perpetuate the cycle of repetitive upper airway collapse. Thus, preventing arousals with medications with specific profiles in patients taking a wake-activating drug like atomoxetine that induces a low arousal threshold, could yield more stable breathing and less OSA.

[0055] Notably, previous animal data showed that the administration of the antimuscarinic atropine could abol- ish the fast, low amplitude EEG activity induced by an adrenergic stimulant of the central nervous system (am- phetamine) and induce low-frequency, high-amplitude brainwaves typical of NREM sleep15. Activating pharyn- geal muscles with adrenergic drugs such as atomoxetine maybe insufficient to treatOSA if the patientswakeup for a minimal reduction in ventilation (namely: low arousal threshold). The concomitant administration of a potent sedative with a powerful activator of upper airway dilator muscles such as atomoxetine could lead to the pharma- cological resolution of OSA in many patients.

[0056] As described herein, although the contempor- ary administration of atomoxetine and oxybutynin re- duced OSA severity (Figure 2) in both REM and NREM sleep, when administered alone, atomoxetine and oxy- butynin did not respectively improve NREM and REM specific AHI as originally hypothesized. An accurate analysis of ventilatory parameters during all night showed that atomoxetine alone accounted for at least 70% of the improvement in ventilation during sleep and improved oxygen saturation compared to placebo, while oxybutynin had a minor effect on ventilation and did not improve oxygen levels (Figures 3A‑3B).

[0057] Atomoxetine was responsible for a reduction in the arousal threshold (waking up more easily), likely because of its adrenergic properties. However, when atomoxetine was administered with oxybutynin, the re- duction in arousal threshold with the combination was a non-statistically-significant 7% (p>0.7, Figure 4). These data suggest that the most important effect of oxybutynin in the combination was to attenuate the alerting effect of atomoxetine.

[0058] This unexpected finding suggested that oxybu- tynin could be replaced by non myorelaxing hypnotics with a more powerful effect on the arousal threshold such asz-drugs (i.e. zolpidem,zopiclone) oragentsenhancing sleep depth and slow wave sleep (i.e. gabapentin, tiaga- bine). The effect of zolpidem and other commonly used hypnotics (zopiclone, temazepam) on genioglossus muscle activity and arousal threshold has been recently tested in 21 subjectswith andwithoutOSAbyCarberry et al. Amongst the hypnotics tested, zolpidem improved the arousal threshold by ~30% and, unexpectedly, increased also themediangenioglossusmuscle responsivenessby 3-fold (p=0.03) compared to placebo16.

[0059] As described herein, drugs that increase sleep depth (and slow wave sleep (SWS) in particular) such as tiagabine or gabapentin could help the resolution ofOSA. We administered the anti-epileptic drug tiagabine to 14 OSA subjects without worsening the AHI or the oxygen saturation during sleep in these patients17. EEG showed an increase in slow wave activity by 16% suggesting that the drug mildly increased sleep depth. The pharmacolo- gical increase in slow wave sleep (SWS) could be an ideal mechanism for raising the arousal threshold to treat OSA, particularly since SWS seems to be a "protective state" against OSA. Ratnavadivel et al. found that 82% of patients with moderate to severe OSA achieve an AHI<15events / hr inSWS18.The reason for improvement likely relates to changes in the non-anatomical factors that contribute to OSA during SWS such as reduced arousability, therebyenablingahigher activationof upper airwaydilatormuscles.Furthermore,we recently showed that, after inducing a reflex activation of the genioglossus muscle with a transient obstruction of the upper airway during sleep, the time during which the activity of the genioglossus remained elevated above baseline after the obstructive stimulus was removed (also called after-discharge, see Figure 5) was 2-fold longer during SWS compared to NREM 2 sleep. These data suggest that a form of neural memory of the upper airway dilator muscles is in place and may help to stiffen the pharynx and stabilize breathing selectively during SWS in OSA19. Thus, asdescribedherein, drugssuchasgabapentin that cause 20‑60% increase of SWS20, 21, are ideal candi- dates for the treatment of OSA in association with ato- moxetine.

[0060] Serotonin neurons in the brainstem are critical for producing both the cortical and respiratory motor response to hypercapnia. Serotonin neuron deficient mice have an impaired hypercapnic ventilatory response (HCVR)26 and lack the ability to arouse from sleep in response to CO2 27. Buchanan was able to restore the EEG arousal in these mice with 5-HT2A receptor stimu- lation, suggesting that this specific sub-receptor is re- sponsible for activating the central nervous system in response to chemosensory (respiratory) stimuli. This notion is supported by human data; Heinzer et al.28 showed that administration of trazodone 100mg (a 5- HT2A antagonist) before bedtime to eight OSA patients increased the arousal threshold in response to hyper- capnia, allowing tolerance of higher CO2 levels without arousal. Eckert et al.29 showed that trazodone could improve arousal threshold by 30% in seven patients with a low arousal threshold, but it did not affect the AHI compared to placebo. By contrast, Smales et al.30 showed that trazodone 100 mg reduced the AHI by 26% in 15 unselected OSA patients.

[0061] Other hypnotics and sedatives were previously tested in OSA patients (zolpidem, zopiclone, eszopi- clone, temazepam, tiagabine) to increase the arousal threshold. These sedatives, rather than targeting the 5- HT2A receptor, act by activating theGABA receptors and by reducing the general excitability of the central nervous system and could be also used in combination with 5 10 15 20 25 30 35 40 45 50 55 8 11 EP 4 635 514 A2 12 atomoxetine and other noradrenergic agents to reduce OSA severity.

[0062] In a physiology trial including 21 individuals with and without OSA, 10 mg of zolpidem increased the arousal threshold by 25% and, unexpectedly, also the genioglossus response to pharyngeal negative pressure as compared to placebo33. Among other Z-drugs, eszo- piclone and zopiclone were studied in OSA patients to measure their effect on the arousal threshold. Eckert et al34, in a 1-night crossover trial including 17 OSA pa- tients, showed that eszopiclone increased the arousal threshold by ~30%.Although the groupdata did not show a significant reduction in AHI overall, those with a low arousal threshold at baseline (8 / 17) had their AHI re- duced by 43%. Carter et al35 showed that zopiclone 7.5 mg administered for 1 night (n=12) increased the arousal threshold by 20% but did not significantly change the AHI compared to placebo. A subsequent parallel-arm trial from thesamegroup, testingzopiclone (n=14) vsplacebo (n=16), showed a non-significant reduction in AHI be- tween the twogroups (‑25% frombaselineand ‑15% from placebo) after 30 days of treatment36. In a four-arm trial by Carberry and coworkers33 zopiclone 7.5 mg signifi- cantly increased arousal threshold (but did not change AHI) vs placebo in a group of 21 healthy individuals and OSA patients. Methods of Treatment

[0063] Themethodsdescribedherein includemethods for the treatment of disorders associated with pharyngeal airway muscle collapse during sleep. In some embodi- ments, the disorder is Obstructive Sleep Apnea (OSA) (defined as an AHI of ≥ 10 events per hour) or Simple Snoring. Generally, the methods include administering a therapeutically effective amount of (i) a norepinephrine reuptake inhibitor and (ii) a non myorelaxing hypnotic agent and / or 5-HT2A inverse agonist or antagonist as known in theart and / or described herein, to a subjectwho is in needof, orwhohasbeendetermined tobe in needof, such treatment.

[0064] As used in this context, to "treat" means to ameliorate at least one symptom of the disorder asso- ciated with pharyngeal airway collapse. Often, pharyn- geal airway collapse during sleep results in snoring an- d / or an interruption in breathing (apnea or hypopnea), arousal from sleep, and reduced oxygenation (hypoxe- mia); thus, a treatment can result in a reduction in one or more of snoring, apneas / hypopneas, sleep fragmenta- tion, and hypoxemia.

[0065] Unexpectedly, administration of a therapeuti- cally effective amount of a norepinephrine reuptake in- hibitor and a non myorelaxing hypnotic agent and / or 5- HT2A inverse agonist or antagonist for the treatment of a subject having a condition associated with pharyngeal airway collapse while the subject is in a non-fully con- scious state, suchasOSA,will result in decreasedAHI. In some embodiments, the administration of a therapeuti- cally effective amount of a norepinephrine reuptake in- hibitor and a non myorelaxing hypnotic agent and / or 5- HT2A inverse agonist or antagonist for the treatment of a subject having a condition associated with pharyngeal airway collapse while the subject is in a non-fully con- scious state, suchasOSA,will result in decreasedAHIby 50% or more. In some embodiments, the administration of a therapeutically effective amount of a norepinephrine reuptake inhibitor and a non myorelaxing hypnotic agent and / or 5-HT2A inverse agonist or antagonist for the treatment of a subject having a condition associated with pharyngeal airway collapse while the subject is in a non- fully conscious state, such as OSA, will result in de- creased AHI by 75% or more. In other further embodi- ments, the administration of a therapeutically effective amount of a norepinephrine reuptake inhibitor and a non myorelaxing hypnotic agent and / or 5-HT2A inverse ago- nist or antagonist for the treatment of a subject having a condition associated with pharyngeal airway collapse while the subject is in a non-fully conscious state, such as OSA, will result in increased ventilation. In yet other embodiments, the administration of a therapeutically effective amount of a norepinephrine reuptake inhibitor and a non myorelaxing hypnotic agent and / or 5-HT2A inverse agonist or antagonist for the treatment of a sub- ject having a condition associated with pharyngeal air- way collapse while the subject is in a non-fully conscious state, such as OSA, will result in increased oxygen blood levels. In still another embodiment, the administration of a therapeutically effective amount of a norepinephrine reuptake inhibitor and a non myorelaxing hypnotic agent and / or 5-HT2A inverse agonist or antagonist for the treatment of a subject having a condition associated with pharyngeal airway collapse while the subject is in a non- fully conscious state, suchasOSA,will result in improved total sleep time, reduced AHI, increased oxygenation, less sleep fragmentation, increased total sleep time, and / or improved subjective sleep quality.

[0066] An effective amount of a norepinephrine reup- take inhibitor and a non myorelaxing hypnotic agent can be administered in one or more administrations, applica- tions or dosages, simultaneously or separately. When administered simultaneously, a norepinephrine reuptake inhibitor and a non myorelaxing hypnotic agent and / or 5- HT2A inverse agonist or antagonist can be formulated as a single dosage form, e.g., a capsule, tablet or solution, containingbothanorepinephrine reuptake inhibitor anda non myorelaxing hypnotic agent, or as separate dosage forms, e.g., one a capsule, tablet or solution, containing a norepinephrine reuptake inhibitor and another capsule, tablet or solution containing a non myorelaxing hypnotic agent and / or 5-HT2A inverseagonist or antagonist. Each of the norepinephrine reuptake inhibitor and the non myorelaxing hypnotic agents and / or 5-HT2A inverse agonist or antagonist can be administered, simulta- neously or separately from one or more times per day tooneormore timesperweek; includingonceeveryother day. In some embodiments, the norepinephrine reuptake 5 10 15 20 25 30 35 40 45 50 55 9 13 EP 4 635 514 A2 14 inhibitor and the non myorelaxing hypnotic agent and / or 5-HT2A inverse agonist or antagonist are administered daily. In someembodiments, theagentsareadministered less than 60, 45, 30, 20, or 15 minutes before a subject wishes or intends to fall asleep. The skilled artisan will appreciate that certain factors may influence the dosage and timing required toeffectively 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, treat- ment of a subject with a therapeutically effective amount of the therapeutic compounds described herein can in- clude a single treatment or a series of treatments.

[0067] Dosage, toxicity and therapeutic efficacy of the therapeutic compounds (i.e., NRI and non myorelaxing hypnotic and / or 5-HT2A inverse agonist or antagonist, in a single composition or in separate compositions) can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determin- ing the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50.

[0068] The data obtained from cell culture assays and animal studies can be used in formulating a range of dosages for use in humans. The dosage of such com- pounds lies preferably within a range of circulating con- centrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administra- tion utilized. The therapeutically effective dose can be estimated initially fromcell cultureassays.Adosemaybe formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as de- termined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography.

[0069] In some embodiments, the methods include administering a dose of 20‑100 mg Atomoxetine (or a dose equivalent thereof of another NRI) and a dose of 2‑12.5 mg zolpidem, e.g., extended release zolpidem (or a dose equivalent thereof of another non myorelaxing hypnotic). In some embodiments, the methods include administering 80 mg Atomoxetine / 12.5 mg zolpidem; 75 mg Atomoxetine / 10 mg zolpidem; 75 mg Atomoxetine / 8 mg zolpidem; 50 mg Atomoxetine / 6 mg zolpidem; or 25 mg Atomoxetine / 4 mg zolpidem. In other embodiments, the methods include administering a dose of 20‑100 mg Atomoxetine (or a dose equivalent thereof of another NRI) and a dose of 2‑12 mg zolpidem (or a dose equiva- lent thereof of another non myorelaxing hypnotic) within an hour of sleep time. In some embodiments, the meth- ods include administering 80 mg Atomoxetine / 12 mg zolpidem; 75 mg Atomoxetine / 10 mg zolpidem; 75 mg Atomoxetine / 8 mg zolpidem; 50 mg Atomoxetine / 6 mg zolpidem; or 25 mg Atomoxetine / 4 mg zolpidem, 15‑10 minutes before sleep time.

[0070] In further embodiments, the methods include administering Atomoxetine / zolpidem in a 6.5 to 1 ratio by weight. In other embodiments, the methods include ad- ministering Atomoxetine / zolpidem in a 6.5 to 1 ratio by weight at 15‑10 minutes before sleep time.

[0071] In some embodiments, Gabapentin, e.g., 600 mg gabapentin, is used in place of zolpidem. In some embodiments, pimvanserin, e.g., 20‑40 mg, e.g., 34 mg pimvanserin, is used in addition to or in placeof zolpidem. Pharmaceutical Compositions and Methods of Ad- ministration

[0072] The methods described herein include the use of pharmaceutical compositions comprising a norepi- nephrine reuptake inhibitor and a non myorelaxing hyp- notic agent and / or 5-HT2A inverse agonist or antagonist as active ingredients. The norepinephrine reuptake in- hibitor and non myorelaxing hypnotic agent and / or 5- HT2A inverse agonist or antagonist can be administered in a single composition or in separate compositions. In some embodiments, the methods include administering a norepinephrine reuptake inhibitor and a non myorelax- ing hypnotic agent and / or 5-HT2A inverse agonist or antagonist, and no other active ingredients, i.e., the norepinephrine reuptake inhibitor and the non myorelax- ing hypnotic agent and / or 5-HT2A inverse agonist or antagonist are the sole active agents.

[0073] Exemplary norepinephrine reuptake inhibitors (NRIs) include the selective NRIs, e.g., Amedalin (UK‑3540‑1), Atomoxetine (Strattera), CP‑39,332, Dale- dalin (UK‑3557‑15), Edivoxetine (LY‑2216684), Esre- boxetine, Lortalamine (LM‑1404), Nisoxetine (LY‑94,939), Reboxetine (Edronax, Vestra), Talopram (Lu 3‑010), Talsupram (Lu 5‑005), Tandamine (AY‑23,946), Viloxazine (Vivalan); and the non-selective NRIs, e.g., Amitriptiline, Amoxapine, Bupropion, Cicla- zindol, Desipramine, Desvenlafaxine, Dexmethilpheni- date, Diethylpropion, Doxepin, Duloxetine, Imipramine, Levomilnacipran, Manifaxine (GW‑320,659), Maproti- line,Methylphenidate,Milnacipran,Nefazodone,Nortrip- tyline, Phendimetrazine, Phenmetrazine, Protryptyline, Radafaxine (GW‑353,162), Tapentadol (Nucynta), Teni- loxazine (Lucelan, Metatone) and Venlafaxine.

[0074] Suitable, but non-limiting, examples of non myorelaxing hypnotics include a benzodiazepine hypno- tic, e.g., temazepam, brotizolam, flurazepam, nitraze- pam, or triazolam; or a non-benzodiazepine hypnotic, e.g., a cyclopyrrolone hypnotic, preferably selected from the group consisting of zolpidem, zopiclone, and eszo- piclone; gabapentin; trazodone; diphenhydramine; su- vorexant; tasimelteon; ramelteon; agomelatine; doxepin; zaleplon; doxylamine; sodium oxybate; or tiagabine.

[0075] Exemplary 5-HT2A inverse agonists include AC‑90179 (Weiner et al., The Journal of Pharmacology 5 10 15 20 25 30 35 40 45 50 55 10 15 EP 4 635 514 A2 16 and Experimental Therapeutics. 299 (1): 268‑76), ketan- serin, nelotanserin, eplivanserin, pimavanserin, and vo- linanserin; antagonists include Trazodone, Mirtazapine, ketanserin, clozapine, olanzapine, quetiapine, risperi- done, iloperidone, perospirone, asenapine, nefazodone, MDL‑100,907, cyproheptadine, pizotifen, LY‑367,265, 2- alkyl‑4-aryl-tetrahydro-pyrimido-azepines, haloperidol, chlorpromazine, hydroxyzine (Atarax), 5-MeO-NBpBrT, and niaprazine. In some embodiments, the 5-HT2A an- tagonist is ketanserin, iloperidone, perospirone, risper- done or nefazodone.

[0076] In some embodiments, the norepinephrine re- uptake inhibitor is Atomoxetine. In some embodiments, the non myorelaxing hypnotic is zolpidem. In some em- bodiments, the 5-HT2A inverse agonist is pimvanserin.

[0077] Pharmaceutical compositions typically include a pharmaceutically acceptable carrier. As used herein the language "pharmaceutically acceptable carrier" in- cludes saline, solvents, dispersion media, coatings, anti- bacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharma- ceutical administration. Supplementary active com- pounds can also be incorporated into the compositions, however the present compositions do not include an antimuscarinic agent (e.g., as described in WO 2018 / 200775).

[0078] Pharmaceutical compositions are typically for- mulated to be compatible with their intended route of administration. Examples of routes of administration in- clude systemic oral or transdermal administration.

[0079] Methodsof formulatingsuitablepharmaceutical 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 Pharmaceu- tical Sciences: a Series of Textbooks and Monographs (Dekker, NY). For example, oral compositions generally include an inert diluent or an edible carrier. For the purpose of oral 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. Pharmaceutically compa- tible 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 traga- canth 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.

[0080] Systemic administration of one or both of the compounds as described herein (i.e., one or both of a norepinephrine reuptake inhibitor and a non myorelaxing hypnotic) canalsobeby transdermalmeans,e.g., usinga patch, gel, lotion, or thin film, 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 be formulated into ointments, salves, gels, or creams as generally known in the art. The gel and / or lotion can be provided in individual sa- chets, 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.

[0081] In one embodiment, the therapeutic com- pounds are prepared with carriers that will protect the therapeutic compounds against rapid elimination from the body, such as a controlled release formulation, in- cluding implants and microencapsulated delivery sys- tems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylac- tic acid. Such formulations can be prepared using stan- dard techniques, or obtained commercially, e.g., from Alza Corporation and Nova Pharmaceuticals, Inc. Lipo- somal suspensions can also be used as pharmaceuti- cally acceptable carriers. These canbepreparedaccord- ing to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0082] The pharmaceutical compositions can be in- cluded in a container, pack, or dispenser together with instructions for administration or use in a method de- scribed herein. EXAMPLES

[0083] The invention is further described in the follow- ing examples, which do not limit the scope of the inven- tion described in the claims. Example 1.

[0084] In a preliminary investigation, nine patients equipped with a pneumotachograph attached to an or- onasal mask to measure ventilation and an esophageal catheter to estimate the arousal threshold, performed a sleep study on each of these 4 conditions: placebo, atomoxetine alone, oxybutynin alone and ato-oxy. Although the contemporary administration of atomoxe- tine and oxybutynin reduced OSA severity (Figure 2) in both REM and NREM sleep, when administered alone, atomoxetine andoxybutynin did not respectively improve NREM and REM specific AHI as originally hypothesized. An accurate analysis of ventilatory parameters during all night showed that atomoxetine alone accounted for at least 70% of the improvement in ventilation during sleep and improved oxygen saturation compared to placebo, while oxybutynin had a minor effect on ventilation (Fig- ures 3A‑3B) and did not improve oxygen levels. Unfortu- nately, atomoxetine was responsible of a reduction in the arousal threshold (waking up more easily) by 18% 5 10 15 20 25 30 35 40 45 50 55 11 17 EP 4 635 514 A2 18 (p=0.03) vs placebo, likely because of its adrenergic properties. However, when atomoxetine was adminis- tered with oxybutynin, the reduction in arousal threshold with the combination was a non-statistically-significant 7% (p>0.7, Figure 4). These data suggest that the most important effect of oxybutynin in the combination was to attenuate the alerting effect of atomoxetine.

[0085] Furthermore,after inducinga reflexactivationof the genioglossus muscle with a transient obstruction of the upper airway during sleep, the time during which the activity of the genioglossus remained elevated above baseline after the obstructive stimulus was removed (also called after-discharge, see Figures 5A-B and Ref. 19) was 2-fold longer during slow wave sleep (SWS) compared to NREM 2 sleep. These data suggest that a form of neural memory of the upper airway dilator muscles is in place and may help to stiffen the pharynx andstabilizebreathingselectivelyduringSWS inOSA19. Example 2. Pilot Study Subjects.

[0086] OSA subjects with a broad range of apnea severity (10 to >60 / hr) are studied in a double blinded, placebo controlled, crossover trial. Treated OSA patients are enrolled, since we do not want to delay treatment to perform these experiments. These individuals are other- wise healthy (except for well-controlled hypertension, diabetes, or hyperlipidemia) with no active medical pro- blems and on no medication that could affect respiration or muscle control. Subjects are 21‑70 years old. Both men and women will have an apnea-hypopnea index (AHI) >10 events / hr during supine NREM sleep. Equipment.

[0087] Subjects are instrumented with standard poly- somnography (PSG) recording sensors. Sleep stageand arousals are measured with electrodes pasted on to the scalp, face, chin, and chest (EEG, EOG, EKG, chin EMG). Paste-on EMG electrodes are placed over the anterior tibialis muscle to detect leg movements. Re- spiratory effort belts are placed around the chest and abdomen to measure breathing movements. Oxygen saturation is measured continuously with a pulse oxime- try probe placed on the fingertip. Snoring is detected with a small microphone positioned over the suprasternal notch. Body position is recorded with a sensor taped to the thoracic belt. Each of these devices is standard for diagnostic PSG and should not be uncomfortable. To measure airflow, a standard CPAP mask is placed over themouth and thenoseandheld in placewith straps. The mask allows monitoring of breathing (inspiratory flow by pneumotachograph that can be integrated to yeld tidal volume) and expired carbon dioxide levels (PCO2) using a calibrated infrared CO2 analyzer (Capnograph / Oxi- meter Monitor). Protocol.

[0088] We test the effect of a study treatment on OSA severity, administering to OSA patients in random order: 1) atomoxetine 80 mg + zolpidem 10 mg; 2) atomoxetine 80 mg + diphenhydramine 50 mg; 3) atomoxetine 80 mg + trazodone 100 mg; 4) atomoxetine 80 mg + gabapentin 300 mg; or 5) placebo.

[0089] After a baseline polysomnography, an in-la- boratory overnight sleep study on the 3rd day of treat- ment is performed approximately one week apart in ran- dom order. Two pills of placebo or drug combinations are administered 15 minutes before lights out. At least 5 minutes of quiet wakefulness are recorded to quantify the subject’s awake ventilation. As much data are re- corded from NREM and REM sleep as possible over the night. Patients are asked to sleep in the supine position at least for 50% of the night. Data Analysis.

[0090] Apneas, hypopneas, arousals, and sleep stages are scored using standard American Academy of Sleep Medicine guidelines22 by a registered polysom- nographic technologist (RPSGT)blinded to the treatment allocation. Hypopneas are defined as reduction in flow ≥30% from baseline, lasting at least 10 seconds and associated with an arousal from sleep or an oxyhemo- globin desaturation ≥ 3%. Phenotypic traits (Vpassive, Vactive, arousal threshold, loop gain) on placebo and on drug nights are automatically calculated from the poly- somnographyusing thealgorithmsdevelopedand tested in our lab23, 24.

[0091] The main outcome of the trial is the change in AHI and it is compared between the arms using a one- way anova followed by post-hoc analysis to compare each treatment arm with placebo, with p<0.025 consid- ered as statistically significant in order to correct for multiple comparisons. Each individual requires four stu- dies (baseline + 3 trial nights). Hypothesized Results.

[0092] The drugs combinations tested are evaluated for a meaningful reduction in in OSA severity (AHI), an increase in oxygen levels (SaO2), and a reduction in collapsibility (Vpassive and Vactive) in both NREM and REM sleep. The results are interpreted to determine whether it is possible to improve sleep apnea severity and sleep quality with a combination of systemically administered drugs in sleeping humans. The analysis of the phenotypic traits during the baseline night provides information on what group of patients is likely to have the best response on the drugs, the phenotypic analysis on the placebo and drugs night will inform about the me- 5 10 15 20 25 30 35 40 45 50 55 12 19 EP 4 635 514 A2 20 chanisms of action of these combinations. Example 3. Alternative Hypnotic Agents

[0093] To determine whether other non-myorelaxing hypnotic agents could be used in place of zolpidem or gabapentin, further trials using zopiclone, eszopiclone, trazodone, or diphenhydramine are used in combination with 80 mg Atomoxetine in subjects with a mild to mod- erate upper airway collapsibility (ventilation during sleep with normal effort was above 50% of eupneic ventilation on placebo). Effects on OSA severity (AHI), oxygen levels (SaO2), and airway collapsibility (Vpassive and Vactive) are evaluated in both NREM and REM sleep. Example 4. Combination of atomoxetine and pima- vanserin for the treatment of OSA

[0094] We administered the recently-approved selec- tive 5-HT2A inverse agonist pimavanserin 34 mg to block the EEG arousal response to CO2 in association with atomoxetine 80 mg and measured the effect of this combination on OSA severity, arousal threshold and collapsibility in 5 patients. These doses were chosen as they are the usual effective doses for attention-deficit disorder and delusion-hallucinations in patients with Par- kinson’s disease, respectively, based on prescribing in- formation. Patients were also instrumented with an or- onasal mask, and in 4 / 5 patients, esophageal catheter and genioglossus intramuscular electrodes. Atomoxe- tine-plus-pimavanserin markedly reduced the AHI from a median [interquartile range] of 31

[34] to 16

[15] event- s / hour (median change: 70

[15] %), improved upper air- way collapsibility (Vpassive1d) by 63

[28] %eupnea (p=0.07), increased the arousal threshold by 32

[20] % (Fig. 6) and increased the genioglossus activity by 110

[244] %.Theeffect on thearousal threshold is noteworthy, because pimavenserin was administered together with atomoxetine, a wake-promoting drug that, as described above, caused a reduction in arousal threshold by ~18% compared to placebo in OSA patients in a previous trial. This means that pimavanserin could actually increase the respiratory arousal threshold by ~50%. REFERENCES

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[0096] It is to be understood that while the invention has been described in conjunction with the detailed de- scription 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. The invention will now be defined by reference to the 5 10 15 20 25 30 35 40 45 50 55 14 23 EP 4 635 514 A2 24 following clauses 1. A method of treating a subject having a condition associated with pharyngeal airway collapse while the subject is in a non-fully conscious state, the method comprising administering to a subject in need thereof an effective amount of (i) a norepi- nephrine reuptake inhibitor (NRI) and (ii) a nonmyor- elaxing hypnotic and / or 5-HT2A inverse agonist or antagonist. 2. The method of clause 1, wherein the NRI is a norepinephrine selective reuptake inhibitor (NSRI). 3. The method of clause 2, wherein the NSRI is selected from the group consisting of Amedalin, Atomoxetine, CP‑39,332, Daledalin, Edivoxetine, Esreboxetine, Lortalamine, Nisoxetine, Reboxetine, Talopram, Talsupram, Tandamine, and Viloxazine. 4. The method of clause 1, wherein the NRI is a norepinephrine non-selective reuptake inhibitor (NNRI) selected from the group consisting of Ami- triptiline, Amoxapine, Bupropion, Ciclazindol, Desi- pramine, Desvenlafaxine, Dexmethilphenidate, Diethylpropion, Doxepin, Duloxetine, Imipramine, Levomilnacipran, Manifaxine, Maprotiline, Methyl- phenidate, Milnacipran, Nefazodone, Nortriptyline, Phendimetrazine, Phenmetrazine, Protryptyline, Radafaxine, Tapentadol, Teniloxazine, and Venla- faxine. 5. The method of clause 1, wherein the NRI is se- lected from the group consisting of Atomoxetine and Reboxetine. 6. The method of clause 5, wherein the NRI is Ato- moxetine. 7. The method of clause 6, wherein the Atomoxetine is administered at a dose of 20 - 100 mg 8. The method of clause 7, wherein the Atomoxetine is administered at a dose of 25‑75 mg. 9. The method of clause 1, wherein the non myor- elaxing hypnotic is a benzodiazepine hypnotic, pre- ferably temazepam, brotizolam, flurazepam, nitra- zepam, or triazolam. 10. The method of clause 1, wherein the non myor- elaxing hypnotic is a non-benzodiazepine hypnotic, preferably a cyclopyrrolone hypnotic, preferably se- lected from the group consisting of zolpidem, zopi- clone, and eszopiclone; gabapentin; trazodone; di- phenhydramine; suvorexant; tasimelteon; ramel- teon; agomelatine; doxepin; zaleplon; doxylamine; sodium oxybate; or tiagabine. 11. The method of clause 1, wherein the non myor- elaxing hypnotic is in an immediate release formula- tion. 12. The method of clause 1, wherein the non myor- elaxing hypnotic is in an extended release formula- tion. 13. The method of any one of clauses 1‑12, wherein the non myorelaxing hypnotic is zolpidem. 14.Themethodof clause13,wherein thezolpidem is administered at a dose of 2‑12.5 mg. 15.Themethodof clause14,wherein thezolpidem is in an immediate release formulationwith adoseof 2 - 10 mg. 16.Themethodof clause14,wherein thezolpidem is in an extended release formulation with a dose of 5 - 12.5 mg. 17. The method of clause 1, wherein the 5-HT2A inverse agonist is AC‑90179, ketanserin, nelotan- serin, eplivanserin, pimavanserin, or volinanserin; or the 5-HT2A antagonist is trazodone, mirtazapine, ketanserin, clozapine, olanzapine, quetiapine, ris- peridone, iloperidone, perospirone, asenapine, ne- fazodone, MDL‑100,907, cyproheptadine, pizotifen, LY‑367,265, 2-alkyl‑4-aryl-tetrahydro-pyrimido-aze- pines, haloperidol, chlorpromazine, hydroxyzine (Atarax), 5-MeO-NBpBrT, or Niaprazine. 18. The method of clause 17, wherein the 5-HT2A inverse agonist or antagonist is pimvanserin, pre- ferably administered at a dose of 20‑40 mg, prefer- ably by 34 mg. 19. The method of any one of clauses 1‑18, wherein the disease or disorder is Obstructive Sleep Apnea or Simple Snoring. 20. The method of clause 19, wherein the disease or disorder is Obstructive Sleep Apnea. 21. The method of clause 1, wherein the non-fully conscious state is sleep. 22. The method of clause 1, wherein the NRI and the non myorelaxing hypnotic are administered in a sin- gle composition. 23. The method of clause 22, wherein the single composition is an oral administration form. 24. The method of clause 23, wherein the oral ad- ministration form is a syrup, pill, tablet, troche, or capsule. 5 10 15 20 25 30 35 40 45 50 55 15 25 EP 4 635 514 A2 26 25. A pharmaceutical composition comprising (i) a norepinephrine reuptake inhibitor (NRI), (ii) a non myorelaxing hypnotic and / or 5-HT2A inverse ago- nist or antagonist, and (iii) a pharmaceutically ac- ceptable carrier. 26. The composition of clause 25, wherein the NRI is a norepinephrine selective reuptake inhibitor (NSRI). 27. The composition of clause 26, wherein the NSRI is selected from the group consisting of Amedalin, Atomoxetine, CP‑39,332, Daledalin, Edivoxetine, Esreboxetine, Lortalamine, Nisoxetine, Reboxetine, Talopram, Talsupram, Tandamine, and Viloxazine. 28. The composition of clause 25, wherein the NRI is a norepinephrine non-selective reuptake inhibitor (NNRI) selected from the group consisting of Ami- triptiline, Amoxapine, Bupropion, Ciclazindol, Desi- pramine, Desvenlafaxine, Dexmethilphenidate, Diethylpropion, Doxepin, Duloxetine, Imipramine, Levomilnacipran, Manifaxine, Maprotiline, Methyl- phenidate, Milnacipran, Nefazodone, Nortriptyline, Phendimetrazine, Phenmetrazine, Protryptyline, Radafaxine, Tapentadol (Nucynta), Teniloxazine (Lucelan, Metatone) and Venlafaxine. 29. The composition of clause 25, wherein the NRI is selected from the group consisting of Atomoxetine and Reboxetine. 30. The composition of clause 29, wherein the NRI is Atomoxetine. 31. The composition of clause 30, wherein the do- sage of Atomoxetine is 20 - 100 mg. 32. The composition of clause 25, wherein the non myorelaxing hypnotic is a benzodiazepine hypnotic, preferably temazepam, brotizolam, flurazepam, ni- trazepam, or triazolam. 33.The composition of clause 25, wherein the non myorelaxing hypnotic is a non-benzodiazepine hyp- notic, preferably a cyclopyrrolone hypnotic, prefer- ably selected from the group consisting of zolpidem, zopiclone, and eszopiclone; gabapentin; trazodone; diphenhydramine; suvorexant; tasimelteon; ramel- teon; agomelatine; doxepin; zaleplon; doxylamine; sodium oxybate; or tiagabine 34. The composition of clause 25, wherein the non myorelaxing hypnotic is in an immediate release formulation. 35. The composition of clause 25, wherein the non myorelaxing hypnotic is in an extended release for- mulation. 36. The composition of any one of clauses 25‑35, wherein the non myorelaxing hypnotic is zolpidem. 37. The composition of clause 36, wherein the zol- pidem is in an immediate release formulation with a dose of 2 - 10 mg. 38. The composition of clause 36, wherein the zol- pidem is in an extended release formulation with a dose of 5 - 12.5 mg. 39. The composition of clause 25, wherein the NRI and thenonmyorelaxinghypnotic are formulated ina single composition. 40. The composition of clause 39, wherein the single composition is an oral administration form. 41. The composition of clause 40, wherein the oral administration form isapill, tablet, troche,or capsule. 42. The composition of any one of clauses 25‑41, for use in treating a subject having a condition asso- ciated with pharyngeal airway collapse while the subject is in a non-fully conscious state. 43.Thecomposition for theuseof clause42,wherein the disease or disorder is sleep apnea or Simple Snoring. 44.Thecomposition for theuseof clause43,wherein the disease or disorder is Obstructive Sleep Apnea. 45.Thecomposition for theuseof clause42,wherein the non-fully conscious state is sleep. 46. A norepinephrine reuptake inhibitor (NRI) and a non myorelaxing hypnotic and / or 5-HT2A inverse agonist or antagonist, for use in treating a subject having a condition associated with pharyngeal air- way collapse while the subject is in a non-fully con- scious state. 47. A kit comprising a norepinephrine reuptake in- hibitor (NRI) and a non myorelaxing hypnotic and / or 5-HT2A inverse agonist or antagonist. 48. The kit of clause 47, for use in treating a subject having a condition associated with pharyngeal air- way collapse while the subject is in a non-fully con- scious state. Claims 1. A norepinephrine reuptake inhibitor (NRI) and a non 5 10 15 20 25 30 35 40 45 50 55 16 27 EP 4 635 514 A2 28 myorelaxing hypnotic for use in a method of treating a subject having a condition associated with phar- yngeal airway collapse while the subject is in a non- fully conscious state, the method comprising admin- istering to a subject in need thereof an effective amount of a norepinephrine reuptake inhibitor (NRI) and a non myorelaxing hypnotic. 2. The NRI and non myorelaxing hypnotic for use of claim 1, wherein the NRI is a norepinephrine selec- tive reuptake inhibitor (NSRI), optionally wherein the NSRI is selected from the group consisting of Ame- dalin, Atomoxetine, CP‑39,332, Daledalin, Edivox- etine, Esreboxetine, Lortalamine, Nisoxetine, Re- boxetine, Talopram, Talsupram, Tandamine, and Vi- loxazine. 3. The NRI and non myorelaxing hypnotic for use of claim 1, wherein the NRI is Atomoxetine, optionally wherein theAtomoxetine is administeredat a doseof 20 - 100 mg. 4. The NRI and non myorelaxing hypnotic for use of claim 2, wherein the NRI is Viloxazine. 5. TheNRIandnonmyorelaxing hypnotic for useof any one of claims 1‑4, wherein the non myorelaxing hypnotic is a benzodiazepine hypnotic, preferably temazepam, brotizolam, flurazepam, nitrazepam, or triazolam orwherein the non myorelaxing hypnotic is a non-benzodiazepine hypnotic, preferably a cyclo- pyrrolone hypnotic, preferably selected from the group consisting of zolpidem, zopiclone, and eszo- piclone; gabapentin; trazodone; diphenhydramine; suvorexant; tasimelteon; ramelteon; agomelatine; doxepin; zaleplon; doxylamine; sodium oxybate; or tiagabine. 6. The NRI and non myorelaxing hypnotic for use of claim 5, wherein the non myorelaxing hypnotic is zolpidem, optionally wherein the zolpidem is admi- nistered at a dose of 2 - 12.5 mg. 7. The NRI and non myorelaxing hypnotic for use of claim 5, wherein the non myorelaxing hypnotic is a non-benzodiazepine hypnotic, optionally wherein the non-benzodiazepine hypnotic is trazodone. 8. TheNRIandnonmyorelaxing hypnotic for useof any one of claims 1‑7, wherein the disease or disorder is Obstructive Sleep Apnea or Simple Snoring, option- ally wherein the disease or disorder is Obstructive Sleep Apnea, and optionally wherein the non-fully conscious state is sleep. 9. TheNRIandnonmyorelaxing hypnotic for useof any one of claims 1‑8, wherein the NRI and the non myorelaxing hypnotic are administered in a single composition, optionally wherein the single composi- tion is an oral administration form, and optionally wherein the oral administration form is a syrup, pill, tablet, troche, or capsule. 10. A pharmaceutical composition comprising (i) a nor- epinephrine reuptake inhibitor (NRI), (ii) a non myor- elaxing hypnotic, and (iii) a pharmaceutically accep- table carrier. 11. The composition of claim 10, wherein the NRI is Atomoxetine. 12. The composition of claim 10, wherein the NRI is a norepinephrine selective reuptake inhibitor (NSRI), optionally wherein the NSRI is Viloxazine. 13. The composition of any one of claims 10‑12, wherein the non myorelaxing hypnotic is zolpidem. 14. The composition of any one of claims 10‑12, wherein the non myorelaxing hypnotic is a non-benzodiaze- pine hypnotic, optionally wherein the non-benzodia- zepine hypnotic is trazodone. 15. The composition of any one of claims 10‑14, for use in treating obstructive sleep apnea. 5 10 15 20 25 30 35 40 45 50 55 17 EP 4 635 514 A2 18 EP 4 635 514 A2 19 EP 4 635 514 A2 20 EP 4 635 514 A2 21 EP 4 635 514 A2 22 EP 4 635 514 A2 23 EP 4 635 514 A2 24 EP 4 635 514 A2 REFERENCES CITED IN THE DESCRIPTION This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. 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[0095] 摘要 用於治療與咽部氣道肌肉塌陷相關的疾病（例如睡眠呼吸暫停和打鼾）的方法和組合 物，適用於處於非完全意識狀態的受試者，包括給予（i）去甲腎上腺素再攝取抑制劑 （NRI）和（ii）非肌肉鬆弛催眠藥和 / 或 5-HT2A 反向激動劑或拮抗劑。

Claims

1. A norepinephrine reuptake inhibitor (NRI) and a non myorelaxing hypnotic for use in a method of treating a subject having a condition associated with pharyngeal airway collapse while the subject is in a non-fully conscious state, the method comprising administering to a subject in need thereof an effective amount of a norepinephrine reuptake inhibitor (NRI) and a non myorelaxing hypnotic.

2. The NRI and non myorelaxing hypnotic for use of claim 1, wherein the NRI is a norepinephrine selective reuptake inhibitor (NSRI), optionally wherein the NSRI is selected from the group consisting of Amedalin, Atomoxetine, CP-39,332, Daledalin, Edivoxetine, Esreboxetine, Lortalamine, Nisoxetine, Reboxetine, Talopram, Talsupram, Tandamine, and Viloxazine.

3. The NRI and non myorelaxing hypnotic for use of claim 1, wherein the NRI is Atomoxetine, optionally wherein the Atomoxetine is administered at a dose of 20 - 100 mg.

4. The NRI and non myorelaxing hypnotic for use of claim 2, wherein the NRI is Viloxazine.

5. The NRI and non myorelaxing hypnotic for use of any one of claims 1-4, wherein the non myorelaxing hypnotic is a benzodiazepine hypnotic, preferably temazepam, brotizolam, flurazepam, nitrazepam, or triazolam or wherein the non myorelaxing hypnotic is a non-benzodiazepine hypnotic, preferably a cyclopyrrolone hypnotic, preferably selected from the group consisting of zolpidem, zopiclone, and eszopiclone; gabapentin; trazodone; diphenhydramine; suvorexant; tasimelteon; ramelteon; agomelatine; doxepin; zaleplon; doxylamine; sodium oxybate; or tiagabine.

6. The NRI and non myorelaxing hypnotic for use of claim 5, wherein the non myorelaxing hypnotic is zolpidem, optionally wherein the zolpidem is administered at a dose of 2 - 12.5 mg.

7. The NRI and non myorelaxing hypnotic for use of claim 5, wherein the non myorelaxing hypnotic is a non-benzodiazepine hypnotic, optionally wherein the non-benzodiazepine hypnotic is trazodone.

8. The NRI and non myorelaxing hypnotic for use of any one of claims 1-7, wherein the disease or disorder is Obstructive Sleep Apnea or Simple Snoring, optionally wherein the disease or disorder is Obstructive Sleep Apnea, and optionally wherein the non-fully conscious state is sleep.

9. The NRI and non myorelaxing hypnotic for use of any one of claims 1-8, wherein the NRI and the non myorelaxing hypnotic are administered in a single composition, optionally wherein the single composition is an oral administration form, and optionally wherein the oral administration form is a syrup, pill, tablet, troche, or capsule.

10. A pharmaceutical composition comprising (i) a norepinephrine reuptake inhibitor (NRI), (ii) a non myorelaxing hypnotic, and (iii) a pharmaceutically acceptable carrier.

11. The composition of claim 10, wherein the NRI is Atomoxetine.

12. The composition of claim 10, wherein the NRI is a norepinephrine selective reuptake inhibitor (NSRI), optionally wherein the NSRI is Viloxazine.

13. The composition of any one of claims 10-12, wherein the non myorelaxing hypnotic is zolpidem.

14. The composition of any one of claims 10-12, wherein the non myorelaxing hypnotic is a non-benzodiazepine hypnotic, optionally wherein the non-benzodiazepine hypnotic is trazodone.

15. The composition of any one of claims 10-14, for use in treating obstructive sleep apnea.

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