[((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester for treating chronic cough

Abstract

The present invention relates generally to the field of therapeutics. More specifically, the present invention relates to a certain compound [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-isopropyl acetate (also referred to herein as "AX-8" or "Gly-O-iPr") as described herein, for use in a method of treating the human or animal body by therapy, more specifically in a method of treating chronic cough (CC), including, for example, refractory chronic cough (RCC) and idiopathic chronic cough (ICC), as described herein.

Description

[0001] Related Applications

[0002] This application is related to United Kingdom (GB) patent application number 1908219.7 filed on June 10, 2019, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates generally to the field of therapy. More specifically, the present invention relates to a compound as described herein, which is [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-isopropyl acetate (also referred to herein as "AX-8" or "Gly-O-iPr"), or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in a method of treating the human or animal body by therapy, more specifically for use in a method of treating chronic cough (CC), including, for example, refractory chronic cough (RCC) and idiopathic chronic cough (ICC), as described herein. Background Art

[0004] A number of publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Each of these publications is incorporated herein by reference in its entirety to the same extent as if each individual publication had been specifically and individually indicated to be incorporated by reference.

[0005] Throughout the specification, including the claims below, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0006] It must be noted that, as used in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutical carrier" includes mixtures of two or more such carriers, etc.

[0007] Herein, ranges are often expressed as from "about" one particular value and / or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when a value is expressed as an approximation by using the antecedent "about," it is understood that the specific value forms another embodiment.

[0008] This disclosure includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

[0009] cough

[0010] A cough is a sudden and often repetitive protective reflex that helps clear the large airways of fluids, irritants, foreign particles, and microorganisms. The cough reflex consists of three phases: inhalation; forceful exhalation against a closed glottis; and a violent release of air from the lungs after the glottis opens, often accompanied by a distinctive sound.

[0011] Cough is a nonspecific response to stimulation anywhere from the pharynx to the lungs. The cough reflex is triggered by mechanical or inflammatory changes or irritants in the airways.

[0012] Cough reflex

[0013] Coughing occurs through stimulation of a complex reflex arc (see, e.g., Polverino et al., 2012; Canning et al., 2014) consisting of:

[0014] • Sensory terminals expressing cough receptors: terminals of sensory afferent fibers innervating extrathoracic locations (e.g., nose, oropharynx, larynx, upper trachea), intrathoracic locations (e.g., lower trachea and large central bronchi), or other locations (e.g., tympanic membrane, diaphragm, esophagus, stomach).

[0015] Afferent pathways: Sensory nerve fibers, primarily the vagus nerve (cranial nerve X) as well as the trigeminal nerve (cranial nerve V) and glossopharyngeal nerve (cranial nerve IX).

[0016] Central pathway (cough center): The central coordination / convergence area of ​​cough located in the brainstem (the core of the cough network is located in the ventrolateral region of the medulla).

[0017] Efferent pathways: Impulses from the cough center travel to the diaphragm, abdominal wall, and muscles via the vagus nerve, phrenic nerve, and spinal motor nerves.

[0018] Epidemic of cough

[0019] Cough is one of the most common reasons for adults and children to visit a general practitioner. For example, at any given time, 20% of the United Kingdom (UK) population suffers from an annoying cough and patients consume 75 million doses of over-the-counter (OTC) cough suppressants each year (see, e.g., Birring et al., 2003). A study that graded cough severity found that in the UK, 7% of the general population suffer from a cough that is sufficient to interfere with daily living activities at least weekly (see, e.g., Ford et al., 2006).

[0020] Classification of cough

[0021] Cough can be divided into: (a) acute, self-limited cough, lasting less than three weeks; (b) subacute cough, lasting for a moderate period of 3-8 weeks; and (c) chronic cough (CC), which lasts longer (usually more than 8 weeks in adults and more than 4 weeks in children).

[0022] Acute cough can also be classified based on its cause: infectious (caused by an infection) or noninfectious. Infectious causes of acute cough include: viral upper respiratory tract infection (common cold); COVID-19 disease; sinus infection; acute bronchitis; pneumonia; and whooping cough. Noninfectious causes of acute cough include: exposure to chemicals, exposure to irritants; and environmental allergies.

[0023] Chronic cough (CC) is commonly seen in clinical practice and is associated with reduced quality of life. It can persist for months and sometimes years and is a bothersome and difficult to treat symptom.

[0024] Chronic cough (CC) as a neurological disorder

[0025] It is widely recognized clinically that CC reflects a neurological state whereby the basal protective cough reflex has shifted to a level of hypersensitivity such that coughing is triggered by low-level stimuli that are usually insufficient to induce coughing (e.g., changes in ambient temperature, deep breathing, laughing, making phone calls, exposure to odors or aerosols, etc.; a concept known as allotussia) and by small amounts of stimuli known to induce coughing (e.g., capsaicin, citric acid, etc.; a concept known as hypertussia) (see, e.g., Chung et al., 2013; Mazzone et al., 2018; Gibson et al., 2015). In most CC patients, this hypersensitivity is also associated with abnormal sensations, such as persistent, rapid coughing and throat irritation, throat itching, or throat itch (see, e.g., Song et al., 2017; Gibson et al., 2015). Both the motor consequences (spontaneous coughing) and sensory consequences of this hypersensitivity are painful for CC patients and should be addressed through treatment.

[0026] This concept is often referred to as cough hypersensitivity syndrome (CHS) or cough reflex hypersensitivity (CRH) (see, e.g., Chung, 2014; Birring, 2017; Song et al., 2017; Morice et al., 2011; Ryan et al., 2018; Mazzone et al., 2018). Conventional wisdom holds that inflammation-induced neurological disorders or damage (neuroinflammation) lead to CHS, whereby neural pathways (in the airways and brain) are affected by a heterogeneous array of factors, including infection as well as physical and chemical irritants (see, e.g., Mazzone et al., 2018; Chung et al., 2013).

[0027] By analogy with neuropathic pain (see, eg, Chung et al., 2013), CHS may be due to: peripheral sensitization; central sensitization (cough center); and / or cortical and subcortical maladaptive plasticity.

[0028] The term sensorineural cough is now often recognized in cough guidelines. It overlaps with laryngeal paresthesias and laryngeal hypersensitivity syndrome (LHS) and cough hypersensitivity (CHS) syndrome (see, e.g., Gibson et al., 2015; Ryan et al., 2018). The term laryngeal hypersensitivity (LHS) is often used interchangeably with sensorineural cough.

[0029] Types of Chronic Cough (CC)

[0030] Some patients explain their chronic cough as a symptom of an established medical condition. Common causes of chronic cough are, for example, asthma, eosinophilic bronchitis, postnasal drip syndrome (PNDS), gastroesophageal reflux disease (GORD), bronchiectasis chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF).

[0031] However, in many cases, despite extensive evaluation and trials of treatments, chronic cough remains unexplained and difficult to treat in those with chronic cough (up to 46% of patients seen in secondary care; see, eg, Pavord et al., 2008; McGarvey, 2005).

[0032] Chronic cough that persists despite evaluation and treatment according to recognized guidelines is often referred to as refractory chronic cough (RCC) (sometimes also called chronic refractory cough), that is, a chronic cough that is refractory to treatment of the associated condition. Chronic cough without a clear cause is often referred to as unexplained or idiopathic chronic cough (ICC). Refractory chronic cough is sometimes also called idiopathic chronic cough, for example, when the cause of the chronic cough is usually no longer the originally associated condition, but some other condition that has not yet been identified (e.g., a neurological disorder) (see, e.g., Gibson et al., 2015; Ryan et al., 2018).

[0033] For example, patients with chronic cough are diagnosed with asthma and treated for asthma. Most asthma symptoms improve; however, the chronic cough does not improve. Patients who were initially thought to have an explanation for their chronic cough (due to asthma) are now diagnosed with refractory chronic cough (because it is refractory to treatment of the associated condition, asthma) or idiopathic chronic cough (because, at this time, the associated condition causing the persistent chronic cough is unknown or not yet known).

[0034] Because patients with unexplained chronic cough often receive specific therapies, such as inhaled corticosteroids or proton pump inhibitors, they may also be classified as having RCC.

[0035] Therefore, the terms refractory chronic cough (RCC), chronic refractory cough, chronic cough of unknown cause, and idiopathic chronic cough (ICC) are often used interchangeably (and sometimes inconsistently and / or incorrectly) in the literature and clinical practice.

[0036] Treatment of cough

[0037] In most cases, cough is treated by treating the underlying cause. However, in some cases (e.g., when the underlying cause cannot be identified, or cannot be easily or quickly treated), symptomatic treatment of the cough is recommended.

[0038] Cough suppressants may be helpful, especially if sleep is disturbed. However, they may cause sputum retention, which may be harmful in patients with chronic bronchitis or bronchiectasis.

[0039] There are multiple drugs that can partially suppress cough, but the cough reflex is extremely difficult to eliminate. The efficacy of most antitussives lacks evidence, and many of them (especially anesthetics) induce adverse side effects. In addition, the abuse and overdose associated with narcotic cough suppressants are major public health issues, especially in the U.S. The British Thoracic Society (British Thoracic Society) guide points out: "there is no effective treatment to control the cough response itself at an acceptable therapeutic ratio" (see, for example, Morice et al., 2006).

[0040] Codeine (a narcotic drug) may be effective but can cause dependence. Dextromethorphan (an opioid derivative that is non-narcotic) and pholcodine (also called hypercodeine) have fewer side effects. Higher doses of morphine or diacetylmorphine may be used for severe, painful coughs in palliative care.

[0041] Benzonatate (sold under the names Tessalong, Tessalon Perles, and Zonatuss) is currently the only non-narcotic cough suppressant available by prescription.

[0042] Sedating antihistamines are used as the cough suppressant component of many combination cough suppressant preparations sold to the public.

[0043] Mucolytics (eg, carbocysteine ​​or erdosteine) are prescribed to facilitate expectoration by reducing sputum viscosity. In some patients with COPD and chronic productive cough, mucolytics may reduce exacerbations. If there is no benefit after a 4-week trial, mucolytic therapy should be discontinued. Steam inhalation with postural drainage is effective in bronchodilation and in some cases of chronic bronchitis.

[0044] Antitussive preparations contain soothing substances such as syrup or glycerine and can be used to relieve irritating, dry coughs. Preparations such as simple throat cough syrups have the advantage of being harmless and inexpensive.

[0045] Expectorants are purported to promote drainage of bronchial secretions, but there is no evidence that any drug specifically promotes expectoration.

[0046] Treatment of chronic cough

[0047] Currently, there is no specific treatment for chronic cough (CC), either as a symptom of a diagnosed condition or as a condition in itself.

[0048] Among CC patients, those with RCC are the patients with the highest needs. For RCC patients, there are only a few treatment options (see, e.g., Gibson et al., 2015; Ryan et al., 2018). For that reason, pharmaceutical companies are currently focusing on RCC patients. In addition, RCC patients provide a useful model for studying antitussive drugs for CC because cough frequency is high and remains stable over time, making such clinical studies strongly demonstrate the therapeutic effect.

[0049] Centrally acting neuromodulators such as morphine (an opioid), amitriptyline (a tricyclic antidepressant and serotonin reuptake inhibitor), gabapentin, and pregabalin (two blockers of some voltage-gated calcium channels expressed in the central nervous system) may be used to treat RCC (see, e.g., Gibson et al., 2015; Ryan et al., 2018).

[0050] Speech therapy techniques have also been shown to be beneficial in the treatment of RCC (see, e.g., Gibson et al., 2015; Ryan et al., 2018).

[0051] Patients and clinicians often try over-the-counter (OTC) medications available for acute cough, such as dextromethorphan, codeine, and menthol, with little success.

[0052] Recent or currently developing treatments for RCC have novel biological targets that were not previously targeted for acute cough, such as α7-nACh, P2X3, NK1, TRPV1, TRPV4, and TRPA1 receptors (see, e.g., Ryan et al., 2018; Abdulqawi et al., 2015; Belvisi et al., 2017; Khalid et al., 2014; Smith et al., 2017a; Smith et al., 2017b; Smith et al., 2020; EudraCT No. 2013-002728-17).

[0053] As a rule of thumb, treatments used for acute cough are often ineffective for RCC, and vice versa.

[0054] Even if treatment is known to be effective for acute cough, Unable toIt is predicted (with reasonable certainty) that it will also be effective in treating chronic cough. For example, two TRPV1 antagonists (XEN-D0501 and SB-705498) inhibit acute cough induced by capsaicin (see, e.g., Belvisi et al., 2017; Khalid et al., 2014), but do not reduce cough frequency in RCC patients. In contrast, MK-7264 (also known as AF-219 and gefapixen), a P2X3 antagonist, is effective in reducing cough frequency in RCC patients, but is ineffective for acute cough induced by the cough irritant capsaicin (a stimulator and agonist of TRPV1) in RCC patients or healthy subjects (see, e.g., Abdulqawi et al., 2015; Smith et al., 2016; Morice et al., 2017).

[0055] In the present case, nonclinical studies have shown that AX-8 inhibits cough induced by an irritant (i.e., capsaicin, a TRPV1 agonist). However, based on the current state of the art, the skilled artisan cannot predict (with reasonable certainty) whether AX-8 also It can effectively treat chronic cough (CC), not to mention refractory chronic cough (RCC).

[0056] Animal models of cough

[0057] There is no perfect animal model for human diseases related to acute or chronic cough. Although existing models are similar to these human diseases, the characteristics of GORD, asthma, COPD and various respiratory infections cannot be reliably reproduced. Since coughing in humans during illness is spontaneous, it would be ideal to study animals that cough spontaneously. But this has never been done, and animals are usually studied in response to cough stimuli provided artificially (see, for example, Canning et al., 2008).

[0058] For COPD, only one model in ferrets has increased spontaneous cough in the morning (but not chronic cough), and all other models have no spontaneous cough (see, e.g., Chow et al., 2017). Multiple animal models of increased cough have been developed, but none reproduce the characteristics of RCC (see, e.g., Bolser, 2004; Xu et al., 2016).

[0059] Furthermore, the physiology and pharmacology of spontaneous and induced cough may differ.

[0060] The molecular mechanisms that cause and maintain CC are poorly understood, which explains the limited availability of antitussive drugs for CC.

[0061] Prospective drugs for the treatment of CC cannot be validated using animal models.

[0062] • Results from currently available animal models (eg, cough induced by inhaled capsaicin or citric acid in guinea pigs) cannot be translated into the efficacy of CC.

[0063] Because animal models of cough in chronic cough have such limited predictive value, Unable to It is not possible to predict (with reasonable certainty) that a particular treatment will actually be useful for treating chronic cough, let alone RCC. This is illustrated by the failure of proof-of-concept trials for treating RCC when studies in animal models have positive results (see, e.g., Belvisi et al., 2017; Khalid et al., 2014; Smith et al., 2017c; Smith et al., 2020; Ludbrook et al., 2019; Mukhopadhyay et al., 2016; Bonvini et al., 2016; EudraCT No. 2013-002728-17).

[0064] Therefore, until the current human clinical trials are completed (and found to be successful), and it has been demonstrated (via clinical trial data) that AX-8 can in fact be used to treat CC in RCC / ICC patients, the results cannot be predicted (with reasonable certainty).

[0065] Known compound AX-8 / Gly-O-iPr

[0066] The compound [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester (also referred to herein as "AX-8" or "Gly-O-iPr") is described in Wei et al., 2012. See, e.g., page 6 therein.

[0067] The invention also describes the use of the compound for treating "cough". See, for example, claim 53 on page 34 thereof.

[0068] Study 4 (see page 14 therein) described the treatment of patients' dry itchy throat and cough associated with allergies to cat litter box dust and exacerbated by seasonal allergies to grass pollen.

[0069] Study 5 (see pages 14-15 therein) describes the treatment of a patient with a severe coughing attack triggered by eating a piece of fish heavily seasoned with chili peppers.

[0070] Study 6 (page 15 therein) describes the treatment of cough in adult patients with episodic asthma exacerbated by seasonal allergies to tree pollens.

[0071] The coughs in the above studies were caused by irritants and allergens.

[0072] Wei et al., 2012, do not provide any teaching or recommendations for the treatment of chronic cough (CC), let alone refractory chronic cough (RCC) or idiopathic chronic cough (ICC). Summary of the invention

[0073] One aspect of the present invention relates to a compound as described herein, which is [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-isopropyl acetate (also referred to herein as "AX-8" or "Gly-O-iPr"), or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in a method of treating the human or animal body by therapy, more specifically in a method of treating chronic cough (CC), including, for example, refractory chronic cough (RCC) and idiopathic chronic cough (ICC), and as described herein.

[0074] Another aspect of the present invention relates to the use of the compound [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-isopropyl acetate (also referred to herein as "AX-8" or "Gly-O-iPr") as described herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for treatment, more specifically for the treatment of chronic cough (CC), including, for example, refractory chronic cough (RCC) and idiopathic chronic cough (ICC), and as described herein.

[0075] Another aspect of the present invention relates to a method of treatment, more specifically, a method for treating chronic cough (CC), including, for example, refractory chronic cough (RCC) and idiopathic chronic cough (ICC) and as described herein, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound as described herein, the compound being [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-isopropyl acetate (also referred to herein as "AX-8" or "Gly-O-iPr") or a pharmaceutically acceptable salt, hydrate or solvate thereof, preferably in the form of a pharmaceutical composition.

[0076] Another aspect of the present invention relates to a kit comprising (a) a compound as described herein, which is [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-isopropyl acetate (also referred to herein as "AX-8" or "Gly-O-iPr"), or a pharmaceutically acceptable salt, hydrate or solvate thereof, preferably as a pharmaceutical composition and provided in a suitable container and / or with suitable packaging; and (b) instructions for use thereof, for example, written instructions on how to administer the compound to treat chronic cough (CC), including, for example, refractory chronic cough (RCC) and idiopathic chronic cough (ICC), and as described herein.

[0077] As will be appreciated by those skilled in the art, features and preferred embodiments of one aspect of the invention will also be relevant to other aspects of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0078] Figure 1 is a graph of median cough frequency (coughs / hour) versus time after treatment (hours) for baseline (open circles) and treatment (filled circles).

[0079] Figure 2 is a graph showing the mean waking cough frequency (coughs / hour) for 12 individual patients, both at baseline and on treatment.

[0080] Figure 3 is a graph showing the mean sleep cough frequency (coughs / hour) for 12 individual patients, both at baseline and on treatment.

[0081] Figure 4 is a graph showing the mean cough frequency (coughs / hour) for 12 individual patients during the 24 hour period following treatment and during the equivalent baseline period.

[0082] Figure 5 is a graph showing the median cough frequency (coughs / hour) for 12 individual patients during the 8 hour period following treatment and during the equivalent baseline period.

[0083] Figure 6 is a graph showing the median cough frequency (coughs / hour) for 12 individual patients during the 4 hour period following treatment and during the equivalent baseline period.

[0084] Figure 7 is a graph of median cough severity (VAS) (mm) versus time after treatment (hours) for baseline (open inverted triangles) and treatment (closed inverted triangles).

[0085] Figure 8 is a graph of median shortness of cough (VAS) (mm) versus time after treatment (hours) for baseline (open diamonds) and treatment (filled diamonds).

[0086] Fig. 9 is a graph of median throat irritation (VAS) (mm) versus time after treatment (hours) for baseline (open squares) and treatment (closed squares).

[0087] Fig.10 is a graph of median throat soothing (VAS) (mm) versus time after treatment (hours) (solid upper triangles).

[0088] Fig.11is a composite graph showing median shortness of cough (VAS) (mm) (filled diamonds), throat irritation (VAS) (mm) (filled squares), and throat soreness (VAS) (mm) (filled upper triangles) on the left and median cough frequency (coughs / hour) versus time after treatment (hours) for baseline (open circles) and treatment (filled circles) on the right.

[0089] Fig.12 It means that if The obtained graphs show the activation of human TRPM8 by AX-8. The dose response curves are presented as calcium signal expressed in relative light units (calculated by area under the curve - AUC, mean ± sem, n = 8) versus AX-8 concentration (μM, logarithmic scale). The half maximal response concentration (EC 50 ) is 0.39μM.

[0090] Fig.13 It means that if Graphs showing activation of human TRPM8 by menthol obtained. Dose response curves are presented as calcium signal expressed in relative light units (calculated by area under the curve - AUC, mean ± sem, n = 8) versus menthol concentration (μM, logarithmic scale). The half-maximal response concentration (EC 50 ) is 2.29μM.

[0091] Fig.14 is a graph showing comparative activation of human TRPA1 and human TRPV1 by AX-8 and its reference agonist. For hTRPA1, the dose response curves of mustard oil (reference TRPA1 agonist) and AX-8 are expressed as a percentage of the maximum response of mustard oil (mean ± SD, n = 4) to the agonist concentration (μM, logarithmic scale). The data show that AX-8 has no significant agonist activity on hTRPA1 at concentrations ≤ 100 μM. For hTRPV1, the dose response curves of capsaicin (reference TRPV1 agonist) and AX-8 are expressed as a percentage of the maximum response of capsaicin (mean ± SD, n = 4) to the agonist concentration (μM, logarithmic scale). The data show that AX-8 has no agonist activity on hTRPV1 at concentrations ≤ 100 μM.

[0092] Fig.15 is a bar graph showing inhibition (%) of AX-8 on capsaicin-evoked responses in guinea pig vagus nerve explants versus concentration of AX-8 (μM). AX-8 (n=3) blocked capsaicin-evoked responses in guinea pig vagus nerve in a dose-dependent manner.

[0093] Fig.16Is a bar graph showing the inhibition (%) of AX-8 (1 μM) on capsaicin-induced responses in guinea pig vagus nerve explants in the presence or absence of the selective TRPM8 antagonist PF-05105679 (PF, 10 μM). Two consecutive 10-minute incubations of four different conditions were performed as follows: vehicle (0.1% DMSO) / vehicle, PF / vehicle, vehicle / AX-8, and PF / AX-8 (n=4). The selective TRPM8 inhibitor PF-05105679 can block the inhibition of the response induced by the irritant capsaicin in guinea pig vagus nerve explants, thereby demonstrating that the effect of AX-8 is dependent on TRPM8.

[0094] Fig.17 It is a bar graph showing the effect of AX-8 on capsaicin-induced cough in conscious guinea pigs. The vehicle did not significantly affect the capsaicin-induced cough in guinea pigs (baseline (V) = 24.8 ± 2.1 coughs / 10 minutes vs. vehicle = 21.4 ± 2.4 coughs / 10 minutes). Spraying 75 μL of a 5 mg / mL AX-8 solution (i.e., 0.375 mg / animal) in the oropharyngeal region suppressed the capsaicin-induced cough in guinea pigs from 25.0 ± 2.0 / 10 minute coughs (baseline (T)) to 9.0 ± 2.0 / 10 minute coughs (**p<0.01). The number of animals in each group was 10 (n=10). DETAILED DESCRIPTION

[0095] Compound

[0096] The present invention relates to a compound as described herein, which is [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-isopropyl acetate (also referred to herein as "AX-8" or "Gly-O-iPr", as shown below) or a pharmaceutically acceptable salt, hydrate or solvate thereof, which is used in a method for treating the human or animal body by therapy, more specifically in a method for treating chronic cough (CC), including, for example, refractory chronic cough (RCC) and idiopathic chronic cough (ICC), and as described herein.

[0097]

[0098] The compounds are structurally related to (-)-menthol and possess the same chiral centers in the same configuration as found in (-)-menthol.

[0099]

[0100] In structural terms, the compound can be conveniently described as the isopropyl ester of glycine amide corresponding to the carboxylic acid of (-)-menthol.

[0101] It may also be conveniently described as p-menthane carboxamide.

[0102] In one embodiment, the compound is [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0103] In one embodiment, the compound is [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt thereof.

[0104] In one embodiment, the compound is [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester.

[0105] use

[0106] The compound [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester (also referred to herein as "AX-8" or "Gly-O-iPr") as described herein can be used, for example, to treat chronic cough (CC), including, for example, refractory chronic cough (RCC) and idiopathic chronic cough (ICC), and as described herein.

[0107] Use in therapeutic approaches

[0108] One aspect of the present invention relates to a compound as described herein, which is [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-isopropyl acetate (also referred to herein as "AX-8" or "Gly-O-iPr") or a pharmaceutically acceptable salt, hydrate or solvate thereof, which is used in a method for treating the human or animal body by therapy, more specifically in a method for treating chronic cough (CC), including, for example, refractory chronic cough (RCC) and idiopathic chronic cough (ICC), and as described herein.

[0109] One aspect of the present invention relates to a compound as described herein, which is [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-isopropyl acetate (also referred to herein as "AX-8" or "Gly-O-iPr") or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with one or more (e.g., 1, 2, 3, 4) additional therapeutic agents as described herein, for use in a method of treating the human or animal body by therapy, more specifically for use in a method of treating chronic cough (CC), including, for example, refractory chronic cough (RCC) and idiopathic chronic cough (ICC), and as described herein.

[0110] Use in the manufacture of medicines

[0111] One aspect of the present invention relates to the use of a compound as described herein [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-isopropyl acetate (also referred to herein as "AX-8" or "Gly-O-iPr") or a pharmaceutically acceptable salt, hydrate or solvate thereof in the manufacture of a medicament for treatment, more specifically for the treatment of chronic cough (CC), including, for example, refractory chronic cough (RCC) and idiopathic chronic cough (ICC), and as described herein.

[0112] In one embodiment, a medicament comprises said compound.

[0113] One aspect of the present invention relates to the use of a compound [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-isopropyl acetate (also referred to herein as "AX-8" or "Gly-O-iPr") as described herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more (e.g., 1, 2, 3, 4) additional therapeutic agents as described herein in the manufacture of a medicament for treatment, more specifically for the treatment of chronic cough (CC), including, for example, refractory chronic cough (RCC) and idiopathic chronic cough (ICC), and as described herein.

[0114] In one embodiment, the medicament comprises the compound and one or more (eg, 1, 2, 3, 4) additional therapeutic agents.

[0115] Treatment

[0116] One aspect of the present invention relates to a method of treatment, more specifically, a method for treating chronic cough (CC), including, for example, refractory chronic cough (RCC) and idiopathic chronic cough (ICC) and as described herein, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound as described herein, the compound being [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-isopropyl acetate (also referred to herein as "AX-8" or "Gly-O-iPr") or a pharmaceutically acceptable salt, hydrate or solvate thereof, preferably in the form of a pharmaceutical composition.

[0117] One aspect of the present invention relates to a method of treatment, more specifically, a method for treating chronic cough (CC), including, for example, refractory chronic cough (RCC) and idiopathic chronic cough (ICC) and as described herein, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound as described herein, the compound being [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-isopropyl acetate (also referred to herein as "AX-8" or "Gly-O-iPr") or a pharmaceutically acceptable salt, hydrate or solvate thereof, preferably in the form of a pharmaceutical composition; and one or more (e.g., 1, 2, 3, 4) additional therapeutic agents as described herein, preferably in the form of a pharmaceutical composition.

[0118] Pill Box

[0119] Another aspect of the present invention relates to a kit comprising (a) a compound as described herein, which is [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-isopropyl acetate (also referred to herein as "AX-8" or "Gly-O-iPr"), or a pharmaceutically acceptable salt, hydrate or solvate thereof, preferably as a pharmaceutical composition and provided in a suitable container and / or with suitable packaging; and (b) instructions for use thereof, for example, written instructions on how to administer the compound to treat chronic cough (CC), including, for example, refractory chronic cough (RCC) and idiopathic chronic cough (ICC), and as described herein.

[0120] In one embodiment, the kit further comprises one or more (eg, 1, 2, 3, 4) additional therapeutic agents, as described herein.

[0121] The written instructions may also include a list of specific indications that the compound is suitable for treating.

[0122] Chronic cough

[0123] As used herein, the term "chronic cough" (CC) refers to a cough that persists for more than about 8 weeks in an adult, or more than about 4 weeks in a child.

[0124] Chronic cough is often considered a symptom of an underlying medical condition.

[0125] In some cases, an associated condition that may lead to chronic cough (i.e., a chronic cough with a clear cause) may be identified. Common causes of chronic cough are, for example, asthma, eosinophilic bronchitis, postnasal drip syndrome (PNDS), gastroesophageal reflux disease (GORD), bronchiectasis chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF).

[0126] In other cases, no associated disorder could be identified (ie, unexplained or idiopathic chronic cough).

[0127] In some cases, an associated disorder can be identified and treated, and chronic cough improves following treatment of the associated disorder.

[0128] In other cases, an associated condition that may cause chronic cough may be identified and treated, but the chronic cough persists despite treatment of the associated condition. Here, a persistent chronic cough may be considered a refractory chronic cough (i.e., refractory to treatment of the associated condition) or an idiopathic chronic cough (i.e., the cause remains unexplained). Such a persistent chronic cough, whether described as an idiopathic chronic cough or a refractory chronic cough, may be considered a condition in itself, rather than just a symptom.

[0129] Therefore, specific treatments for chronic cough can be used to improve the conditions of chronic cough in patients with: no identified associated conditions (idiopathic chronic cough); with identified associated conditions that cause chronic cough but cannot be treated; with treatable associated conditions that cause chronic cough but with chronic cough that is refractory to the treatment of the associated conditions (refractory chronic cough).

[0130] In many cases, idiopathic / refractory chronic cough has an identifiable origin or medical history, such as an earlier medical condition with chronic cough as a symptom that causes persistent chronic cough despite treatment of the condition. This persistent chronic cough is usually not related to the earlier condition but is often related to neurological changes that occur simultaneously with or after the earlier treatment.

[0131] For example, consider two patients with chronic cough as a symptom. Both were correctly diagnosed with asthma (related condition). Both were treated for asthma (related condition). For both patients, most of the asthma symptoms improved. However, for the first patient, the chronic cough improved, while for the second patient, it did not. This second patient, who was initially thought to have an explanation for the chronic cough (due to asthma), is now diagnosed with refractory chronic cough (because it is refractory to treatment of the related condition asthma) or idiopathic chronic cough (because, at this time, the related condition that causes the persistent chronic cough is unknown, or is not yet known).

[0132] In one embodiment, the treatment is treatment of chronic cough.

[0133] In one embodiment, the chronic cough is a chronic cough with a known cause.

[0134] In one embodiment, the chronic cough is a chronic cough that is a symptom of, associated with, or caused by a diagnosed condition.

[0135] In one embodiment, the chronic cough is a chronic cough that is a symptom of, associated with, or caused by a diagnosed cough-related disorder.

[0136] In one embodiment, the chronic cough is a chronic cough that is a symptom of, associated with, or caused by asthma, eosinophilic bronchitis, postnasal drip syndrome (PNDS), gastroesophageal reflux disease (GORD), bronchiectasis chronic obstructive pulmonary disease (COPD), or idiopathic pulmonary fibrosis (IPF).

[0137] In one embodiment, the chronic cough is idiopathic chronic cough (ICC).

[0138] In one embodiment, the chronic cough is refractory chronic cough (RCC).

[0139] In one embodiment, the chronic cough is refractory chronic cough (RCC) that persists after evaluation and treatment of cough-related disorders, eg, according to generally accepted guidelines.

[0140] In one embodiment, the chronic cough is refractory chronic cough (RCC) that persists after evaluation and treatment of asthma, eosinophilic bronchitis, postnasal drip syndrome (PNDS), gastroesophageal reflux disease (GORD), bronchiectasis chronic obstructive pulmonary disease (COPD), or idiopathic pulmonary fibrosis (IPF), e.g., according to recognized guidelines.

[0141] In one embodiment, chronic cough (including, for example, idiopathic chronic cough and refractory chronic cough) is a symptom of, associated with, or caused by allotussia.

[0142] In one embodiment, chronic cough (including, for example, idiopathic chronic cough and refractory chronic cough) is a symptom of, associated with, or caused by hypertussia.

[0143] In one embodiment, chronic cough (including, for example, idiopathic chronic cough and refractory chronic cough) is a symptom of, associated with, or caused by cough hypersensitivity syndrome (CHS).

[0144] In one embodiment, chronic cough (including, for example, idiopathic chronic cough and refractory chronic cough) is a symptom of, associated with, or caused by a cough hypersensitivity reflex (CHR).

[0145] In one embodiment, chronic cough (including, for example, idiopathic chronic cough and refractory chronic cough) is a symptom of, associated with, or caused by laryngeal paresthesia.

[0146] In one embodiment, chronic cough (including, for example, idiopathic chronic cough and refractory chronic cough) is a symptom of, associated with, or caused by laryngeal hypersensitivity syndrome (LHS).

[0147] In one embodiment, the chronic cough (including, for example, idiopathic chronic cough and refractory chronic cough) is a sensorineural cough.

[0148] In one embodiment, chronic cough (including, for example, idiopathic chronic cough and refractory chronic cough) is a symptom of, associated with, or caused by: peripheral sensitization; central sensitization (cough center); and / or cortical and / or subcortical maladaptive plasticity.

[0149] In one embodiment, chronic cough (including, for example, idiopathic chronic cough and refractory chronic cough) is a symptom of, associated with, or caused by vagal neuropathy.

[0150] In one embodiment, chronic cough (including, for example, idiopathic chronic cough and refractory chronic cough) is a symptom of, associated with, or caused by airway inflammation.

[0151] In one embodiment, chronic cough (including, for example, idiopathic chronic cough and refractory chronic cough) is a symptom of, associated with, or caused by neurogenic inflammation and / or neuroinflammation.

[0152] treat

[0153] The term "treatment" as used herein in the context of treating a disorder generally relates to treatment and therapy, whether human or animal (e.g., in veterinary applications), in which some desired therapeutic effect is obtained, e.g., inhibiting the progression of the disorder, and includes reducing the rate of progression, stopping the rate of progression, alleviating the symptoms of the disorder, ameliorating the disorder, and curing the disorder. Also included is treatment as a preventative measure (i.e., prevention). For example, the term "treatment" encompasses use in patients who have not yet developed a disorder but are at risk of developing a disorder.

[0154] For example, treatment of chronic cough (including, for example, treatment of refractory chronic cough) includes preventing cough, reducing the incidence of cough (e.g., acute cough), reducing the frequency of cough (e.g., cough frequency), reducing the severity of cough (e.g., cough severity), alleviating symptoms of cough (e.g., alleviating throat irritation), etc.

[0155] In one embodiment, treatment is reduction of one or more or all of the following: cough frequency, cough severity, shortness of cough, and throat irritation.

[0156] In one embodiment, the treatment is reducing the frequency of coughing.

[0157] In one embodiment, treatment is reducing the frequency of coughs per hour.

[0158] In one embodiment, treatment is reducing the median cough frequency per hour.

[0159] In one embodiment, treatment is reducing the average frequency of coughs per hour.

[0160] In one embodiment, treatment is reducing the frequency of coughing per hour while awake.

[0161] In one embodiment, treatment is reducing the median cough frequency per hour while awake.

[0162] In one embodiment, treatment is reducing the average frequency of coughs per hour while awake.

[0163] In one embodiment, treatment is reducing the frequency of coughing per hour during sleep.

[0164] In one embodiment, treatment is reducing median cough frequency per hour during sleep.

[0165] In one embodiment, treatment is reducing the average cough frequency per hour during sleep.

[0166] In one embodiment, treatment is reducing the degree of cough latency.

[0167] In one embodiment, the treatment is reduction of shortness of cough.

[0168] In one embodiment, the treatment is reduction of throat irritation.

[0169] In one embodiment, the treatment reduces the frequency of coughing.

[0170] In one embodiment, treatment reduces the frequency of coughs per hour.

[0171] In one embodiment, treatment reduces the median cough frequency per hour.

[0172] In one embodiment, treatment reduces the average frequency of coughs per hour.

[0173] In one embodiment, treatment reduces the frequency of coughing per hour of waking time.

[0174] In one embodiment, treatment reduces median cough frequency per hour while awake.

[0175] In one embodiment, treatment reduces the average cough frequency per hour while awake.

[0176] In one embodiment, treatment reduces the frequency of coughing per hour during sleep.

[0177] In one embodiment, treatment reduces median cough frequency per hour during sleep.

[0178] In one embodiment, treatment reduces the average cough frequency per hour during sleep.

[0179] In one embodiment, the treatment reduces cough severity.

[0180] In one embodiment, the treatment reduces shortness of cough.

[0181] In one embodiment, the treatment reduces throat irritation.

[0182] As used herein, the term "therapeutically effective amount" relates to that amount of a compound, or material, composition or dosage form containing a compound, effective to produce some desired therapeutic effect commensurate with a reasonable benefit / risk ratio when administered according to the desired treatment regimen.

[0183] Route of administration

[0184] The compound [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester (also referred to herein as "AX-8" or "Gly-O-iPr") as described herein, or a pharmaceutical composition comprising the compound, can be administered to the subject by any convenient route of administration, whether systemically / peripherally or locally (i.e., at the desired site of action).

[0185] In a preferred embodiment, the route of administration is topical.

[0186] Routes of administration include: oral (e.g., by ingestion); oromucosal; buccal (e.g., between the gums and the cheek); sublingual (e.g., under the tongue); transdermal (including, e.g., by patches, plasters, etc.); transmucosal (including, e.g., by patches, plasters, etc.); intranasal (e.g., by nasal spray, drops, or from a nebulizer or dry powder delivery device); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g., through the mouth or nose).

[0187] In a preferred embodiment, the route of administration is oral.

[0188] In a preferred embodiment, the route of administration is topical oral.

[0189] In a preferred embodiment, the route of administration is oral mucosal.

[0190] In a preferred embodiment, the route of administration is topical to the oral mucosa.

[0191] In a preferred embodiment, the route of administration is buccal.

[0192] In a preferred embodiment, the route of administration is topical buccal.

[0193] In a preferred embodiment, the route of administration is sublingual.

[0194] In a preferred embodiment, the route of administration is topical sublingual.

[0195] In a preferred embodiment, the route of administration is intranasal.

[0196] In a preferred embodiment, the route of administration is topical intranasal.

[0197] In a preferred embodiment, the route of administration is transmucosal.

[0198] In a preferred embodiment, the route of administration is topical transmucosal.

[0199] dose

[0200] Those skilled in the art will appreciate that the appropriate dosage of the compound [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino] -isopropyl acetate (also referred to herein as "AX-8" or "Gly-O-iPr") as described herein or a composition comprising the compound may vary from patient to patient. Determining the optimal dosage will generally involve balancing the level of therapeutic benefit and any risk or adverse side effects. The selected dosage level will depend on a variety of factors, including the activity of the compound, the route of administration, the time of administration, the excretion rate of the compound, the duration of treatment, other drugs, compounds and / or materials used in combination, the severity of the disorder, and the type, sex, age, weight, condition, general health and previous medical history of the patient. The amount of the compound and the route of administration will ultimately be at the discretion of the physician, veterinarian or clinician, but in general the dosage will be selected to obtain a local concentration at the site of action that achieves the desired effect without causing substantially harmful or toxic side effects.

[0201] Administration can be achieved in a single dose, continuously or intermittently (e.g., at appropriate time intervals, in divided doses) throughout the course of treatment. Methods for determining the most effective mode of administration and dosage are well known to those skilled in the art and will vary with the formulation used for treatment, the purpose of treatment, the target cell being treated, and the subject being treated. Single or multiple administrations can be performed according to the dosage level and pattern selected by the treating physician, veterinarian, or clinician.

[0202] In one embodiment, the dosage is in the range of about 1 μg to about 5 mg of the compound per kg body weight of the subject per day.

[0203] In one embodiment, the dosage is in the range of about 5 μg to about 2 mg of the compound per kg body weight of the subject per day.

[0204] In one embodiment, the dosage is in the range of about 15 μg to about 0.7 mg of the compound per kg body weight of the subject per day.

[0205] In one embodiment, the dosage is in the range of about 30 μg to about 0.4 mg of the compound per kg body weight of the subject per day.

[0206] In one embodiment, the dosage is in the range of about 70 μg to about 0.3 mg of the compound per kg body weight of the subject per day.

[0207] Similarly, in one embodiment, the dosage is in the range of about 0.07 mg to about 350 mg of the compound per day.

[0208] In one embodiment, the dosage is in the range of about 0.35 mg to about 140 mg of the compound per day.

[0209] In one embodiment, the dosage is in the range of about 1 mg to about 50 mg of the compound per day.

[0210] In one embodiment, the dosage is in the range of about 2 mg to about 30 mg of the compound per day.

[0211] In one embodiment, the dosage is in the range of about 5 mg to about 20 mg of the compound per day.

[0212] When the compound is a salt, ester, amide, prodrug or the like, the administration amount is calculated based on the parent compound, so the actual weight to be used is increased proportionally.

[0213] Treatment options

[0214] The compound or pharmaceutical composition comprising the compound may be administered according to any suitable treatment plan or regimen.

[0215] Most likely, administration will be performed "on demand" by the patient, according to the patient's needs. For example, a patient may be instructed to self-administer the compound or a pharmaceutical composition comprising the compound when a cough is anticipated (e.g., as a prophylaxis); immediately after a cough has started; after a prolonged cough; etc.

[0216] As described herein, a single administration of 5 mg ODT was found to have efficacy that lasted up to about 8 hours, and thus it is expected that 2 to 4 administrations per day may be sufficient.

[0217] In one embodiment, the treatment regimen is 1 to 5 administrations per day (ie, 1 to 5 administrations per day).

[0218] In one embodiment, the treatment regimen is 1 to 4 administrations per day (ie, 1 to 4 administrations per day).

[0219] In one embodiment, the treatment regimen is 2 to 5 administrations per day (ie, 2 to 5 administrations per day).

[0220] In one embodiment, the treatment regimen is 2 to 4 administrations per day (ie, 2 to 4 administrations per day).

[0221] In one embodiment, the treatment regimen is 2 times daily administration (ie, administration twice per day).

[0222] In one embodiment, the treatment regimen is 3 times daily administration (ie, administration 3 times per day).

[0223] In one embodiment, the treatment regimen is 4 administrations per day (ie, 4 administrations per day).

[0224] In one embodiment, the treatment regimen is practiced on a case-by-case basis (PRN) (eg, as needed, as the situation presents, etc.).

[0225] preparation

[0226] Although it is possible to administer the compound [((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino] -isopropyl acetate (also referred to herein as "AX-8" or "Gly-O-iPr") as described herein alone, it is preferably provided as a pharmaceutical formulation (e.g., composition, formulation, medicament) comprising a compound as described herein and one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g., wetting agents), masking agents, colorants, flavoring agents, and sweeteners. The formulation may also contain other active agents, such as other therapeutic or prophylactic agents.

[0227] Pharmaceutical compositions and methods of preparing pharmaceutical compositions are described herein, which methods include mixing a compound with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art (e.g., carriers, diluents, excipients, etc.). If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dose) of the compound.

[0228] The term "pharmaceutically acceptable" as used herein relates to compounds, ingredients, materials, compositions, dosage forms, etc. that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a contemplated subject (e.g., a human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each carrier, diluent, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0229] Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical textbooks, e.g. Remington's Pharmaceutical Sciences , 18th ed., Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients , 5th edition, 2005.

[0230] The preparation can be prepared by any method well known in the pharmaceutical field. Such methods include the step of associating the compound with a carrier constituting one or more auxiliary ingredients. In general, the preparation is prepared by uniformly and intimately associating the compound with a carrier (e.g., a liquid carrier, a finely divided solid carrier, etc.), and then shaping the product (if necessary).

[0231] The formulations may be prepared to provide fast or slow release; immediate, delayed, timed, or sustained release; or a combination thereof.

[0232] The formulation may suitably be in the form of a liquid, solution (e.g., aqueous, non-aqueous), suspension (e.g., aqueous, non-aqueous), emulsion (e.g., oil-in-water, water-in-oil), elixir, syrup, dragee, mouthwash, drops, tablets (including, e.g., coated tablets), granules, powder, lozenge, pastille, capsule (including, e.g., hard and soft gelatin capsules), cachet, pill, ampoule, bolus, tincture, gel, paste, ointment, cream, lotion, oil, foam, spray, mist or aerosol.

[0233] In one embodiment, the compound is formulated as a spray.

[0234] In one embodiment, the compound is formulated as an aerosol.

[0235] In one embodiment, the compound is formulated as an aerosol.

[0236] The preparation can be suitably provided as a patch, adhesive plaster, bandage, dressing, etc., which is impregnated with one or more compounds and optionally one or more other pharmaceutically acceptable ingredients, including, for example, penetration, permeation and absorption enhancers. The preparation can also be suitably provided in the form of a reservoir or depot.

[0237] The compound may be dissolved, suspended, or mixed with one or more other pharmaceutically acceptable ingredients.

[0238] Formulations suitable for oral administration (e.g., by ingestion) include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, and boluses.

[0239] In one embodiment, the compound is formulated as a tablet.

[0240] In one embodiment, the compound is formulated as an orally disintegrating tablet (ODT), also known as an orodispersible tablet, orally dissolving tablet, rapid-dissolving tablet, fast-disintegrating tablet, or fast-dissolving tablet. As contemplated herein, an ODT is a pharmaceutical dosage form that disintegrates in saliva within a few minutes of topical application to the surface of the tongue. Preferably, the disintegration time is long enough to allow the compound to coat the mucosa. The main advantages of using an ODT to deliver a compound are ease of administration (e.g., oral administration) and delivery to the site of action (e.g., local rather than systemic).

[0241] A typical ODT consists primarily of an inert vehicle, diluent, or carrier. The pharmaceutical agent (i.e., AX-8) is dispersed within this carrier. The ODT will dissolve when placed on the back of the tongue, thereby releasing the pharmaceutical agent so that it may come into contact with tissues of the lower oropharynx (LRO). A typical diluent, carrier, or vehicle may be a "polyol," which is interpreted to describe the following substances: xylitol, mannitol, sorbitol, maltitol, isomalt, maltotriitol, lactitol, and β-linked pyranose-sorbitol. Flavoring agents such as sweeteners, aspartame, sucralose, or alitame may be added to mask any taste. Typically, the mixture is granulated into a uniformly dispersed blend; dispersants, anti-caking agents, and / or lubricants may be added; and the mixture is then pressed to form the ODT. As an example, the ODT used in the studies described herein comprises (Mannitol, CL-SF, SR 30D), sorbitol, anhydrous colloidal dioxide and magnesium stearate.

[0242] In one embodiment, the compound is formulated as an ODT containing from about 0.5 mg to about 50 mg of the compound.

[0243] In one embodiment, the compound is formulated as an ODT containing from about 1 to about 30 mg of the compound.

[0244] In one embodiment, the compound is formulated as an ODT containing from about 2 to about 20 mg of the compound.

[0245] In one embodiment, the compound is formulated as an ODT containing from about 2 to about 10 mg of the compound.

[0246] In one embodiment, the compound is formulated as an ODT containing about 5 mg of the compound.

[0247] In one embodiment, the compound is formulated as an ODT containing from about 50 mg to about 250 mg of the compound.

[0248] When the compound is a salt, ester, amide, prodrug or the like, the administration amount is calculated based on the parent compound, so the actual weight to be used is increased proportionally.

[0249] Preparations suitable for buccal administration include mouthwashes, lozenges, pastilles, and patches, adhesive plasters, reservoirs, and depots. Lozenges typically contain compounds of a flavoring base, typically sucrose and gum arabic or tragacanth. Pastilles typically contain compounds in an inert matrix such as gelatin and glycerol, or sucrose and gum arabic. Mouthwashes typically contain compounds in a suitable liquid carrier.

[0250] Suitable formulations for sublingual administration include tablets, lozenges, pastilles, capsules and pills.

[0251] Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), mouthwashes, sprays, aerosols, lozenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.

[0252] Suitable formulations for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots and reservoirs.

[0253] Tablets can be made by conventional means, for example, compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing a compound in a free-flowing form such as a powder or granules in a suitable machine, the compound optionally mixed with the following substances: one or more binders (e.g., povidone, gelatin, gum arabic, sorbitol, tragacanth, hydroxypropyl methylcellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silicon dioxide); disintegrants (e.g., sodium starch glycolate, cross-linked polyvidone, cross-linked sodium carboxymethylcellulose); surface active or dispersing or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methylparaben, propylparaben, sorbic acid); flavoring agents, flavor enhancers, and sweeteners. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the compound therein using, for example, hydroxypropylmethylcellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with a coating (e.g. to affect release), such as an enteric coating, to provide release in parts of the intestinal tract other than the stomach.

[0254] Ointments are typically prepared from the compound and a paraffinic or a water-miscible ointment base.

[0255] Creams are typically prepared from the compound and an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least about 30% w / w of a polyol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, 1,3-butylene glycol, mannitol, sorbitol, glycerol, and polyethylene glycol, and mixtures thereof. Topical preparations may desirably include compounds that enhance absorption or penetration of the compound through the skin or other diseased areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

[0256] Emulsions are usually prepared from a compound and an oil phase, which may optionally contain only an emulsifier (otherwise known as a purgative), or the oil phase may contain a mixture of at least one emulsifier with a fat or oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. Oil and fat are also preferably included. In summary, emulsifiers with or without stabilizers constitute the so-called emulsifying wax, and waxes together with oils and / or fats constitute the so-called emulsifying ointment base, which forms the oily dispersed phase of a cream formulation.

[0257] Suitable emulsifiers and emulsion stabilizers include Tween 60, Span 80, cetearyl alcohol, myristyl alcohol, monostearate and sodium lauryl sulfate. The selection of suitable oil or fat of preparation is based on realizing the desired cosmetic properties, because the solubility of compound in most oils that can be used in pharmaceutical emulsion preparations can be very low. Therefore, emulsifiable paste should preferably be non-greasy, non-staining and washable product, and it has suitable consistency to avoid leakage from pipe or other containers. Straight or branched, monobasic or dibasic alkyl esters can be used, such as diisoadipate, stearic acid isocetyl ester, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or the blend of branched esters called as Crodamol CAP, and the last three are preferred esters. Depending on the desired properties, these materials can be used alone or in combination. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used.

[0258] Suitable formulations for intranasal administration wherein the carrier is a liquid include, for example, nasal spray, nasal drops, or aerosol administration by nebulizer, including aqueous or oily solutions of the compound.

[0259] Formulations suitable for intranasal administration wherein the carrier is a solid include those presented as a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns, which are administered by snorting, i.e., by rapid inhalation through the nasal passages from a container of the powder held near the nose.

[0260] Formulations suitable for pulmonary administration (eg, by inhalation or insufflation therapy) include those presented in the form of an aerosol spray from pressurized packs with the aid of a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.

[0261] In one embodiment, the compound is formulated as an aerosol spray.

[0262] Combination therapy

[0263] The term "treatment" includes combination therapy and therapy, wherein two or more treatments or therapies are combined, for example, sequentially or simultaneously. For example, the compound [((1R, 2S, 5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-isopropyl acetate (also referred to herein as "AX-8" or "Gly-O-iPr") as described herein can also be used in combination therapy, for example, in conjunction with other agents, such as one or more antitussives, expectorants, mucolytics, decongestants, nasal decongestants, first generation antihistamines, antihistamines, opioid analgesics, non-opioid analgesics, antipyretics, etc. and combinations thereof.

[0264] The particular combination will be determined by the physician who will select the dosage using his common general knowledge and dosing regimens known to skilled practitioners.

[0265] The agents (i.e., compound, plus one or more other agents) can be administered simultaneously or sequentially, and can be administered in different dosage regimens and by different routes. For example, when administered sequentially, the agents can be administered at closely spaced intervals (e.g., a period of 5-10 minutes) or at longer intervals (e.g., 1, 2, 3, 4 or more hours apart or even longer periods of time apart when necessary), the precise dosage regimen being commensurate with the nature of the therapeutic agent.

[0266] The agents (ie, the compound, plus one or more other agents) can be formulated together in a single dosage form, or alternatively, the separate agents can be formulated separately and provided together in the form of a kit, optionally with instructions for their use.

[0267] Subjects / Patients

[0268] The subject / patient can be a mammal, a placental mammal, a marsupial (e.g., a kangaroo, a wombat), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), a murine (e.g., a mouse), a lagomorph (e.g., a rabbit), an avian (e.g., a bird), a canine (e.g., a dog), a feline (e.g., a cat), an equine (e.g., a horse), a porcine (e.g., a pig), an ovine (e.g., a sheep), a bovine (e.g., a cow), a primate, an ape (e.g., a monkey or ape), a monkey (e.g., a marmoset, a baboon), an ape (e.g., a gorilla, a chimpanzee, an orangutan, a gibbon), or a human.

[0269] In a preferred embodiment, the subject / patient is a human.

[0270] Formulating compounds for the treatment of chronic cough

[0271] Also described herein is a compound comprising:

[0272] [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof, the compound is configured for treating chronic cough.

[0273] In one embodiment, [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is formulated for use in treating chronic cough of defined cause.

[0274] In one embodiment, [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for treating chronic cough as a symptom of, associated with or caused by a diagnosed condition.

[0275] In one embodiment, [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for treating chronic cough as a symptom of, associated with or caused by a diagnosed cough-related disorder.

[0276] In one embodiment, [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for treating chronic cough that is a symptom of, associated with or caused by asthma, eosinophilic bronchitis, postnasal drip syndrome (PNDS), gastroesophageal reflux disease (GORD), bronchiectasis chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF).

[0277] In one embodiment, [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is formulated for use in treating idiopathic chronic cough (ICC).

[0278] In one embodiment, [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is formulated for use in treating refractory chronic cough (RCC).

[0279] In one embodiment, [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for treating refractory chronic cough (RCC) that persists after evaluation and treatment of a cough-related disorder.

[0280] In one embodiment, [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for treating refractory chronic cough (RCC) that persists after evaluation and treatment of asthma, eosinophilic bronchitis, postnasal drip syndrome (PNDS), gastroesophageal reflux disease (GORD), bronchiectasis chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF).

[0281] In one embodiment, [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is formulated for use in treating chronic cough that is a symptom of, associated with or caused by allotussia.

[0282] In one embodiment, [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is formulated for treating chronic cough that is a symptom of, associated with, or caused by hypertussia.

[0283] In one embodiment, [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for treating chronic cough that is a symptom of, associated with or caused by cough hypersensitivity syndrome (CHS).

[0284] In one embodiment, [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for treating chronic cough that is a symptom of, associated with or caused by cough hypersensitivity reflex (CHR).

[0285] In one embodiment, [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for treating chronic cough that is a symptom of, associated with or caused by laryngeal paresthesia.

[0286] In one embodiment, [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for treating chronic cough that is a symptom of, associated with or caused by laryngeal hypersensitivity syndrome (LHS).

[0287] In one embodiment, [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is formulated for use in treating chronic cough that is a sensorineural cough.

[0288] In one embodiment, [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for treating chronic cough that is a symptom of, associated with or caused by: peripheral sensitization; central sensitization (cough center); and / or cortical and / or subcortical maladaptive plasticity.

[0289] In one embodiment, [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is formulated for use in treating chronic cough that is a symptom of, associated with or caused by vagal neuropathy.

[0290] In one embodiment, [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for treating chronic cough that is a symptom of, associated with or caused by airway inflammation.

[0291] In one embodiment, [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for treating chronic cough that is a symptom of, associated with or caused by neurogenic inflammation and / or neuroinflammation.

[0292] In one embodiment, wherein [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is configured for use in treating:

[0293] Reduce coughing frequency;

[0294] Reduce the frequency of coughing per hour;

[0295] Reduced median hourly cough frequency;

[0296] Reduce the average cough frequency per hour;

[0297] Reduce the frequency of coughing per hour of waking;

[0298] Reduced median cough frequency per hour of wakefulness;

[0299] Reduce the average cough frequency per hour while awake;

[0300] Reduce the frequency of coughing per hour during sleep;

[0301] Reduced median cough frequency per hour during sleep;

[0302] Reduce the average cough frequency per hour during sleep;

[0303] Reduce cough severity;

[0304] Reduce shortness of breath coughing; and / or

[0305] Reduces throat irritation.

[0306] In one embodiment, [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is formulated for:

[0307] topical oral administration of said compound;

[0308] topical oromucosal administration of the compound;

[0309] topical buccal administration of the compound;

[0310] topical sublingual administration of said compound;

[0311] topical intranasal administration of the compound; or

[0312] topical transmucosal administration of said compound;

[0313] In one embodiment, [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is formulated for:

[0314] Doses in the range of about 1 μg to about 5 mg of the compound per kilogram of body weight per day;

[0315] dosages ranging from about 5 μg to about 2 mg of the compound per kilogram of body weight per day;

[0316] dosages ranging from about 15 μg to about 0.7 mg of the compound per kilogram of body weight per day;

[0317] A dosage in the range of about 30 μg to about 0.4 mg of the compound per kilogram of body weight per day; or

[0318] Dosages within the range of about 70 μg to about 0.3 mg of the compound per kilogram of body weight per day.

[0319] In one embodiment, [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is formulated for:

[0320] dosages ranging from about 0.07 mg to about 350 mg of the compound per day;

[0321] dosages ranging from about 0.35 mg to about 140 mg of the compound per day;

[0322] Doses ranging from about 1 mg to about 50 mg of the compound per day;

[0323] A dosage in the range of about 2 mg to about 30 mg of the compound per day; or

[0324] Dosages in the range of about 5 mg to about 20 mg of the compound per day.

[0325] In one embodiment, [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is formulated for:

[0326] A treatment regimen of 1 to 5 administrations per day;

[0327] A treatment regimen of 1 to 4 administrations per day;

[0328] A treatment regimen of 2 to 5 applications per day;

[0329] A treatment regimen of 2 to 4 administrations per day;

[0330] A treatment regimen of twice daily administration;

[0331] A regimen of 3 times daily administration; or

[0332] The treatment regimen was administered 4 times per day.

[0333] In one embodiment, [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is formulated for use in a remedial response (PRN) treatment regimen.

[0334] In one embodiment, [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is formulated as:

[0335] tablet;

[0336] Orally disintegrating tablet (ODT);

[0337] Sprays;

[0338] Aerosols; or

[0339] aerosol.

[0340] Methods of making drugs

[0341] Also described herein is a method of making a medicament, the method comprising:

[0342] A medicament for treating chronic cough is prepared, wherein the medicament contains the compound [((1R, 2S, 5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-isopropyl acetate or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0343] In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound for treating chronic cough of defined cause.

[0344] In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound for treating chronic cough as a symptom of, associated with, or caused by the diagnosed condition.

[0345] In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound for treating chronic cough as a symptom of, associated with, or caused by a diagnosed cough-related disorder.

[0346] In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound for treating chronic cough that is a symptom of, associated with, or caused by asthma, eosinophilic bronchitis, postnasal drip syndrome (PNDS), gastroesophageal reflux disease (GORD), bronchiectasis chronic obstructive pulmonary disease (COPD), or idiopathic pulmonary fibrosis (IPF).

[0347] In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound for treating idiopathic chronic cough (ICC).

[0348] In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound for treating refractory chronic cough (RCC).

[0349] In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound for treating refractory chronic cough (RCC) that persists after evaluation and treatment of a cough-related disorder.

[0350] In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound for treating refractory chronic cough (RCC) that persists after evaluation and treatment of asthma, eosinophilic bronchitis, postnasal drip syndrome (PNDS), gastroesophageal reflux disease (GORD), bronchiectasis chronic obstructive pulmonary disease (COPD), or idiopathic pulmonary fibrosis (IPF).

[0351] In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound for treating chronic cough that is a symptom of, associated with, or caused by allotussia.

[0352] In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound for treating chronic cough that is a symptom of, associated with, or caused by hypertussia.

[0353] In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound for treating chronic cough that is a symptom of, associated with, or caused by cough hypersensitivity syndrome (CHS).

[0354] In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound for treating chronic cough that is a symptom of, associated with, or caused by cough hypersensitivity reflex (CHR).

[0355] In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound for treating chronic cough that is a symptom of, associated with, or caused by laryngeal paresthesia.

[0356] In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound for treating chronic cough that is a symptom of, associated with, or caused by laryngeal hypersensitivity syndrome (LHS).

[0357] In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound for treating chronic cough that is a sensorineural cough.

[0358] In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound for treating chronic cough that is a symptom of, associated with, or caused by: peripheral sensitization; central sensitization (cough center); and / or cortical and / or subcortical maladaptive plasticity.

[0359] In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound for treating chronic cough that is a symptom of, associated with, or caused by vagal neuropathy.

[0360] In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound for treating chronic cough that is a symptom of, associated with, or caused by airway inflammation.

[0361] In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound for treating chronic cough that is a symptom of, associated with, or caused by neurogenic inflammation and / or neuroinflammation.

[0362] In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound to:

[0363] Reduce coughing frequency;

[0364] Reduce the frequency of coughing per hour;

[0365] Reduced median hourly cough frequency;

[0366] Reduce the average cough frequency per hour;

[0367] Reduce the frequency of coughing per hour of waking;

[0368] Reduced median cough frequency per hour of wakefulness;

[0369] Reduce the average cough frequency per hour while awake;

[0370] Reduce the frequency of coughing per hour during sleep;

[0371] Reduced median cough frequency per hour during sleep;

[0372] Reduce the average cough frequency per hour during sleep;

[0373] Reduce cough severity;

[0374] Reduce shortness of breath coughing; and / or

[0375] Reduces throat irritation.

[0376] In one embodiment, preparing a medicament containing the compound comprises preparing the medicament for use in:

[0377] topical oral administration of said compound;

[0378] topical oromucosal administration of the compound;

[0379] topical buccal administration of the compound;

[0380] topical sublingual administration of said compound;

[0381] topical intranasal administration of the compound; or

[0382] topical transmucosal administration of the compound;

[0383] In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound as:

[0384] Doses in the range of about 1 μg to about 5 mg of the compound per kilogram of body weight per day;

[0385] dosages ranging from about 5 μg to about 2 mg of the compound per kilogram of body weight per day;

[0386] dosages ranging from about 15 μg to about 0.7 mg of the compound per kilogram of body weight per day;

[0387] A dosage in the range of about 30 μg to about 0.4 mg of the compound per kilogram of body weight per day; or

[0388] Dosages within the range of about 70 μg to about 0.3 mg of the compound per kilogram of body weight per day.

[0389] In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound as:

[0390] dosages ranging from about 0.07 mg to about 350 mg of the compound per day;

[0391] dosages ranging from about 0.35 mg to about 140 mg of the compound per day;

[0392] Doses ranging from about 1 mg to about 50 mg of the compound per day;

[0393] A dosage in the range of about 2 mg to about 30 mg of the compound per day; or

[0394] Dosages in the range of about 5 mg to about 20 mg of the compound per day.

[0395] In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound as:

[0396] A treatment regimen of 1 to 5 administrations per day;

[0397] A treatment regimen of 1 to 4 administrations per day;

[0398] A treatment regimen of 2 to 5 applications per day;

[0399] A treatment regimen of 2 to 4 administrations per day;

[0400] A treatment regimen of twice daily administration;

[0401] A regimen of 3 times daily administration; or

[0402] The treatment regimen was administered 4 times per day.

[0403] In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound as a pro-active (PRN) treatment regimen.

[0404] In one embodiment, preparing a medicament containing the compound comprises preparing a medicament containing the compound as:

[0405] tablet;

[0406] Orally disintegrating tablet (ODT);

[0407] Sprays;

[0408] Aerosols; or

[0409] aerosol.

[0410] Treatments for chronic cough

[0411] Also described herein is a method of treating chronic cough in a patient, the method comprising:

[0412] A therapeutically effective amount of the compound [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-acetic acid isopropyl ester or a pharmaceutically acceptable salt, hydrate or solvate thereof is administered to a patient in need of treatment for chronic cough.

[0413] In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for a chronic cough with an identified cause.

[0414] In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for chronic cough that is a symptom of, associated with, or caused by the diagnosed condition.

[0415] In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for chronic cough that is a symptom of, associated with, or caused by a diagnosed cough-related disorder.

[0416] In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for chronic cough that is a symptom of, associated with, or caused by asthma, eosinophilic bronchitis, postnasal drip syndrome (PNDS), gastroesophageal reflux disease (GORD), bronchiectasis chronic obstructive pulmonary disease (COPD), or idiopathic pulmonary fibrosis (IPF).

[0417] In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for idiopathic chronic cough (ICC).

[0418] In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for refractory chronic cough (RCC).

[0419] In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for refractory chronic cough (RCC) that persists after evaluation and treatment of a cough-related disorder.

[0420] In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for refractory chronic cough (RCC) that persists after evaluation and treatment of asthma, eosinophilic bronchitis, postnasal drip syndrome (PNDS), gastroesophageal reflux disease (GORD), bronchiectasis chronic obstructive pulmonary disease (COPD), or idiopathic pulmonary fibrosis (IPF).

[0421] In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for chronic cough that is a symptom of, associated with, or caused by allotussia.

[0422] In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for chronic cough that is a symptom of, associated with, or caused by hypertussia.

[0423] In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for chronic cough that is a symptom of, associated with, or caused by cough hypersensitivity syndrome (CHS).

[0424] In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for chronic cough that is a symptom of, associated with, or caused by cough hypersensitivity reflex (CHR).

[0425] In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for chronic cough that is a symptom of, associated with, or caused by laryngeal paresthesia.

[0426] In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for chronic cough that is a symptom of, associated with, or caused by laryngeal hypersensitivity syndrome (LHS).

[0427] In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for chronic cough that is a sensorineural cough.

[0428] In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for chronic cough that is a symptom of, associated with, or caused by: peripheral sensitization; central sensitization (cough center); and / or cortical and / or subcortical maladaptive plasticity.

[0429] In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for chronic cough that is a symptom of, associated with, or caused by vagal neuropathy.

[0430] In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for chronic cough that is a symptom of, associated with, or caused by airway inflammation.

[0431] In one embodiment, the administering step comprises administering the compound to a patient in need of treatment for chronic cough that is a symptom of, associated with, or caused by neurogenic inflammation and / or neuroinflammation.

[0432] In one embodiment, the administering step comprises administering the compound to the patient to:

[0433] Reduce coughing frequency;

[0434] Reduce the frequency of coughing per hour;

[0435] Reduced median hourly cough frequency;

[0436] Reduce the average cough frequency per hour;

[0437] Reduce the frequency of coughing per hour of waking;

[0438] Reduced median cough frequency per hour of wakefulness;

[0439] Reduce the average cough frequency per hour while awake;

[0440] Reduce the frequency of coughing per hour during sleep;

[0441] Reduced median cough frequency per hour during sleep;

[0442] Reduce the average cough frequency per hour during sleep;

[0443] Reduce cough severity;

[0444] Reduce shortness of breath coughing; and / or

[0445] Reduces throat irritation.

[0446] In one embodiment, the administering step comprises administering the compound to a patient in need of treatment by:

[0447] topical oral administration of said compound;

[0448] topical oromucosal administration of the compound;

[0449] topical buccal administration of the compound;

[0450] topical sublingual administration of said compound;

[0451] topical intranasal administration of the compound; or

[0452] topical transmucosal administration of the compound;

[0453] In one embodiment, the administering step comprises administering the compound to a patient in need of treatment at a dosage of:

[0454] Doses in the range of about 1 μg to about 5 mg of the compound per kilogram of body weight per day;

[0455] dosages ranging from about 5 μg to about 2 mg of the compound per kilogram of body weight per day;

[0456] dosages ranging from about 15 μg to about 0.7 mg of the compound per kilogram of body weight per day;

[0457] A dosage in the range of about 30 μg to about 0.4 mg of the compound per kilogram of body weight per day; or

[0458] Dosages within the range of about 70 μg to about 0.3 mg of the compound per kilogram of body weight per day.

[0459] In one embodiment, the administering step comprises administering the compound to a patient in need of treatment at a dosage of:

[0460] dosages ranging from about 0.07 mg to about 350 mg of the compound per day;

[0461] dosages ranging from about 0.35 mg to about 140 mg of the compound per day;

[0462] Doses ranging from about 1 mg to about 50 mg of the compound per day;

[0463] A dosage in the range of about 2 mg to about 30 mg of the compound per day; or

[0464] Dosages in the range of about 5 mg to about 20 mg of the compound per day.

[0465] In one embodiment, the administering step comprises administering the compound to a patient in need of treatment as follows:

[0466] A treatment regimen of 1 to 5 administrations per day;

[0467] A treatment regimen of 1 to 4 administrations per day;

[0468] A treatment regimen of 2 to 5 applications per day;

[0469] A treatment regimen of 2 to 4 administrations per day;

[0470] A treatment regimen of twice daily administration;

[0471] A regimen of 3 times daily administration; or

[0472] The treatment regimen was administered 4 times per day.

[0473] In one embodiment, the administering step comprises administering the compound as a pro-active (PRN) treatment regimen to a patient in need of treatment.

[0474] In one embodiment, the administering step comprises administering the compound to a patient in need of treatment as:

[0475] tablet;

[0476] Orally disintegrating tablet (ODT);

[0477] Sprays;

[0478] Aerosols; or

[0479] aerosol.

[0480] Clinical Trial 1

[0481] The first clinical trial using the compound [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-isopropyl acetate (also referred to herein as "AX-8" or "Gly-O-iPr") for the treatment of RCC was initiated but ended prematurely. The basic details of the trial are set forth in the table below.

[0482] Currently, some details are available online:

[0483] https: / / www.clinicaltrialsregister.eu / ctr-search / trial / 2016-004803-30 / GB

[0484]

[0485] Clinical Trial 2

[0486] A second clinical trial (open-label Phase IIa) using the compound [((1R, 2S, 5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-isopropyl acetate (also referred to herein as "AX-8" or "Gly-O-iPr") for the treatment of RCC has just been completed. The basic details of the trial are set forth in the table below.

[0487] Currently, some details are available online:

[0488] https: / / www.clinicaltrialsregister.eu / ctr-search / trial / 2017-003108-27 / GB

[0489]

[0490] After the completion of the second clinical trial (described in detail below), it was found that the compound has unexpected antitussive properties in RCC patients, thereby reducing the frequency of coughs per hour during waking hours, throat irritation, shortness of cough and cough severity. No adverse reactions related to the compound were observed.

[0491] As demonstrated in clinical trials, a 5 mg dose of the compound improved cough in RCC patients by reducing cough frequency and also the visual analogue scale (VAS) scores of all assessed cough characteristics (ie, cough severity, shortness of cough, throat irritation).

[0492] This was unexpected because MK-7264 (also known as AF-219 and gefapirazan), a more advanced RCC drug currently in development (Phase 3 clinical trials began in March 2018), was effective in reducing cough frequency but was less effective in improving VAS scores in RCC patients (see, e.g., Abdulqawi et al., 2015; Smith et al., 2017a; Smith et al., 2017b; Smith et al., 2020). Cough severity was significantly improved only for doses of 50 mg and 1200 mg per day, with taste-related adverse events (i.e., dysgeusia, hypogeusia, or loss of taste) occurring in 81% and 100% of patients, respectively. Significant improvement in shortness of cough was shown only with the 1200 mg per day dose. Phase 3 clinical trials (NCT03449134 and NCT03449147, still ongoing as of June 2020) are studying 15 mg and 45 mg doses of MK-7264.

[0493] AX-8 is the only compound that has been shown to reduce throat irritation in patients with RCC.

[0494] Research objectives

[0495] AX-8 bioavailability and safety have been previously addressed in a Phase 1 study in healthy human subjects. However, until now, AX-8 has not been studied in patients with chronic cough (CC). This study is a preliminary investigation of the efficacy, safety, and tolerability of AX-8 for the treatment of refractory chronic cough (RCC).

[0496] The primary objective of the study was to evaluate the effectiveness of AX-8 (study drug) for the treatment of RCC and related upper respiratory tract symptoms in reducing the frequency of awake cough after one dose of treatment (orally disintegrating tablets (ODT) with 5 mg AX-8, administered orally and dissolved on the tongue) compared with baseline, with the aim of planning a future randomized controlled trial.

[0497] A secondary objective of the study was to evaluate the duration of effectiveness of AX-8 in reducing objective cough frequency per hour over a 24-hour monitoring period following 1 dose of treatment.

[0498] Another secondary objective of the study was to evaluate the effectiveness of AX-8 in: (a) reducing cough severity as measured by a visual analog scale (VAS); (b) reducing throat irritation and shortness of cough (VAS); and (c) eliciting a sensation of throat moisturization (VAS).

[0499] Another secondary objective of the study is to evaluate the safety and tolerability of AX-8 treatment in patients with RCC.

[0500] An exploratory objective (added to the study after initiation) was to evaluate the pharmacokinetic (PK) characteristics of AX-8.

[0501] Ethics, approval, and location

[0502] The study protocol including all relevant documents was reviewed and approved by the appropriate independent ethics committee. The study was conducted according to the current version of the Declaration of Helsinki (52nd WMA Conference, Edinburgh, Scotland, October 2000). The study was conducted according to the guidelines of the International Conference on Harmonisation (ICH) on good clinical practice (GCP). The study was conducted in accordance with the requirements of the Medicines and Healthcare products Regulatory Agency (MHRA). All patients provided written informed consent (ICF) for participation in the study before screening. The study was conducted at NIHR Manchester Clinical Research Facility (CRF), Manchester University NHS Foundation Trust (MFT), Southmoor Rd, Wythenshawe, Manchester M23 9LT, UK.

[0503] Research time

[0504] The study consisted of five phases with a total study duration of approximately 4 weeks:

[0505]

[0506]

[0507] During the screening period, subjects were assessed for eligibility and recruited.

[0508] On Day 0 (Visit 2; baseline visit), eligible participants underwent 24-hour cough monitoring and assessed quickness of cough (UTC), cough severity, and throat irritation over 4 hours using a VAS in the clinic and tracked in a home patient diary.

[0509] Subjects were asked to fast overnight (at least 8 hours) prior to the Day 0 visit. Breakfast was provided on the unit at least 30 minutes before the subject had their cough monitor installed. No food was allowed for 4 hours after the cough monitor was installed. No fluids were allowed until the cough monitor was installed, and no fluids (including water) were allowed until 2 hours after the cough monitor was installed; after 2 hours, only a reasonable amount of water was allowed. After 4 hours, there were no more food or fluid restrictions.

[0510] On Day 1 (Visit 3; treatment visit), eligible subjects received one 5 mg AX-8 ODT. Cough monitoring was performed over 24 hours and different VASs for UTC, cough severity, throat irritation, throat lubrication, and taste perception were assessed in the clinic within 4 hours after dosing and followed up at home with a patient diary.

[0511] Subjects were asked to fast overnight (at least 8 hours) before the first day visit. Breakfast was provided in the unit at least 30 minutes before the subject received the AX-8 dose. No food was allowed within 4 hours after the dose was administered. Liquids were not allowed until the dose was administered, and liquids (including water) were not allowed until 2 hours after the dose. After 2 hours, only a reasonable amount of water was allowed. After 4 hours, there were no more food or liquid restrictions.

[0512] The primary efficacy endpoint was assessed after one day of treatment.

[0513] On Day 2 (Visit 4; follow-up visit), the cough monitor was removed and the patient diary was returned.

[0514] An End-of-Study Visit was conducted between 7-14 days after Day 1 (Visit 5; End-of-Study Visit).

[0515] Subjects who withdraw from the study after receiving study drug and before completing the End-of-Study Visit are asked to complete an Early Exit Visit (EWV), whereby the same procedures as the End-of-Study Visit are performed.

[0516] recruit

[0517] Adult subjects with a history of RCC and associated upper respiratory tract symptoms (ie, throat irritation / itching associated with coughing episodes) were recruited into the study.

[0518] Inclusion criteria:

[0519] Subjects must meet the following criteria to be recruited into the study:

[0520] Women and men between 18 and 80 years old (inclusive).

[0521] Diagnosed RCC or unexplained cough lasting for at least one year (see British Thoracic Society (BTS) guidelines) and associated upper respiratory tract symptoms (throat or larynx irritation, itching, dryness or discomfort) lasting for at least 8 weeks. Regularity of cough pattern and expected daily cough episodes occurring throughout the day, as determined by medical history.

[0522] Chest radiograph or chest computed tomography within the past 5 years did not demonstrate any abnormalities that were considered by the principal investigator and medical monitor to be significantly contributing to chronic cough.

[0523] Cough severity VAS score ≥40 mm at the screening visit.

[0524] Cough severity VAS score ≥40 mm at baseline visit.

[0525] All female subjects of reproductive potential must use highly effective contraception (i.e., a pregnancy prevention method with a failure rate of <1% per year) from the time of the initial screening visit until 4 weeks after the last dose of study drug.

[0526] Body mass index (BMI) < 33 kg / m at baseline visit 2 .

[0527] ·Willing and able to comply with all aspects of the program.

[0528] Provide written informed consent.

[0529] Exclusion criteria:

[0530] Subjects meeting any of the following criteria were not eligible to participate in the study:

[0531] · Previous treatment with AX-8.

[0532] Hypersensitivity or intolerance to AX-8 or other TRPM8 agonists (e.g. menthol, menthol-like compounds) or any of the excipients of AX-8 ODT.

[0533] Current smokers or individuals who have quit smoking in the past 12 months or have quit smoking for > 20 pack-years.

[0534] Forced expiratory volume in one second (FEV1) / forced vital capacity (FVC) < 60%.

[0535] History of upper or lower respiratory tract infection or recent significant change in pulmonary status within 4 weeks of baseline visit.

[0536] History of cystic fibrosis.

[0537] · History of opioid use within 1 week of the baseline visit, if used to treat RCC. Opioid use is permitted if required for other indications, provided the subject has been on a stable dose for at least 1 week prior to the baseline visit and is still experiencing a bothersome cough. Subjects must remain on a stable dose for the duration of the study until the follow-up visit.

[0538] ·Concurrent treatment with contraindicated medications is required.

[0539] Treatment with a biologic therapy within 8 weeks or 5 half-lives prior to the baseline visit, whichever is longer.

[0540] Treatment with any investigational therapy within 4 weeks prior to the baseline visit.

[0541] Clinically significant liver function abnormalities, defined as total bilirubin, alanine aminotransferase (ALT), or aspartate aminotransferase (AST) >2 times the upper limit of normal (ULN) during screening.

[0542] Clinically significant renal dysfunction, defined as estimated glomerular filtration rate (eGFR) < 60 ml / min.

[0543] Any positive test for drugs of abuse (unless the subject's medication can explain this).

[0544] History of malignancy within 5 years before baseline visit, excluding completely treated and non-metastatic basal cell carcinoma or cutaneous squamous cell carcinoma.

[0545] History of major psychiatric illness (including major depression, bipolar disorder, or schizophrenia), suicidal ideation, or suicide attempt.

[0546] Known active hepatitis infection.

[0547] · Known history of human immunodeficiency virus (HIV) infection.

[0548] The presence of any medical condition or disability that, in the opinion of the investigator, may interfere with safety or efficacy assessments in this trial or jeopardize the safety of the subject, including clinically significant ECG abnormalities during the Screening Visit, Baseline Visit, or Treatment Visit.

[0549] Female subjects who are currently pregnant or breastfeeding, or male subjects with pregnant or breastfeeding partners.

[0550] Women of childbearing potential who are unable or unwilling to use highly effective contraception (to prevent pregnancy).

[0551] Patients can withdraw from the study at any time without giving a reason. Researchers can also withdraw patients from the trial if they think it is appropriate for safety or ethical reasons or if it is considered detrimental to the patient's health. The study protocol states that a subject must stop the study if the following events occur between recruitment and drug administration:

[0552] · Female subjects are pregnant.

[0553] The subject decides to discontinue the study, or the subject decides to withdraw consent for the study.

[0554] Any medical condition that, in the opinion of the investigator, may compromise the safety of the subject if the study drug is administered.

[0555] The investigator believes that discontinuation of the drug is in the best interest of the subject.

[0556] Ultimately, no patient dropped out of the study and therefore no EWV was performed.

[0557] A total of 16 patients were screened. A total of 12 patients were treated and completed the study. Efficacy and safety data were analyzed for 12 patients. A sample size of 10-15 patients was considered sufficient to evaluate the antitussive effect of a single dose of treatment in terms of magnitude and duration compared with baseline measurements.

[0558] treat

[0559] Subjects took a single orally disintegrating tablet (ODT) containing 5 mg of AX-8 in the morning on the first day of the treatment period (Day 1). This investigational medicinal product (IMP) was allowed to dissolve on the tongue. The patient was observed for 5 minutes to ensure that the tablet dissolved on the tongue and was not swallowed.

[0560] ODT was administered on Day 1 (Visit 3; Treatment Visit) after the cough monitor was removed on Day 0 (Visit 2, Baseline Visit) and before 10 AM (because RCC patients cough primarily during the day).

[0561] AX-8 ODT also contains (Mannitol, CL-SF, SR 30D), sorbitol, anhydrous colloidal silica, and magnesium stearate. The IMP batch was number 17081402 (expiration date November 2018). ODT was kept in the original packaging (i.e., HDPE bottle with polypropylene screw cap containing 50 tablets) until administration. ODT was stored in a secure, temperature-controlled (not exceeding 30°C), controlled-access location at the study site.

[0562] The 5 mg AX-8 dose was selected for this study based on the favorable safety and tolerability profile of AX-8 at the 5 mg ODT dose level, as demonstrated in a Phase 1 study in healthy volunteers. In the study, AX-8 was well tolerated in 12 subjects exposed to a single dose of AX-8, with no significant adverse events (AEs).

[0563] All study treatments were administered by the study investigator or designated staff. To ensure medication accountability, the investigator or designated agent maintained preparatory records of the date and amount of medication received, to whom it was dispensed, and an accounting of any accidental or intentional destruction of supplies; these details were recorded on the Medication Accountability Form. All unused clinical supplies and the Medication Accountability Form were returned at the end of the study.

[0564] Prior and concurrent therapy

[0565] Concurrent therapy included any therapy (including over-the-counter (OTC) medications) used by the subject from the start of treatment to the follow-up period. Records of all medications used were maintained for each subject throughout the study. The information reported included a description of the medication type, treatment cycle, dosing regimen, route of administration, and medication indication.

[0566] Subjects using oral contraceptives, hormone replacement therapy, or other maintenance therapy that is not excluded may continue to use it during the study. Records of all concurrent therapies will be maintained for each subject.

[0567] The following therapies and products were excluded within the last 6 hours before and during all visit days:

[0568] Consumption of cough drops, over-the-counter cough syrups, chewing gum, caffeine, cayenne pepper, or products containing mint and / or menthol within the last 6 hours before and during the visit date.

[0569] From 1 week before the baseline visit (Day 0, Visit 2) to the end of the follow-up visit (Day 2, Visit 4), the following therapies were excluded:

[0570] Opioids (including codeine and morphine). Opioids (including codeine) were allowed if required for other indications, provided that the subject had been on a stable dose for at least one week prior to the baseline visit (Day 0) and was still experiencing a bothersome cough. Subjects had to remain on a stable dose for the duration of the treatment period.

[0571] From 2 weeks prior to the baseline visit (Day 0, Visit 2) to the end-of-study visit (Visit 5), the following cough therapies were excluded:

[0572] · Dextromethorphan;

[0573] ·Guaifenesin.

[0574] From 2 weeks prior to the baseline visit (Day 0, Visit 2) to the end-of-study visit (Visit 5), the following therapies were excluded:

[0575] Pregabalin, gabapentin, thalidomide, or amitriptyline for the treatment of cough. Pregabalin, gabapentin, thalidomide, or amitriptyline is permitted if required for other indications, if the subject is on a stable dose and is still experiencing a bothersome cough. Subjects must remain on a stable dose for the duration of the treatment period.

[0576] From 2 weeks prior to the baseline visit (Day 0, Visit 4) to the end-of-study visit (Visit 5), the following therapies were excluded:

[0577] Systemic immunosuppressive / immunomodulatory therapy (including but not limited to PDE4 inhibitors, cyclosporine, mycophenolate mofetil, methotrexate, azathioprine, or phototherapy);

[0578] Any investigational therapy.

[0579] From 2 weeks prior to the baseline visit (Day 0, Visit 8) to the end-of-study visit (Visit 5), the following therapies were excluded:

[0580] Biological therapy;

[0581] Investigational biological therapies.

[0582] During the 12 weeks prior to the Baseline Visit (Day 0, Visit 2) until the End-of-Study Visit (Visit 5), the following therapies were excluded:

[0583] Treatment with ACE inhibitors.

[0584] From the Treatment Visit (Day 1, Visit 3) to the End of Study Visit (Visit 5), subjects were asked to take appropriate measures to minimize exposure to UV radiation (eg, sunlight, tanning booths).

[0585] Efficacy evaluation

[0586] Objective cough frequency:

[0587] Objective cough frequency was measured as 24-hour recordings using a custom-made digital recording device (VitaloJAK, Vitalograph, Ltd).

[0588] VitaloJAK TM VitaloJAK is a semi-automated 24-hour ambulatory cough monitoring system (Vitalograph; Buckinghamshire, England) that operates in a manner that fully replicates routine practice. The 24-hour recordings are compressed using an algorithm using custom-designed compression software. TM A reliable, robust and efficient tool for objective measurement of cough frequency. Importantly, it reduces 24-hour recordings by up to 98%, while retaining close to 100% of the recorded cough sounds. It is worn like a Holter monitor, with a single sensor fixed to the patient's chest wall. An optional second channel via a conventional microphone (e.g. worn on the patient's shirt) allows for quality assurance through manual intervention. The device itself attaches to pants, skirt, etc.

[0589] Severity of cough:

[0590] Cough severity was scored at designated time points according to a 100-mm visual analogue scale (VAS). Patients were asked to indicate their assessment by marking (e.g., with a pen) a position along the 100-mm line between two extremes (e.g., “no cough” and “worst cough”).

[0591] Quick cough (UTC):

[0592] Shortness of cough was scored according to the 100 mm VAS at the indicated time points.

[0593] Throat irritation:

[0594] Throat irritation was scored according to the 100 mm VAS at designated time points.

[0595] Soothes the throat:

[0596] Throat soothing was scored according to the 100 mm VAS at designated time points.

[0597] Global Rating of Change Scale (GRCS):

[0598] The subjects used the GRCS to rate their overall status during the designated period (4-hour period after dose; 24-hour period after dose). It consists of a 14-point scale ranging from "very good" to "very poor."

[0599] Taste Questionnaire:

[0600] Brief taste observations (qualitative) were completed. Freshness, basic taste (ie, sweet, sour, bitter and salty) and palatability were scored on a 100 mm VAS at designated time points.

[0601] Safety Assessment

[0602] Safety assessments included monitoring and recording of protocol-defined adverse events (AEs) and serious adverse events (SAEs); vital signs; physical examinations; clinical laboratory evaluations; electrocardiograms (ECGs); and other protocol-specified tests that were considered critical to the safety evaluation of the study drug.

[0603] Vital signs included measurements of heart rate, sitting blood pressure, respiratory rate, and temperature. Vital signs were assessed at designated time points and at unscheduled study visits as clinically indicated. Subjects' height and weight were also measured.

[0604] Physical examinations were performed at designated time points and at unscheduled study visits when clinically indicated and covered major body systems (evaluation of the ears, eyes, nose and throat, head, neck, thyroid, nervous system, respiratory system, cardiovascular system, lymph nodes, abdomen, skin, musculoskeletal, and nervous system).

[0605] Samples for hematology, chemistry, urinalysis, and serum pregnancy testing (when necessary) were collected at designated time points and at unscheduled study visits when clinically indicated and analyzed at local laboratories unless otherwise specified.

[0606] Laboratory evaluation includes the following:

[0607] Hematology: Hematocrit, hemoglobin, red blood cell count, red blood cell indices, platelets, white blood cell count, white blood cell differential (neutrophils, lymphocytes, monocytes, basophils, eosinophils).

[0608] Chemistry: sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen, creatinine, eGFR, calcium, phosphorus, magnesium, albumin, ALT, AST, alkaline phosphatase, total bilirubin, LDH, uric acid, total protein, lipids.

[0609] Pregnancy Testing: All females of reproductive potential underwent a local urine pregnancy test. A positive or equivocal urine pregnancy test result was confirmed by a serum pregnancy test analyzed at the local laboratory. A serum pregnancy test was performed at the Screening Visit (Visit 1).

[0610] Urinalysis: pH, specific gravity, bilirubin, glucose, ketones, leukocytes, nitrites, blood, protein, urobilinogen, microscopic analysis.

[0611] Standard 12-lead ECGs were performed at designated time points and at unscheduled study visits as clinically indicated.

[0612] Assessment of lung function tests (FEV1, FVC, and FEV1 / FVC ratio) using spirometry:

[0613] Forced expiratory volume in one second (FEV1) is the amount of air that is exhaled in one second using a spirometer.

[0614] Forced vital capacity (FVC) is the total amount of air that can be exhaled in one breath.

[0615] FEV1 divided by FVC (FEV1 / FVC), which is the ratio of the total volume that can be exhaled in one second.

[0616] Activities and Assessment Timetable

[0617] Informed consent was obtained prior to any protocol-specified procedure, including discontinuation of any excluded therapy.

[0618] Screening Visit (Visit 1):

[0619] Screening assessments will be conducted during the 14-day period prior to the baseline visit. The screening period may be extended beyond 14 days if any additional follow-up of the results of any screening assessment is required.

[0620] The following screening procedures were performed (not specified in the order below):

[0621] ·Inclusion / exclusion criteria review.

[0622] Demographics and medical history (including history of chronic cough, any medication history within 30 days prior to the screening visit, and history of chronic cough treatment within 1 year prior to the screening visit).

[0623] Physical examination.

[0624] Vital signs (including height and weight).

[0625] 12-lead ECG.

[0626] Spirometry.

[0627] Chest X-ray or CT chest (if not done within the past 5 years).

[0628] Laboratory testing:

[0629] Serum pregnancy test in females of reproductive potential.

[0630] ·Serology

[0631] ·Chemical

[0632] Urinalysis.

[0633] Urine drug screen.

[0634] VAS assessment of cough severity.

[0635] ·VAS assessment of shortness of cough.

[0636] ·VAS assessment of throat irritation.

[0637] Schedule a baseline visit.

[0638] Baseline Visit (Visit 2; Day 0):

[0639] At the baseline visit, the following procedures and assessments were performed (not specified in the order below):

[0640] ·Inclusion / exclusion criteria review.

[0641] Update medical history.

[0642] · Record all concurrent medication use.

[0643] Vital signs.

[0644] 12-lead ECG.

[0645] Laboratory testing:

[0646] Urine pregnancy test in females of reproductive potential.

[0647] Urine drug screen.

[0648] • Subjects were provided with a VAS diary and instructed to complete the +5 and +6 hour VAS assessments at home (see below).

[0649] • Connect and activate cough monitor for baseline visit (preferably before 10 AM).

[0650] VAS assessment of cough severity:

[0651] Before the cough monitor is installed:

[0652] -30 minutes.

[0653] After the cough monitor is installed:

[0654] +1, +2, +3, +4, +5, +6 hours.

[0655] ·VAS assessment of shortness of cough:

[0656] Before the cough monitor is installed:

[0657] -30 minutes.

[0658] After the cough monitor is installed:

[0659] +1, +2, +3, +4, +5, +6 hours.

[0660] Throat irritation VAS assessment:

[0661] Before the cough monitor is installed:

[0662] -30 minutes.

[0663] After the cough monitor is installed:

[0664] +1, +2, +3, +4, +5, +6 hours.

[0665] Arrange treatment visits.

[0666] VAS assessments at +5 and +6 hours were completed by the patient at home using a VAS diary. VAS assessments at all other time points were completed in the unit. A time window of + / - 5 minutes was allowed at all VAS time points.

[0667] Treatment Visit (Visit 3; Day 1):

[0668] At least 24 hours after connecting the baseline visit cough monitor on Day 0, and preferably before 10 AM, clinic staff performed the following activities (not specified in the order below):

[0669] Remove the baseline visit cough monitor.

[0670] Update medical history.

[0671] · Record all concurrent medication use.

[0672] ·Inclusion / exclusion criteria review.

[0673] Patients were included in the study if all inclusion and exclusion criteria were met.

[0674] Vital signs: Pre-dose and 4 hours post-dose.

[0675] · 12-lead ECG (pre-dose).

[0676] Laboratory testing:

[0677] Urine test for drugs of abuse.

[0678] Collect pharmacokinetic (PK) samples.

[0679] • Subjects were provided with a VAS diary and instructed to complete the +5 and +6 hour VAS assessments at home (see below).

[0680] ·Before dosing, connect and activate the treatment visit cough monitor.

[0681] • Administer the dose of study drug (preferably before 10 AM).

[0682] VAS assessment of cough severity:

[0683] Before dose:

[0684] -30 minutes.

[0685] After the dose:

[0686] +1, +2, +3, +4, +5, +6 hours.

[0687] ·VAS assessment of shortness of cough:

[0688] Before dose:

[0689] -30 minutes.

[0690] After the dose:

[0691] +1, +2, +3, +4, +5, +6 hours.

[0692] Throat irritation VAS assessment:

[0693] Before dose:

[0694] -30 minutes.

[0695] After the dose:

[0696] +1, +2, +3, +4, +5, +6 hours.

[0697] Throat soothing VAS assessment:

[0698] Before dose:

[0699] -30 minutes.

[0700] After the dose:

[0701] +1, +2, +3, +4, +5, +6 hours.

[0702] GRCS assessment 4 hours after dose.

[0703] Arrange follow-up visits.

[0704] Subjects may leave the unit following the 4-hour post-dose assessment once the investigator has determined that it is safe to do so.

[0705] VAS assessments at +5 and +6 hours were completed by the patient at home using a VAS diary. VAS assessments at all other time points were completed in the unit. A time window of + / - 5 minutes was allowed at all VAS time points.

[0706] Follow-up Visit (Visit 4; Day 2):

[0707] At least 24 hours after connection of the treatment visit cough monitor (Day 1), clinic staff performed the following activities (not specified in the order below):

[0708] Removed cough monitor from treatment visits.

[0709] · Collect and check VAS diaries for completeness.

[0710] Overall impression of treatment day (24 hours):

[0711] VAS assessment of cough severity.

[0712] ·VAS assessment of shortness of cough.

[0713] ·VAS assessment of throat irritation.

[0714] · VAS assessment of throat soothing.

[0715] GRCS assessment.

[0716] · Record all adverse events.

[0717] · Record all concurrent medication use.

[0718] Arrange end-of-study visit.

[0719] End of study visit (Visit 5):

[0720] The following procedures and assessments were performed in the clinic between Days 7 and 14. During this visit, clinic staff performed the following procedures and assessments (not specified in the order below):

[0721] VAS assessment of cough severity.

[0722] ·VAS assessment of shortness of cough.

[0723] ·VAS assessment of throat irritation.

[0724] GRCS assessment.

[0725] Vital signs.

[0726] ·weight.

[0727] Physical examination.

[0728] 12-lead ECG.

[0729] Laboratory testing:

[0730] ·Serology

[0731] ·Chemical

[0732] Urinalysis.

[0733] · Urine pregnancy test for females of reproductive potential. · Record all adverse events.

[0734] · Record all concurrent medication use.

[0735] The table below summarizes the timing of the various procedures and evaluations.

[0736]

[0737]

[0738]

[0739] Notes:

[0740]

[0741]

[0742] end

[0743] The primary efficacy endpoint was the change from baseline in objective cough frequency during waking hours within 24 hours after one dose of treatment.

[0744] Key secondary efficacy endpoints were:

[0745] Change from baseline in objective cough frequency per hour during the 24-hour monitoring period.

[0746] Proportion of subjects with a ≥30% reduction in 24-hour cough frequency per hour.

[0747] Proportion of subjects achieving a ≥30% reduction in hourly waking cough frequency.

[0748] Change from baseline in cough severity VAS.

[0749] Change from baseline in VAS for shortness of cough.

[0750] Change from baseline in throat irritation.

[0751] ·Throat soothing VAS.

[0752] Global Rating of Change Scale (GRCS):

[0753] Efficacy variables

[0754] The 24-hour cough frequency (coughs per hour) for a given visit was calculated as follows:

[0755] 24-hour cough frequency = (total number of cough events during the monitoring period (24-hour interval)) / 24.

[0756] The waking cough frequency (coughs per hour) was defined as follows:

[0757] Awake cough frequency = (total number of cough events while the subject was awake during the monitoring period (24-hour interval)) / (total duration (in hours) while the subject was awake during the monitoring period (24-hour interval)).

[0758] Wakefulness duration (hours) was defined as the time between waking and sleeping during the 24-hour monitoring period.

[0759] Cough data contained all cough events that occurred during the 24-hour monitoring period as well as information on "sleep time" and "awake time." Any period with a recording duration of <4 hours was considered missing.

[0760] In general, each 24-hour period consists of a wake monitoring period and a sleep monitoring period. If the subject does not wake up before the end of the recording period, it is assumed that the subject has been sleeping for the remainder of the period. The period will then be missing wake time, and the remainder of the period will be considered under the sleep monitoring period. For any period missing sleep time and wake time, the entire 24-hour period is considered to be in the wake monitoring period, unless the period terminates recording early.

[0761] On each collection day, cough counts, actual cough monitoring duration (in hours), and coughs per hour were derived separately for the total 24-hour period, awake and asleep periods.

[0762] The percent change in waking cough per hour was defined as follows:

[0763] Percent change in awake cough frequency = [(change from baseline in awake cough frequency x 100) / (baseline awake cough frequency)].

[0764] The proportion of participants with a ≥30% decrease in awake cough frequency from baseline was calculated as the number of participants with a ≤-30% change in awake cough frequency divided by the total number of participants with available data.

[0765] When presenting the geometric means (95% confidence intervals (CI)) of 24-hour cough frequencies, any observations of zero coughs per hour were replaced with a cough rate of 0.1 / hour to calculate the geometric mean.

[0766] Patient Engagement

[0767] Sixteen patients were screened between Dec 12, 2017, and May 16, 2018, and 11 patients completed the end-of-study visit between Jan 8, 2018, and June 11, 2018.

[0768] The table below summarizes patient participation.

[0769]

[0770]

[0771] Patient Demographics

[0772] The table below summarizes the demographics of the 12 patients.

[0773]

[0774] (*) No data were available for 4 of the 12 patients.

[0775] Results - Cough Frequency

[0776] Raw hourly cough count data relative to dosing time were plotted as the full analysis set and examined as an initial step.

[0777] Figure 1 is a graph of median cough frequency (coughs / hour) versus time after treatment (hours) for baseline (open circles) and treatment (filled circles).

[0778] The data demonstrated that treatment with a single dose of 5 mg AX-8 produced an improvement in cough frequency per hour compared to baseline over a period of approximately 8 hours.

[0779] The table below shows the summary cough frequency data for each of the five time windows (24 hours; awake; asleep; 8 hours; 4 hours).

[0780]

[0781]

[0782] For awake and asleep cough frequency, the Wilcoxon signed rank test was used to compare baseline and treatment data due to the skewed nature of the data. The data are summarized in the table below.

[0783]

[0784] IQR = interquartile range.

[0785] These data show a significant reduction in cough frequency during waking hours (from 64.1 to 54.8; a 14.5% reduction). During sleep, cough frequency was much lower and more variable, and therefore, although the cough rate was numerically reduced (from 7.1 to 3.7; a 48% reduction), the difference may not be statistically significant for the sample size used (12 patients).

[0786] For 24 hours, 8 hours and 4 hours cough frequency, the general estimation equation (GEE) model was used to compare baseline and treatment data. Before analysis, these cough count data were transformed by natural logarithm (Ln) to normalize the distribution of data. Since some individuals had zero cough counts per hour, 0.1 was added to all values ​​before conversion. The data are summarized in the table below.

[0787]

[0788] SE = standard error. CI = confidence interval.

[0789] These data indicate that cough frequency per hour was significantly improved for treatment during the 4-hour period and the 8-hour period compared to baseline. It appears that the effect may have diminished after 8 hours, and therefore, cough frequency was not significantly reduced when analyzed over the entire 24-hour recording period.

[0790] Figure 2-6 Data for individual subjects for each of the five time windows (awake; asleep; 24 hours; 8 hours; 4 hours) are shown in .

[0791] Figure 2 is a graph showing the mean waking cough frequency (coughs / hour) for 12 individual patients, both at baseline and on treatment.

[0792] Figure 3 is a graph showing the mean sleep cough frequency (coughs / hour) for 12 individual patients, both at baseline and on treatment.

[0793] Figure 4 is a graph showing the mean cough frequency (coughs / hour) for 12 individual patients during the 24 hour period following treatment and during the equivalent baseline period.

[0794] (Then determine Figure 2 , Figure 3 and Figure 4 The values ​​reported in the are the "average" values, not the "median" values ​​originally reported. )

[0795] Figure 5 is a graph showing the median cough frequency (coughs / hour) for 12 individual patients during the 8 hour period following treatment and during the equivalent baseline period.

[0796] Figure 6 is a graph showing the median cough frequency (coughs / hour) for 12 individual patients during the 4 hour period following treatment and during the equivalent baseline period.

[0797] Data proves:

[0798] 4 / 12 subjects (33.3%) experienced a ≥30% reduction in hourly waking cough frequency.

[0799] • 4 / 12 subjects (33.3%) experienced a ≥ 30% reduction in 24-hour cough frequency per hour.

[0800] • 5 / 12 subjects (41.7%) experienced a ≥30% reduction in 4-hour cough frequency per hour.

[0801] 7 / 12 subjects (58.3%) experienced a ≥30% reduction in 8-hour cough frequency per hour.

[0802] Results - cough severity and associated sensations

[0803] At various time points, patients were asked to report cough severity, throat irritation, shortness of cough, and throat moistening using a 100-mm visual analogue scale (VAS).

[0804] Data from the Screening and End-of-Study Visits, as well as data from the Follow-up Visits (assessments throughout the ≥24-hour period post-dose), are shown in the table below.

[0805]

[0806] (a) It was subsequently determined that these values ​​were “median” values, rather than the “mean” values ​​initially reported.

[0807] (b) It was subsequently determined that the values ​​initially reported (shown in parentheses) were incorrectly calculated.

[0808] The data showed that cough severity was significantly reduced after treatment (from 61.5 at screening, to 47.0 at follow-up, then recovered to 64.0 at the end of the study). Similarly, the data showed that throat irritation was significantly reduced after treatment (from 55.0 at screening, to 9.0 at follow-up, then recovered to 47.0 at the end of the study). Finally, the data showed that shortness of cough was also reduced after treatment (from 51.5 at screening, to 46.0 at follow-up, then recovered to 57.0 at the end of the study).

[0809] Figure 7-10 Data are shown for cough severity, throat irritation, shortness of cough, and throat soreness immediately before treatment and hourly for 6 hours after treatment. (Throat soreness was assessed every half hour for the first 3 hours after treatment.)

[0810] Figure 7 is a graph of median cough severity (VAS) (mm) versus time after treatment (hours) for baseline (open inverted triangles) and treatment (closed inverted triangles).

[0811] Figure 8 is a graph of median shortness of cough (VAS) (mm) versus time after treatment (hours) for baseline (open diamonds) and treatment (filled diamonds).

[0812] Fig. 9 is a graph of median throat irritation (VAS) (mm) versus time after treatment (hours) for baseline (open squares) and treatment (closed squares).

[0813] Fig.10 is a graph of median throat soothing (VAS) (mm) versus time after treatment (hours) (solid upper triangles).

[0814] Cough severity data showed that patients experienced sustained relief beginning in the first hour of monitoring over a 6-hour period (see Figure 7 The shortness of cough data also showed improvements from the first hour that persisted over the 6 hours of monitoring, with a clear maximum at approximately 3 hours (see Figure 8 Throat irritation data also demonstrated improvements from the first hour that persisted over the 6-hour monitoring period; however, baseline treatment was lower compared to the baseline day (see Fig. 9 The throat soothing data showed an increase only at 30 minutes, with little perceptible difference at 1 hour and beyond (see Fig.10 ).

[0815] Fig.11 is a composite graph showing median shortness of cough (VAS) (mm) (filled diamonds), throat irritation (VAS) (mm) (filled squares), and throat soreness (VAS) (mm) (filled upper triangles) on the left and median cough frequency (coughs / hour) versus time after treatment (hours) for baseline (open circles) and treatment (filled circles) on the right.

[0816] When data on throat irritation, shortness of cough, and throat moistening overlap with data on cough frequency (baseline and treatment) (see Fig.11 ), the temporal relationship between the sensation and the possible antitussive effect can be assessed. The data suggest that the throat soothing sensation precedes (and has resolved before) the subsequent improvement in throat irritation and shortness of cough. This suggests that the primary mechanism of action is not antagonistic stimulation. This also suggests that the observed effects (e.g., reduced cough frequency) are not simply due to a placebo effect, as patients will experience the immediate effect (i.e., throat soothing) to resolve. The data also suggest that improvements in throat irritation and shortness of cough may be precursors to improvements in cough frequency.

[0817] Outcome-Global Rating of Change Scale (GRCS)

[0818] The Global Rating of Change Scale (GRCS) assessment data obtained 4 hours after treatment and 24 hours after treatment are summarized in the table below.

[0819]

[0820] *One patient provided GRCS at 4 hours instead of 24 hours.

[0821] Efficacy Conclusion

[0822] Based on the data described, the following conclusions can be drawn:

[0823] In this uncontrolled, pilot study, AX-8 significantly reduced cough frequency during waking hours in patients with refractory chronic cough (RCC) compared to baseline (no treatment).

[0824] The effects appear to be most pronounced within 4-8 hours.

[0825] The effect was accompanied by a reduction in patient-reported cough severity.

[0826] The effects were also accompanied by a reduction in patient-reported throat irritation and shortness of breath, both cough-related sensations in patients with refractory chronic cough.

[0827] Throat soothing was only experienced transiently and appeared to precede improvements in cough frequency, cough severity, and cough-related sensations.

[0828] Additional Studies: Mode of Action

[0829] The mode of action of the compound [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-isopropyl acetate (also referred to herein as "AX-8" or "Gly-O-iPr") in treating chronic cough (CC) (including, for example, refractory chronic cough (RCC) and idiopathic chronic cough (ICC)) is not fully understood, in part because the mechanism of CC (including, for example, RCC, ICC) remains poorly understood.

[0830] The compounds are agonists of the transient receptor potential melanostatin 8 (TRPM8) cationic ion channel, also known as the cold and menthol receptor 1 (CMR1).

[0831] However, evidence suggests that the unique combination of several properties of the compound (e.g., localized mode of action; high potency; high selectivity with respect to TRPM8; high efficacy for specific target tissues, such as non-keratinized stratified epithelium - NKSE) results in unexpected efficacy in the treatment of CC (including, e.g., RCC, ICC) as compared to other TRPM8 agonists and known antitussive drugs.

[0832] Menthol is a typical agonist of TRPM8 ion channels. For decades, menthol has been used for over-the-counter (OTC) antitussive treatment. The efficacy of menthol is recognized in acute cough, although some studies have failed to demonstrate significant antitussive effects (see, e.g., Kenia et al., 2008; Haidl et al., 2001). Menthol has never been shown to improve chronic cough in CC patients; on the contrary, it has been shown to improve induced cough (see, e.g., Millqvist et al., 2013). In addition, menthol can induce adverse reactions such as airway irritation, dyspnea, increased mucus production accompanied by decreased ciliary activity, leading to mucus stagnation, chest tightness and potential respiratory failure, mainly in children when inhaled; and acid reflux and heartburn when taken orally (see, e.g., Gavliakova et al., 2013).

[0833] The antitussive effects of menthol (see, e.g., Maher et al., 2014) and some of its side effects may be due to its activity on targets other than TRPM8. Dozens of publications have demonstrated that menthol can significantly affect the functional properties of many different classes of channels and receptors, including TRP channels (TRPA1, TRPV1, TRPV3; see, e.g., Takaishi et al., 2016), other ligand-gated channels (e.g., GABAa, glycine, nACh, and 5-HT3 receptors), G protein-coupled receptors (e.g., kappa-opioid receptors; see, e.g., Galeotti et al., 2002), and voltage-gated channels (e.g., voltage-gated sodium and calcium channels) (for a review, see Oz et al., 2017).

[0834] Camphor and eucalyptol, each of which is an agonist of the TRPM8 ion channel, are also used in over-the-counter (OTC) treatments for colds and coughs. Like menthol, they are poorly selective and subject to potential adverse effects (see, e.g., Gavliakova et al., 2013).

[0835] Using a fluorescent imaging plate reader Assay (study performed by ChanTest / Charles River) to evaluate AX-8 potency. Fluo-8 calcium assay and fluorescence imaging plate reader (FLIPRTETRA TM ) instrument was used to evaluate the in vivo effects of cloned human TRPM8 channels expressed in CHO cells. Changes in fluorescence intensity, reflecting calcium flux through hTRPM8, were measured, and the area under the signal (area under the curve, AUC) was calculated and expressed in relative light units. Changes caused by the vehicle (HEPES buffered saline solution, HB-PS) were subtracted. The half maximal response concentration (EC 50 ), indicating that AX-8 is almost 6 times more potent than menthol as a TRPM8 agonist (EC 50 = 0.39 μM and 2.29 μM, n = 8; see Fig.12 and Fig.13 ).

[0836] Similarly, using Calcium assay (at 100 μM, a concentration more than 10-fold the maximal response; see Fig.12) were used to evaluate the selectivity against hTRPA1 (expressed in CHO) and hTRPV1 (expressed in HEK-293). In fact, menthol has been shown to have bimodal activity against TRPA1 (see, e.g., Karashima et al., 2007) and inhibit TRPV1 (see, e.g., Takaishi et al., 2016), two thermosensitive ion channels associated with TRPM8 and expressed in nociceptors (sensory neurons that respond to noxious stimuli). For agonist effect evaluation, the effect of AX-8 was evaluated in the absence of positive control agonists. The maximum signal evoked in the presence of the corresponding agonist (300 μM mustard oil for TRPA1; 3 μM capsaicin for TRPV1) was set to 100% activation, and the signal in the presence of vehicle control (HB-PS) was set to 0% activation. For antagonist effect evaluation, the channel was activated with the corresponding positive control agonist (100 μM mustard oil for TRPA1; 0.1 μM capsaicin for TRPV1). The effect of AX-8 on inhibiting the signal was examined after agonist stimulation and compared with the corresponding positive control antagonist (3 μM ruthenium red). For each channel, the signal elicited in the presence of the corresponding positive control agonist was set to 100 (0% inhibition), and the signal elicited in the presence of the corresponding positive control antagonist was set to 0 (100% inhibition). The assay showed that AX-8 was selective for TRPM8 channels, and no agonistic or antagonistic interactions with TRPV1 and TRPA1 channels were observed (for agonistic effects, see Fig.14 ).

[0837] Fig.12 It means that if The obtained graphs show the activation of human TRPM8 by AX-8. The dose response curves are presented as calcium signal expressed in relative light units (calculated by area under the curve - AUC, mean ± sem, n = 8) versus AX-8 concentration (μM, logarithmic scale). The half maximal response concentration (EC 50 ) is 0.39μM.

[0838] Fig.13 It means that if Graphs showing activation of human TRPM8 by menthol obtained. Dose response curves are presented as calcium signal expressed in relative light units (calculated by area under the curve - AUC, mean ± sem, n = 8) versus menthol concentration (μM, logarithmic scale). The half-maximal response concentration (EC 50 ) is 2.29μM.

[0839] Fig.14is a graph showing comparative activation of human TRPA1 and human TRPV1 by AX-8 and its reference agonist. For hTRPA1, the dose response curves of mustard oil (reference TRPA1 agonist) and AX-8 are expressed as a percentage of the maximum response of mustard oil (mean ± SD, n = 4) to the agonist concentration (μM, logarithmic scale). The data show that AX-8 has no significant agonist activity on hTRPA1 at concentrations ≤ 100 μM. For hTRPV1, the dose response curves of capsaicin (reference TRPV1 agonist) and AX-8 are expressed as a percentage of the maximum response of capsaicin (mean ± SD, n = 4) to the agonist concentration (μM, logarithmic scale). The data show that AX-8 has no agonist activity on hTRPV1 at concentrations ≤ 100 μM.

[0840] In addition, an off-target pharmacology study was performed (SafetyScreen87 assay performed by Eurofins Pharma Discovery Services). This assay package consists of 87 major molecular targets, including 13 enzymes and 74 binding assays, representing potential safety issues. No significant response was observed at 100 μM AX-8, confirming the high selectivity of AX-8 within its effective concentration range.

[0841] The vagus nerve is the main afferent pathway of the cough reflex circuit. Therefore, the ability of AX-8 to inhibit capsaicin-induced depolarization on the isolated guinea pig vagus nerve and its dependence on TRPM8 were evaluated. The tissue was measured using an O2 / CO2 gassing, grease gap recording system as described previously (see, for example, et al., 2009). In brief, after the tissue stabilized, it was exposed to stimulation (capsaicin, 1 μM, TRPV1 agonist for 2 minutes) and then washed. This operation was then repeated to confirm the basal response. After washing, the tissue was incubated with vehicle or AX-8 (10nM-1mM) for 10 minutes. After this, the tissue was re-stimulated with capsaicin (in the presence of vehicle or AX-8). After the washing phase, the tissue was stimulated with capsaicin to demonstrate tissue viability and response recovery.

[0842] In the case of using TRPM8 antagonist PF-05105679 (PF, 10 μM), after producing two reproducible responses to capsaicin, the nerve was incubated with TRPM8 antagonist or vehicle (0.1% DMSO) for 10 minutes, and then incubated with AX-8 or vehicle for 10 minutes. The nerve was then re-stimulated with capsaicin in the presence of PF / vehicle and AX-8 / vehicle, and the percentage of inhibition of the original response was calculated. After the washing period, the nerve was then re-stimulated with capsaicin to determine vitality. The depolarization level was recorded at each stage. The data were recorded as the percentage of inhibition (caused by vehicle or test compound) of the actual depolarization level and the average value of the initial control record.

[0843] This study showed that AX-8 inhibited capsaicin-evoked responses in guinea pig vagus nerve explants by up to 80% in a dose-dependent manner (see Fig.15 , n=3, i.e. tissues from 3 different guinea pigs). This inhibition was abrogated by pre-administration of the TRPM8 antagonist PF-05105679, confirming that the effect of AX-8 is mediated by the selective activation of TRPM8 (see Fig.16 , n=4). In contrast, menthol inhibits capsaicin-evoked responses in guinea pig vagus nerve explants in a TRPM8-independent manner (see, e.g., Maher et al., 2014).

[0844] Fig.15 is a bar graph showing inhibition (%) of AX-8 on capsaicin-evoked responses in guinea pig vagus nerve explants versus concentration of AX-8 (μM). AX-8 (n=3) blocked capsaicin-evoked responses in guinea pig vagus nerve in a dose-dependent manner.

[0845] Fig.16 Is a bar graph showing the inhibition (%) of AX-8 (1 μM) on capsaicin-induced responses in guinea pig vagus nerve explants in the presence or absence of the selective TRPM8 antagonist PF-05105679 (PF, 10 μM). Two consecutive 10-minute incubations of four different conditions were performed as follows: vehicle (0.1% DMSO) / vehicle, PF / vehicle, vehicle / AX-8, and PF / AX-8 (n=4). The selective TRPM8 inhibitor PF-05105679 can block the inhibition of the response induced by the irritant capsaicin in guinea pig vagus nerve explants, thereby demonstrating that the effect of AX-8 is dependent on TRPM8.

[0846] The antitussive effect of AX-8 was evaluated in a standardized guinea pig cough model (see, e.g., Brozmanova et al., 2012; Dong et al., 2016). Guinea pigs were placed in a plethysmography chamber and exposed to aerosolized capsaicin solution (0.1 mM) for 10 minutes to induce coughing. Cough frequency was detected as a transient change in airflow in the chamber, and the signal was recorded by a pressure sensor and a computer. In addition, audio amplification counts were also recorded electronically. Coughs during the 10-minute exposure period were counted. The experiment was visually monitored by the researcher. A 5 mg / mL AX-8 solution was prepared by dissolving AX-8 in anhydrous ethanol at 200 mg / mL and then diluting a solution of sweet potato powder at 4 mg / mL in saline (i.e., vehicle).

[0847] Record the baseline frequency of coughing in response to exposure to capsaicin mist in control (vehicle only) and treatment (AX-8) group animals (n = 10 animals per group). After 7 days, the animals were anesthetized with diethyl ether, and the tip of the micro-spray syringe was placed in the oral cavity using a small animal laryngoscope. The vehicle or AX-8 was applied to the oropharyngeal region (n = 10 animals per group) in an amount of 75 μL per animal. This corresponds to a dose of 0.375 mg per animal. Ten minutes after application, the guinea pigs were exposed to capsaicin mist and the number of coughs was recorded.

[0848] AX-8 solution significantly inhibited capsaicin-induced cough (p < 0.01, see Fig.17 ).

[0849] Fig.17 It is a bar graph showing the effect of AX-8 on capsaicin-induced cough in conscious guinea pigs. Vehicle did not significantly affect capsaicin-induced cough in guinea pigs (baseline (V) = 24.8 ± 2.1 coughs / 10 minutes vs. vehicle = 21.4 ± 2.4 coughs / 10 minutes). Spraying 75 μL of 5 mg / mL AX-8 solution (i.e., 0.375 mg / animal) in the oropharyngeal region suppressed capsaicin-induced cough in guinea pigs from 25.0 ± 2.0 / 10 minute coughs (baseline (T)) to 9.0 ± 2.0 / 10 minute coughs (**p<0.01). The number of animals in each group was 10 (n=10).

[0850] Similarly, the presumed site of action of the investigational medical product (IMP) containing AX-8 for the treatment of CC (including, for example, RCC, ICC) is on the upper respiratory and digestive tracts: the oropharyngeal mucosal surface - behind the buccal cavity - and the esophagus. Therefore, the expected mode of action of AX-8 as an antitussive is by activating the sensory nerve endings expressing TRPM8 in this region. The lining mucosa of the oral cavity and esophagus is a typical example of non-keratinized stratified squamous epithelium (NKSE). Compared with keratinized epithelial tissue and other related coolants (e.g., Gly-OEt also known as WS-5, see, for example, Wei et al., 2012), AX-8 is a potent, long-acting and selective coolant for non-keratinized epithelial tissue (and permeable keratinized tissue, such as eyelid skin). These unique properties not only distinguish AX-8 from other TRPM8 agonists, but are also likely to work synergistically to produce the unexpected efficacy of AX-8 as an effective antitussive for the treatment of CC (including, for example, RCC, ICC).

[0851] References

[0852] Various publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. The full citations for these publications are provided below.

[0853] Each of these publications is incorporated by reference into the present disclosure in its entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

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Claims

1. Use of [((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-isopropyl acetate or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating chronic cough, wherein the chronic cough is refractory chronic cough or idiopathic chronic cough.

2. The use according to claim 1, wherein: The chronic cough is an idiopathic chronic cough.

3. The use according to claim 1, wherein: The chronic cough is a refractory chronic cough.

4. The use according to claim 1, wherein: The chronic cough is refractory chronic cough that persists after evaluation and treatment of asthma, eosinophilic bronchitis, postnasal drip syndrome, gastroesophageal reflux disease, bronchiectasis chronic obstructive pulmonary disease, or idiopathic pulmonary fibrosis.

5. The use according to any one of claims 1 to 4, in: The refractory chronic cough or idiopathic chronic cough is associated with allotussia.

6. The use according to any one of claims 1 to 4, in: The refractory chronic cough or idiopathic chronic cough is associated with hypertussia.

7. The use according to any one of claims 1 to 4, in: The refractory chronic cough or idiopathic chronic cough is associated with cough hypersensitivity syndrome.

8. The use according to any one of claims 1 to 4, in: The refractory chronic cough or idiopathic chronic cough is associated with a cough hypersensitivity reflex.

9. The use according to any one of claims 1 to 4, in: The refractory chronic cough or idiopathic chronic cough is associated with laryngeal paresthesia.

10. The use according to any one of claims 1 to 4, in: The refractory chronic cough or idiopathic chronic cough is associated with laryngeal hypersensitivity syndrome.

11. The use according to any one of claims 1 to 4, in: The refractory chronic cough or idiopathic chronic cough is a sensorineural cough.

12. The use according to any one of claims 1 to 4, in: The refractory chronic cough or idiopathic chronic cough is associated with peripheral sensitization; central sensitization of cough; and / or cortical and / or subcortical maladaptive plasticity.

13. The use according to any one of claims 1 to 4, in: The refractory chronic cough or idiopathic chronic cough is associated with vagal neuropathy.

14. The use according to any one of claims 1 to 4, in: The refractory chronic cough or idiopathic chronic cough is associated with airway inflammation.

15. The use according to any one of claims 1 to 4, in: The refractory chronic cough or idiopathic chronic cough is associated with neurogenic inflammation and / or neuroinflammation.

16. The use according to any one of claims 1 to 4, in: The treatment is carried out by oral administration of the drug; or The treatment is performed by transmucosal administration of the drug.

17. The use according to any one of claims 1 to 4, in: The treatment is carried out by oral administration of the drug; or The treatment is carried out by intranasal administration of the drug.

18. The use according to any one of claims 1 to 4, wherein: The treatment is carried out by oromucosal administration of the drug.

19. The use according to any one of claims 1 to 4, wherein: The treatment is carried out by buccal administration of the drug.

20. The use according to any one of claims 1 to 4, wherein: The treatment is carried out by sublingual administration of the drug.

21. The use according to any one of claims 1 to 4, wherein: The drug is formulated as tablets.

22. The use according to any one of claims 1 to 4, wherein: The drug is formulated as an orally disintegrating tablet; The medicament is formulated as a spray; or The drug is formulated as an aerosol.

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