Methods and compositions for treating sleep apnea

Abstract

Pharmaceutical compositions comprising (i) a P2X3 receptor antagonist and (ii) a carbonic anhydrase inhibitor (CAI), and methods of treating sleep apnea and conditions associated with pharyngeal airway collapse are described herein.

Description

Attorney Docket No.277901-567842 METHODS AND COMPOSITIONS FOR TREATING SLEEP APNEA CROSS-REFERENCE TORELATEDAPPLICATION

[0001] This application claims priority to U.S. provisional patent application no.63 / 656,395, filed June 5, 2024, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0002] The present invention provides pharmaceutical compositions comprising (i) a P2X3 receptor antagonist and (ii) a carbonic anhydrase inhibitor, and related methods of treating sleep apnea. 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. The National Commission on Sleep Disorders Research identified sleep disorders as a major public health burden. OSA is the most common and serious of these sleep disorders and affects millions of people in the United States (US). OSA is characterized by repetitive collapse or ‘obstruction’ of the pharyngeal airway during sleep, manifesting as repetitive episodes of hypopnea (i.e., shallow breathing) or apnea (i.e., paused breathing). These episodes of hypopnea or apnea may lead to arousal from sleep, sleep fragmentation, excessive daytime sleepiness, and / or neuropsychological impairment.

[0004] Research has shown that a number of pathogenic factors, or traits, contribute to the development of OSA. The most important factors are the presence of an anatomically small, collapsible upper airway, a loss of pharyngeal muscle tone or responsiveness and an increased ventilatory instability during sleep.

[0005] Central sleep apnea (CSA) is common, although less prevalent in the general population than OSA. It is a disorder characterized by repetitive cessation or decrease of both airflow and ventilatory effort during sleep. CSA is often associated with other medical conditions, especially heart failure, atrial fibrillation, and cerebrovascular diseases. Patients with CSA typically present with symptoms of disrupted sleep, such as fatigue, excessive daytime sleepiness, poor subjective 1 60678557.3Attorney Docket No.277901-567842 sleep quality, insomnia, inattention, and poor concentration. The prevalence of CSA syndrome is greater among adults who are older than 65 years than among younger adults. This may reflect the higher frequency of comorbid conditions that influence breathing during sleep among older adults. Long-term OSA and CSA are associated with increased mortality and a number of adverse cardiovascular, neurocognitive, metabolic, and daytime functioning consequences.

[0006] In the Sleep Health Heart Study, a population-based study that included 5804 community-dwelling adults aged 40 years and older, the overall prevalence of CSA on polysomnography (PSG) was 0.9%, while 2.7% had predominant OSA with a CSA component. While continuous positive airway pressure (CPAP) and related mechanical therapies improve sleep characteristics and address oxygenation issues caused by upper airway obstruction, patients with CSA (or mixed OSA and CSA) often find incomplete relief with CPAP alone. For example, patients with high-loop gain (high-LG) sleep apnea, even when most events are obstructive, often show treatment-emergent central sleep apneas when treatment with PAP is started. CPAP is not designed to treat central sleep apneas, and the central sleep apneas consequently increase sleep fragmentation and decrease compliance with PAP. The central sleep apneas may require ventilatory pressure support from more sophisticated devices such as Bilevel PAP (BPAP) or adaptive servo ventilation (ASV), but outcomes vary. Recently, ASV devices have been contraindicated for treating a specific subpopulation of patients with heart failure and low ejection fraction. This decision stems from recent negative trials, one of which demonstrated harm.

[0007] Moreover, many patients, perhaps most, find these devices uncomfortable or intolerable, and most estimates indicate that fewer than 50% of patients prescribed PAP use it more than 4 hours per night, if at all. Efforts to develop pharmacologic therapies, such as antidepressants, stimulants, and hormonal agents, for the treatment of OSA have been ongoing for at least 20 years, with no approved therapies thus far.

[0008] As many patients with OSA and CSA cannot use PAP because they find it intolerable, or because it lacks efficacy, this represents a significant health concern; OSA and CSA are associated with numerous co-morbidities and increased mortality and alternative options, such as drugs that stabilize breathing and prevent obstructive and central sleep apneas are needed. 2 60678557.3Attorney Docket No.277901-567842 SUMMARY

[0009] 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 (i) a P2X3 receptor antagonist (ii) a carbonic anhydrase inhibitor (CAI).

[0010] Another aspect of the present invention provides a method of treating sleep apnea comprising administering to a subject in need thereof an effective amount of (i) a P2X3 receptor antagonist (ii) a carbonic anhydrase inhibitor (CAI).

[0011] Another aspect of the present invention provides a method of treating central sleep apnea (CSA) comprising administering to a subject in need thereof an effective amount of (i) a P2X3 receptor antagonist (ii) a carbonic anhydrase inhibitor (CAI).

[0012] Another aspect of the present invention provides a method of treating mixed OSA and CSA comprising administering to a subject in need thereof an effective amount of (i) a P2X3 receptor antagonist (ii) a carbonic anhydrase inhibitor (CAI).

[0013] Embodiments of these aspects of the invention may include one or more of the following optional features.

[0014] In some embodiments, the P2X3 receptor antagonist is selected from the group consisting of sivopixant, gefapixant, filapixant (BAY1902607), camlipixant, eliapixant (BAY1817080), relicpixant(QR052107B), AF-130, WT-1-2.0, AF-220, AF-221, AF-353, TCR1672, HS-10383, WT-1108, ASN-009, FA-006, P2X3, AZ-1, AZ-2, GA-8SMOL-PAIN, HRS-2261, 12D4, NEO-5024, OSX-300, OSX-300 Backups, piromelatine, RO-85, TDI-06, A- 317491, and any combination thereof, including pharmaceutically acceptable salts thereof. In some embodiments, the P2X3 receptor antagonist is selected from the group consisting of sivopixant, gefapixant, filapixant, camlipixant, eliapixant, relicpixant, AF-130, TCR1672, HS- 10383, and any combination thereof, including pharmaceutically acceptable salts thereof. In some embodiments, the P2X3 receptor antagonists is sivopixant or a pharmaceutically acceptable salt thereof. In some embodiments, P2X3 receptor antagonist is sivopixant or a pharmaceutically acceptable salt thereof and is administered at a dose of from about 100 mg to about 600 mg. In some embodiments, P2X3 receptor antagonist is sivopixant or a pharmaceutically acceptable salt thereof and is administered at a dose of from about 250 mg to about 500 mg. In some embodiments, P2X3 receptor antagonist is sivopixant or a pharmaceutically acceptable salt 3 60678557.3Attorney Docket No.277901-567842 thereof and is administered at a dose of from about 150 mg to about 450 mg. In some embodiments, P2X3 receptor antagonist is sivopixant or a pharmaceutically acceptable salt thereof and is administered at a dose of 150 mg. In some embodiments, P2X3 receptor antagonist is sivopixant or a pharmaceutically acceptable salt thereof and is administered at a dose of 300 mg. In some embodiments, P2X3 receptor antagonist is sivopixant or a pharmaceutically acceptable salt thereof and is administered at a dose of 450 mg.

[0015] In some embodiments, the CAI is selected from the group consisting of acetazolamide, dichlorophenamide, dorzolamide, brinzolamide, methazolamide, zonisamide, ethoxzolamide, topiramate, xipamide, sultiame, and any combination thereof, including pharmaceutically acceptable salts thereof. In some embodiments, the CAI is acetazolamide or a pharmaceutically acceptable salt thereof. In some embodiments, the CAI is sultiame or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, the CAI is acetazolamide or a pharmaceutically acceptable salt thereof and is administered at a dosage of from about 250 mg to about 750 mg. In some embodiments, the acetazolamide or pharmaceutically acceptable salt thereof is administered at a dosage of about 500 mg.

[0017] In some embodiments, the CAI is sultiame or a pharmaceutically acceptable salt thereof and is administered at a dosage of from about 25 mg to about 500 mg. In some embodiments, the sultiame or pharmaceutically acceptable salt thereof is administered at a dosage of from about 100 mg to about 400 mg. In some embodiments, the sultiame or pharmaceutically acceptable salt thereof is administered at a dosage of from about 200 to about 300 mg. In some embodiments, the sultiame or pharmaceutically acceptable salt thereof is administered at a dosage of from about 200 mg to about 250 mg. In some embodiments, the sultiame or pharmaceutically acceptable salt thereof is administered at a dosage of 200 mg. In some embodiments, the sultiame or pharmaceutically acceptable salt thereof is administered at a dosage of 250 mg. In some embodiments, the sultiame or pharmaceutically acceptable salt thereof is administered at a dosage of 300 mg. In some embodiments, the sultiame or pharmaceutically acceptable salt thereof is administered at a dosage of 400 mg.

[0018]

[0019] In some embodiments, the P2X3 receptor antagonist and CAI are administered in the absence of an antimuscarinic therapy. In some embodiments, the P2X3 receptor antagonist and 4 60678557.3Attorney Docket No.277901-567842 CAI are administered in the absence of a hypnotic therapy. In some embodiments, the P2X3 receptor antagonist and CAI are the only active agents administered in the method of treatment. In some embodiments, the P2X3 receptor antagonist and CAI 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.

[0020] In some embodiments, the condition associated with pharyngeal airway collapse is sleep apnea. In some embodiments, the condition associated with pharyngeal airway collapse is 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 condition associated with pharyngeal airway collapse is central sleep apnea (CSA). In some embodiments, the condition associated with pharyngeal airway collapse is complex sleep apnea. In some embodiments, the condition associated with pharyngeal airway collapse is sleep apnea with a central component. In some embodiments, the condition associated with pharyngeal airway collapse is mixed OSA and CSA. In some embodiments, the condition associated with pharyngeal airway collapse is high-LG sleep apnea. In some embodiments, the subject is in a non-fully conscious state. In some embodiments, the non-fully conscious state is sleep.

[0021] In some embodiments, the method of treating sleep apnea is a method of treating obstructive sleep apnea (OSA). In some embodiments, the method of treating sleep apnea is a method of treating central sleep apnea (CSA). In some embodiments, the method of treating sleep apnea is a method of treating complex sleep apnea. In some embodiments, the method of treating sleep apnea is a method of treating sleep apnea with a central component. In some embodiments, the method of treating sleep apnea is a method of treating mixed OSA and CSA. In some embodiments, the method of treating sleep apnea is a method of treating high-LG sleep apnea.

[0022] In some embodiments, the method of treatment reduces the subject’s AHI4 from baseline by at least about 42%. In some embodiments, the method of treatment reduces the subject’s AHI4 from baseline by at least about 52%.

[0023] Another aspect of the present invention provides a pharmaceutical composition comprising (i) P2X3 receptor antagonist and (ii) a CAI, and (iii) a pharmaceutically acceptable carrier. 5 60678557.3Attorney Docket No.277901-567842

[0024] Embodiments of this aspect of the invention may include one or more of the following optional features.

[0025] In some embodiments, the P2X3 receptor antagonist is selected from the group consisting of sivopixant, gefapixant, filapixant (BAY1902607), camlipixant, eliapixant (BAY1817080), relicpixant(QR052107B), AF-130, WT-1-2.0, AF-220, AF-221, AF-353, TCR1672, HS-10383, WT-1108, ASN-009, FA-006, P2X3, AZ-1, AZ-2, GA-8SMOL-PAIN, HRS-2261, 12D4, NEO-5024, OSX-300, OSX-300 Backups, piromelatine, RO-85, TDI-06, A- 317491, and any combination thereof, including pharmaceutically acceptable salts thereof. In some embodiments, the P2X3 receptor antagonist is selected from the group consisting of sivopixant, gefapixant, filapixant, camlipixant, eliapixant, relicpixant, AF-130, TCR1672, HS- 10383, and any combination thereof, including pharmaceutically acceptable salts thereof. In some embodiments, the P2X3 receptor antagonist is sivopixant or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, the CAI is selected from the group consisting of acetazolamide, dichlorophenamide, dorzolamide, brinzolamide, methazolamide, zonisamide, ethoxzolamide, topiramate, xipamide, sultiame, and any combination thereof, including pharmaceutically acceptable salts thereof. In some embodiments, the CAI is acetazolamide or a pharmaceutically acceptable salt thereof. In some embodiments, the CAI is sultiame or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, sivopixant or a pharmaceutically acceptable salt thereof is present in an amount of from about 100 mg to about 600 mg. In some embodiments, sivopixant or a pharmaceutically acceptable salt thereof is present in an amount of from about 250 mg to about 500 mg. In some embodiments, sivopixant or a pharmaceutically acceptable salt thereof is present in an amount of from about 150 mg to about 450 mg. In some embodiments, sivopixant or a pharmaceutically acceptable salt thereof is present in an amount of 150 mg. In some embodiments, sivopixant or a pharmaceutically acceptable salt thereof is present in an amount of 300 mg. In some embodiments, sivopixant or a pharmaceutically acceptable salt thereof is present in an amount of 450 mg.

[0028] In some embodiments, acetazolamide or a pharmaceutically acceptable salt thereof is present in an amount of from about 250 mg to about 750 mg. In some embodiments, 6 60678557.3Attorney Docket No.277901-567842 acetazolamide or a pharmaceutically acceptable salt thereof is present in an amount of about 500 mg.

[0029] In some embodiments, sultiame or a pharmaceutically acceptable salt thereof is present in an amount of from about 25 mg to about 500 mg. In some embodiments, sultiame or a pharmaceutically acceptable salt thereof is present in an amount of from about 100 mg to about 400 mg. In some embodiments, sultiame or a pharmaceutically acceptable salt thereof is present in an amount of from about 200 mg to about 300 mg. In some embodiments, sultiame or a pharmaceutically acceptable salt thereof is present in an amount of from about 200 mg to about 250 mg. In some embodiments, the sultiame or pharmaceutically acceptable salt thereof is present in an amount of 200 mg. In some embodiments, the sultiame or pharmaceutically acceptable salt thereof is present in an amount of 250 mg. In some embodiments, the sultiame or pharmaceutically acceptable salt thereof is present in an amount of 300 mg. In some embodiments, the sultiame or pharmaceutically acceptable salt thereof is present in an amount of 400 mg.

[0030] In some embodiments, the composition does not include an antimuscarinic agent. In some embodiments, the composition does not include a hypnotic. In some embodiments, the P2X3 receptor antagonist and CAI are the sole active agents in the pharmaceutical composition. In some embodiments, the P2X3 receptor antagonist and CAI are formulated 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.

[0031] In some embodiments, the pharmaceutical composition is for use in treating a subject having a condition associated with pharyngeal airway collapse. In some embodiments, the condition associated with pharyngeal airway collapse is sleep apnea. In some embodiments, the condition associated with pharyngeal airway collapse is 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 condition associated with pharyngeal airway collapse is central sleep apnea (CSA). In some embodiments, the condition associated with pharyngeal airway collapse is complex sleep apnea. In some embodiments, the condition associated with pharyngeal airway collapse is sleep apnea with a central component. In some embodiments, the condition associated with pharyngeal airway collapse is mixed OSA and CSA. In some embodiments, the condition associated with 7 60678557.3Attorney Docket No.277901-567842 pharyngeal airway collapse is high-LG sleep apnea. In some embodiments, the subject is in a non-fully conscious state. In some embodiments, the non-fully conscious state is sleep.

[0032] In some embodiments, the pharmaceutical composition is for use in treating sleep apnea. In some embodiments, the pharmaceutical composition is for use in treating obstructive sleep apnea (OSA). In some embodiments, the pharmaceutical composition is for use in treating central sleep apnea (CSA). In some embodiments, the pharmaceutical composition is for use in treating complex sleep apnea. In some embodiments, the pharmaceutical composition is for use in treating sleep apnea with a central component. In some embodiments, the pharmaceutical composition is for use in treating mixed OSA and CSA. In some embodiments, the pharmaceutical composition is for use in treating high-LG sleep apnea.

[0033] Provided herein is a P2X3 receptor antagonist and a CAI, for use in treating a subject having a condition associated with pharyngeal airway collapse. Also provided herein is a P2X3 receptor antagonist and a CAI, for use in treating sleep apnea

[0034] Further provided herein is a P2X3 receptor antagonist and a CAI, for use in the manufacture of a medicament for treating a subject having a condition associated with pharyngeal airway collapse. Also provided herein is a P2X3 receptor antagonist and a CAI, for use in the manufacture of a medicament for treating sleep apnea.

[0035] 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.

[0036] Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims. BRIEFDESCRIPTIONOFTHEDRAWINGS

[0037] The following figures are provided by way of example and are not intended to limit the scope of the claimed invention. 8 60678557.3Attorney Docket No.277901-567842

[0038] FIG.1 shows the study schematic described in Example 1.

[0039] FIG.2 is a chart showing the change in LG1 from baseline for placebo vs. sivopixant (S-918).

[0040] FIG.3 is a plot showing the change in AHI4 on sivopixant (S-918) vs. placebo as a function of the LGn baseline for each patient.

[0041] FIG.4 shows the study schematic described in Example 2. DETAILED DESCRIPTION

[0042] 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. 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 result of the diaphragm contracting against an occluded airway, forcing the abdominal wall to distend out and the chest wall to cave inward.

[0043] Increasing efforts to breathe lead to an arousal from sleep, visualisable on an EEG, 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 . 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, WR. et al., The new AASM criteria for scoring hypopneas: Impact on the apnea hypopnea index. SLEEP 2009;32(2):150-157).

[0044] 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, T. et al., WMJ 2009; 108:246; Peppard, PE. et al., Am J Epidemiol 2013; 177:1006.) 9 60678557.3Attorney Docket No.277901-567842

[0045] The present leading treatment is continuous positive airway pressure (CPAP). CPAP is effective in virtually all patients with OSA, 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, TE. 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.

[0046] Loop gain (LG) is an engineering concept that refers to the ratio of a corrective ventilatory response to a disturbance. If the response exceeds the disturbance (i.e., LG>1), then self-sustaining periodic breathing with central sleep apneas may result. Patients with OSA frequently exhibit "high LG" or "ventilatory instability" at baseline. In this scenario, minor disturbances, like mild hypopneas followed by arousals from sleep, trigger an exaggerated corrective ventilatory response (hyperpnea), leading to central apnea if the arterial carbon dioxide tension (PaCO2) drops below the apneic threshold. The central apnea, in turn, prompts a reciprocal corrective response, establishing a pattern of periodic breathing.

[0047] High LG plays a critical role in the pathophysiology of both OSA and CSA. Typically, patients with over 50% of central respiratory events are diagnosed with CSA, while those with a predominant occurrence of obstructive events are diagnosed with OSA. However, there is a significant overlap between these two disorders. CSA and OSA often coexist in patients with concurrent cardiovascular diseases, such as atrial fibrillation, chronic obstructive coronary disease and heart failure. These conditions are characterized by an increased sensitivity of peripheral chemoreceptors, associated with sympathetic hyperactivity.

[0048] 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., Hudgel, DA. et al., Chest.1991 Aug;100(2):416-21; Brownell LG. et al., N Engl J Med 1982, 307:1037-1042; Sangal RB. et al., Sleep Med.2008 Jul;9(5):506-10. Epub 2007 Sep 27; Marshall, NS. et al. Sleep 2008 Jun;31(6):824-31; Eckert, DJ. et al., Clin Sci (Lond).2011 Jun;120(12);505-14; Taranto-Montemurro, L. et al., Sleep 2017 Feb 1;40(2):ZSW047. There remains a need for further therapies for treating conditions associated with pharyngeal airway collapse such as sleep apnea. 10 60678557.3Attorney Docket No.277901-567842

[0049] 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, L. et al., The Combination of Atomoxetine and Oxybutynin Greatly Reduces Obstructive Sleep Apnea Severity. A Randomized, Placebo-controlled, Double-Blind Crossover Trial. Am J Respir Crit Care Med 2019 May 15;199(10):1267-1276.

[0050] There remains a need for further therapies for treating sleep apnea and conditions associated with pharyngeal airway collapse.

[0051] Sivopixant is a P2X3 receptor antagonist. The P2X3 receptor is mainly expressed in small-diameter primary afferents (C and Aδ fibers), which are associated with sensory reception and transmission. Previous research has established that P2X3 receptors in the carotid body undergo pathological upregulation in disease models relevant to OSA / CSA. This upregulation leads to hyperreflexia in chemoreceptive petrosal neurons and heightened activity of the sympathetic nervous system in spontaneously hypertensive rats. Pathological upregulation also occurs in petrosal chemoreceptive neurons in rats with heart failure, while the expression of other receptors, e.g., P2X2 receptors, that could form a heterodimeric receptor with P2X3 receptor, is not altered in heart failure. In experiments involving rats that developed heart failure and CSA following coronary artery occlusion, the administration of a P2X3 antagonist resulted in breathing stabilization and a reduction in Apnea-Hypopnea Index (AHI). Sivopixant (also called S-918) is the generic name of the pharmaceutical substance with the chemical name (2S)- 3-[3-[(4-chlorophenyl)methyl]-2,6-dioxo-4-(4-pyridin-2-yloxyanilino)-1,3,5-triazin-1-yl]-2- methylpropanoic acid, and its pharmaceutical salts. Sivopixant may be prepared in accordance with the International Publication Nos. WO2014 / 200078 and WO2021 / 054421.

[0052] Acetazolamide is a sulfonamide belonging to the CAI class and exerts its pharmacological effects through the inhibition of the carbonic anhydrase enzyme, especially at the kidney level, crucial for regulating acid-base balance and electrolyte transport. Acetazolamide is the generic name of the pharmaceutical substance with the chemical name N- 11 60678557.3Attorney Docket No.277901-567842 (5-Sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide, and its pharmaceutical salts. Acetazolamide is available as a generic medication as well as sold under the trade names Diamox, Dacarb, and others.

[0053] Acetazolamide is a respiratory stimulant used in healthy adults at high-altitude (where it augments and stabilizes respiration) and has additionally been administered safely to treat long- term for glaucoma and heart failure. Acetazolamide stimulates ventilation by reducing the reabsorption of bicarbonates in the kidneys. This leads to a transient metabolic acidosis and relative hyperventilation.

[0054] Sultiame (alternatively spelled as sulthiame) is a sulfonamide and inhibitor of the enzyme carbonic anhydrase. It is used as an anticonvulsant and in recent studies showed promise in reducing sleep disordered breathing and other symptoms of obstructive sleep apnea (OSA).

[0055] Previous phase 1 and 2 studies support that sivopixant is safe and well tolerated in single doses up to 1000 mg in healthy adult volunteers, and multiple doses up to 300 mg both in healthy adult volunteers and patients with OSA. In a previous phase 2 study in 31 patients with moderate to severe OSA, 300 mg of sivopixant administered before bed showed a small improvement in AHI. However, the development of sivopixant was suspended / discontinued following the study, due to no meaningful efficacy in patients with moderate to severe OSA.

[0056] Upon data analysis of the phase 2 study, among the entire efficacy analysis population, in patients with unstable breathing (12 cases), the sivopixant group showed improvement in apnea / hypopnea frequency (AHI4), suggesting efficacy, compared to the placebo group (p=0.0161)

[0057] Sivopixant is a highly selective antagonist of P2X3 receptors: Plasma concentration of Sivopixant 300mg and more doses reach over 90% inhibition in P2X3 and P2X2 / 3 receptor inhibition curve at Tmax. Sivopixant attenuates hypoxic chemoreflex: Sivopixant 15 and 50 mg / kg significantly decreased hypoxic ventilatory response in a dose-dependent manner in rats. Baseline ventilation was not affected by Sivopixant. Sivopixant’s impact on LG is attributed to its suppressive effect on peripheral chemosensitivity, leading to a reduced ventilatory response to hypoxia. The central component of chemoreflex, which regulates the slow responses to hypoxia and hypercapnia, is unlikely to be affected by sivopixant since this compound and its metabolites do not cross the blood-brain barrier. 12 60678557.3Attorney Docket No.277901-567842

[0058] Carbonic anhydrase inhibitors have a distinct and complementary mechanism of action on LG. Specifically, while sivopixant reduces the sensitivity of peripheral chemoreceptors (controller gain), the CAI primarily operates at the kidney level, stimulating ventilation through central and peripheral chemoreceptors and increasing the elimination of bicarbonates. CAIs, such as acetazolamide, generate transient metabolic acidosis and relative hyperventilation. The lower PCO2 from increased ventilation reduces PCO2 variations for a given change in ventilation (reduced plant gain). A reduction in plant gain (and consequentially in LG) reduces ventilatory control instability and improves CSA and OSA.

[0059] In patients with OSA, sivopixant has shown effectiveness in mitigating the instability of the ventilatory control system, commonly known as LG. See Fig.2. Sivopixant's impact on LG is attributed to its inhibitory effect on peripheral chemoreceptors, leading to a reduced fast response to hypoxia and hypercapnia. The slow, central response to hypoxia and hypercapnia is likely not affected by sivopixant, also because of its scarce permeability to the blood brain barrier.

[0060] Data analysis of the clinical trial data for sivopixant suggests that sivopixant will be most effective in individuals with high-LG sleep apnea. See Fig.3. Patients exhibiting CSA or a mixed pattern of central and obstructive sleep apnea tend to have higher LG compared to those experiencing OSA alone. Gefapixant has also been studied in OSA. There was almost no difference in AHI after administration of gefapixant compared to placebo (AHI ratio for placebo: 0.86; AHI ratio for gefapixant: 0.97) (ClinicalTrials.gov Identifier: NCT03882801).

[0061] Acetazolamide has been extensively studied in patients with sleep apnea, both CSA and OSA, showing a dose-dependent benefit on the severity of respiratory disorders during sleep, with maximal efficacy at approximately 500mg / day. Acetazolamide has been previously studied in patients with OSA, CSA, and both stable and decompensated heart failure, with favorable outcomes. A meta-analysis of acetazolamide in OSA and CSA concluded that short-term acetazolamide improved both OSA and CSA, but that rigorous studies with long-term follow up are warranted to assess acetazolamide’s value for the chronic treatment of patients with sleep apnea. Schmickl et al., Chest.2020 Dec;158(6):2632-2645. doi: 10.1016 / j.chest.2020.06.078. Epub 2020 Aug 5. Definitions 13 60678557.3Attorney Docket No.277901-567842

[0062] As used in this context, to “treat” means to ameliorate at least one symptom of sleep apnea or a 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).

[0063] 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.

[0064] 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 for effective treatment in 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.

[0065] 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, 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 14 60678557.3Attorney Docket No.277901-567842 overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0066] As used herein, an “antimuscarinic therapy” refers to the administration of an antimuscarinic agent. Antimuscarinic agents include but are not limited to atropine, propantheline, bethanechol, solifenacin, darifenacin, tolterodine, fesoterodine, trospium, oxybutynin, anisotropine, benztropine, biperiden, clidinium, cycrimine, dicyclomine, diphemanil, diphenidol, ethopropazine, glycopyrrolate, hexocyclium, isopropamide, mepenzolate, methixene, methscopolamine, oxyphencyclimine, oxyphenonium, procyclidine, scopolamine, tridihexethyl, and trihexyphenidyl. Subjects receiving treatment according to the present disclosure in the absence of an antimuscarinic therapy do not receive administration of an antimuscarinic agent.

[0067] 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.

[0068] 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.

[0069] “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. 15 60678557.3Attorney Docket No.277901-567842

[0070] “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.)

[0071] 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.

[0072] 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.

[0073] 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.

[0074] The following is a list of abbreviation found throughout the present disclosure. List of Abbreviations ^ AHI apnea-hypopnea index ^ AE adverse event ^ Bang Body mass index, Age, Neck circumference, and Gender criteria ^ BMI body mass index 16 60678557.3Attorney Docket No.277901-567842 ^ CFR Code of Federal Regulations ^ CNS central nervous system ^ CPAP continuous positive air pressure ^ CYP2D6 cytochrome P4502D6 ^ CYP3A4 cytochrome P4503A4 ^ DSM-5 Diagnostic and Statistical Manual of Mental Disorders, 5th edition ^ DSST Digit symbol substitution test ^ ECG electrocardiogram ^ EEG electroencephalogram ^ ESS Epworth Sleepiness Scale ^ eCRF electronic case report form(s) ^ EDC electronic data capture ^ EOS end of study ^ FSH follicle-stimulating hormone ^ GCP Good Clinical Practice ^ HB Hypoxic Burden ^ HRT hormone replacement therapy ^ ICF informed consent form ^ ICH International Conference on Harmonisation ^ IEC Independent Ethics Committee ^ IRB Institutional Review Board ^ ISI Insomnia Severity Index ^ OSA obstructive sleep apnea ^ OTC over-the-counter ^ MAOI monoamine oxidase inhibitor ^ PK pharmacokinetic(s) ^ PSG polysomnography ^ PVT Psychomotor vigilance test ^ QHS 1 dose every night at bedtime ^ SAE serious adverse event 17 60678557.3Attorney Docket No.277901-567842 ^ SAP Statistical Analysis Plan ^ SoA Schedule of Activities ^ STOP Snoring, Tiredness, Observed apnea, and Blood pressure criteria ^ SUSAR suspected unexpected serious adverse reaction ^ tcPCO2 transcutaneous PCO2 ^ ULN upper limit of normal ^ US United States ^ WOCBP woman of childbearing potential Methods of Treatment

[0075] The methods described herein include methods for the treatment of disorders associated with pharyngeal airway muscle collapse during sleep. The methods described herein also include methods for the treatment of sleep apnea. In some embodiments, the disorder is sleep apnea (e.g., obstructive sleep apnea (OSA), central sleep apnea (CSA), complex sleep apnea, sleep apnea with a central component, mixed OSA and CSA, or high-loop gain sleep apnea) or snoring (e.g., simple snoring). Generally, the methods include administering a therapeutically effective amount of (i) a P2X3 receptor antagonist (e.g., sivopixant or a pharmaceutically acceptable salt thereof), and (ii) a carbonic anhydrase inhibitor (e.g., acetazolamide or a pharmaceutically acceptable salt thereof or sultiame or a pharmaceutically acceptable salt thereof), to a subject who is in need of, or who has been determined to be in need of, such treatment.

[0076] In certain embodiments, the methods include administering an effective amount of (i) sivopixant or a pharmaceutically acceptable salt thereof and (ii) acetazolamide or a pharmaceutically acceptable salt thereof, to a subject who is in need of, or who has been determined to be in need of, such treatment.

[0077] In certain embodiments, the methods include administering an effective amount of (i) sivopixant or a pharmaceutically acceptable salt thereof and (ii) sultiame or a pharmaceutically acceptable salt thereof, to a subject who is in need of, or who has been determined to be in need of, such treatment.

[0078] In some embodiments, the subject being treated has been diagnosed as having CSA. In some embodiments, the subject being treated has been diagnosed as having OSA and / or CSA, 18 60678557.3Attorney Docket No.277901-567842 and with high-LG. In some embodiments, the subject being treated has been diagnosed as having OSA and / or CSA, and with cardiovascular disease.

[0079] In some embodiments, the methods include administering a dose of sivopixant or a pharmaceutically acceptable salt thereof from about 50 mg to about 1,000 mg. In some embodiments, the methods include administering a dose of sivopixant or a pharmaceutically acceptable salt thereof from about 100 mg to about 600 mg. In some embodiments, the dose of sivopixant or a pharmaceutically acceptable salt thereof is from about 250 mg to about 500 mg. In some embodiments, the dose of sivopixant or a pharmaceutically acceptable salt thereof is from about 300 mg to 450 mg. In some embodiments, the dose of sivopixant or a pharmaceutically acceptable salt thereof is from about 100 mg to about 300 mg. In some embodiments, the dose of sivopixant or a pharmaceutically acceptable salt thereof is from about 300 mg to about 600 mg. In some embodiments, the dose of sivopixant or a pharmaceutically acceptable salt thereof is from about 400 mg to about 600 mg. In some embodiments, the dose of sivopixant or a pharmaceutically acceptable salt thereof is from about 200 mg to about 400 mg. In some embodiments, the dose of sivopixant or a pharmaceutically acceptable salt thereof is from about 150 mg to about 450 mg. In some embodiments, the dose of sivopixant or a pharmaceutically acceptable salt thereof is about 150 mg. In some embodiments, the dose of sivopixant or a pharmaceutically acceptable salt thereof is about 300 mg. In some embodiments, the dose of sivopixant or a pharmaceutically acceptable salt thereof is about 450 mg.

[0080] In some embodiments, the methods include administering a dose of from about 50 mg to about 1000 mg acetazolamide or a pharmaceutically acceptable salt thereof (or a dose equivalent thereof of another CAI). In some embodiments, the dose of acetazolamide or a pharmaceutically acceptable salt thereof is from about 100 mg to about 800 mg. In some embodiments, the dose of acetazolamide or a pharmaceutically acceptable salt thereof is from about 250 mg to about 750 mg. In some embodiments, the dose of acetazolamide or a pharmaceutically acceptable salt thereof is from about 500 mg to about 750 mg. In some embodiments, the dose of acetazolamide or a pharmaceutically acceptable salt thereof is from about 450 mg to about 650 mg. In some embodiments, the dose of acetazolamide or a pharmaceutically acceptable salt thereof is about 500 mg.

[0081] In some embodiments, the methods include administering a dose of from about 25 mg to about 500 mg sultiame or a pharmaceutically acceptable salt thereof (or a dose equivalent 19 60678557.3Attorney Docket No.277901-567842 thereof of another CAI). In some embodiments, the dose of sultiame or a pharmaceutically acceptable salt thereof is from about 100 mg to about 400 mg. In some embodiments, the dose of sultiame or a pharmaceutically acceptable salt thereof is from about 200 mg to about 300 mg. In some embodiments, the dose of sultiame or a pharmaceutically acceptable salt thereof is from about 200 mg to about 250 mg. In some embodiments, the dose of sultiame or a pharmaceutically acceptable salt thereof is about 200 mg. In some embodiments, the dose of sultiame or a pharmaceutically acceptable salt thereof is about 250 mg. In some embodiments, the dose of sultiame or a pharmaceutically acceptable salt thereof is about 300 mg. In some embodiments, the dose of sultiame or a pharmaceutically acceptable salt thereof is about 400 mg.

[0082] In some embodiments, the (i) P2X3 receptor antagonist (ii) carbonic anhydrase inhibitor, are the sole active agents administered in the methods described herein (e.g., without another active agent, such as a hypnotic, an antimuscarinic agent and / or a complementary medicament or sleep aid). In some embodiments, (i) sivopixant or a pharmaceutically acceptable salt thereof and (ii) acetazolamide or a pharmaceutically acceptable salt thereof, are the sole active agents administered in the methods described herein (e.g., without another active agent, such as a hypnotic, an antimuscarinic agent and / or a complementary medicament or sleep aid). In some embodiments, (i) sivopixant or a pharmaceutically acceptable salt thereof and (ii) sultiame or a pharmaceutically acceptable salt thereof, are the sole active agents administered in the methods described herein (e.g., without another active agent, such as a hypnotic, an antimuscarinic agent and / or a complementary medicament or sleep aid). In some embodiments, the method includes an additional therapy with an additional active agent.

[0083] In some embodiments, the patient treated according to the present methods has an average ODI4 between 7 and 55 events per hour, inclusive and average SpO2 greater than or equal to 88% from continuous home pulse oximetry recordings at screening. In some embodiments, the patient has an AHI4 of greater than 10 and less than or equal to 60 events per hour. In some embodiments, the patient has at minimum, 25% central or mixed apnea (as proportion of total apneas) with a minimum of 2.5 central or mixed apneas per hour of sleep. In some embodiments, the patient has evidence of clear Cheyne-Stokes breather pattern during the baseline PSG (regardless of central apnea component). In some embodiments, the patient has evidence of OSA with loop gain at natural frequency (LGn) > 0.5 at the baseline PSG (regardless of central apnea component). In some embodiments, the patient has average SpO2during sleep 20 60678557.3Attorney Docket No.277901-567842 of greater than or equal to 88%. In some embodiments, the patient has a BMI between 18.5 and 40 kg / m2for men and between 18.5 and 42 kg / m2for women. In some embodiments, the patient has one or more of the following comorbidities: stable heart failure with reduced ejection fraction (NYHA class 1-3 inclusive) with or without atrial fibrillation; heart failure with preserved ejection fraction (NYHA class 1-3 inclusive) and hypertension (BP>120 / 80 mmHg at screening visit despite treatment with greater than or equal to 2 antihypertensives) with or without atrial fibrillation; persistent atrial fibrillation (continuous and sustained for more than 7 days, rate controlled with resting heart rate < 100 bpm) without heart failure; history of primary (essential) hypertension with BP at screening visit > 130 / 80 mmHg despite the treatment with 2 or more antihypertensives; evidence of complex sleep apnea (CPAP-emergent central sleep apnea with documented central apnea index > 5 events / h on CPAP within 1 year from screening). Pharmaceutical Compositions

[0084] Also provided herein are pharmaceutical compositions comprising (i) a P2X3 receptor antagonist and (ii) a carbonic anhydrase inhibitor (CAI). The active ingredients can be in a single composition or in separate compositions. In certain embodiments, the pharmaceutical compositions include (i) sivopixant or a pharmaceutically acceptable salt thereof and (ii) acetazolamide or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical compositions include (i) sivopixant or a pharmaceutically acceptable salt thereof and (ii) sultiame or a pharmaceutically acceptable salt thereof.

[0085] Exemplary P2X3 receptor antagonists include sivopixant, gefapixant, filapixant (BAY1902607), camlipixant, eliapixant (BAY1817080), relicpixant(QR052107B), AF-130, WT- 1-2.0, AF-220, AF-221, AF-353, TCR1672, HS-10383, WT-1108, ASN-009, FA-006, P2X3, AZ-1, AZ-2, GA-8SMOL-PAIN, HRS-2261, 12D4, NEO-5024, OSX-300, OSX-300 Backups, piromelatine, RO-85, TDI-06, and A-317491, including pharmaceutically acceptable salts thereof.

[0086] In some embodiments, the P2X3 receptor antagonist is sivopixant or a pharmaceutically acceptable salt thereof. In some embodiments, the P2X3 receptor antagonist is gefapixant or a pharmaceutically acceptable salt thereof. In some embodiments, the P2X3 receptor antagonist is gefapixant citrate. 21 60678557.3Attorney Docket No.277901-567842

[0087] Exemplary CAIs include acetazolamide, dichlorophenamide, dorzolamide, brinzolamide, methazolamide, zonisamide, ethoxzolamide, topiramate, xipamide, and sultiame, including pharmaceutically acceptable salts thereof.

[0088] In some embodiments, the carbonic anhydrase inhibitor is acetazolamide or a pharmaceutically acceptable salt thereof. In some embodiments, the carbonic anhydrase inhibitor is sultiame or a pharmaceutically acceptable salt thereof.

[0089] Pharmaceutical compositions typically include a pharmaceutically acceptable carrier. As used herein the language "pharmaceutically acceptable carrier" includes saline, solvents, dispersion media, diluents, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.

[0090] Pharmaceutical compositions are typically formulated to be compatible with its intended route of administration. Examples of routes of administration include systemic oral, transdermal administration, and parenteral administration.

[0091] Methods of formulating suitable pharmaceutical compositions using pharmaceutically acceptable carriers 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 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. 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.

[0092] 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. In some 22 60678557.3Attorney Docket No.277901-567842 embodiments, a composition may be prepared in accordance with the International Publication No. WO2021 / 230308.

[0093] 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.

[0094] 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.

[0095] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration or use in a method described herein.

[0096] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration or use in a method described herein.

[0097] In some embodiments, the pharmaceutical composition does not contain an antimuscarinic agent. In some embodiments, the pharmaceutical composition does not contain a hypnotic.

[0098] In some embodiments, the (i) P2X3 receptor antagonist and (ii) carbonic anhydrase inhibitor, are the sole active agents present in the pharmaceutical composition. In some embodiments, (i) sivopixant or a pharmaceutically acceptable salt thereof and (ii) acetazolamide or a pharmaceutically acceptable salt thereof, are the sole active agents present in the pharmaceutical composition. In some embodiments, (i) sivopixant or a pharmaceutically 23 60678557.3Attorney Docket No.277901-567842 acceptable salt thereof and (ii) sultiame or a pharmaceutically acceptable salt thereof, are the sole active agents present in the pharmaceutical composition. In some embodiments, the pharmaceutical composition does not contain another active agent (e.g., a hypnotic, an antimuscarinic agent and / or a complementary medicament or sleep aid). In some embodiments, the pharmaceutical composition contains an additional active agent.

[0099] In some embodiments, the pharmaceutical composition is for use in treating a condition associated with pharyngeal airway muscle collapse during sleep. In some embodiments, the condition associated with pharyngeal airway muscle collapse is sleep apnea (e.g., obstructive sleep apnea (OSA), central sleep apnea (CSA), complex sleep apnea, sleep apnea with a central component, mixed OSA and CSA, or high-loop gain sleep apnea) or snoring (e.g., simple snoring).

[0100] In some embodiments, the pharmaceutical composition is for use in treating sleep apnea. In some embodiments, the sleep apnea is obstructive sleep apnea (OSA), central sleep apnea (CSA), complex sleep apnea, sleep apnea with a central component, mixed OSA and CSA, or high-loop gain sleep apnea. Combinations

[0101] Also provided herein is a P2X3 receptor antagonist and a carbonic anhydrase inhibitor (CAI), for use in treating a subject having a condition associated with pharyngeal airway collapse. In some embodiments, the condition associated with pharyngeal airway muscle collapse is sleep apnea (e.g., obstructive sleep apnea (OSA), central sleep apnea (CSA), complex sleep apnea, sleep apnea with a central component, mixed OSA and CSA, or high-loop gain sleep apnea) or snoring (e.g., simple snoring). In some embodiments, the combination does not contain another active agent (e.g., a hypnotic, an antimuscarinic agent and / or a complementary medicament or sleep aid). In some embodiments, the combination contains an additional active agent.

[0102] Further provided herein is a P2X3 receptor antagonist and a CAI, for use in treating sleep apnea, and optionally wherein the P2X3 receptor antagonist and CAI are the sole active agents. In some embodiments, the sleep apnea is obstructive sleep apnea (OSA), central sleep apnea (CSA), complex sleep apnea, sleep apnea with a central component, mixed OSA and CSA, or high-loop gain sleep apnea. 24 60678557.3Attorney Docket No.277901-567842

[0103] Also provided herein is a P2X3 receptor antagonist and a CAI, for use in treating snoring, and optionally wherein the P2X3 receptor antagonist and CAI are the sole active agents. EXAMPLES

[0104] The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

[0105] Exemplary clinical protocols are provided in Examples 1 and 2 for treatment of sleep apnea with acetazolamide and sivopixant. Similar protocols may also be carried out for treatment of sleep apnea with sultiame and sivopixant, or other combinations as described herein. For example, the same protocol as Example 1 or 2 may be followed but with administration of an appropriate dose of sultiame replacing the administration of acetazolamide. Example 1: A First Exemplary Phase 2a Randomized, Controlled, Dose Escalation, Parallel-Arm, Safety and Efficacy Study of Sivopixant Alone and in Combination with Acetazolamide

[0106] The RESTEADY trial is designed to evaluate the safety and efficacy of sivopixant alone and in combination with acetazolamide in patients with high-loop gain (high-LG) sleep apnea but differ in other characteristics such as degree or type of cardiovascular abnormality. Overall design

[0107] The RESTEADY trial is composed of 2 parts: in PART A the subjects will be exposed to 3 doses of sivopixant (150, 300, 450 mg) or placebo. During this part of the trial, dose escalation of sivopixant will stop for each participant if an intolerable taste disturbance, a known dose-limiting effect of sivopixant, or other substantial safety or tolerability issue is identified, with subsequent continued dosing at the preceding lower dose. In PART B, acetazolamide 500 mg will first be tested alone to confirm and quantify prior reports of efficacy, followed by testing in combination with sivopixant, initially at a dose of 150 mg and subsequently at a dose 450 mg (or at the highest well-tolerated identified for the patient in PART A). Participants who do not tolerate acetazolamide 500 mg in the initial period of PART B can be reduced to 250 mg (assuming non-serious, non-severe tolerability issues related to 500 mg). For participants who reduce to 250 mg, subsequent combination with sivopixant is with 250 mg acetazolamide.

[0108] During the screening period, home continuous overnight pulse oximetry tests will assist in identifying and excluding patients with a low baseline average oxygen saturation (SpO2<88%) 25 60678557.3Attorney Docket No.277901-567842 and / or without signs of sleep apnea before patients proceed to the in-lab PSG. Subsequently, eligible patients will be randomly assigned to either active treatment or placebo, in a ratio of 3:1, stratified by subpopulation (stable heart failure with reduced ejection fraction / stable heart failure with preserved ejection fraction and hypertension / persistent atrial fibrillation).

[0109] Patients randomized to active treatment will then receive escalating doses of sivopixant alone followed by acetazolamide and then the combination of sivopixant and acetazolamide, as follows: PART A - 3 nights run-in: 150 mg sivopixant dosed at home with continuous pulse oximetry assessment each night. If well tolerated, - 7 nights with 300 mg sivopixant, of which initial 6 nights dosing are at home with continuous pulse oximetry assessment each night, and final 1 night dosing in lab to perform PSG. If well tolerated, - 7 nights with 450 mg sivopixant, of which initial 6 nights dosing are at home with continuous pulse oximetry assessment each night, and final 1 night dosing in lab to perform PSG.

[0110] From PART A, the maximum well-tolerated dose for each participant will be determined. After a week without dosing, this maximum dose will be used in PART B, in combination with acetazolamide, as follows: PART B: ^ 3 nights of acetazolamide 500mg alone, of which the initial 2 nights dosing is at home with continuous pulse oximetry assessment each night, and the third night dosing is in lab to perform PSG; ^ 3 nights of 500mg acetazolamide + 150mg sivopixant, 3 nights dosing at home with continuous pulse oximetry assessment each night. Participants who do not tolerate acetazolamide 500 mg in the initial period of PART B can be reduced to 250 mg. ^ 7 nights of 500mg acetazolamide + 450mg sivopixant (or maximum well-tolerated dose of sivopixant), of which initial 6 nights dosing is at home with continuous pulse oximetry assessment each night, and 1 night dosing in hospital to perform PSG. Participants who 26 60678557.3Attorney Docket No.277901-567842 do not tolerate acetazolamide 500 mg in the initial period of PART B can be reduced to 250 mg.

[0111] Study drug dosing occurs approximately 30 minutes before bedtime with 150 mg sivopixant tablets or matching placebo, and 250 mg acetazolamide as over-encapsulated tablets. Dose escalation will be based on tolerability and safety, as assessed at clinic visits, telephone contacts with participants, and at-home pulse-oximetry. Study treatment is defined as any investigational drug(s), marketed product(s), placebo, or medical device(s) intended to be administered to a study participant according to the study protocol.

[0112] About 40 participants will be enrolled with 3:1 ratio of active treatment vs placebo. The study design is depicted in Fig.1. The target population will be selected from cardiology clinics or sleep centers with the goal of a similar proportion amongst subpopulations. To enroll, subjects need to have a previous diagnosis of at least one or more of the following medical conditions: ^ Stable heart failure with reduced ejection fraction (NYHA class 1-3 inclusive) ; ^ Heart failure with preserved ejection fraction (NYHA class 1-3 inclusive) with hypertension (BP>130 / 85 mmHg at screening visit despite the treatment with ≥2 medications); ^ Persistent atrial fibrillation (rate controlled with resting HR<90bpm).

[0113] Participants diagnosed with heart failure and atrial fibrillation must have standard care for at least 3 weeks before the first screening visit. Participants who fit more than one subpopulation category can enroll. In addition, enrollment efforts will preferentially target patients with hypertension treated with two or more drugs, i.e., at least somewhat resistant to treatment, and patients with a history of treatment-emergent CSA (complex sleep apnea). Study Participants

[0114] Eligible 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 to the community. Participant must be able to understand the nature of the study and must have the opportunity to have any questions answered. Participants must be able to provide written informed consent and meet all the inclusion criteria and none of the exclusion criteria recited below. Inclusion Criteria 27 60678557.3Attorney Docket No.277901-567842

[0115] Patients currently using PAP will be eligible for inclusion in the study if they express willingness to discontinue treatment for a minimum of 7 days before baseline SpO2 assessments, until the study completion.

[0116] Both men and women must be ≥18 and ≤80 years of age at the time of informed consent to participate. In addition, subjects need to meet the following inclusion criteria to participate in the study: ^ BMI between 18.5 and 35 kg / m2 for men, or 37 kg / m2 for women, inclusive; ^ Patients currently using Positive Airway Pressure (PAP) will be eligible for inclusion in the study if: o Non-compliant to CPAP (less than 4 hr / night for 5 days / week) and they express willingness to discontinued treatment for a minimum of 7 days before the baseline SpO2 assessments o Patients who discontinued PAP ^ Naïve to PAP

[0117] Participants are required to have the following measures for study inclusion: ^ Average oxygen desaturation index 4 (ODI4) ≥7 events / h and ≤55 events / h and average SpO2 ≥ 88% from continuous home pulse oximetry recordings at screening; ^ AHI4 (Hypopneas defined by 4% oxygen desaturation) of >10 to ≤60 events / h; o At minimum of 25% central or mixed apneas (as proportion of total apneas) with a minimum of 2.5 central or mixed apneas / hour of sleep; or o Evidence of clear Cheyne-Stokes breathing pattern during the baseline PSG (regardless of central apnea component); ^ Average SpO2 during sleep ≥ 88%. Exclusion criteria

[0118] Subjects with the following vital signs, symptoms, or medical conditions at screening will be excluded from the study: ^ Sustained SpO2<93% during wakefulness or mean SpO2<88% during sleep, calculated from PSG at screening; ^ Dyspnea at rest or patients with heart failure class IV NYHA; 28 60678557.3Attorney Docket No.277901-567842 ^ Blood pressure <90 / 50 mmHg or >160 / 100 mmHg; ^ Recent (<3 months) episode of acute myocardial infarction or acute decompensated heart failure; ^ History of stroke; ^ History of sustained ventricular tachyarrhythmias or other severe arrhythmias without defibrillator implanted; ^ Heart failure primarily caused by valvular, post-partum cardiomyopathy or active myocarditis; ^ History of obesity-hypoventilation syndrome or respiratory disturbance due to opioids; ^ History of bronchiectasis and uncontrolled asthma; ^ History of chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted (European Respiratory Society criteria); ^ Started treatment with β-blockers <3 months before screening. Patients not taking β- blockers or taking β-blockers for >3 months can be enrolled; ^ Narcolepsy, restless leg syndrome requiring medication, REM sleep behavior disorder; ^ Pronounced anatomical abnormalities of upper airway (adenoid vegetations, grade ≥3 tonsillar hypertrophy, etc.), pronounced micrognathia, or pronounced incomplete development of the lower jaw; ^ History of schizophrenia, schizoaffective disorder or bipolar disorder according to Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) or International Classification of Disease tenth edition criteria. ^ Medically unexplained positive screen for drugs of abuse (excluding THC / marijuana) or history of substance use disorder as defined in DSM-V within 24 months prior to Screening Visit; ^ A significant illness or infection requiring medical treatment in the past 30 days as determined by investigator; ^ Clinically significant cognitive dysfunction as determined by investigator. ^ Women who are pregnant or nursing; ^ Use of another investigational agent within 30 days or 5 half-lives, whichever is longer, prior to dosing; 29 60678557.3Attorney Docket No.277901-567842 ^ Hepatic transaminases >2X the upper limit of normal (ULN), total bilirubin >1.5X ULN (unless confirmed Gilbert syndrome), estimated glomerular filtration rate < 40 ml / min.

[0119] 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 1 week prior to first PSG and are not used during participation in the study (through V6). These would include a history of chronic oxygen therapy or concomitant use of medications from the list of disallowed medications.

[0120] Additional criteria excluding subjects from study participation include the following: ^ Night- or shift-work sleep schedule causing the major sleep period to be during the day; ^ Employment as a commercial driver or operator of heavy or hazardous equipment; ^ Typically smoking more than 10 cigarettes or 2 cigars per day, or inability to abstain from smoking during overnight PSG visits; ^ Unwilling to use specified contraception; or ^ History of regular alcohol consumption of more than 14 standard units per week (males) or more than 7 standard units per week (females), or unwillingness to limit alcohol consumption to no greater than 2 units / day (males), 1 unit per day (females). Alcohol is not to be consumed within 3 hours of bedtime or on PSG nights. ^ Unwilling to agree to limit during the study period caffeinated beverage intake (e.g., coffee, cola, tea) to 400 mg / day or less of caffeine, not to be used within 3 hours of bedtime. ^ Any condition 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. ^ Participant considered by the investigator, for any reason, an unsuitable candidate to receive sivopixant or acetazolamide or unable or unlikely to understand or comply with the dosing schedule or study evaluations. Safety Monitoring

[0121] Adverse event (AE) / severe adverse event (SAE) monitoring, clinical laboratory, pregnancies, 12-lead ECG, physical exam including vital signs, DSST, mMRC dsypnea scale. 30 60678557.3Attorney Docket No.277901-567842 Home continuous overnight pulse oximetry, downloaded to the study site daily, will be monitored for overnight desaturation events that are deemed adverse events, e.g. due to depth, duration, frequency, and similarly for changes in pulse that are considered adverse events. Home pulse oximetry data will be examined prior to any dose escalation and between PART A and PART B.

[0122] In-lab PSG will be monitored for events on any recording channel or per observation of the technician that would be classified as adverse events, including desaturations, arrhythmias, EEG activity, transcutaneous PCO2 (tcPCO2) or abnormality of patient mental status or behavior. Adverse Events

[0123] An adverse event (AE) is any untoward medical occurrence in a participant or clinical study participant, 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. For example, an event meeting the AE definition may include: ^ 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; and ^ Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a concomitant medication.

[0124] An 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. 31 60678557.3Attorney Docket No.277901-567842

[0125] "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 lack of efficacy will be reported as an AE or SAE if they fulfill the definition of an AE or SAE.

[0126] Events considered to not meeting the AE definition include any clinically significant abnormal laboratory findings or other abnormal safety assessments which are associated with the underlying disease / disorder being studied, unless judged by the Investigator to be more severe than expected for the participant’s condition. For example, this may include the following: ^ A medical or surgical procedure (e.g., endoscopy, appendectomy) condition that results from the procedure is not an AE; ^ Situations in which an untoward medical occurrence did not occur (social and / or convenience admission to a hospital); or ^ 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. Severe Adverse Events

[0127] 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).

[0128] Any untoward medical occurrence that at any dose results in death or is life threatening is considered a severe adverse event (SAE). 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.

[0129] A SAE is an event that requires 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 was necessary, the AE should be considered serious. Hospitalization for elective treatment of a pre-existing condition that did not worsen from 32 60678557.3Attorney Docket No.277901-567842 baseline is not considered an AE. A SAE resulting in a persistent disability / incapacity causes 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.

[0130] 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.

[0131] Examples of 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.

[0132] When an AE / SAE occurs, it is the responsibility of the Investigator to review all documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) related to the event and record all relevant AE / SAE information in the eCRF. It is not acceptable for the Investigator to send photocopies of the participant’s medical records in lieu of completion of the AE / SAE eCRF page. There may be instances when copies of medical records for certain cases are requested by the Sponsor. In this case, all participant identifiers, with the exception of the participant number, will be blinded on the copies of the medical records before submission to the Sponsor.

[0133] The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and / or other clinical information. In such cases, the diagnosis (not the individual signs / symptoms) will be documented as the AE / SAE. The Investigator will make an assessment of intensity for each AE and SAE reported during the study and assign it to one of the following categories: ^ Mild: an event that is easily tolerated by the participant, causing minimal discomfort and not interfering with everyday activities; ^ Moderate: an event that causes sufficient discomfort and interferes with normal everyday activities; 33 60678557.3Attorney Docket No.277901-567842 ^ Severe: An event that prevents 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.

[0134] An event is defined as ‘serious’ when it meets at least one of the predefined outcomes described in the definition of an SAE, not when it is rated as severe. Assessment of Causality

[0135] The Investigator is obligated to assess the relationship between study treatment and each occurrence of each AE / 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.

[0136] There may be situations in which an SAE has occurred and the Investigator has minimal information to include in the initial report to the Sponsor. However, it is important that the Investigator assesses causality for every event before the initial transmission of the SAE data to the Sponsor. The Investigator may change his / her opinion of causality in light of follow-up 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. Follow-up of AE and SAE

[0137] 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 Sponsor 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. If a participant dies during participation in the study, the Investigator will provide the Sponsor with a copy of any post-mortem findings including histopathology. New or updated information will be recorded in the originally completed eCRF. 34 60678557.3Attorney Docket No.277901-567842 Reporting SAE

[0138] The Investigator must report any SAEs to the Sponsor within 24 hours of becoming aware of the event. When calling 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. The Investigator and the Sponsor will review each SAE report and the Sponsor will evaluate the seriousness and the causal relationship of the event to study treatment. In addition, the Sponsor will evaluate the expectedness according to the reference documents (Investigator’s Brochure or US product labeling for sivopixant or acetazolamide). Based on the Investigator and Sponsor’s assessment of the event, a decision will be made concerning the need for further action.

[0139] 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. 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 off-line, then the site can report this information on a paper SAE form or by telephone.

[0140] All SAEs will be recorded from signing of informed consent 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 study treatment.

[0141] Any AE that is serious, associated with the use of the study treatment, and Suspected Unexpected Serious Adverse Reactions (SUSARs) has additional reporting requirements. If the SUSAR is fatal or life threatening, associated with study treatment, and unexpected, regulatory authorities and 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 IECs will be notified within 15 calendar days after the Sponsor learns of the event.

[0142] The Sponsor will notify the Investigators in a timely fashion of relevant information about SUSARs that could adversely affect the safety of participants. Follow-up information may be submitted if necessary. The Sponsor will also provide annual safety updates to the regulatory 35 60678557.3Attorney Docket No.277901-567842 authorities and IECs responsible for the study. These updates will include information on SUSARs and other relevant safety findings. Individual, Subgroup, and Overall Study Dose Escalation / Reduction and Stopping Criteria

[0143] A Dose Escalation and Safety Committee will evaluate data for each patient prior to dose-escalations, and will evaluate aggregate data to determine continued subgroup enrollment and overall study continuation. The Committee will be composed by the site investigator and 2 medical monitors from the sponsor side. Individual Participant Criteria ^ Within-patient dose escalation in PART A will stop for an individual patient if intolerable taste disturbance or other safety or tolerability issue is identified that is considered dose- limiting. Subsequent dosing for that patient is at the preceding lower dose, if otherwise considered safe. ^ Participants who do not tolerate acetazolamide 500 mg in the initial period of PART B can be reduced to 250 mg (assuming non-serious, non-severe tolerability issues related to 500 mg). For participants who reduce to 250 mg, subsequent combination with sivopixant is with 250 mg acetazolamide. ^ Individual patient dosing is stopped for any serious adverse event that is considered drug- related, or any other drug-related adverse event that is considered to place the patient at unreasonable risk of harm unless dosing is discontinued. Subgroup Stopping Criteria

[0144] Safety will be evaluated according to subgroups (i.e., stable heart failure with reduced ejection fraction / heart failure with preserved ejection fraction, and hypertension / persistent atrial fibrillation) on an ongoing basis. Additional enrolment in that subgroup may be paused or stopped if the severity or frequency of adverse events is considered predictive of unacceptable tolerability in patients with similar baseline characteristics. Dosing of all patients within a subgroup will be stopped if similar serious or potentially serious adverse events occur in multiple patients in a manner that suggests similar risk in other patients within that subgroup.

[0145] Worsening clinical CHF status using NYHA criteria, uncontrolled arrhythmias, loss of rate control in atrial fibrillation, myocardial infarction, unstable angina, elevated troponin levels (cTnT and cTnI) above the 99th percentile upper reference limit, and >4% worsening of average 36 60678557.3Attorney Docket No.277901-567842 oxygen saturation during sleep from baseline or average SpO2 during sleep <86% will be considered stopping criteria in subgroups and individual subjects.

[0146] Pausing or stopping enrollment or dosing of a subgroup will not affect enrollment or dosing of other subgroups if ongoing safety is considered acceptable in those subgroups.

[0147] The overall enrollment of the study will continue to approximately 40 so long as the safety of additional enrollment and dosing is considered acceptable for at least one of the study subgroups. Overall Study Stopping Criteria

[0148] Dosing of all study patients will be stopped if similar serious or potentially serious drug-related adverse events occur in multiple patients in a manner that suggests risk in other patients without regard to disease subgroup (i.e. stable heart failure with reduced ejection fraction / heart failure with preserved ejection fraction and hypertension / persistent atrial fibrillation) or other baseline disease characteristics. Table 1. Schedule of Activities Part A dosing Wash Part B dosing Non- out oS all 6± 21 WOCBP only 37 60678557.3Attorney Docket No.277901-567842 Part A dosing Wash Part B dosing Non- out PSG Scree SV 1503d SV 4507d 1 k AZ 5003d AZ 500+SV 150 oS all2 See Table 4 for complete list including “hematology” and “serum chemistry” group of tests, plus urinalysis. 3 Collected in the morning, after PSG 4 Blood samples are taken at 2 timepoints: in the evening before dosing and in the morning after the subjects wakes up. 5 Occurs in the morning after PSG if the patient qualifies at on-site screening. 6 Study medication administered at lights out; dose on PSG nights is from supply dispensed to the participant. Patient will self-dose study drug during PSG. 38 60678557.3Attorney Docket No.277901-567842 Part A dosing Wash Part B dosing Non- out PSG Scree SV 1503d SV 4507d 1 k AZ 5003d AZ 500+SV 150 oS all ↔ ↔Somni; PGI-S = patient global impression of severity-fatigue; ESS = Epworth Sleepiness Scale; ISI = Insomnia Severity Scale; mMRC = modified medical research council; PSG = polysomnography; SAE = serious adverse event; SAQLI = Sleep Apnea Quality of Life Index; WOCBP = women of childbearing potential; PROMIS = Patient Reported Outcomes Measurement Information System; PVT = psychomotor vigilance test. Table 2. Endpoints Endpoints Primar ^ Ch n in AHI4 SV+AZ rm v b lin t V6 PSG7 Administered at similar time on morning of each PSG visit 8 Vital signs include seated blood pressure in triplicate, pulse, respiratory rate; vital signs on PSG nights taken the evening before and the morning after PSG. 9 Site contacts participant by telephone every 2 days of each at-home dosing period for safety evaluation and reminder of study activities. Only 1 call mid-week will be performed during the washout week. . 39 60678557.3Attorney Docket No.277901-567842 Table 2. Endpoints Endpoints Exploratory^ Change in AHI4, HB4, ODI3, AHI3a, treatments vs baseline and s - ntPrescreening

[0149] Participants will undergo initial pre-screening to determine potential study eligibility. Participants selected for further screening should have: ^ a previous history of OSA, CSA, or be at high risk (e.g. as assessed by STOP-Bang Questionnaire score) AND 40 60678557.3Attorney Docket No.277901-567842 ^ suffer from at least one of the following comorbidities: o Stable heart failure with reduced ejection fraction (NYHA class 1-3 inlcusive) o Heart failure with preserved ejection fraction (NYHA class 1-3 inclusive) and hypertension (BP>130 / 85 mmHg at screening visit despite the treatment with ≥2 medications) o Persistent atrial fibrillation (rate controlled with resting HR<90bpm)1

[0150] In addition, enrollment efforts will preferentially target patients with hypertension treated with 2 or more drugs, i.e., at least somewhat resistant to treatment, and patients with a history of treatment-emergent CSA (complex sleep apnea). Visit 1 Screening

[0151] Individuals who remain eligible for the study following pre-screening attend the following activities at Visit 1: ^ Informed consent o Per Good Clinical Practice (GCP) guidelines when conducting a trial, the patient’s primary care provider should be informed about the subject’s enrollment in the trial, after obtaining the subjects consent to release this information. ^ After consent, contact information is recorded for the patient’s primary care provider and the investigator informs the provider about the participant’s involvement in the study. Being under the care of a primary care provider is not required for participation in the study but should be encouraged. o Per GCP, during and following a subject’s participation in the trial the investigator should inform a participant when medical care is needed for intercurrent illness(es) of which the investigator becomes aware (including medical conditions present at baseline that may require ongoing management such as hypertension or diabetes). ^ Demographics and medical history, including medications and history of PAP use or other treatments for OSA. ^ Physical examination, height, weight, vital signs, clinical laboratory testing, urine drugs of abuse test, pregnancy test, 12-lead ECG 41 60678557.3Attorney Docket No.277901-567842 ^ Participants at V1 receive a validated device assessing continuous pulse oximetry, connected to an app that are downloaded to the patient compatible smartphone. They are instructed to perform three overnight SpO2assessments at home immediately following V1. The results of these pulse oximeter tests will be accessible to the investigator the day after recording through web-based software linked to the smartphone app. If the average oxygen desaturation index (ODI4, representing the number of desaturations ≥4% per hour of sleep) from the three assessments is ≥7, ≤55, and the average overnight SpO2is ≥88%, participants will be contacted to undergo an in-lab PSG; if these criteria are not met, the participant is discontinued from screening and is asked to ship or deliver back the pulse oximeter device to the site. If deemed eligible, the pulse oximetry assessments conducted during screening will serve as a baseline for future at-home on-treatment assessments. Visit 2

[0152] Participants who meet all non-PSG enrollment criteria at V1 and pass home oximetry assessments are eligible for the screening / baseline PSG at Visit 2. The following activities occur at Visit 2: ^ Medical and concomitant therapy (medication or device) monitoring ^ Vital signs (triplicate blood pressure, heart rate, respiratory rate, body temperature) are measured both the evening of admission to the PSG lab (day 1 of visit) and the morning after the PSG (day 2 of visit). ^ Overnight urine collection for urinary catecholamine dosing, from arrival to the sleep lab in the evening to discharge in the morning. ^ PSG with tcPCO2; V2 PSG will serve as baseline for calculation of PSG efficacy outcomes. ^ The following PROs are assessed the evening of the PSG o ESS, PROMIS-Fatigue, PROMIS-Sleep Impairment, PROMIS-Sleep Disturbance, mMRC ^ DSST is assessed the morning after the PSG. ^ Randomization: For enrollment purposes, the V2 PSG is read by the site the morning after the PSG (endpoint calculation is based on a separate re-read of the PSG at a later date by the central reading center). If the AHI(4%)[hypopneas defined by 4% oxygen desaturation] of the V2 PSG is ≥10 and ≤60 events / h, ≥25% of apneas are central or 42 60678557.3Attorney Docket No.277901-567842 mixed, with a minimum of 2.5 events / h of central apnea / index, average SpO2during sleep is ≥88%, OR if the patient exhibits a pattern of Cheney-Stokes breathing sustained for at least 15 minutes during sleep, the patient is randomized.

[0153] Participants who meet all enrollment criteria are randomized on the morning of V2 to one of 2 parallel treatment arms in PART A of the study, with a ratio of 3:1 for sivopixant vs placebo. IP supply for the following 10 days will be distributed before discharge the morning after the PSG of Visit 2. The first 3 days of dosing sivopixant are with a lower run-in dose of 150 mg or matching placebo, followed by 300 mg or matching placebo taken for 1 week. PART A, first 9-days at home escalation dosing

[0154] Participants dose the study drug each night at home immediately prior to lights out for the first 10 days (3 days for the 150mg run-in period and 6 days at 300mg) or matching placebo.

[0155] Every night at home, randomized patients perform a continuous pulse oximetry recording using a validated device connected to a smartphone app. Results will be readily available for next-day reading at the sites and will be used to monitor potential adverse events of the treatments while at home. Adverse events, concomitant medication monitoring and review of study procedures and visit schedule will occur by telephone every 2 days of each at-home dosing period, starting the day after the first at home night dosing.

[0156] Within-patient dose escalation of sivopixant in PART A is stopped for an individual patient if an intolerable taste disturbance or other safety or tolerability issue emerging from at- home pulse oximetry data, phone calls and inpatient visits is identified that is considered dose- limiting. Subsequent dosing for that patient is at the preceding lower dose, if otherwise considered safe. A Dose Escalation and Safety Committee composed by the site PI and two medical monitors from the Sponsor side will evaluate data for each patient prior to dose- escalations to determine continued subgroup enrollment and overall study continuation. Visit 3

[0157] At completion of the 6 days 300 mg period, participants return for an inpatient PSG with tcPCO2at V3. Any unused drug from the previous period are collected, and participants are evaluated for drug safety and tolerability. If the participant arrives at the site without previously dispensed IMP, the IMP should be retrieved whenever practicable. If previously dispensed IMP is determined to be not available for dosing, the site can access replacement IMP for dosing. One 43 60678557.3Attorney Docket No.277901-567842 dose of IMP is taken by the participant under observation by site personnel, at lights out at the start of the PSG with tcPCO2. The following activities occur at V3: ^ AE / SAE and concomitant therapy (medication or device) monitoring. ^ Vital signs (triplicate blood pressure, heart rate, respiratory rate, body temperature) are measured both the evening of admission to the PSG lab (day 1 of visit) and the morning after the PSG (day 2 of visit); after an initial measurement in sitting position, blood pressure is also measured after 5 minutes supine (1 measurement) and within 3 minutes after standing (1 measurement); weight is also assessed. ^ Overnight urine collection for urinary catecholamine dosing, from arrival to the sleep lab in the evening to discharge in the morning. ^ PSG with tcPCO2, with IMP dosing. ^ The following PROs are assessed the evening of the PSG: o ESS, PROMIS-Fatigue, PROMIS-Sleep Impairment, PROMIS-Sleep Disturbance, mMRC, and ISI ^ DSST is assessed the morning after the PSG. ^ Drug accountability ^ Review of study procedures and future study visits

[0158] V3 PSG data is sent to the central PSG reading center; findings of V3 PSG do not affect subsequent study activities. Drug for the remaining seven days of PART A is dispensed at Visit 3. PART A, 6-days at home at maximum dosing

[0159] After the safety committee confirm the patient eligibility for dose escalation, participants dose study drug each night at home immediately prior to lights out for 6 days at 450mg or matching placebo.

[0160] Every night at home, randomized patients perform a continuous pulse oximetry recording using a validated device connected to a smartphone app. Results will be readily available for next-day reading at the sites and will be used to monitor potential adverse events of the treatments while at home. Adverse events, concomitant medication monitoring and review of study procedures and visit schedule occur by telephone every 2 days of each at-home dosing period, starting the day after the first at home night dosing. 44 60678557.3Attorney Docket No.277901-567842 Visit 4

[0161] At completion of the 6 days 450 mg period, participants return for an inpatient PSG with tcPCO2 at V4. Any unused drug from the previous period are collected, and participants are evaluated for drug safety and tolerability. If the participant arrives at the site without previously dispensed IMP, the IMP should be retrieved whenever practicable. If previously dispensed IMP is determined to be not available for dosing, the site can access replacement IMP for dosing. One dose of IMP is taken by the participant under observation by site personnel, at lights out at the start of the PSG with tcPCO2.

[0162] The following activities occur at V4: ^ AE / SAE and concomitant therapy (medication or device) monitoring. ^ Vital signs (triplicate blood pressure, heart rate, respiratory rate, body temperature) are measured both the evening of admission to the PSG lab (day 1 of visit) and the morning after the PSG (day 2 of visit); after an initial measurement in sitting position, blood pressure is also measured after 5 minutes supine (1 measurement) and within 3 minutes after standing (1 measurement); weight is also assessed. ^ Overnight urine collection for urinary catecholamine dosing, from arrival to the sleep lab in the evening to discharge in the morning. ^ PSG with tcPCO2, with IMP dosing. ^ The following PROs are assessed the evening of the PSG: o ESS, PROMIS-Fatigue, PROMIS-Sleep Impairment, PROMIS-Sleep Disturbance, mMRC, and ISI ^ DSST is assessed the morning after the PSG. ^ Drug accountability ^ Review of study procedures and future study visits

[0163] V4 PSG data is sent to the central PSG reading center; findings of V4 PSG do not affect subsequent study activities. Drug for the following 3 days of PART B, to be taken after a washout period of 7 days, is dispensed at Visit 4. Contact / Call during washout period 45 60678557.3Attorney Docket No.277901-567842

[0164] The site contacts the participant at least once during the 7-days washout period for AE / SAE and concomitant therapy (medication or device) monitoring, and review of study procedures and future study visits. PART B – first 2-days of home dosing

[0165] The study drug (either acetazolamide or placebo) are provided to randomized participants on the morning after the PSG at Visit 4. After 1-week washout period, there is an initial 3-day randomized drug treatment period. Participants are instructed to take the study drug each night at home right before bedtime for these 2 days and 1 day in hospital before the PSG.

[0166] Every night at home, randomized patients perform a continuous pulse oximetry recording using a validated device connected to a smartphone app. Results are readily available for next-day reading at the sites and will be used to monitor potential adverse events of the treatments while at home. Adverse events, concomitant medication monitoring and review of study procedures and visit schedule will occur by telephone the day after the first at home night dosing. Visit 5

[0167] After completing the 2-day regimen of acetazolamide at 500 mg, participants return for an inpatient PSG with tcPCO2at Visit 5. Any unused medication is collected, and participants undergo evaluation for drug safety and tolerability. If the participant arrives at the site without previously dispensed IMP, the IMP should be retrieved whenever practicable. If previously dispensed IMP is determined to be not available for dosing, the site can access replacement IMP for dosing. One dose of IMP is taken by the participant under observation by site personnel, at lights out at the start of the PSG with tcPCO2. The following activities occur at V5: ^ AE / SAE and concomitant therapy (medication or device) monitoring. ^ Vital signs (triplicate blood pressure, heart rate, respiratory rate, body temperature) are measured both the evening of admission to the PSG lab (day 1 of visit) and the morning after the PSG (day 2 of visit); after an initial measurement in sitting position, blood pressure is also measured after 5 minutes supine (1 measurement) and within 3 minutes after standing (1 measurement); weight is also assessed. ^ Overnight urine collection for urinary catecholamine dosing, from arrival to the sleep lab in the evening to discharge in the morning. 46 60678557.3Attorney Docket No.277901-567842 ^ PSG with tcPCO2, with IMP dosing. ^ The following PROs are assessed the evening of the PSG: o ESS, PROMIS-Fatigue, PROMIS-Sleep Impairment, PROMIS-Sleep Disturbance, mMRC, and ISI ^ DSST is assessed the morning after the PSG. ^ Drug accountability ^ Review of study procedures and future study visits V5 PSG data is sent to the central PSG reading center.

[0168] Drug for the remaining seven days of the study are dispensed at Visit 5. Participants who do not tolerate acetazolamide 500 mg in the initial period of PART B can be reduced to 250 mg (assuming non-serious, non-severe tolerability issues related to 500 mg). For participants who reduce to 250 mg, subsequent combination with sivopixant is with 250 mg acetazolamide. PART B – 9-days of home escalation dosing

[0169] Participants are instructed to take the study drug each night at home right before bedtime for the following 9 days starting with a regimen of acetazolamide 500 + sivopixant 150mg for 3 nights and followed by acetazolamide 500 + sivopixant 450mg for 6 nights. Acetazolamide can be reduced to 250mg if the 500mg dose was not tolerated in the previous 3 days. Sivopixant 450 mg can be lowered to a better-tolerated dose determined in PART A.

[0170] Every night at home, randomized patients perform a continuous pulse oximetry recording using a validated device connected to a smartphone app. Results will be readily available for next-day reading at the sites and are used to monitor potential adverse events of the treatments while at home. Adverse events, concomitant medication monitoring and review of study procedures and visit schedule occur by telephone every 2 days, starting the day after the first at-home night dosing.

[0171] Within-patient dose escalation of sivopixant in PART B will stop for an individual patient if intolerable taste disturbance or other safety or tolerability issue is identified that is considered dose-limiting. Subsequent dosing for that patient is at the preceding lower dose, if otherwise considered safe. Visit 6 47 60678557.3Attorney Docket No.277901-567842

[0172] After 9 days of at-home dosing with sivopixant (3 days at 150 mg and 6 days at 450 mg or lower tolerated dose determined from Part A) + acetazolamide 500mg (or 250mg) study drug, participants return with their study drug for an inpatient PSG with tcPCO2 at V6. Any unused medication is collected, and participants undergo evaluation for drug safety and tolerability. If the participant arrives at the site without previously dispensed IMP, the IMP should be retrieved whenever practicable. If previously dispensed IMP is determined to be not available for dosing, the site can access replacement IMP for dosing. One dose of IMP is taken by the participant under observation by site personnel, at lights out at the start of the PSG with tcPCO2. V6 PSG data is sent to the central PSG reading center.

[0173] The following activities occur at V6: ^ AE / SAE and concomitant therapy (medication or device) monitoring. ^ Vital signs (triplicate blood pressure, heart rate, respiratory rate, body temperature) are measured both the evening of admission to the PSG lab (day 1 of visit) and the morning after the PSG (day 2 of visit); after an initial measurement in sitting position, blood pressure is also measured after 5 minutes supine (1 measurement) and within 3 minutes after standing (1 measurement); weight is also assessed. ^ Overnight urine collection for urinary catecholamine dosing, from arrival to the sleep lab in the evening to discharge in the morning. ^ PSG with tcPCO2, with IMP dosing. ^ The following PROs are assessed the evening of the PSG: o ESS, PROMIS-Fatigue, PROMIS-Sleep Impairment, PROMIS-Sleep Disturbance, mMRC, and ISI ^ DSST is assessed the morning after the PSG. ^ Drug accountability ^ Review of study procedures and future study visits. End of Study call

[0174] An End of Study call is conducted after 1 week following the end of study drug dosing to collect AE / SAE (including possible effects of drug discontinuation) and concomitant therapy (medication or device) monitoring. Overall study duration will be up to 10 weeks. End of Study Definition 48 60678557.3Attorney Docket No.277901-567842

[0175] 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). 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 globally. Study Drug(s) Administered

[0176] Study drug is taken 30 minutes prior to lights out, and consists of the following dosage levels, either 1 tablet of sivopixant 150 mg, or 2 tablets of sivopixant 150 mg (sivopixant 300mg), or 3 tablets of sivopixant 150 mg (sivopixant 450) plus 1 tablet for Acetazolamide 250mg, or 2 tablets acetazolamide 250 mg, as shown below in Table 3. Table 3. Study treatment dosage and route of administration Study treatment name Sivopixant Acetazolamide Matching placeboConcomitant Therapy

[0177] Concomitant therapy with the medications listed below is disallowed. For medication that is typically used by the participant intermittently, occasionally, or as-needed (e.g. occasional use of a non-prescription sleep aid), it is sufficient that the medication not be used for at least one week prior to Visit 2 and for the duration of the study. Other disallowed medication would typically preclude enrollment unless the medication can be discontinued at least 1 month prior to Visit 2 without jeopardizing the participant’s health or the stability of the participant’s condition. The following medications are disallowed: digoxin, methyldigoxin, beta methyldigoxin, opioids, mecamylamine, methenamine, sodium phosphates, and chronic use of more than 500 mg / day of Aspirin. 49 60678557.3Attorney Docket No.277901-567842

[0178] Medications with effects on heart function and anticoagulation are generally allowed according to Investigator’s opinion if dose and frequency is stable for 3 months prior to enrollment, including but not limited to the following drug classes: ^ Antihypertensives (angiotensin-converting-enzyme / angiotensin II receptor; blocker / neprilysin inhibitors, calcium channel blockers, diuretics, beta-blockers etc.); ^ Anticoagulants (apixaban, dabigatran, edoxaban, rivaroxaban, warfarin); ^ Aldosterone antagonists (spironolactone, eplerenone); ^ Hydralazine and Nitrates; ^ If Channel Blockers (ivabradine); ^ Sodium Channel Blockers (flecainide, propafenone, quinidine); or ^ Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors (dapagliflozin, empagliflozin).

[0179] Medications that do not have substantial effects on the central nervous system (CNS), respiration, muscle activity or heart function are generally allowed according to Investigator’s opinion, if dose and frequency is stable for 1 month prior to enrollment and during the course of the study, including, but not necessarily limited to, the following drugs and drug classes: ^ Statins; ^ Alpha-1 antagonists (e.g., tamsulosin); ^ Chronic use of sedatives; ^ Muscle relaxants; ^ Antiemetics; ^ Proton pump inhibitors and histamine h2 receptor blockers; ^ Over-the-counter (OTC) antacids; ^ Antihistamines; ^ Chronic use of Eszopiclone, zolpidem, or zaleplon; ^ Melatonin; ^ Non-steroidal anti-inflammatory drugs and acetaminophen; ^ Laxatives; ^ Erectile dysfunction drugs; ^ Inhaled corticosteroids (e.g., fluticasone); ^ Antidiabetics; 50 60678557.3Attorney Docket No.277901-567842 ^ Ocular hypotensives and other ophthalmics (e.g., timolol); ^ Hormonal therapy (e.g., estrogen replacement or anti-estrogens) and hormonal contraceptives; ^ Thyroid medications; ^ OTC topicals (e.g., topical pain relievers); or ^ Osteoporosis drugs. Safety and Efficacy Scales and Tests

[0180] 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 ESS score (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. The ESS is administered approximately the same time of day prior to PSG recordings on Visit 3 and Visit 6

[0181] PROMIS (Patient-Reported Outcomes Measurement Information System) sleep impairment, sleep disturbance, and fatigue measures were developed with modern 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 corresponded to greater sleep disturbance or sleep-related impairment. The PROMIS measures are administered at the baseline / screening PSG Visit 3 and at PSG Visit 6, at approximately the same time prior to each PSG recording.

[0182] The Modified Medical Research Council (mMRC) dyspnea scale is a tool for assessing the severity of dyspnea, or shortness of breath, in individuals with respiratory conditions. This scale categorizes breathlessness into five grades (0 to 4), with higher grades indicating increased impairment. Grade 0 represents no breathlessness, while Grade 4 signifies severe breathlessness that limits the individual's ability to perform daily activities.

[0183] Insomnia Severity Index (ISI) is a self-report questionnaire with 7 items used as a brief screening tool for insomnia. Participants are asked to rate on a 5-point Likert scale (0-4) their severity of sleep onset, sleep maintenance, and early morning awakening problems, sleep dissatisfaction, interference of sleep difficulties with daytime functioning, noticeability of sleep 51 60678557.3Attorney Docket No.277901-567842 problems by others, and distress caused by the sleep difficulties. Total ISI score (sum of 7 items) ranges from 0 to 28. The higher the ISI score, the higher the insomnia severity.

[0184] The Digit Symbol Substitution Test (DSST) measures a range of cognitive and motor operations including motor speed, attention, visuo-perceptual functions, and some aspects of associative learning. The DSST requires participants to match symbols to numbers according to a key located on the tablet computer screen. The DSST is used in this study primarily as a safety measure for psychomotor impairment related to residual next-day effects of study drug dosed at bedtime. The DSST is administered the morning after baseline / screening PSG Visit 3, PSG Visit 5, and PSG Visit 6, at approximately the same time after each PSG recording. Polysomnography Methods

[0185] Standard overnight PSG with tcPCO2recording and data interpretation will be performed in accordance with the American Academy of Sleep Medicine (AASM) scoring manual. Participants will be instrumented with standard PSG electrodes. PCO2 will be assessed using tcPCO2sensors. Time of lights out will be established according to the participants’ habitual schedule and kept similar across the PSG study nights. The participants 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.

[0186] PSG with tcPCO2studies of randomized participants will be scored by a centralized PSG center, blinded to treatment assignment. The V2 and V3 PSGs will also be scored separately by the study site solely for purposes of determining study eligibility. PSGs of individuals who are not randomized are not scored centrally. Safety Assessments

[0187] Planned time points for all safety assessments are provided in the SoA. Safety monitoring will be guided by the established safety profiles of sivopixant and acetazolamide. Safety assessments will include physical examinations, measurement of vital signs, continuous overnight measurements of SpO2 at home, monitoring and recording of AEs, SAEs, and pregnancies, and recording of study or treatment discontinuations. Effects on OSA-CSA, sleep parameters (e.g., sleep time and sleep stages), and PCO2will be monitored by PSG with tcPCO2. 52 60678557.3Attorney Docket No.277901-567842 Physical Examinations

[0188] The general physical examination at screening includes an assessment of general appearance and a review of physical systems (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). Investigators should pay special attention to clinical signs related to previous serious illnesses or surgery. Vital Signs

[0189] Assessment of vital signs (seated blood pressure, pulse rate, body temperature, respiratory rate) will be performed at the time points indicated in the SoA. Vital signs will be measured at all visits in a seated position after 5 minutes rest and will include temperature, respiratory rate, systolic and diastolic blood pressure, and pulse. Measurements should be made in the same arm of the participant at each visit. Systolic and diastolic blood pressure will be measured 3 times, each at least 2 minutes apart in sitting position. In order to detect potential orthostatic hypotension due to treatment, during the treatment visits, BP will be measured also after 5 minutes in supine position (1 time) and within 3 minutes from standing (1 time). The method used to measure body temperature at screening should be maintained throughout the study for each participant, and should be indicated (e.g., ear, mouth, armpit). Electrocardiograms

[0190] A 12-lead ECG will be obtained 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 semi-supine position after the participant has rested in this position for at least 10 minutes. Clinical Laboratory Tests

[0191] The tests detailed in Table 4 will be performed by local laboratory. Blood for testing is obtained from non-fasting participants. Additional tests may be performed at any time during the study as determined necessary by the Investigator or required by local regulations. Investigators must document their review of each laboratory safety report. 53 60678557.3Attorney Docket No.277901-567842 Table 4. Protocol-Required Safety Laboratory Assessments Hematology Hematocrit Hemoglobin dblood urea nitrogen; HbA1c = hemoglobin A1c (glycated hemoglobin); hCG = human chorionic gonadotropin; RBC = red blood cell count; WBC= white blood cell; WOCBP = women of childbearing potential. 54 60678557.3Attorney Docket No.277901-567842 Adverse Events (AE) and Serious Adverse Events (SAE)

[0192] The definitions of AEs and SAEs are described above. Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). The Investigator and any qualified designees are responsible for detecting, documenting, and reporting events that meet the definition of an AE or SAE and remain responsible for following up on AEs that are serious, considered related to the study drug, the study, or that caused the participant to discontinue the study and / or study drug.

[0193] All AEs and SAEs will be collected from randomization until the end of the study at the time points specified in the SoA. All SAEs will be recorded and reported to the Sponsor or designee within 24 hours. The Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being available. Investigators are not obligated to 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 above.

[0194] 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. After the initial AE / SAE report, the Investigator is required to follow each participant at subsequent visits / contacts. All SAEs will be followed until resolution, stabilization, until the event is otherwise explained, or the participant is lost to follow-up. Further information on follow-up procedures is described above.

[0195] Prompt notification (within 24 hours) by the Investigator to the Sponsor 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 clinical investigation are met. 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 55 60678557.3Attorney Docket No.277901-567842 regulatory requirements and Sponsor policy and forwarded to Investigators as necessary. An Investigator who receives an Investigator 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. Treatment of Overdose

[0196] In the event of an overdose, the Investigator should refer to the investigator brochure for sivopixant and to the approved product label for acetazolamide for advice on overdose and the: ^ 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.

[0197] 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 Pharmacokinetics

[0198] Dosing of sivopixant and its metabolite sivopixant acyl glucuronide as well as acetazolamide will be assessed in the evening and in the morning of each PSG visits. Evening blood will be obtained before the administration of the medication, while morning blood will be obtained after awakening not to disturb sleep continuity. Sample Size Determination for Statistical Considerations

[0199] The sample size for this study was adequately powered for the goals of this exploratory, proof-of-concept investigation, to provide meaningful insights into the intervention's potential efficacy and safety profile, laying a foundation for future research. From previous experiments of acetazolamide in OSA / CSA (obstructive / central sleep apnea), we can assume that acetazolamide alone at 500 mg improves AHI by 35-40% vs placebo.

[0200] It is hypothesized that sivopixant could potentially increase acetazolamide effect by 20- 30%. Therefore, the anticipated effect of sivopixant + 500 mg acetazolamide vs baseline is in the range of 42-52%. Assuming an AHI4 baseline value of 20.4 (similar to a previous trial with a 56 60678557.3Attorney Docket No.277901-567842 population of comparable severity), a 42-52% decrease results in an end of study value of 11.8 to 9.8, which would be change from baseline of 8.6 to 10.6. Therefore the effect size (Mean Change / SD) to detect is in the range of 0.88(8.6 / 9.8) to 1.08(10.6 / 9.8). With 24 patients in the active arm (Sivopixant + 500 mg Acetazolamide), and assuming a SD of 9.6, the study will have ~80% power to detect a difference from baseline of ~5.7, based on a two-sided 5% alpha level and a paired t-test. Assuming a 20% dropout rate, we will enroll 30 patients in the active arm and 10 patients on placebo. The placebo arm will be mostly used for comparison of subjective efficacy, safety, and tolerability in an exploratory analysis. No interim analysis is planned. For the purposes of analysis, the following analysis sets are defined in Table 5. Table 5. Populations for Analyses Population Description st r

[0201] Example 2: A Second Exemplary Phase 2a Randomized, Controlled, Dose Escalation, Parallel-Arm, Safety and Efficacy Study of Sivopixant Alone and in Combination with Acetazolamide

[0202] The RESTEADY trial is designed to assess the safety and efficacy of sivopixant alone and in combination with acetazolamide in patients who share the key pathophysiological feature 57 60678557.3Attorney Docket No.277901-567842 of high-LG sleep apnea but differ in other characteristics such as degree or type of cardiovascular abnormality.

[0203] Overall design

[0204] The RESTEADY trial is composed of 2 parts: in PART A the subjects will be exposed to 3 doses of sivopixant (150, 300, 450 mg) or placebo. During this part of the trial, dose escalation of sivopixant will stop for each participant if an intolerable taste disturbance, a known dose-limiting effect of sivopixant, or other substantial safety or tolerability issue is identified, with subsequent continued dosing at the preceding lower dose. In PART B, acetazolamide 500 mg will first be tested alone to confirm and quantify prior reports of efficacy, followed by testing in combination with sivopixant, initially at a dose of 150 mg and subsequently at a dose 450 mg (or at the highest well-tolerated identified for the patient in PART A). Participants who do not tolerate acetazolamide 500 mg in the initial period of PART B can be reduced to 250 mg (assuming non-serious, non-severe tolerability issues related to 500 mg). For participants who reduce to 250 mg, subsequent combination with sivopixant is with 250 mg acetazolamide.

[0205] During the screening period, home continuous overnight pulse oximetry tests will assist in identifying and excluding patients with a low baseline average oxygen saturation (SpO2<88%) and / or without signs of sleep apnea before patients proceed to the in-lab PSG. Subsequently, eligible patients will be randomly assigned to either active treatment or placebo, in a ratio of 3:1, stratified by subpopulation (uncontrolled hypertension / complex sleep apnea / stable heart failure with reduced ejection fraction / heart failure with preserved ejection fraction and hypertension / persistent atrial fibrillation).

[0206] Patients randomized to active treatment will then receive escalating doses of sivopixant alone followed by acetazolamide and then the combination of sivopixant and acetazolamide, as follows:

[0207] PART A - 3 nights run-in: 150 mg sivopixant dosed at home with continuous pulse oximetry assessment each night. If well tolerated, - 7 nights with 300 mg sivopixant, of which initial 6 nights dosing are at home with continuous pulse oximetry assessment each night, and final 1 night dosing in lab to perform PSG. If well tolerated, 58 60678557.3Attorney Docket No.277901-567842 - 7 nights with 450 mg sivopixant, of which initial 6 nights dosing are at home with continuous pulse oximetry assessment each night, and final 1 night dosing in lab to perform PSG.

[0208] From PART A, the maximum well-tolerated dose for each participant will be determined. After a week without dosing, this maximum dose will be used in PART B, in combination with acetazolamide, as follows:

[0209] PART B - 3 nights of acetazolamide 500 mg alone, of which the initial 2 nights dosing is at home with continuous pulse oximetry assessment each night, and the third night dosing is in lab to perform PSG; participants who do not tolerate acetazolamide 500 mg in the initial period of PART B can be reduced to 250mg. - 3 nights of 500mg acetazolamide + 150mg sivopixant, 3 nights dosing at home with continuous pulse oximetry assessment each night. Participants who do not tolerate acetazolamide 500 mg in the initial period of PART B can be reduced to 250 mg. - 7 nights of 500mg acetazolamide + 450mg sivopixant (or maximum well-tolerated dose of sivopixant), of which initial 6 nights dosing is at home with continuous pulse oximetry assessment each night, and 1 night dosing in hospital to perform PSG. Participants who do not tolerate acetazolamide 500 mg in the initial period of PART B can be reduced to 250 mg.

[0210] Dosing of study drug occurs approximately 30 minutes before bedtime.

[0211] Dose escalation will be based on tolerability and safety, as assessed at clinic visits, telephone contacts with participants, and at-home pulse-oximetry.

[0212] The Schedule of Activities (SoA) is shown below. 59 60678557.34 )gnisodBtra P tuohsa W gnisodagaAtr ,40 )xilap bonerrow uytnr duar)na d VGS 12X X X X oolmsaeo P3eotmh of oi05d7P+(vig sto aos tans rihanoll100eg=eiyloMspese-tw aeitiurb V 3ni )VtS tmaos 9-2X Xpmr,hchtloiflAhod 1+(S;ep ==oeGct sluaegnS eaidiCSupfoirrtu man m-IP O,et sdoctd oitalG;ldao P ic etracyiadun deOazi zm3 1at;eno V X X Xeuuolopepir 2 mrt yoherftluli 26dcgicR na t nirereae afa R=ah fcZrr t evepH troan eru e eb yae / gA fe it ssno lbh yse aerhlide(tni en;ttni nir Pr la= p pew tlkc sael tereersG2 SV X X X XevevciSIdo et eenetca Pe eS B1es sfdeolMb ybocnitw- e fo / g–)2reo mOden d Rtanadim bllsenosi et +(vdoieinfiP;espic lliawaeen eil 28a12-=ssdloaietd itr c stsircesOp V X X Eer u ap1n mnlcpyleidg Sa B SA:smei =toni stntaninlpscO p ylSaC Ir 9 / 01ob Rg natngin.seelred s M,a,er )peO8ao gnl-8fC8 irlawtite-eCRelsnotCeinaatiolig Mirsn vtm;aelaoc itbtibign ietivitiluEd ud w Rcu-IMipvrmoiernelV8S9ca01naeco elP norya dsniSI,a ag8biGacgi n-rtaP,mou-etotabeitu fSds sln ae atimwni cn o’occibtaad clihdA p ScP Dw(M OntesiSI-I aen p V E Allstn / r e .3RmrdpMG Puso , gy Feio m7DS / tair 5PiaeeO RSitE P P58plSafA7msP i E606Attorney Docket No.277901-567842

[0213] Investigational Product ^ Sivopixant tablets or matching placebo, 150 mg ^ Acetazolamide tablets, over-encapsulated or matching placebo 250 mg

[0214] Participants

[0215] A total of about 60 participants will be enrolled. Our target population will be selected among cardiology clinics or sleep centers, in the following 5 main subpopulations, with a goal of similar proportion amongst subpopulations. ^ Stable heart failure with reduced ejection fraction (NYHA class 1-3 inclusive) with or without atrial fibrillation ^ Heart failure with preserved ejection fraction (NYHA class 1-3 inclusive) and hypertension (BP>120 / 80 mmHg at screening visit despite the treatment with ≥2 antihypertensives) with or without atrial fibrillation ^ Persistent atrial fibrillation (continuous and sustained for more than 7 days, rate controlled with resting HR<100bpm)1without heart failure ^ History of primary (essential) hypertension with BP at screening visit >130 / 80 mmHg despite the treatment with >2 antihypertensives ^ Evidence of complex sleep apnea (CPAP-emergent central sleep apnea with documented CAI>5 events / h on CPAP within 1 year from screening) Participants who fit more than 1 subpopulation category can enroll.

[0216] Safety Monitoring 63 60678557.3Attorney Docket No.277901-567842 ^ AE / SAE monitoring, clinical laboratory, pregnancies, 12-lead ECG, physical exam including vital signs, mMRC dyspnea scale. ^ Home continuous overnight pulse oximetry will be monitored by the central scoring center daily for overnight desaturation events that are deemed adverse events, e.g. due to depth, duration, frequency, and similarly for changes in pulse that are considered adverse events. Daily reports of home continuous overnight pulse oximetry will be sent to sites by the central scoring center. Home pulse oximetry data will be examined prior to any dose escalation and between PART A and PART B. ^ In-lab PSG will be monitored for events on any recording channel or per observation of the technician that would be classified as adverse events, including desaturations, arrhythmias, EEG activity, PCO2 monitoring (if available at the site) or abnormality of patient mental status or behavior. ^ All skin reactions will be evaluated as potentially representing an initial sign of a more serious reaction (Stevens-Johnson Syndrome), and investigational medicinal product (IMP) will be discontinued as appropriate. ^ Abnormal laboratory values will be evaluated as representing potentially an initial sign of more serious reactions (fulminant hepatic necrosis, agranulocytosis, aplastic anemia, other blood dyscrasias, and anaphylaxis), and IMP will be discontinued as appropriate.

[0217] Individual, Subgroup, and Overall Study Dose Escalation / Reduction and Stopping Criteria

[0218] A Dose Escalation and Safety Committee will evaluate data for each patient prior to dose-escalations and will evaluate aggregate data to determine continued subgroup enrollment and overall study continuation.

[0219] Individual Participant Criteria ^ Within-patient dose escalation in PART A, dose escalation will stop for an individual patient if intolerable taste disturbance or other safety or tolerability issue is identified that is considered dose-limiting. Subsequent dosing for that patient may proceed at the preceding lower dose, if otherwise considered safe. ^ Participants who do not tolerate acetazolamide 500 mg in the initial period of PART B can be reduced to 250 mg (assuming non-serious, non-severe tolerability issues related to 500 mg). 64 60678557.3Attorney Docket No.277901-567842 For participants who reduce to 250 mg, subsequent combination with sivopixant is with 250 mg acetazolamide. ^ Individual patient dosing is stopped for any serious adverse event or CTCAE grade ≥ 3 AEs, regardless of causality determination, and would result in study drug discontinuation, with subsequent safety review, or any other adverse event that is considered to place the patient at unreasonable risk of harm unless dosing is discontinued. ^ The following findings from the home continuous overnight pulse oximetry will determine dose reduction or discontinuation for a participant: o >4% worsening of average oxygen saturation from baseline, or o Average SpO2 is <86%, or o ODI4 averaged between nights on the same IP dose is >90 events / h, accompanied toby consistent worsening of time spent in SpO2≤90% (T90) and average SpO2, or o HR averaged between nights on the same IP dose is >120 bpm or is increased by >20bpm from baseline.

[0220] Subgroup Stopping Criteria ^ Safety will be evaluated on an ongoing basis according to subgroup (i.e. uncontrolled hypertension / complex sleep apnea / stable heart failure with reduced ejection fraction / heart failure with preserved ejection fraction and hypertension / persistent atrial fibrillation); additional enrolment in that subgroup may be paused or stopped if the severity or frequency of adverse events is considered predictive of unacceptable tolerability in patients with similar baseline characteristics. Any similar serious or CTCAE grade ≥ 3 AEs in >1 patient would result in enrollment pause and dosing termination for that subgroup, pending safety data review ^ Worsening clinical CHF status using NYHA criteria, uncontrolled arrhythmias, loss of rate control in atrial fibrillation, myocardial infarction, unstable angina, elevated troponin levels (cTnT and cTnI) above the 99thpercentile upper reference limit, and >4% worsening of average oxygen saturation during sleep from baseline or average SpO2 during sleep <86% will be considered stopping criteria in subgroups and individual subjects. ^ Pausing or stopping enrollment or dosing of a subgroup will not affect enrollment or dosing of other subgroups if ongoing safety is considered acceptable in those subgroups. 65 60678557.3Attorney Docket No.277901-567842 ^ The overall enrollment of the study will continue to approximately 60 so long as the safety of additional enrollment and dosing is considered acceptable for at least one of the study subgroups.

[0221] Overall Study Stopping Criteria ^ Dosing of all study patients will be stopped if similar serious or CTCAE grade ≥3 adverse events occur in >1 patient in different subgroups in a manner that suggests risk in other patients without regard to disease subgroup (i.e. uncontrolled hypertension / complex sleep apnea / stable heart failure with reduced ejection fraction / heart failure with preserved ejection fraction and hypertension / persistent atrial fibrillation) or other baseline disease characteristics.

[0222] Endpoints Endpoints nd on. s60678557.3Attorney Docket No.277901-567842Safety Endpoints^ Home pulse oximetry^ Physical exam, vital signs, clinical laboratory assessment % ea = S n, p p study designed to test safety, tolerability and efficacy of escalating doses of sivopixant taken alone and in combination with acetazolamide. While the schedule for visits and dose escalations is designed to occur in a continuous manner, it will be possible, with prior approval from either the medical monitor or the sponsor, to introduce gaps between dose escalations or extend the washout period, as deemed necessary for patient safety or to facilitate visit scheduling.

[0225] Pre-screening

[0226] Participants will undergo initial pre-screening to determine potential study eligibility.

[0227] Participants selected for further screening should have: 1. A previous history of OSA, CSA, or a high clinical suspicion (e.g. as assessed by STOP-Bang Questionnaire score) AND 2. Suffer from at least one of the following comorbidities: i. Stable heart failure with reduced ejection fraction (NYHA class 1-3 inclusive) with or without atrial fibrillation ii. Heart failure with preserved ejection fraction (NYHA class 1-3 inclusive) and hypertension (BP>120 / 80 mmHg at screening visit despite the treatment with ≥2 antihypertensives) with or without atrial fibrillation iii. Persistent atrial fibrillation ((continuous and sustained for more than 7 days, rate controlled with resting HR<100bpm)1) without heart failure iv. History of primary (essential) hypertension with BP at screening visit >130 / 80 mmHg despite the treatment with >2 antihypertensives 67 60678557.3Attorney Docket No.277901-567842 v. Evidence of complex sleep apnea (CPAP-emergent central sleep apnea with documented CAI>5 events / h on CPAP within 1 year from screening)

[0228] Visit 1 (screening)

[0229] Individuals who remain eligible for the study following pre-screening attend Visit 1. The following activities occur at Visit 1: ^ Informed consent o Per Good Clinical Practice (GCP) guidelines when conducting a trial, the patient’s primary care provider should be informed about the subject’s enrollment in the trial, after obtaining the subjects consent to release this information. ^ After consent, contact information is recorded for the patient’s primary care provider and the investigator informs the provider about the participant’s involvement in the study. Being under the care of a primary care provider is not required for participation in the study but should be encouraged. o Per GCP, during and following a subject’s participation in the trial the investigator should inform a participant when medical care is needed for intercurrent illness(es) of which the investigator becomes aware (including medical conditions present at baseline that may require ongoing management such as hypertension or diabetes). ^ Demographics and medical history, including medications and history of PAP use or other treatments for OSA. ^ Physical examination (General Appearance Dermatologic, Head, Eyes, Ears, Nose, Mouth / Throat / Neck, Thyroid, Lymph Nodes, Respiratory, Cardiovascular, Gastrointestinal, Extremities, Musculoskeletal, Neurologic, Psychiatric), height, weight, vital signs, clinical laboratory testing, urine drugs of abuse test, pregnancy test, 12-lead ECG ^ Participants at V1 receive a validated device assessing continuous pulse oximetry, connected to an app that is downloaded to the patient compatible smartphone. They are instructed to perform three overnight SpO2 assessments at home immediately following V1. The results of these pulse oximeter tests will be accessible to the investigator the day after recording through web-based software linked to the smartphone app. The central scoring center will provide the site with a report at the end of baseline home pulse oximeter assessments, summarizing findings and eligibility status of the subject. If the average oxygen desaturation index (ODI4, representing the number of desaturations ≥4% per hour of sleep) from the three assessments is between 7 and 55 68 60678557.3Attorney Docket No.277901-567842 events / h, inclusive, and the average overnight SpO2 is ≥88%, participants will be contacted by the site to undergo an in-lab PSG; if these criteria are not met, the participant is discontinued from screening and is asked to ship or deliver back the pulse oximeter device to the site. If deemed eligible, the pulse oximetry assessments conducted during screening will serve as a baseline for future at-home on-treatment assessments.

[0230] Visit 2 (PSG)

[0231] Participants who meet all non-PSG enrollment criteria at V1 and pass home oximetry assessments are eligible for the screening / baseline PSG at Visit 2. The following activities occur at Visit 2: ^ Medical and concomitant therapy (medication or device) monitoring ^ Vital signs (triplicate blood pressure, heart rate, respiratory rate, body temperature) are measured both the evening of admission to the PSG lab (day 1 of visit) and the morning after the PSG (day 2 of visit). ^ Overnight urine collection for urinary catecholamine assessment, from arrival to the sleep lab in the evening to discharge in the morning. ^ PSG with ring pulse oximetry; V2 PSG will serve as baseline for calculation of PSG efficacy outcomes. The patients will be required to bring to the visit the ring pulse oximeter provided by the sponsor during the screening and the associated mobile device. The ring pulse oximeter will be used in addition to the native PSG pulse oximeter for research and comparison purposes. ^ The following PROs are assessed the evening of the PSG - ESS, PROMIS-Fatigue-8a, PROMIS-Sleep Impairment-8a, PROMIS-Sleep Disturbance-8a, mMRC, and PGI items.

[0232] Visit 2 PSG data are sent to the central PSG reading center. The central scoring center contacts the site typically within 1 week with PSG results and whether the participant remains eligible for the study, and the site schedules the participant for Visit 3 or notifies the participant of ineligibility for the study, accordingly.

[0233] If the AHI4 (hypopneas defined by 4% oxygen desaturation) of the V2 PSG is ≥10 and ≤60 events / h, ≥25% of apneas are central or mixed, with a minimum of 2.5 events / h of central apnea / index, average SpO2 during sleep is ≥88%, OR if the patient exhibits a pattern of Cheney- Stokes breathing sustained for at least 15 minutes during sleep, OR if the analysis of the 69 60678557.3Attorney Docket No.277901-567842 respiratory flow pattern shows OSA with a loop gain (LGn)>0.5, even in absence of CSA the patient is eligible. The screening PSG may be repeated under certain circumstances if deemed inadequate to determine participant eligibility, such as inadequate sleep time.

[0234] Participants who meet all enrollment criteria will complete a qualitative 45-minute interview via audio conferencing with Health Outcomes Solutions (HOS), a consulting firm with expertise in qualitative research. The interview will be conducted after the site confirms eligibility into the study, but prior to randomization. The interview is being conducted to better understand the symptoms of sleep apnea and to evaluate the content, clarity, and relevance of the PROs (ESS, PROMIS-Fatigue-8a, PROMIS-Sleep Impairment-8a, PROMIS-Sleep Disturbance- 8a [SDM1], PGI items, and mMRC).

[0235] Visit 3 (Randomization)

[0236] Only individuals who are found to be eligible on all enrollment criteria continue to Visit 3. The following activities occur at Visit 3 for patients with eligible PSG results: ^ Medical and concomitant therapy (medication or device) monitoring. ^ Vital signs (triplicate blood pressure, heart rate, respiratory rate, body temperature). ^ Randomization to one of 2 parallel treatment arms in PART A of the study, with a ratio of 3:1 for sivopixant vs placebo. ^ Participants are instructed on IMP dosing and IMP is dispensed before discharge. The IMP is dispensed as a blister package including a lower run-in dose of sivopixant 150mg or matching placebo for the first 3 days followed by 300 mg of sivopixant or matching placebo. ^ 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 (and at lights out at PSG visits). o Reminder to perform at-home overnight pulse oximeter every night the IMP is taken.

[0237] PART A, first 9-days at home escalation dosing

[0238] Participants dose study drug each night at home immediately prior to lights out for the first 9 days (3 days for the 150mg run-in period and 6 days at 300mg) or matching placebo.

[0239] Every night at home, randomized patients perform a continuous pulse oximetry recording using a validated device connected to a smartphone app. Results will be readily 70 60678557.3Attorney Docket No.277901-567842 available for next-day reading at the sites and will be used to monitor potential adverse events of the treatments while at home. Adverse events, concomitant medication monitoring and review of study procedures and visit schedule will occur by telephone every 2 days of each at-home dosing period, starting the day after the first at home night dosing.

[0240] Within-patient dose escalation of sivopixant in PART A is stopped for an individual patient if an intolerable taste disturbance or other safety or tolerability issue emerging from at- home pulse oximetry data, phone calls and inpatient visits is identified that is considered dose- limiting. Subsequent dosing for that patient is at the preceding lower dose, if otherwise considered safe. A Dose Escalation and Safety Committee composed by the site PI and two medical monitors from the Sponsor side will evaluate data for each patient prior to dose- escalations to determine continued subgroup enrollment and overall study continuation.

[0241] The following findings from the home continuous overnight pulse oximetry will determine dose reduction or discontinuation for a participant: ^ >4% worsening of average oxygen saturation from baseline, or ^ Average SpO2 is <86%, or ^ ODI4 averaged between nights on the same IP dose is >90 events / h, accompanied by consistent worsening of time spent in SpO2≤90% (T90) and average SpO2, or ^ HR averaged between nights on the same IP dose is >120 bpm or is increased by >20bpm from baseline.

[0242] Visit 4

[0243] At completion of the 6 days 300 mg period, participants return for an inpatient PSG at V4. Any unused drugs from the previous period are collected, and participants are evaluated for drug safety and tolerability. If the participant arrives at the site without previously dispensed IMP, the IMP should be retrieved whenever practicable. If previously dispensed IMP is determined to be not available for dosing, the site can access replacement IMP for dosing. One dose of IMP is taken by the participant under observation by site personnel, at lights out at the start of the PSG. The following activities occur at V4: ^ AE / SAE and concomitant therapy (medication or device) monitoring. ^ Vital signs (triplicate blood pressure, heart rate, respiratory rate, body temperature) are measured both the evening of admission to the PSG lab (day 1 of visit) and the morning after the PSG (day 2 of visit); after an initial measurement in sitting position, blood pressure is also 71 60678557.3Attorney Docket No.277901-567842 measured after 5 minutes supine (1 measurement) and within 3 minutes after standing (1 measurement); weight is also assessed. ^ Overnight urine collection for urinary catecholamine assessment, from arrival to the sleep lab in the evening to discharge in the morning. ^ PSG with ring pulse oximetry, with IMP dosing. The patients will be required to bring to the visit the ring pulse oximeter provided by the sponsor during the screening and the associated mobile device. The ring pulse oximeter will be used in addition to the native PSG pulse oximeter for research and comparison purposes. ^ The following PROs are assessed the evening of the PSG: ESS, PROMIS-Fatigue-8a, PROMIS-Sleep Impairment-8a, PROMIS-Sleep Disturbance-8a, mMRC and PGI items. ^ Drug accountability. ^ Review of study procedures and future study visits. V4 PSG data is sent to the central PSG reading center; findings of V4 PSG do not affect subsequent study activities. Drug for the remaining seven days of PART A is dispensed at Visit 4.

[0244] PART A, 6-days at home at maximum dosing

[0245] After the safety committee confirm the patient eligibility for dose escalation, participants dose study drug each night at home immediately prior to lights out for 6 days at 450mg or matching placebo.

[0246] Every night at home, randomized patients perform a continuous pulse oximetry recording using a validated device connected to a smartphone app. Results will be readily available for next-day reading at the sites and will be used to monitor potential adverse events of the treatments while at home. Adverse events, concomitant medication monitoring and review of study procedures and visit schedule occur by telephone every 2 days of each at-home dosing period, starting the day after the first at home night dosing.

[0247] Visit 5

[0248] At completion of the 6 days 450 mg period, participants return for an inpatient PSG at V5. Any unused drug from the previous period is collected, and participants are evaluated for drug safety and tolerability. If the participant arrives at the site without previously dispensed IMP, the IMP should be retrieved whenever practicable. If previously dispensed IMP is determined to be not available for dosing, the site can access replacement IMP for dosing. One 72 60678557.3Attorney Docket No.277901-567842 dose of IMP is taken by the participant under observation by site personnel, at lights out at the start of the PSG.

[0249] The following activities occur at V5: ^ AE / SAE and concomitant therapy (medication or device) monitoring. ^ Vital signs (triplicate blood pressure, heart rate, respiratory rate, body temperature) are measured both the evening of admission to the PSG lab (day 1 of visit) and the morning after the PSG (day 2 of visit); after an initial measurement in sitting position, blood pressure is also measured after 5 minutes supine (1 measurement) and within 3 minutes after standing (1 measurement); weight is also assessed. ^ Overnight urine collection for urinary catecholamine assessment, from arrival to the sleep lab in the evening to discharge in the morning. ^ PSG with ring pulse oximetry, with IMP dosing. The patients will be required to bring to the visit the ring pulse oximeter provided by the sponsor during the screening and the associated mobile device. The ring pulse oximeter will be used in addition to the native PSG pulse oximeter for research and comparison purposes. ^ The following PROs are assessed the evening of the PSG: - ESS, PROMIS-Fatigue-8a, PROMIS-Sleep Impairment-8a, PROMIS-Sleep Disturbance-8a, mMRC and PGI items. ^ Drug accountability. ^ Review of study procedures and future study visits. V5 PSG data is sent to the central PSG reading center; findings of V5 PSG do not affect subsequent study activities. Drug for the following 3 days of PART B, to be taken after a washout period of 7 days, is dispensed at Visit 5.

[0250] PART B, first 2-days of home dosing

[0251] The study drug (either acetazolamide or placebo) is provided to randomized participants on the morning after the PSG at Visit 5. After 1-week washout period, there is an initial 3-day randomized drug treatment period. Participants are instructed to take the study drug each night at home right before bedtime for these 2 days and 1 day in hospital before the PSG.

[0252] Every night at home, randomized patients perform a continuous pulse oximetry recording using a validated device connected to a smartphone app. Results are readily available 73 60678557.3Attorney Docket No.277901-567842 for next-day reading at the sites and will be used to monitor potential adverse events of the treatments while at home. Adverse events, concomitant medication monitoring and review of study procedures and visit schedule will occur by telephone the day after the first at home night dosing.

[0253] Visit 6 After completing the 2-day regimen of acetazolamide at 500 mg, participants return for an inpatient PSG at Visit 6. Any unused medication is collected, and participants undergo evaluation for drug safety and tolerability. If the participant arrives at the site without previously dispensed IMP, the IMP should be retrieved whenever practicable. If previously dispensed IMP is determined to be not available for dosing, the site can access replacement IMP for dosing. One dose of IMP is taken by the participant under observation by site personnel, at lights out at the start of the PSG. The following activities occur at V6: ^ AE / SAE and concomitant therapy (medication or device) monitoring. ^ Vital signs (triplicate blood pressure, heart rate, respiratory rate, body temperature) are measured both the evening of admission to the PSG lab (day 1 of visit) and the morning after the PSG (day 2 of visit); after an initial measurement in sitting position, blood pressure is also measured after 5 minutes supine (1 measurement) and within 3 minutes after standing (1 measurement); weight is also assessed. ^ Overnight urine collection for urinary catecholamine assessment, from arrival to the sleep lab in the evening to discharge in the morning. ^ PSG with ring pulse oximetry, with IMP dosing. The patients will be required to bring to the visit the ring pulse oximeter provided by the sponsor during the screening and the associated mobile device. The ring pulse oximeter will be used in addition to the native PSG pulse oximeter for research and comparison purposes. ^ The following PROs are assessed the evening of the PSG: - ESS, PROMIS-Fatigue-8a, PROMIS-Sleep Impairment-8a, PROMIS-Sleep Disturbance-8a, mMRC and PGI items. ^ Drug accountability. ^ Review of study procedures and future study visits. V6 PSG data is sent to the central PSG reading center. 74 60678557.3Attorney Docket No.277901-567842 Drug for the remaining 10 days of the study are dispensed at Visit 6. Participants who do not tolerate acetazolamide 500 mg in the initial period of PART B can be reduced to 250 mg (assuming non-serious, non-severe tolerability issues related to 500 mg). For participants who reduce to 250 mg, subsequent combination with sivopixant is with 250 mg acetazolamide.

[0254] PART B, 9-days of home escalation dosing

[0255] Participants are instructed to take the study drug each night at home right before bedtime for the following 9 days starting with a regimen of acetazolamide 500 + sivopixant 150mg for 3 nights and followed by acetazolamide 500 + sivopixant 450mg for 6 nights. Acetazolamide can be reduced to 250mg if the 500mg dose was not tolerated in the previous 3 days. Sivopixant 450 mg can be lowered to a better tolerated dose determined in PART A.

[0256] Every night at home, randomized patients perform a continuous pulse oximetry recording using a validated device connected to a smartphone app. Results will be readily available for next-day reading at the sites and are used to monitor potential adverse events of the treatments while at home. Adverse events, concomitant medication monitoring and review of study procedures and visit schedule occur by telephone every 2 days, starting the day after the first at-home night dosing.

[0257] Within-patient dose escalation of sivopixant in PART B will stop for an individual patient if intolerable taste disturbance or other safety or tolerability issue is identified that is considered dose-limiting. Subsequent dosing for that patient is at the preceding lower dose, if otherwise considered safe.

[0258] The following findings from the home continuous overnight pulse oximetry will determine dose reduction or discontinuation for a participant: ^ >4% worsening of average oxygen saturation from baseline, or ^ Average SpO2 is <86%, or ^ ODI4 averaged between nights on the same IP dose is >90 events / h, accompanied by consistent worsening of time spent in SpO2≤90% (T90) and average SpO2, or ^ HR averaged between nights on the same IP dose is >120 bpm or is increased by >20bpm from baseline.

[0259] Visit 7

[0260] After 9 days of at-home dosing with sivopixant (3 days at 150 mg and 6 days at 450 mg or lower tolerated dose determined from Part A) + acetazolamide 500mg (or 250mg) study drug, 75 60678557.3Attorney Docket No.277901-567842 participants return with their study drug for an inpatient PSG at V7. Any unused medication is collected, and participants undergo evaluation for drug safety and tolerability. If the participant arrives at the site without previously dispensed IMP, the IMP should be retrieved whenever practicable. If previously dispensed IMP is determined to be not available for dosing, the site can access replacement IMP for dosing. One dose of IMP is taken by the participant under observation by site personnel, at lights out at the start of the PSG. The following activities occur at V7: ^ AE / SAE and concomitant therapy (medication or device) monitoring. ^ Vital signs (triplicate blood pressure, heart rate, respiratory rate, body temperature) are measured both the evening of admission to the PSG lab (day 1 of visit) and the morning after the PSG (day 2 of visit); after an initial measurement in sitting position, blood pressure is also measured after 5 minutes supine (1 measurement) and within 3 minutes after standing (1 measurement); weight is also assessed. ^ Overnight urine collection for urinary catecholamine assessment, from arrival to the sleep lab in the evening to discharge in the morning. ^ PSG with ring pulse oximetry, with IMP dosing. The patients will be required to bring to the visit the ring pulse oximeter provided by the sponsor during the screening and the associated mobile device. The ring pulse oximeter will be used in addition to the native PSG pulse oximeter for research and comparison purposes. ^ The following PROs are assessed the evening of the PSG: - ESS, PROMIS-Fatigue-8a, PROMIS-Sleep Impairment-8a, PROMIS-Sleep Disturbance-8a, mMRC and PGI items. ^ Drug accountability. ^ Review of study procedures and future study visits. V7 PSG data is sent to the central PSG reading center.

[0261] End of Study call

[0262] An End of Study call is conducted after 1 week following the end of study drug dosing to collect AE / SAE (including possible effects of drug discontinuation) and concomitant therapy (medication or device) monitoring. Overall study duration will be up to 10 weeks. A total of 60 participants will be enrolled, with 3:1 ratio of active treatment vs placebo.

[0263] The study schema is shown in FIG.4. 76 60678557.3Attorney Docket No.277901-567842

[0264] Study Population

[0265] Eligible 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 to the community.

[0266] Participants must be able to provide written consent and meet all the inclusion criteria and none of the exclusion criteria.

[0267] Inclusion Criteria Age and Sex 1. ≥18 and ≤85 years of age for both men and women at the time of informed consent. Medical conditions 2. To enroll, subjects need to have a previous diagnosis of at least one or more of the following comorbidities - Stable heart failure with reduced ejection fraction (NYHA class 1-3 inclusive) with or without atrial fibrillation - Heart failure with preserved ejection fraction (NYHA class 1-3 inclusive) and hypertension (BP>120 / 80 mmHg at screening visit despite the treatment with ≥2 antihypertensives) with or without atrial fibrillation - Persistent atrial fibrillation (continuous and sustained for more than 7 days, rate controlled with resting HR<100bpm)1without heart failure - History of primary (essential) hypertension with BP at screening visit >130 / 80 mmHg despite the treatment with >2 antihypertensives - Evidence of complex sleep apnea (CPAP-emergent central sleep apnea with documented CAI>5 events / h on CPAP within 1 year from screening) 3. Standard care for heart failure and atrial fibrillation for at least 3 weeks before the screening visit OSA measures 4. Average ODI4 between 7 and 55 events / h, inclusive, and average SpO2 ≥88% from continuous home pulse oximetry recordings at screening. 5. AHI4 (Hypopneas defined by 4% oxygen desaturation) of >10 to ≤60 events / h 77 60678557.3Attorney Docket No.277901-567842 a. At minimum of 25% central or mixed apneas (as proportion of total apneas) with a minimum of 2.5 central or mixed apneas / hour of sleep b. OR evidence of clear Cheyne-Stokes breathing pattern during the baseline PSG (regardless of central apnea component). c. OR evidence of OSA with LGn >0.5 at the baseline PSG (regardless of central apnea component) 6. Average SpO2 during sleep ≥88% Weight 7. BMI between 18.5 and 40 kg / m2for men, or 42 kg / m2for women, inclusive Male participants 8. If male and sexually active with female partner(s) of childbearing potential, participant must agree, from Study Day 1 through 1 week after the last dose of study drug, to practice the protocol specified contraception. Male participants must refrain from donating sperm for the duration of the study and for 3 months after the last dose of study treatment. Female participants 9. If a woman of childbearing potential (WOCBP), the participant must agree, from Study Day 1 through 1 week after the last dose of study drug, to practice the protocol specified contraception. All WOCBP must have negative result of a serum pregnancy test performed at screening. 10. If female and of non-childbearing potential, the participant must be either postmenopausal or permanently sterile (e.g. bilateral oophorectomy, bilateral salpingectomy or hysterectomy). Informed Consent 11. Participant voluntarily agrees to participate in this study and signs an Institutional Review Board (IRB)-approved informed consent prior to performing any of the Screening Visit procedures. 12. Participant must be able to understand the nature of the study and must have the opportunity to have any questions answered. 13. Patients currently using PAP will be eligible for inclusion in the study if they express willingness to discontinue treatment for a minimum of 7 days before baseline SpO2 assessments, until the study completion.

[0268] Exclusion criteria Vital signs and symptoms 78 60678557.3Attorney Docket No.277901-567842 1. Sustained SpO2<93% during wakefulness or mean SpO2<88% during sleep, calculated from PSG at screening 2. Dyspnea at rest or patients with heart failure class IV NYHA 3. Blood pressure <90 / 50 mmHg or >160 / 100 mmHg at V1. Medical Conditions 4. Recent (<3 months) episode of acute myocardial infarction or acute decompensated heart failure. 5. History of stroke. 6. History of sustained ventricular tachyarrhythmias or other severe arrhythmias without defibrillator implanted. 7. Heart failure primarily caused by valvular, post-partum cardiomyopathy or active myocarditis 8. History of obesity-hypoventilation syndrome or respiratory disturbance due to opioids. 9. History of bronchiectasis and uncontrolled asthma. 10. History of severe chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted (European Respiratory Society criteria) 11. Started treatment with 13-blockers <3 months before screening. Patients not taking 13- blockers or taking 13-blockers for >3 months can be enrolled. 12. Narcolepsy, restless leg syndrome requiring medication, REM sleep behavior disorder. 13. Pronounced anatomical abnormalities of upper airway (adenoid vegetations, grade ≥3 tonsillar hypertrophy, etc.), pronounced micrognathia, or pronounced incomplete development of the lower jaw. 14. History of schizophrenia, schizoaffective disorder or bipolar disorder according to Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) or International Classification of Disease tenth edition criteria. 15. Medically unexplained positive screen for drugs of abuse (excluding THC / marijuana) or history of substance use disorder as defined in DSM-V within 24 months prior to Screening Visit. 16. A significant illness or infection requiring medical treatment in the past 30 days as determined by investigator. 17. Clinically significant cognitive dysfunction as determined by investigator. 79 60678557.3Attorney Docket No.277901-567842 18. Women who are pregnant or nursing. 19. History of kidney stones Prior / Concomitant Therapy 20. 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 1 week before the baseline SpO2 assessments and are not used during participation in the study (through V7). Patients that are non-compliant to CPAP (less than 4hr / night for 5 days / week) can be enrolled, as well as patients who are naïve to PAP and patients who discontinued PAP previously. PAP compliant patients cannot be enrolled. 21. History of chronic oxygen therapy. 22. Concomitant use of medications from the list of disallowed medications. Prior / Concurrent Clinical Study Experience 23. Use of another investigational agent within 30 days or 5 half-lives, whichever is longer, prior to dosing. Diagnostic Assessments 24. Hepatic cirrhosis, hepatictransaminases > 2X the upper limit of normal (ULN), total bilirubin >1.5X ULN (unless confirmed Gilbert syndrome), estimated glomerular filtration rate < 40 ml / min. 25. Participants with reduced sodium and / or potassium blood serum levels. 26. Participants with suprarenal gland failure. 27. Participants with hyperchloremic acidosis. Other Exclusions 28. Night- or shift-work sleep schedule which causes the major sleep period to be during the day. 29. Employment as a commercial driver or operator of heavy or hazardous equipment. 30. Typically smoking more than 10 cigarettes or 2 cigars per day, or inability to abstain from smoking during overnight PSG visits. 31. Unwilling to use specified contraception. 32. History of regular alcohol consumption of more than 14 standard units per week (males) or more than 7 standard units per week (females), or unwillingness to limit alcohol consumption 80 60678557.3Attorney Docket No.277901-567842 to no greater than 2 units / day (males), 1 unit per day (females). Alcohol is not to be consumed within 3 hours of bedtime or on PSG nights. 33. Unwilling to agree to limit during the study period caffeinated beverage intake (e.g., coffee, cola, tea) to 400 mg / day or less of caffeine, not to be used within 3 hours of bedtime. 34. Any condition that in the investigator’s opinion would present an unreasonable risk to the participant, including recent (<1 year) motor vehicle accident due to drowsy driving, or which would interfere with their participation in the study or confound study interpretation. 35. Participant considered by the investigator, for any reason, an unsuitable candidate to receive sivopixant or acetazolamide or unable or unlikely to understand or comply with the dosing schedule or study evaluations. 36. Allergy to study drugs

[0269] Meals, Dietary and Surgical Restrictions

[0270] Diet should be generally stable during the study, e.g., new diet programs should not be initiated. Patients should not undergo any elective surgeries that could potentially affect the primary endpoint during the course of the study.

[0271] Caffeine, Alcohol, and Tobacco 1. During the outpatient portions of the study, participants should refrain from more than 2 standard units per day for men or 1 unit / day for women of alcohol, consumed no less than 3 hours prior to bedtime. Alcohol should not be consumed on PSG nights. 2. Moderate consumption of caffeinated beverages, containing up to a total of 400 mg of caffeine per day (e.g. four 8 oz. cups of coffee), is permitted during the study period, consumed no less than 3 hours prior to bedtime. 3. Participants should abstain from smoking or chewing tobacco products during overnight PSG visits.

[0272] Activity

[0273] There are no restrictions on physical activity during the study other than that physical activity should be generally stable during the study (e.g., new exercise programs should not be initiated).

[0274] Screen Failures

[0275] Screen failures are defined as participants who consent to participate in the clinical study but do not meet criteria for participation in the study. Rescreening, or repeating specific 81 60678557.3Attorney Docket No.277901-567842 screening tests, is permitted with prior consent of the Sponsor if initial results were missing or uninterpretable or represented a transient or reversible status, 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. A minimal set of information on all participants who consent to participate 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, reason for screen failure, and any serious adverse events (SAEs).

[0276] Study treatment is defined as any investigational drug(s), marketed product(s), placebo, or medical device(s) intended to be administered to a study participant according to the study protocol.

[0277] Study Drug(s) Administered Study drug is taken 30 mins prior to lights out and consists of either 1 tablet of sivopixant 150 mg, or 2 tablets of sivopixant 150 mg (sivopixant 300mg) or 3 tablets of sivopixant 150 mg (sivopixant 450 mg) plus 1 tablet for Acetazolamide 250mg or 2 tablets acetazolamide 250 mg (See Acetazolamide prescribing information for additional details.). The following formulations are used in this study: Study treatment name Sivopixant Acetazolamide Matching placebo

[0278] Concomitant Therapy

[0279] Concomitant therapy with the medications listed below is disallowed. For medication that is typically used by the participant intermittently, occasionally, or as needed (e.g. occasional 82 60678557.3Attorney Docket No.277901-567842 use of a non-prescription sleep aid), it is sufficient that the medication not be used for at least one week prior to Visit 2 and for the duration of the study. Other disallowed medication would typically preclude enrollment unless the medication can be discontinued at least 1 month prior to Visit 2 without jeopardizing the participant’s health or the stability of the participant’s condition. Digoxin, methyldigoxin, beta-methyldigoxin. Opioids Mecamylamine Methenamine Sodium Phosphates Chronic use of more than 500 mg / day of Aspirin Other carbonic anhydrase inhibitors (zonisamide, topiramate, etc) Lithium Medications with effects on heart function, anticoagulation and GLP-1 RA are generally allowed according to Investigator’s opinion if dose and frequency is stable for 3 months prior to enrollment, including but not limited to the following drug classes: GLP-1 receptor agonists (semaglutide, tirzepatide, liraglutide, exenatide and dulaglutide) if weight loss in the previous 2 months is <5% of their body weight Antihypertensives (angiotensin-converting-enzyme / angiotensin II receptor blocker / neprilysin inhibitors, calcium channel blockers, diuretics, beta-blockers etc.) Anticoagulants (apixaban, dabigatran, edoxaban, rivaroxaban, warfarin) Aldosterone antagonists (spironolactone, eplerenone) Hydralazine and Nitrates If Channel Blockers (ivabradine) Sodium Channel Blockers (flecainide, propafenone, quinidine) Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors (dapagliflozin, empagliflozin)

[0280] Medications that do not have substantial effects on respiration, muscle activity or heart function are generally allowed according to Investigator’s opinion, if dose and frequency is stable for 1 month prior to enrollment and during the course of the study, including, but not necessarily limited to, the following drugs and drug classes: Statins Alpha-1 antagonists (e.g., tamsulosin) 83 60678557.3Attorney Docket No.277901-567842 Chronic use of sedatives - hypnotics Muscle relaxants Antiemetics Proton pump inhibitors and histamine h2 receptor blockers Over-the-counter (OTC) antacids Antihistamines Chronic use of Eszopiclone, zolpidem, or zaleplon Melatonin Non-steroidal anti-inflammatory drugs and acetaminophen Laxatives 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 OTC topicals (e.g., topical pain relievers) Osteoporosis drugs

[0281] Study Assessments and Procedures

[0282] Study procedures and their timing are summarized in the SoA. Adherence to the study design requirements, including those specified in the SoA, is essential and required for study conduct.

[0283] All screening evaluations must be completed and reviewed to confirm that potential participants meet 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.

[0284] The maximum amount of blood collected from each participant over the duration of the study, excluding any extra assessments that may be required for safety or technical issues, will not exceed approximately 110 mL.

[0285] Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the samples, as per the Investigator or designee’s discretion. 84 60678557.3Attorney Docket No.277901-567842

[0286] Safety and Efficacy Scales and Tests ^ 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 ESS score (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. The ESS is administered approximately the same time of day prior to PSG recordings on Visits 2, 4, 5, 6 and 7. ^ PROMIS (Patient-Reported Outcomes Measurement Information System) sleep impairment, sleep disturbance, and fatigue measures were developed with modern 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 corresponded to greater sleep disturbance or sleep-related impairment. The PROMIS measures are administered on Visits 2, 4, 5, 6 and 7, at approximately the same time prior to each PSG recording. ^ The Modified Medical Research Council (mMRC) dyspnea scale is a tool for assessing the severity of dyspnea, or shortness of breath, in individuals with respiratory conditions. This scale categorizes breathlessness into five grades (0 to 4), with higher grades indicating increased impairment. Grade 0 represents no breathlessness, while Grade 4 signifies severe breathlessness that limits the individual's ability to perform daily activities. ^ Patient Global Impression of Change (PGI-C) / Patient Global Impression of Severity (PGI-S) for Fatigue are each single-item scales of the patient’s global, i.e., overall impression of either change from pre-treatment in fatigue (PGI-C) or severity of fatigue proximate to the timepoint measured (PGI-S).

[0287] Polysomnography

[0288] Methods: Standard overnight PSG recording and data interpretation will be performed in accordance with the American Academy of Sleep Medicine (AASM) scoring manual. Participants will be instrumented with standard PSG electrodes. A ring pulse oximeter will be used in addition to the native PSG pulse oximeter for research and comparison purposes. Time of lights out will be established according to the participants’ habitual schedule and kept similar across the PSG study nights. The participants will be given 8 hours of time-in-bed. 85 60678557.3Attorney Docket No.277901-567842

[0289] 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.

[0290] Scoring: PSG studies of randomized participants will be scored by a centralized PSG center, blinded to treatment assignment. PSGs of individuals who are not randomized are not scored centrally.

[0291] Safety Assessments

[0292] Planned time points for all safety assessments are provided in the SoA. Safety monitoring will be guided by the established safety profiles of sivopixant and acetazolamide. Safety assessments will include physical examinations, measurement of vital signs, continuous overnight measurements of SpO2 at home, monitoring and recording of AEs, SAEs, and pregnancies, and recording of study or treatment discontinuations. Effects on OSA-CSA, sleep parameters (e.g., sleep time and sleep stages).

[0293] Physical Examinations

[0294] The general physical examination at screening includes an assessment of general appearance and a review of physical systems (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). Investigators should pay special attention to clinical signs related to previous serious illnesses or surgery.

[0295] Vital Signs

[0296] Assessment of vital signs (seated blood pressure, pulse rate, body temperature, respiratory rate) will be performed at the time points indicated in the SoA.

[0297] Vital signs will be measured at all visits in a seated position after 5 minutes rest and will include temperature, respiratory rate, systolic and diastolic blood pressure, and pulse.

[0298] Measurements should be made in the same arm of the participant at each visit.

[0299] Systolic and diastolic blood pressure will be repeated for a total of 3 measurements, each at least 2 minutes apart in sitting position. In order to detect potential orthostatic hypotension due to treatment, during the treatment visits, BP will be measured after 5 minutes in supine position (1 time) and within 3 minutes from standing (1 time).

[0300] The method used to measure body temperature at screening should be maintained throughout the study for each participant, and should be indicated (e.g., ear, mouth, armpit). 86 60678557.3Attorney Docket No.277901-567842

[0301] Electrocardiograms

[0302] A 12-lead ECG will be obtained 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 semi-supine position after the participant has rested in this position for at least 10 minutes.

[0303] Clinical Safety Laboratory Assessments

[0304] The Investigator must review the laboratory report and document this review. The laboratory reports must be filed with the source documents.

[0305] All protocol-required laboratory assessments must be conducted in accordance with the laboratory manual and the SoA.

[0306] If laboratory values from laboratory assessments not specified in the protocol and performed at the institution’s local laboratory 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.

[0307] Adverse Events and Serious Adverse Events

[0308] Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized representative).

[0309] The Investigator and any qualified designees are responsible for detecting, documenting, and reporting events that meet the definition of an AE or SAE and remain responsible for following up on AEs that are serious, considered related to the study drug or the study, or that caused the participant to discontinue the study and / or study drug.

[0310] Time Period and Frequency for Collecting AE and SAE Information

[0311] All AEs and SAEs will be collected from informed consent until the end of the study at the timepoints specified in the SoA.

[0312] The Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being available.

[0313] 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.

[0314] Pharmacokinetics 87 60678557.3Attorney Docket No.277901-567842

[0315] Dosing of sivopixant and its metabolite sivopixant acyl glucuronide as well as acetazolamide will be assessed in the evening and in the morning of each PSG visit. Evening blood will be obtained before the administration of the medication, while morning blood will be obtained after awakening not to disturb sleep continuity. The dates and times of all administrations and blood draws will be recorded by EDC.

[0316] Statistical Considerations

[0317] Sample Size Determination

[0318] The sample size for this study was adequately powered for the goals of this exploratory, proof-of-concept investigation, to provide meaningful insights into the intervention's potential efficacy and safety profile, laying a foundation for future research.

[0319] From previous experiments of acetazolamide in OSA / CSA (obstructive / central sleep apnea) we can assume that acetazolamide alone at 500mg improves AHI by 35-40% vs placebo. It is hypothesized that Sivopixant could potentially increase the acetazolamide effect by 20-30%. Therefore, the anticipated effect of Sivopixant + 500 mg Acetazolamide vs Baseline is in the range of 42-52%. Assuming an AHI4 baseline value of 20.4 (similar to a previous trial with a population of comparable severity) a 42-52% decrease results in an end of study value of 11.8 to 9.8, which would be change from baseline of 8.6 to 10.6. Therefore, the effect size (Mean Change / SD) to detect is in the range of 0.88(8.6 / 9.8) to 1.08(10.6 / 9.8). With 24 patients in the active arm (Sivopixant + 500 mg Acetazolamide), and assuming a SD of 9.8, the study will have ~80% power to detect a difference from baseline of ~5.7, based on a two-sided 5% alpha level and a paired t-test.

[0320] With 36 patients in the active arm (45 participants minus 20% dropout rate) and assuming an SD of 9.8, the study will have more than 90% power to detect a difference from baseline of 5.7, based on a two-sided 5% alpha level and a paired t-test. Assuming a 20% dropout rate, we will enroll a minimum of 30 patients in the active arm and 10 patients on placebo, and a maximum of 45 patients in the active arm and 15 patients on placebo. The placebo arm will be mostly used for comparison of subjective efficacy, safety and tolerability as exploratory analysis. 88 60678557.3

Claims

Attorney Docket No.277901-567842 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 of (i) P2X3 receptor antagonist and (ii) a carbonic anhydrase inhibitor (CAI).

2. The method of claim 1, wherein the P2X3 receptor antagonist prevents the activation of P2X3 receptors by ATP.

3. The method of claim 2, wherein the P2X3 receptor antagonist is selected from the group consisting of sivopixant, gefapixant, filapixant (BAY1902607), camlipixant, eliapixant (BAY1817080), relicpixant(QR052107B), AF-130, WT-1-2.0, AF-220, AF-221, AF-353, TCR1672, HS-10383, WT-1108, ASN-009, FA-006, P2X3, AZ-1, AZ-2, GA-8SMOL-PAIN, HRS-2261, 12D4, NEO-5024, OSX-300, OSX-300 Backups, piromelatine, RO-85, TDI-06, A- 317491 or a pharmaceutically acceptable salt thereof.

4. The method of claim 1, wherein the P2X3 receptor antagonist is sivopixant or a pharmaceutically acceptable salt thereof.

5. The method of claim 1, wherein the P2X3 receptor antagonist is gefapixant or a pharmaceutically acceptable salt thereof.

6. The method of claim 1, wherein the P2X3 receptor antagonist is filapixant or a pharmaceutically acceptable salt thereof.

7. The method of claim 1, wherein the P2X3 receptor antagonist is camlipixant or a pharmaceutically acceptable salt thereof.

8. The method of claim 1, wherein the CAI is selected from the group consisting of acetazolamide, dichlorophenamide, dorzolamide, brinzolamide, methazolamide, zonisamide, ethoxzolamide, topiramate, xipamide, and sultiame, or a pharmaceutically acceptable salt thereof. 89 60678557.3Attorney Docket No.277901-567842 9. The method of claim 8, wherein the CAI is acetazolamide or a pharmaceutically acceptable salt thereof.

10. The method of claim 8, wherein the CAI is sultiame or a pharmaceutically acceptable salt thereof.

11. The method of any one of claims 1-10, wherein the P2X3 receptor antagonist is sivopixant or a pharmaceutically acceptable salt thereof and is administered at a dose of from about 100 to about 600 mg.

12. The method of claim 11, wherein the sivopixant or pharmaceutically acceptable salt thereof is administered at a dose of from about 150 to about 450 mg.

13. The method of any one of claims 1-9 or 11-12, wherein the CAI is acetazolamide or a pharmaceutically acceptable salt thereof and is administered at a dosage of from about 250 mg to about 750 mg.

14. The method of claim 13, wherein the acetazolamide or pharmaceutically acceptable salt thereof is administered at a dosage of about 500 mg.

15. The method of any one of claims 1-8 or 10-12 wherein the CAI is sultiame or a pharmaceutically acceptable salt thereof and is administered at a dosage of from about 25 mg to about 500 mg.

16. The method of claim 15 wherein the sultiame or pharmaceutically acceptable salt thereof is administered at a dosage of from about 200 mg to about 300 mg.

17. The method of any one of claims 1-16, wherein the P2X3 receptor antagonist and CAI are the sole active agents.

18. The method of any one of claims 1-17, wherein the P2X3 receptor antagonist and CAI are administered in a single composition.

19. The method of claim 18, wherein the single composition is an oral administration form. 90 60678557.3Attorney Docket No.277901-567842 20. The method of claim 19, wherein the oral administration form is a syrup, pill, tablet, troche, or capsule.

21. The method of any one of claims 1-20, wherein the condition associated with pharyngeal airway collapse is sleep apnea.

22. The method of claim 21, wherein the condition associated with pharyngeal airway collapse is obstructive sleep apnea (OSA).

23. The method of any one of claims 1-20, wherein the condition associated with pharyngeal airway collapse is snoring.

24. The method of claim 23, wherein the condition associated with pharyngeal airway collapse is simple snoring.

25. The method of any one of claims 1-20, wherein the condition associated with pharyngeal airway collapse is high-loop gain (high-LG) sleep apnea.

26. The method of any one of claims 1-20, wherein the condition associated with pharyngeal airway collapse is central sleep apnea (CSA).

27. The method of any one of claims 1-20, wherein the condition associated with pharyngeal airway collapse is complex sleep apnea or mixed OSA and CSA.

28. The method of any one of claims 1-20, wherein the condition associated with pharyngeal airway collapse is sleep apnea with a central component.

29. The method of any one of claims 1-28, wherein the subject is in a non-fully conscious state.

30. The method of claim 29, wherein the non-fully conscious state is sleep.

31. A pharmaceutical composition comprising (i) P2X3 receptor antagonist and (ii) a carbonic anhydrase inhibitor (CAI), and (iii) a pharmaceutically acceptable carrier.

32. The pharmaceutical composition of claim 31, wherein the P2X3 receptor antagonist is selected from the group consisting of sivopixant, gefapixant, filapixant (BAY1902607), 91 60678557.3Attorney Docket No.277901-567842 camlipixant, eliapixant (BAY1817080), relicpixant(QR052107B), AF-130, WT-1-2.0, AF-220, AF-221, AF-353, TCR1672, HS-10383, WT-1108, ASN-009, FA-006, P2X3, AZ-1, AZ-2, GA- 8SMOL-PAIN, HRS-2261, 12D4, NEO-5024, OSX-300, OSX-300 Backups, piromelatine, RO- 85, TDI-06, A-317491, or a pharmaceutically acceptable salt thereof.

33. The pharmaceutical composition of claim 31 or 32, wherein the CAI is selected from the group consisting of acetazolamide, dichlorophenamide, dorzolamide, brinzolamide, methazolamide, zonisamide, ethoxzolamide, topiramate, xipamide, and sultiame, or a pharmaceutically acceptable salt thereof.

34. The pharmaceutical composition of any one of claims 31-33, wherein the P2X3 receptor antagonist is sivopixant or a pharmaceutically acceptable salt thereof.

35. The pharmaceutical composition of any one of claims 31-33, wherein the P2X3 receptor antagonist is gefapixant or a pharmaceutically acceptable salt thereof.

36. The pharmaceutical composition of any one of claims 31-33, wherein the P2X3 receptor antagonist is camlipixant or a pharmaceutically acceptable salt thereof.

37. The pharmaceutical composition of any one of claims 31-36, wherein the CAI is acetazolamide or a pharmaceutically acceptable salt thereof.

38. The pharmaceutical composition of any one of claims 31-36, wherein the CAI is sultiame or a pharmaceutically acceptable salt thereof.

39. The pharmaceutical composition of any one of claims 31-38, wherein the P2X3 receptor antagonist is sivopixant or a pharmaceutically acceptable salt thereof and is present in an amount of from about 100 to about 600 mg.

40. The pharmaceutical composition of claim 39, wherein the sivopixant or pharmaceutically acceptable salt thereof is present in an amount of from about 150 to about 450 mg.

41. The pharmaceutical composition of any one of claims 31-37 or 39-40, wherein the CAI is acetazolamide or a pharmaceutically acceptable salt thereof and is present in an amount of from about 250 mg to about 750 mg. 92 60678557.3Attorney Docket No.277901-567842 42. The pharmaceutical composition of claim 41, wherein the acetazolamide or pharmaceutically acceptable salt thereof is present in an amount of about 500 mg.

43. The pharmaceutical composition of any one of claims 31-36 or 38-40, wherein the CAI is sultiame or a pharmaceutically acceptable salt thereof and is present in an amount of from about 25 mg to about 500 mg.

44. The pharmaceutical composition of claim 43, wherein the sultiame or pharmaceutically acceptable salt thereof is present in an amount of from about 200 mg to about 300 mg.

45. The pharmaceutical composition of any one of claims 31-44, wherein the P2X3 receptor antagonist and CAI are the sole active agents.

46. The pharmaceutical composition of any one of claims 31-45, wherein the P2X3 receptor antagonist and CAI are administered in a single composition.

47. The pharmaceutical composition of claim 46, wherein the single composition is an oral administration form.

48. The pharmaceutical composition of claim 47, wherein the oral administration form is a syrup, pill, tablet, troche, or capsule.

49. The pharmaceutical composition of any one of claims 31-48, for use in treating a subject having a condition associated with pharyngeal airway collapse.

50. The pharmaceutical composition of claim 49, wherein the condition associated with pharyngeal airway collapse is sleep apnea.

51. The pharmaceutical composition of claim 50, wherein the condition associated with pharyngeal airway collapse is obstructive sleep apnea (OSA).

52. The pharmaceutical composition of claim 49, wherein the condition associated with pharyngeal airway collapse is snoring.

53. The pharmaceutical composition of claim 52, wherein the condition associated with pharyngeal airway collapse is simple snoring. 93 60678557.3Attorney Docket No.277901-567842 54. The pharmaceutical composition of any one of claims 31-48, for use in treating sleep apnea.

55. The pharmaceutical composition of claim 54, wherein the sleep apnea is high-loop gain (high-LG) sleep apnea.

56. The pharmaceutical composition of claim 54, wherein the sleep apnea is central sleep apnea (CSA).

57. The pharmaceutical composition of claim 54, wherein the sleep apnea is complex sleep apnea or mixed OSA and CSA.

58. The pharmaceutical composition of claim 54, wherein the sleep apnea is sleep apnea with a central component.

59. The pharmaceutical composition of any one of claims 49-58, wherein the subject is in a non- fully conscious state.

60. The pharmaceutical composition of claim 59, wherein the non-fully conscious state is sleep.

61. A P2X3 receptor antagonist and a carbonic anhydrase inhibitor (CAI), for use in treating a subject having a condition associated with pharyngeal airway collapse.

62. A P2X3 receptor antagonist and a carbonic anhydrase inhibitor (CAI), for use in treating sleep apnea.

63. A P2X3 receptor antagonist and a carbonic anhydrase inhibitor (CAI), for use in treating snoring.

64. A method of treating sleep apnea comprising administering to a subject in need thereof an effective amount of (i) P2X3 receptor antagonist and (ii) a carbonic anhydrase inhibitor (CAI).

65. The method of claim 64, wherein the P2X3 receptor antagonist is sivopixant or a pharmaceutically acceptable salt thereof.

66. The method of claim 64 or 65, wherein the carbonic anhydrase inhibitor (CAI) is acetazolamide or a pharmaceutically acceptable salt thereof. 94 60678557.3Attorney Docket No.277901-567842 67. The method of claim 64 or 65, wherein the carbonic anhydrase inhibitor (CAI) is sultiame or a pharmaceutically acceptable salt thereof.

68. The method of any one of claims 64-67, wherein the sleep apnea is obstructive sleep apnea (OSA).

69. The method of any one of claims 64-67, wherein the sleep apnea is central sleep apnea (CSA).

70. The method of any one of claims 64-67, wherein the sleep apnea is complex sleep apnea or mixed OSA and CSA.

71. The method of any one of claims 64-67, wherein the sleep apnea is high-LG sleep apnea.

72. The method of any one of claims 64-67, wherein the sleep apnea is sleep apnea with a central component.

73. The method or use of any preceding claim, wherein the treatment reduces a subject’s AHI4 from baseline by at least about 42%.

74. The method or use of any preceding claim, wherein the treatment reduces a subject’s AHI4 from baseline by at least about 52%. 95 60678557.3

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