Treatment of swallowing disorders

Abstract

The present invention relates to oxytocin receptor agonists for use in the treatment or prevention of dysphagia in subjects suffering from autonomic nervous system dysfunction.

Description

[Technical Field]

[0001] This invention relates particularly to the treatment and management of dysphagia in subjects with autonomic nervous system dysfunction. [Background technology]

[0002] Swallowing in adults and children is a complex mechanism based on the coordinated movements of the mouth, pharynx, and esophagus. The swallowing mechanism involves three stages: the oral stage, the pharyngeal stage, and the esophageal stage. Each stage of the swallowing process relies on major muscle groups innervated by a subset of cranial nerves.

[0003] In the oral stage, food is brought to the mouth, chewed by the movements of the jaw and tongue, mixed with saliva, and a bolus is formed for swallowing. The pharyngeal stage begins when the bolus is pushed back onto the tongue. The pharyngeal muscles pull the larynx forward, lift the hyoid bone and close the epiglottis, protecting the airway as the bolus passes through the pharynx. In conjunction, the soft palate muscles rise to close the nasopharynx, preventing aspiration into the nasal sinuses. Finally, in the esophageal stage, the esophageal sphincter relaxes to allow the bolus to enter the esophagus, and then closes as peristaltic waves push the food toward the stomach.

[0004] Only the oral stage requires conscious effort. Once it enters the pharynx, the food bolus moves into the stomach by involuntary reflexes (Maynard et al., Annual Review of Neuroscience, 2020, 4:316-36).

[0005] Dysphagia is a medical term referring to a disorder of swallowing, i.e., dysfunction in one or more stages of the swallowing process. Dysphagia can be characterized by several symptoms, including coughing before and after swallowing, choking, hoarseness, reflux, persistent drooling, aspiration, food ingestion, and improper chewing. Patients with dysphagia often complain of a sensation of food sticking to or getting stuck in the throat or chest, and / or discomfort in the chest or throat. At times, dysphagia can be asymptomatic (i.e., undetectable even to a physician without instruments), while potentially leading to serious health complications.

[0006] In fact, malnutrition and dehydration, aspiration pneumonia, deterioration of overall health, chronic lung disease, suffocation, and even death can all result from dysphagia.

[0007] As of today, considering the prevalence of dysphagia in the population and the associated morbidity, dysphagia is a major health concern.

[0008] In this regard, recent studies have shown that patients with autonomic nervous system dysfunction, such as those with certain neurodegenerative diseases or those with neurodevelopmental disorders like Prader-Willi syndrome, have a high prevalence of dysphagia.

[0009] Prader-Willi syndrome (PWS) is a complex genetic neurodevelopmental disorder resulting from the loss of expression of paternally imprinted genes on chromosomes 15q11-q13, causing hypothalamic dysfunction.

[0010] From birth to 9 months of age, infants with PWS exhibit feeding difficulties and poor appetite, often accompanied by severe hypotonia. Conversely, after 2 years, toddlers with PWS then exhibit premature excessive weight gain, leading to severe obesity accompanied by bulimia and satiety deficiency.

[0011] At all ages, the phenotype includes endocrine disorders (growth hormone deficiency, hypogonadism, hypothyroidism), learning disabilities, and behavioral and psychiatric disorders. Patients with PWS also exhibit several clinical symptoms that indicate autonomic nervous system (ANS) dysfunction, such as oropharyngeal and bowel motility disorders, abnormal thermoregulation, altered sleep control, insensitivity to hypoxic and hypercapnic blood, altered pain perception, and decreased salivary secretion (Haqq et al., 2012, Clinical Obesity 1, pp. 175-183).

[0012] While feeding difficulties in infants have been extensively reported, dysphagia in children and adults with PWS (Percutaneous Wounded Throat Syndrome) remained undervalued until recently, despite the high incidence of lung infections and sudden death in this population.

[0013] Recent studies have shown that asymptomatic dysphagia is very prevalent in children and adults with pharyngeal dysphagia (PWS). This study, conducted using videofluoroscopy (VFS) of swallowing, showed that children and adults with PWS have impaired pharyngeal and esophageal swallowing, with problems in swallowing timing, clearance, and respiratory cycle-swallowing coordination. All patients enrolled in this study had esophageal stasis, and most had pharyngeal residue, but were unaware of it (Gross et al., American Journal of Genetics, 2016, Part A, pp. 1-11).

[0014] Currently, there are few options for managing dysphagia, especially in patients with ANS dysfunction. Existing treatment approaches aim to safely support adequate nutrition and hydration while minimizing the risk of choking and pulmonary infection. These approaches are primarily based on dietary modifications and compensatory techniques such as techniques, posture / positioning skills, biofeedback, and oral motor training. In some cases, anti-reflux and motility-promoting drugs may also be administered. However, these approaches are not curative and may not be feasible for patients with cognitive or intellectual disabilities. Unfortunately, if a patient's swallowing safety and efficiency do not reach a sufficient functional level, or if swallowing function cannot adequately support nutrition and hydration, enteral nutrition, such as via a nasogastric tube or gastrostomy, becomes the only remaining option.

[0015] As of today, there is a need for new treatments to manage dysphagia, particularly in patients with ANS dysfunction. [Prior art documents] [Patent Documents]

[0016] [Patent Document 1] WO2009 / 122285 [Patent Document 2] WO2014 / 111356

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Non-licensed literature

[0017] [Non-licensed document 1] Maynardら, Annual Review of Neuroscience, 2020, 4:316~36 pages [Non-licensed document 2] Haqqら, 2012, clinical obesity 1, pages 175~183 [Non-licensed document 3] Grossら, American Journal of Genetics, 2016, パートA, pages 1~11

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[0018] This invention relates to the use of oxytocin receptor agonists in the treatment or prevention of dysphagia in subjects suffering from autonomic nervous system dysfunction.

[0019] In some embodiments, dysphagia is characterized by impaired motility of the oropharynx and / or esophagus. Dysphagia may be associated with solids and / or liquids, preferably both. In preferred embodiments, the subject suffers from a neurodevelopmental disorder. In additional or alternative embodiments, the subject suffers from hypothalamic dysfunction.

[0020] In some embodiments, the neurodevelopmental disorder is preferably a hereditary neurodevelopmental disorder selected from the group consisting of Prader-Willi syndrome and Prader-Willi-like syndrome, Fragile X syndrome, DiGeorge / 22q11.2 deletion syndrome, Down syndrome, Rett syndrome, Noonan syndrome, CHARGE syndrome, Kabuki syndrome, Troyer syndrome, Christianson syndrome, Smith-Magenis syndrome, Alstrom syndrome, symptomatic obesity, familial autonomic dysfunction, and Williams syndrome. In other embodiments, the neurodevelopmental disorder is selected from the group consisting of autism spectrum disorder, cerebral palsy, intellectual disability, and fetal alcohol spectrum disorder (FSAD).

[0021] In preferred embodiments, the subjects are at least 6 months old and are in a transitional period to dietary diversification or are already on a diversified diet. Preferably, the subjects are at least 1 year old. For example, the subjects may be infants, children, or teenagers. The subjects may also be adults.

[0022] In some embodiments, dysphagia is characterized by the following clinical signs: - Stasis of the pharynx or esophagus - Pharyngeal residue, - Abnormal closure of the esophageal sphincter, especially the upper esophageal sphincter. - Esophageal dilation, preferably upper esophageal dilation or megaesophagus - Propulsion obstruction - Delay in the onset of swallowing - Dissynchronization with the respiratory cycle - Inhalation, including asymptomatic inhalation, - Reduced peristalsis, - Prolonged esophageal passage, and - Nasopharyngeal or esophageal reflux Characterized by at least one of the above, the clinical signs may be evaluated by videofluoroscopy.

[0023] In some further embodiments, subjects have experienced, are experiencing, or are at risk of experiencing one or more of the following disorders: esophageal bolus obstruction, pulmonary aspiration, recurrent lung infection, aspiration pneumonia, suffocation, reflux, nasal reflux, and rumination.

[0024] The target oxytocin receptor agonists are oxytocin, carbetocin, and [Thr] 4 ]OT, HO[Thr 4 ]OT, [Thr 4 Gly 7 ]OT, HO[Thr 4 Gly 7 This includes OT, lipo-oxytocin-1 (LOT-1), demoxitocin, melotosin, demoxitocin, lipo-oxytocin-1 (LOT-1), TC OT 39, and WAY-267464, LIT-001. Preferred oxytocin receptor agonists are oxytocin, carbetocin, and combinations thereof.

[0025] Another object of the present invention is the use of oxytocin in the treatment of dysphagia in subjects with neurodevelopmental disorders. The neurodevelopmental disorder is preferably Prader-Willi syndrome or Prader-Willi-like disorder. Subjects are preferably at least 6 months of age and are in the transition period to dietary diversification or are already on a diversified diet. Subjects may have asymptomatic dysphagia. Oxytocin can be administered via the intranasal route, preferably in a daily dose of 2 IU to 48 IU. [Brief explanation of the drawing]

[0026] [Figure 1] This diagram shows the different steps involved in a clinical study (see the Examples section). [Figure 2] This figure shows a video fluorescence fluoroscopy scoring chart related to swallowing and esophageal transit used during clinical trials. [Modes for carrying out the invention]

[0027] As described in the background section above, Prader-Willi syndrome (PWS) is a complex genetic neurodevelopmental disorder characterized by several distinct nutritional stages, including a neonatal stage in which infants with PWS exhibit feeding difficulties, anorexia, and growth retardation, and a subsequent stage in which children or adults exhibit excessive weight gain leading to obesity with overeating and a lack of satiety. Individuals with PWS also present with several clinical symptoms that strongly suggest autonomic nervous system (ANS) dysfunction, such as oropharynx, esophageal, and bowel motility disorders, thermoregulatory abnormalities, altered sleep control, insensitivity to hypoxic and hypercapnic blood, altered pain perception, and decreased salivation.

[0028] In the PWS population, a higher incidence of pulmonary infections and sudden death has been reported compared to healthy individuals and patients with similar intellectual disabilities.

[0029] Recent studies have demonstrated that adults and children with PWS suffer from asymptomatic dysphagia characterized by a high risk of esophageal stasis, pharyngeal residue, silent aspiration, and impaired respiratory cycle-swallowing coordination.

[0030] The applicants performed systematic videofluoroscopy (VFS) in children with PWS and identified a high prevalence of dysphagia and risk factors for aspiration in this population. Therefore, the applicants sought treatment options to manage dysphagia in patients with PWS, and more generally, in individuals with ANS dysfunction.

[0031] Oxytocin (OT) is a naturally occurring hypothalamic hormone. It has peripheral hormonal activity and acts as a neurotransmitter and neuromodulator in the brain via OT receptors. OT plays a crucial role in regulating social interaction and mother-child bonding. Synthetic OT is marketed under the trade names Syntocinon® or Pitocin® for labor induction, postpartum care, and lactation promotion. OT has been or is currently being evaluated in several clinical trials, for example, for the treatment of social impairment in patients with autism, or for the treatment of bulimia and obsessive-compulsive disorder in adult patients with PWS. The applicants recently completed a Phase II clinical trial demonstrating that intranasal administration of OT was well tolerated and significantly improved feeding and social skills in PWS infants under 6 months of age (Tauber et al., 2017, Pediatrics, 139, 2 e2 0162976).

[0032] However, to the best of the applicants' knowledge, the potential effectiveness of OT for dysphagia in children and adults, particularly in PWS, has never been reported or suggested in the prior art.

[0033] As shown in the Examples section, the applicants demonstrated that oxytocin is effective in managing dysphagia in subjects with ANS dysfunction.

[0034] In particular, the applicant demonstrated that in a 6-year-old patient with Prader-Willi syndrome exhibiting severe dysphagia, daily administration of oxytocin for three weeks completely normalized peristalsis and upper esophageal sphincter closure, thereby improving esophageal transit.

[0035] Interestingly, the applicants also demonstrated the efficacy of daily oxytocin administration in a 14-year-old patient with hypothalamic dysfunction associated with neurodevelopmental disorders and dysphagia. Treatment with oxytocin was able to normalize oropharyngeal initiation and synchronization, as well as esophageal transit.

[0036] Furthermore, the applicants are currently conducting a clinical trial aimed at evaluating the effects of chronic administration of oxytocin (OT) on dysphagia in children and adolescents with PWS aged 2 to 14 years.

[0037] Based on this data, the applicants believe that oxytocin can improve swallowing patterns in patients with PWS and other patients with autonomic nervous system dysfunction by improving oral, pharyngeal, and esophageal motility.

[0038] Therefore, the present invention relates to the use of oxytocin receptor agonists in the treatment or prevention of dysphagia, particularly in subjects suffering from autonomic nervous system dysfunction, such as subjects with PWS.

[0039] The present invention also relates to a pharmaceutical composition comprising an oxytocin receptor agonist for use in the treatment or prevention of dysphagia, particularly in subjects suffering from autonomic nervous system dysfunction, such as those with PWS.

[0040] In another embodiment, the present invention also relates to a method for treating or preventing (e.g., delaying the onset of) dysphagia, particularly in subjects suffering from autonomic nervous system dysfunction, such as subjects with PWS, comprising administering a therapeutically effective dose of oxytocin receptor agonist to the subject, preferably via an intranasal route.

[0041] In a further embodiment, the present invention relates to the use of oxytocin receptor agonists in the manufacture of agents for treating or preventing dysphagia, particularly in subjects with autonomic nervous system dysfunction, such as subjects with neurodevelopmental disorders like PWS.

[0042] In a particular embodiment, the present invention relates to the use of oxytocin receptor agonists or pharmaceutical compositions thereof for treating oral and / or pharyngeal and / or esophageal motility disorders and / or swallow-respiratory disynchronization in subjects with dysphagia.

[0043] In a further embodiment, the present invention relates to the use of oxytocin receptor agonists or pharmaceutical compositions thereof for treating or reducing the occurrence of symptoms of dysphagia selected from the group consisting of pharyngeal residue, nasal and / or esophageal reflux, aspiration, entry, propulsion impairment, and combinations thereof.

[0044] In another embodiment, the present invention relates to the use of oxytocin receptor agonists or pharmaceutical compositions thereof to prevent respiratory infections, including aspiration pneumonia, and / or suffocation in subjects with dysphagia, preferably subjects with autonomic nervous system dysfunction, such as neurodevelopmental disorders including PWS.

[0045] As will be described in more detail below, the subjects are preferably on a diversified diet or in a diversified diet, and are at least 6 months old.

[0046] A preferred subgroup of patients with dysphagia is those with neurodevelopmental disorders, particularly hereditary neurodevelopmental disorders such as PWS and PW-like disorders.

[0047] A detailed description of the present invention is provided below:

[0048] ·Definition As used herein, “treatment of dysphagia” or “to treat dysphagia” includes curing, delaying, alleviating, or slowing the progression of dysphagia, or curing, delaying, alleviating, or slowing the progression of one or more related symptoms and / or disorders, and preventing, reducing, slowing, reversing, or eliminating one or more symptoms or disorders associated with dysphagia. For example, in the context of the present invention, oxytocin receptor agonists may be used to reduce or alleviate one or more symptoms of dysphagia in subjects such as silent aspiration, oropharyngeal and esophageal motility disorders, propulsion disorders, dissynchronization with the respiratory cycle, esophageal and / or nasopharyngeal reflux, prolonged esophagogastric transit, and / or aspiration involving esophageal or pharyngeal residue.

[0049] "Prevention of dysphagia" includes preventing or delaying the onset of dysphagia or one or more symptoms or complications associated with dysphagia. In some embodiments, this term also refers to minimizing the risk (or probability) of a patient developing such symptoms or complications compared to a patient who has not been administered the compound of the present invention. For example, in the context of the present invention, an oxytocin receptor agonist may be used to prevent or minimize the risk of experiencing respiratory infections such as aspiration pneumonia or choking in a subject with dysphagia who may also have a neurodevelopmental disorder. As a further example, an oxytocin receptor agonist may be used to delay the onset or progression of dysphagia in a subject with a neurodegenerative disorder.

[0050] As used herein, “therapeutic dose” means the amount of oxytocin receptor agonist that prevents, eliminates, slows, reduces, treats or delays one or more symptoms or complications of dysphagia in a subject.

[0051] The term "pharmaceutically acceptable" refers to a composition, compound, salt, etc., that is suitable for contact with or can be administered to the target tissue within the bounds of sound medical judgment, without excessive toxicity or other complications commensurate with a reasonable benefit / risk ratio.

[0052] • Dysphagia As used herein, the term “dysphagia” refers to any dysphagia, i.e., a dysfunction in one or more stages of the swallowing process, namely the oral cavity, pharynx, and / or esophagus.

[0053] As described in the background section, swallowing in adults and children is a complex mechanism based on the coordinated movements of the mouth, pharynx, and esophagus. The swallowing mechanism consists of three stages: the oral stage, the pharyngeal stage, and the esophageal stage.

[0054] In the context of the present invention, the subject may suffer from oropharyngeal dysphagia, esophageal dysphagia, or oropharyngeal-esophageal dysphagia, depending on the stage at which the swallowing disorder occurs.

[0055] In a preferred embodiment, the subject suffers from oral, pharyngeal, and esophageal swallowing disorder.

[0056] Oral-pharyngeal dysphagia generally refers to disorders occurring in the oral cavity, pharynx, and the uppermost part of the esophagus (around the upper esophageal sphincter), while esophageal dysphagia refers to disorders occurring in the esophagus (including the lower esophageal sphincter). Oral-pharyngeal-esophageal dysphagia refers to diseases occurring in both the oral cavity, pharynx, and esophagus.

[0057] In fact, problems can occur at each stage of swallowing. For example, L. van den Engel-Hoek et al. (Journal of Neuromuscular Disease 2 (2015), pp. 357-369) describe the following problems that can occur at each stage (the list is not exhaustive): - During the oral (preparation) stage: Insufficient lip closure and disrupted tongue movement can lead to food loss from the mouth and chewing problems, as well as problems with bolus formation and delayed transport within the mouth due to reduced tongue strength, which can result in delayed introduction into the oropharynx. - During the pharyngeal stage: retention in the pharynx due to reduced tongue elevation, poor control of the oral bolus, and reduced posterior tongue propulsion causing a delay in the initiation of pharyngeal swallowing; nasal reflux due to dysregulation of pharyngeal contraction or insufficient closure of the nasopharynx region; entry of food into the subepiglottic region or (silent) aspiration due to impaired timing and coordination; post-swallowing residue in the valley and piriform sinuses due to decreased activity of the submandibular muscles; reduced retraction of the tongue base; or reduced pharyngeal contraction (pharyngeal motor dysfunction). - During the esophageal stage: Residue on the upper esophageal sphincter due to limited sphincter opening, or residue or accumulation in the proximal esophagus due to mobility issues.

[0058] In certain embodiments, the subject suffers from dysphagia associated with oral pharyngeal esophageal motility disorders (OPOD).

[0059] In certain embodiments, subjects with dysphagia may exhibit one or more dysfunctions in oral and pharyngeal propulsion, initiation and synchronization, and / or esophageal motility, as enumerated in the chart shown in Figure 2.

[0060] In the context of the present invention, dysphagia may relate to solids and / or liquids, preferably both, i.e., the subject exhibits dysphagia in both liquids and solids.

[0061] Individuals with dysphagia may complain of a sensation of food sticking to or getting stuck in their throat or chest, and / or discomfort in their chest or throat. They may also have visible or directly observable symptoms such as coughing before or after swallowing, choking, hoarseness, reflux, persistent drooling, improper chewing, shortness of breath, sore throat, and heartburn.

[0062] However, in some subjects, dysphagia may be asymptomatic; that is, dysphagia does not present with visible symptoms in the subject, and the subject does not experience any sensations associated with dysphagia. For example, the subject may not experience any sensation of food sticking to or obstructing the throat or esophagus, and / or may not recognize the presence of aspiration or intrusion even if a serious aspiration / intrusion occurs. This may be due to accompanying cognitive problems or sensory impairments, such as impaired pain perception, as in the case of subjects with Prader-Willi syndrome.

[0063] As used herein, “aspiration” describes a swallowing disorder in which food, liquid, or saliva intended for the stomach enters the airway or lungs instead. When this occurs, the subject continues to breathe, but generally coughs to remove food or fluid from the lungs. However, sometimes the subject is unaware that aspiration is occurring and does not cough at all. Such cases are known as “silent aspiration.”

[0064] As used herein, "choking" refers to a swallowing disorder in which food becomes lodged in the airway, blocking the flow of air. Sometimes, the Heimlich maneuver is necessary to clear the lodged food from the airway.

[0065] In some embodiments of the present invention, subjects with dysphagia have chest or throat discomfort including a feeling of food sticking, and / or one or more dysphagia selected from the group consisting of coughing before and after swallowing, choking, hoarseness, reflux including rumination, persistent drooling, improper chewing, awareness of aspiration or intrusion, and heartburn.

[0066] In other embodiments, the subject suffers from asymptomatic dysphagia.

[0067] In the context of this invention, the term "dysphagia" generally refers to "functional dysphagia," meaning that, from an etiological standpoint, the dysphagia is not explained by structural, mucosal, or histological lesions or abnormalities such as head and neck tumors, Zenker's diverticulum, luminal stenosis, surgical resection of the oropharynx / larynx, radiation injury, anterior cervical spine surgery, or extrinsic compression (e.g., goiter, cervical vertebral spurs, or esophageal vascular compression as in the case of Rusolian dysphagia). In particular, the term "dysphagia" in the context of this invention does not include Rusolian dysphagia or aortic dysphagia.

[0068] In the context of the present invention, the term "dysphagia" does not include dysphagia caused by autoimmune connective tissue diseases, such as scleroderma or other diseases that damage connective tissue.

[0069] The exact mechanism of functional dysphagia is unknown, but it may be related to inappropriate sensory and muscle-motor disorders in the swallowing organs, or dysfunction of the central integration center.

[0070] Furthermore, in some embodiments, the subject does not have severe congenital malformations in the oral cavity, including the mouth, lips, and tongue, the pharynx, the airway, and the swallowing organs, including the esophagus and its sphincter (both upper and lower).

[0071] However, in certain embodiments, subjects may exhibit some mild congenital anomalies of the swallowing organs compared to healthy subjects, such as Ozzy or high palate, or mild facial asymmetry. Furthermore, prolonged dysphagia in subjects may cause changes in one or more parts of the swallowing organs. For example, subjects with PWS who experience prolonged difficulty swallowing may develop megaesophagus.

[0072] As will be further explained below, in the context of the present invention, subjects suffering from dysphagia also exhibit autonomic nervous system dysfunction.

[0073] Dysfunction of the ANS (Anterior Nucleotide System) can contribute to dysphagia by impairing, for example, oral, pharyngeal, and esophageal motility, synchronization between swallowing and respiratory cycles, sensory perception, and the integration and control of information in the central integration center.

[0074] In certain embodiments, the swallowing disorder in the subject is at least in part, preferably, caused by ANS dysfunction selected from the group consisting of motility disorders of the oropharynx and / or esophagus, dissynchronization between the respiration and swallowing cycles, sensory disturbances in the swallowing organs and central integration centers, and combinations thereof.

[0075] As used herein, “motor disorder” refers to abnormalities in the regulation of contraction / relaxation and muscle activity of the oral cavity and / or pharynx and / or esophagus. The term “motor disorder” may also encompass abnormalities in the peristaltic movement of the pharynx and / or esophagus, particularly reduced esophageal peristalsis.

[0076] As described above, subjects with dysphagia may have esophageal motility disorders that can be characterized by one or more of the following features: slow esophageal transit, poor esophageal clearance (e.g., evidenced by the presence of esophageal residue), esophageal reflux (e.g., retrograde movement of the bolus from the lower esophagus to the upper esophagus), abnormal peristalsis, and combinations thereof.

[0077] Dysphagia can be diagnosed and investigated using several methods, including esophageal manometry, videofluoroscopy (VFS) or X-ray radiography with contrast agents (barium X-ray), swallowing evaluation using fiber optic endoscopy (FEES), pH monitoring, endoscopic examinations such as pharyngoscopy or esophagoscopy, esophageal and gastric passage, and imaging studies.

[0078] Notably, videofluorescence fluoroscopy (VFS) is a representative method for dynamically studying the oral, pharyngeal, and esophageal mechanisms of dysphagia. VFS was used by the inventors to characterize dysphagia and evaluate the efficacy of oxytocin in patients with Prader-Willi syndrome, as illustrated in the examples.

[0079] In fact, VFS allows for the characterization of the main signs of oropharyngeal dysfunction, particularly pharyngeal swallowing delay, aspiration, nasopharyngeal reflux, esophageal motility disorders, and pharyngeal residue.

[0080] To quantify swallowing disorders in a subject using VFS, for example, the videofluorescence scoring chart for swallowing and esophageal transit shown in Figure 2 may be used.

[0081] In some other or additional embodiments, dysphagia is characterized by one or more clinical signs, such as: - Oral and pharyngeal motor disorders and / or esophageal motor disorders, especially pharyngeal and / or esophageal stasis. - Abnormal closure of the esophageal sphincter, especially the upper esophageal sphincter. - Esophageal dilation, preferably upper esophageal dilation, or megaesophagus - Propulsion obstruction, - Dissynchronization with the respiratory cycle, - Esophageal reflux disease and / or nasopharyngeal reflux disease, - Aspiration, including silent aspiration - Invasion, e.g., invasion of food into the larynx - Prolonged esophageal and gastric transit, e.g., esophageal transit, and / or - Residue from the esophagus or pharynx.

[0082] Such clinical signs are preferably demonstrated by VFS.

[0083] In a preferred embodiment, a subject with dysphagia exhibits at least one (e.g., one, two, three, four, five, or even all) of the following clinical symptoms: - Oral and pharyngeal motor disorders and esophageal motor disorders, especially pharyngeal and / or esophageal stasis. - Dissynchronization with the respiratory cycle, - Nasopharyngeal and / or esophageal reflux, - Aspiration, including silent aspiration - Invasion, for example, entry of food into the larynx, and - Residue from the esophagus or pharynx.

[0084] Such clinical symptoms can be demonstrated by VFS.

[0085] In certain embodiments of the present invention, dysphagia may be characterized by motor impairment affecting the oral cavity and / or pharynx and / or esophagus. For example, dysphagia may be characterized by both oropharyngeal motor impairment and esophageal motor impairment, such motor impairments preferably demonstrated by VFS and / or manometry tests.

[0086] In another embodiment, dysphagia may be characterized by, for example, slow pharyngeal transit with pharyngeal residue, slow esophageal transit with esophageal residue, esophageal reflux, abnormal upper esophageal sphincter closure, delayed oropharyngeal initiation and synchronization, and combinations thereof. Needless to say, administration of oxytocin receptor agonists in such patients makes it possible to alleviate, and even treat, at least one of the above clinical symptoms.

[0087] For example, oxytocin receptor agonists can alleviate, prevent, or treat swallowing disorders selected from the group consisting of aspiration including silent aspiration, oropharyngeal motility disorders, esophageal motility disorders, esophageal stasis, upper esophageal sphincter closure abnormalities, pharyngeal residue, reflux, dissynchronization with the respiratory cycle, propulsion disorders, and combinations thereof.

[0088] For example, oxytocin receptor agonists may be used to improve or normalize esophageal motility, oral and pharyngeal propulsion, and / or oropharyngeal initiation and synchronization in subjects with dysphagia. As shown in case reports, oxytocin receptor agonists may be used to improve, and even normalize, esophageal motility, such as esophageal transit and peristalsis, upper esophageal sphincter closure, and / or pharyngeal transit.

[0089] Even in asymptomatic cases, dysphagia can lead to serious health problems and complications, particularly due to aspiration, especially silent aspiration.

[0090] In some embodiments, subjects with dysphagia have experienced or are at risk of experiencing dysphagia complications selected from the group consisting of esophageal bolus obstruction, chronic respiratory infections including recurrent lung infections, exacerbations of chronic obstructive pulmonary disease (COPD) and aspiration pneumonia, suffocation, sudden death, and combinations thereof.

[0091] Dysphagia, especially when associated with silent aspiration, can also increase the risk of sudden death due to choking.

[0092] In another aspect, dysphagia can lead to malnutrition, weight loss due to dehydration, and growth disorders in children.

[0093] Administration of oxytocin receptor agonists in the subjects may treat or prevent one or more of the complications listed above, particularly respiratory infections including aspiration pneumonia, and suffocation.

[0094] • Disorders involving autonomic nervous system dysfunction and swallowing patterns. In the context of the present invention, subjects with dysphagia may further exhibit autonomic nervous system (ANS) dysfunction or dysregulation.

[0095] The autonomic nervous system (ANS), formerly known as the vegetative nervous system, is a branch of the peripheral nervous system that supplies smooth muscles and glands and influences the functions of internal organs. The autonomic nervous system is a control system that operates primarily unconsciously and regulates bodily functions such as heart rate, digestion, respiratory rate, pupillary response, and urination, as well as reflexes such as coughing, sneezing, swallowing, and vomiting. The ANS includes peripheral and central neurons. It includes 1) afferent pathways that transmit sensory information, 2) integration centers at levels such as the brainstem (including the solitary pathway), hypothalamus, and limbic system, and 3) efferent control pathways to muscles or glands.

[0096] The nervous system (ANS) can be divided into the sympathetic and parasympathetic nervous systems. Some authors include the enteric nervous system in the ANS. Physiologically, both the sympathetic and parasympathetic nervous systems function by maintaining a dynamic balance in response to rest and stress.

[0097] ANS dysfunction refers to alterations in the function of the autonomic nervous system that can cause dysregulation of one or more bodily functions. ANS dysfunction can lead to a variety of serious problems affecting multiple organ systems, including tachycardia, sleep disorders, dysphagia, hypotension, orthostatic hypotension, and others.

[0098] In certain cases, individuals with dysphagia suffer from a disorder classified as an autonomic nervous system disorder, also known as autonomic nervous system dysfunction.

[0099] Autonomic nervous system dysfunction refers to a disorder that can affect all or part of the autonomic nervous system (ANS). Autonomic nervous system dysfunction can cause a variety of problems, such as blood pressure problems, breathing problems, or swallowing problems, and can be hereditary, caused by injury, or triggered by conditions such as diabetes, Parkinson's disease, neurodegenerative diseases, autoimmune diseases, alcoholism, or Riley-Day syndrome, which is also known as familial autonomic nervous system dysfunction.

[0100] In more specific cases, subjects with dysphagia often suffer from autonomic nervous system disorders, particularly those selected from neurodegenerative diseases.

[0101] Therefore, in the context of the present invention, dysphagia may be a symptom or complication of autonomic nervous system dysfunction, preferably neurodegenerative disorder, in the subject.

[0102] Preferred neurodegenerative diseases include, but are not limited to, amyotrophic lateral sclerosis, muscular dystrophy, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Lewy body dementia, frontotemporal dementia, vascular dementia, Huntington's disease, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, and Creutzfeldt-Jakob disease.

[0103] Dysfunction of the autonomic nervous system can also be observed in conditions that are not classified as autonomic nervous system disorders, or have not yet been classified as such.

[0104] Dysregulation of the autonomic nervous system has been demonstrated in various neurodevelopmental disorders, including autism spectrum disorder (ASD), Rett syndrome, and Prader-Willi syndrome (PWS).

[0105] On the other hand, dysphagia is a frequent complication of neurodevelopmental disorders that can be observed not only perinatally but also thereafter. This fact underlies the vulnerability of the gene networks associated with infant feeding, feeding, and swallowing (SFS) mechanisms, as well as the transition to feeding and swallowing in children and adults, to genetic mutations and environmental disruption. The applicants believe that dysregulation or dysfunction of the ANS may contribute to dysphagia observed in neurodevelopmental disorders by impairing, for example, oropharyngeal and esophageal motility, synchronization between swallowing and respiratory cycles, and sensation in the swallowing organs or central integration centers.

[0106] Therefore, in some aspects of the present invention, subjects with dysphagia suffer from neurodevelopmental disorders. Thus, dysphagia can be a symptom or complication of the neurodevelopmental disorder in the subject.

[0107] As used herein, neurodevelopmental disorders refer to a group of disorders characterized by severely affected behavioral features resulting from changes in early brain development. Most neurodevelopmental disorders are characterized by changes in the development and maturation of the nervous system that affect the function of nerve cells and the construction of neural networks, both of which are necessary for i) perception and integration of sensory information, ii) construction and adjustment of adaptive responses, iii) control of effectors (i.e., motor and endocrine responses), and iv) construction and maintenance of functional neuronal networks involved in learning and memory processes. Neurodevelopmental disorders result in brain dysfunction, such as impairments in the sensory or motor systems, speech, language, or more generally, oral changes, many cognitive impairments (e.g., in learning, memory, organizing, and / or planning abilities), or a combination thereof.

[0108] While not bound by any particular theory, hypothalamic dysfunction may be a contributing factor to swallowing difficulties in the subject.

[0109] In some more specific embodiments, the subjects suffer from neurodevelopmental disorders with or associated with hypothalamic dysfunction.

[0110] Such neurodevelopmental disorders will be discussed later, but include, for example, Prader-Willi syndrome and Prader-Willi-like syndrome, and fetal alcohol spectrum disorder (FSAD).

[0111] The term "neurodevelopmental" disorder encompasses both hereditary and non-hereditary neurodevelopmental disorders.

[0112] In some embodiments, the subjects suffer from non-hereditary neurodevelopmental disorders, i.e., neurodevelopmental disorders for which no genetic cause has been identified. In such cases, the neurodevelopmental disorder may be caused by environmental damage, such as exposure to other harmful substances in utero, including alcohol, drugs, and pesticides. In some other embodiments, the neurodevelopmental disorder is idiopathic or congenital, without a clear cause, and is suspected to be caused by a combination of genetic and / or environmental and / or epigenetic factors.

[0113] Non-hereditary neurodevelopmental disorders with swallowing patterns include, but are not limited to, intellectual disability, autism spectrum disorder (ASD), fetal alcohol spectrum disorder (FSAD), including fetal alcohol syndrome, neonatal abstinence syndrome, cerebral palsy, and congenital heart disease.

[0114] In another embodiment, the subject suffers from a hereditary neurodevelopmental disorder, i.e., a neurodevelopmental disorder caused by, for example, aneuploidy, disomy, chromosomal deletion, gene mutation and / or epigenetic changes that affect genomic imprinting.

[0115] Hereditary neurodevelopmental disorders with dysphagia patterns include, but are not limited to, Prader-Willi syndrome and Prader-Willi-like syndrome, Fragile X syndrome, DiGeorge / 22q11.2 deletion syndrome, Down syndrome, Rett syndrome, Noonan syndrome, CHARGE syndrome, Kabuki syndrome, Troyer syndrome, Christianson syndrome, Smith-Magenis syndrome, Alstrom syndrome, symptomatic obesity, familial autonomic dysfunction, and Williams syndrome. Dysphagia can also be observed in patients with hereditary neurodevelopmental disorders such as Pierre Robin syndrome, optic septal dysplasia (SOD), and ROHHAD (rapid-onset obesity, hypothalamic dysfunction, hypoventilation, autonomic dysfunction) syndrome.

[0116] In a preferred embodiment, subjects with dysphagia suffer from Prader-Willi syndrome (PWS) or a PW-like disorder. Further details regarding this subgroup of patients are described below.

[0117] ·subject The terms "subject" or "patient" refer to any mammal, including human and veterinary subjects.

[0118] Individuals suffering from dysphagia can be of any age and gender. The subjects are preferably human.

[0119] For example, the target audience may include infants, children, young people, adolescents, and adults, including the elderly.

[0120] It is noteworthy that infant feeding differs significantly from feeding and swallowing in children and adults. This is because the immaturity of the oropharynx region, more precisely, the elevated position of the larynx and hyoid bone, allows the immature epiglottis to catch on the underside of the soft palate, creating separate pathways for nasal breathing and liquid swallowing simultaneously. Therefore, infant feeding is a continuous action, not paused for breathing as in adults. Initially, feeding is controlled by brainstem reflexes, but these disappear with age. During the first year, the neck grows, the hyoid bone and larynx descend, the epiglottis flattens, and the soft palate matures, facilitating the transition to solid food between 4 and 6 months of age. Subsequently, the mobilization of oropharynx muscles gradually changes and the pharynx grows, leading to the development of a complete swallowing mechanism (Maynard et al., Annual Review of Neuroscience, 2020, 4:316-36).

[0121] In a preferred embodiment, the subject is in the process of transitioning to a diversified diet or is already on a diversified diet, i.e., can consume both solid and liquid foods. More preferably, the subject is not consuming only liquid foods.

[0122] The transition to solid foods usually occurs between 4 and 6 months of age.

[0123] Therefore, subjects with swallowing difficulties are preferably at least 6 months old, for example, at least 9 months old or at least 1 year old.

[0124] The mechanisms of suckling, feeding, and swallowing are innate and reflex-driven behaviors, but they transition to voluntary behaviors during infancy. The rooting reflex disappears around 7 months of age in normal infants. After 12 months of age, the suckling / swallowing reflex is completely lost, and swallowing becomes a voluntary movement.

[0125] In other words, a 12-month-old child undergoes morphological and functional changes that lead to different swallowing mechanisms.

[0126] Therefore, in a preferred embodiment, the subject is at least 1 year old.

[0127] In some embodiments, the target age is under 50 years old, for example, under 40, under 30, or under 20 years old.

[0128] In certain embodiments, the subjects are under 18 years of age, preferably up to 16 years of age.

[0129] Typically, subjects with swallowing difficulties are children aged 1 to 16 years, preferably 2 to 15 years.

[0130] As mentioned above, the subjects may have neurodegenerative disorders or neurodevelopmental disorders, preferably hereditary neurodevelopmental disorders such as PWS or Prader-Willi syndrome.

[0131] In some embodiments, the subjects suffer from cognitive impairment and / or intellectual disability.

[0132] In some other or further embodiments, the subject suffers from poor oral skills.

[0133] In some alternative or additional embodiments, the subject suffers from an eating disorder during infancy, preferably during the neonatal period. The eating disorder preferably refers to a feeding disorder.

[0134] In some other embodiments, the subjects have not received oxytocin treatment during infancy, particularly within the first six months after birth.

[0135] • Target oxytocin receptor agonists The term “agonist” refers to any compound that interacts with a target to selectively cause or promote an increase in the activation of the target. In the context of the present invention, the target is an “oxytocin receptor,” preferably a “human oxytocin receptor.”

[0136] Notably, the preferred oxytocin receptor agonist is oxytocin (OT) itself, a mammalian nonapeptide expressed in the hypothalamus, which can be readily synthesized by a very well-known procedure. The formula for oxytocin is as follows:

[0137] [ka]

[0138] Alternatively, the oxytocin receptor agonist may be any compound capable of activating the oxytocin receptor in a preferably selective manner. The compound can be of any type. It is preferably present in quantities up to 3000 g.mol. -1 These can be selected from chemical agents, antibodies and their fragments, and nucleic acid ligands such as aptamers.

[0139] As used herein, "aptamers" (also called nucleic acid aptamers) typically refer to synthetic single-stranded polynucleotides, typically containing 20 to 150 nucleotides in length, capable of binding to target molecules with high affinity. Aptamers are characterized by their three-dimensional structure, which can play a crucial role in their interaction with target molecules.

[0140] As used herein, the term “antibody” refers to immunoglobulin or its fragments or derivatives, and includes any polypeptide containing an antigen-binding domain, whether produced in vitro or in vivo. This term includes, but is not limited to, polyclonal, monoclonal, monospecific, multispecific (e.g., bispecific), humanized, single-chain, chimeric, synthetic, recombinant, hybrid, mutant, and grafted antibodies. The term “antibody” also includes antibody fragments such as Fab, F(ab')2, Fv, scFv, Fd, dAb, etc., and other antibody fragments that retain antigen-binding function, i.e., the ability to specifically bind to a target (e.g., VHH derived from single-chain antibodies).

[0141] Various oxytocin receptor agonists have been described in the prior art. Furthermore, the prior art also describes several in vivo or in vitro assays for evaluating whether a given molecule is an oxytocin receptor agonist.

[0142] For example, one can refer to Manning et al. (J. Neuroendocrinol, 2012, 24(4):609-628), which discusses binding and functional assays in cell lines expressing the hOT receptor based on cyclic AMP accumulation. As another example, agonist activity against the OT receptor can be measured by the method described in WO2009 / 122285. In this method, the agonist activity of a compound against the hOT receptor is determined in a transcriptional reporter gene assay by transiently transfecting a Chinese hamster ovary (CHO) cell line with DNA expressing the hOT receptor in conjunction with a reporter DNA containing an intracellular calcium-responsive promoter element that modulates firefly luciferase expression. Cells are exposed to serial dilutions of the compound, diluted 10-fold per dose, for 5 hours, then the cells are lysed, luciferase activity is measured, and the efficacy and EC50 value of the compound are determined by nonlinear regression. Oxytocin (OT) is used as an internal control in each experiment, and the compound is tested in at least three independent experiments.

[0143] More specific functional assays can be found in Busnelli et al. (The Journal of Biological Chemistry, 2012, vol. 287, pp. 3617-3629), where functionally selective ligands for the human OT receptor are screened using a BRET-based biosensor assay. For a review of OT receptor agonists, see, for example, Manning et al., Journal of Neuroendocrinology, 2012, 24, pp. 609-628.

[0144] In some embodiments, oxytocin receptor agonists are selective for oxytocin receptors, more precisely for human OT receptors, meaning they do not significantly bind to and / or activate other receptors.

[0145] In some other embodiments, the oxytocin receptor agonist can also bind to and further activate other receptors such as V1a, V1b, and V2 receptors, but preferably binds with lower potency (e.g., an EC50 at least 1.5-fold, preferably at least 10-fold, 20-fold, 50-fold, or 100-fold higher than the EC50 for the oxytocin receptor) than to the oxytocin receptor.

[0146] In certain aspects, the invention also relates to the use of agonists of V1a, V1b, and / or V2 receptors that can also activate the oxytocin receptor. Such compounds of interest include, for example, vasopressin, arginine vasopressin, arginine vasotocin, vasotocin, and their analogs.

[0147] In a preferred embodiment, the oxytocin receptor agonist is a synthetic chemical molecule. It is a peptide or non-peptide molecule, preferably having a maximum of 3000 g.mol -1 or a maximum of 2000 g.mol -1 and is.

[0148] Non-peptide agonists of the oxytocin receptor are described, for example, in WO2014 / 111356 and include, for example, TC OT39, LIT-001, and WAY-267464.

[0149] Preferably, the oxytocin receptor agonist is a peptide, particularly an analog of oxytocin, i.e., a compound having a chemical structure similar to that of oxytocin. An analog of oxytocin can differ from oxytocin by one or several amino acid modifications (e.g., 1, 2, 3, 4, or 5 modifications selected from insertions, deletions, or substitutions including non-natural amino acids) or one or several chemical modifications.

[0150] Analogs of oxytocin are described, for example, in WO2016 / 044131, WO2011 / 035330, and WO2009 / 122285.

[0151] For illustrative purposes only, the agonist of the present invention may be a compound of formula (I) as described in WO2016 / 044131,

[0152] [ka]

[0153] Here, in the formula, Each of W and X is independently CH2 and S, except that both W and X are not both CH2; A is an amino acid selected from the group consisting of alanine; tyrosine; and phenylalanine, in which the phenyl ring is substituted with a 5- or 6-membered heteroaromatic ring; and phenylalanine; in which the phenyl ring is substituted with a halogen, C1-4 alkoxy, C1-4 alkylhydroxy, C1-4 alkyl, or amino. B is an amino acid selected from the group consisting of isoleucine and glycine in which the α-carbon is substituted with a C4-6 cycloalkyl group; C is an amino acid selected from the group consisting of proline whose side chain is optionally substituted with a hydroxyl, C1-4 alkoxy, halogen, or azide, and proline whose side chain is optionally interrupted with a heteroatom, and the interrupted side chain is optionally substituted with a C1-4 alkyl; D is an amino acid selected from the group consisting of leucine; homoleucine; isoleucine; and glycine in which the α-carbon is substituted with a C4-6 cycloalkyl group; E is an amino acid selected from the group consisting of glycine and azaglycine. In some examples, W is CH2 and X is S. In some examples, A is phenylalanine, in which the phenyl ring is substituted with a C1-4 alkoxy.

[0154] In some embodiments, the oxytocin receptor agonist is carbetocin, [Thr] 4 ]OT, HO[Thr 4 ]OT, [Thr 4 Gly 7 ]OT, HO[Thr 4 Gly7 The group consists of OT, lipo-oxytocin-1 (LOT-1), demoxitocin, melotosin (development code name FE-202767), pharmaceutically acceptable salts thereof, and combinations thereof.

[0155] In some preferred embodiments, the oxytocin receptor agonist is selected from oxytocin, carbetocin, pharmaceutically acceptable salts thereof, and combinations thereof.

[0156] • Route of administration, regimen, and formulation Oxytocin receptor agonists can be administered by any conventional route, including, but not limited to, oral, sublingual, intravenous, intramuscular, intranasal, pulmonary (e.g., by inhalation), or subcutaneous routes.

[0157] In fact, depending on the agonist used, a person skilled in the art can determine the best route for use, particularly in terms of its bioavailability and stability.

[0158] The preferred routes of administration are intranasal and oral. The more preferred route of administration is the nasal / intranasal route.

[0159] As used herein, intranasal administration refers to the delivery of a drug within the nasal cavity.

[0160] The effective dose of oxytocin receptor agonist to be administered to the subject can be determined by observing results obtained under similar conditions using conventional techniques. The effective therapeutic dose may vary depending on the subject's genotype, type and associated dysphagia, clinical symptoms of dysphagia observed in the subject, severity of dysphagia, progression of dysphagia over time, route of administration, adjunctive therapies involved, the patient's age, weight, general medical condition, and medical history.

[0161] The daily dose of oxytocin receptor agonist administered to the target individual depends on the agonist's potency, but is generally up to 500 mg, for example, up to 400 mg, 300 mg, 200 mg, 100 mg, 50 mg, 40 mg, 30 mg, 20 mg, 10 mg, 5 mg, 1 mg, 0.5 mg, or 0.2 mg.

[0162] By convention, oxytocin dosages are expressed in International Units (IU) for labeling purposes. 1 IU is approximately equivalent to 1,667 μg of oxytocin (which is equivalent to 1 mg of oxytocin being equivalent to 600 IU) (see OXYTOCIN: ADOPTED TEXT FOR THE INTERNATIONAL PHARMACOPOEIA, WHO, June 2010).

[0163] In the context of the present invention, the daily dose of oxytocin is generally less than 100 IU (i.e., 166.7 μg), and is preferably between 1 IU (1,667 μg) and 50 IU (83.35 μg).

[0164] For example, the daily dose of oxytocin is typically 2 IU to 50 IU, preferably 4 IU to 32 IU, or 4 IU to 24 IU.

[0165] As a further example, carbetocin can be administered in daily doses of up to 30 mg per day, typically ranging from 3 mg to 30 mg per day.

[0166] Oxytocin receptor agonists may be administered once daily, every other day, or several times a day, for example, twice, three, or four times a day. OT receptor agonists may be administered with or without food, preferably without food, for example, before meals. Administration of oxytocin receptor agonists may be continued for one week to several weeks, or one month to several months, typically for as long as necessary.

[0167] Oxytocin receptor agonists are typically formulated into pharmaceutical compositions to be administered to a target. Oxytocin receptor agonists can be formulated in any suitable pharmaceutical composition according to standard methods, such as those described in Remington: The Science and Practice of Pharmacy (Lippincott Williams & Wilkins; 21st edition, 2005). Pharmaceutically acceptable excipients that may be used are described in particular in Handbook of Pharmaceuticals Excipients, American Pharmaceutical Association (Pharmaceutical Press; 6th revised edition, 2009). Typically, therapeutic agents are mixed with one or more excipients to obtain the desired pharmaceutical form. Suitable excipients include, but are not limited to, solvents such as water or water / ethanol mixtures, fillers, carriers, diluents, binders, anticaking agents, plasticizers, disintegrants, lubricants, fragrances, buffers, stabilizers, colorants, dyes, antioxidants, anti-adhesion agents, softeners, preservatives, surfactants, waxes, emulsifiers, wetting agents, isotonic agents, and lubricants. Examples of diluents include, but are not limited to, microcrystalline cellulose, starch, modified starch, dibasic calcium phosphate dihydrate, calcium sulfate trihydrate, calcium sulfate dihydrate, calcium carbonate, monosaccharides or disaccharides such as lactose, glucose, and sucrose, mannitol, galactose and sorbitol, xylitol, glycerol, and combinations thereof. Examples of binders include, but are not limited to, starches such as potato starch, wheat starch, and corn starch; gums such as tragacanth gum, acacia gum, and gelatin; hydroxypropyl cellulose, hydroxyethyl cellulose, and hydroxypropyl methylcellulose; polyvinylpyrrolidone, copovidone, polyethylene glycol, and combinations thereof.Examples of lubricants include, but are not limited to, fatty acids and their derivatives such as calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, zinc stearate, or stearic acid, or polyalkylene glycols such as PEG. Flow promoters may be selected from colloidal silica, silicon dioxide, talc, etc. Examples of disintegrants include, but are not limited to, croscarmellose salts such as crospovidone and croscarmellose sodium, starch and their derivatives. Examples of surfactants include, but are not limited to, polysorbates and their derivatives such as simethicone, triethanolamine, Tween® 20 or Tween® 40, fatty alcohols such as poloxamer, lauryl alcohol, and cetyl alcohol, phospholipids, and alkyl sulfates such as sodium dodecyl sulfate (SDS). Examples of stabilizers particularly useful for freeze-drying include sugars such as mannitol, sucrose, dextrose, and trehalose, amino acids, hydroxypropyl-β-cyclodextrin, and serum albumin. Examples of emulsifiers include, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, polyethylene glycol, and fatty acid esters of sorbitan, or mixtures thereof. Preservatives include, but are not limited to, parabens, chlorobutanol, benzalkonium chloride, benzoic acid, sorbic acid, and their salts. Antioxidants include ascorbic acid, ascorbyl palmitate, tocopherol, and combinations thereof.Examples of buffers include phosphoric acid, tris(hydroxymethyl)aminomethane hydrochloride (TRIS.HCl), 4-morpholine propanesulfonic acid (MOPS), 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES), PIPES, 2,2-bis(hydroxymethyl)-2,2',2''-nitrilotriethanol (BIS-TRIS), TRIS-glycine, bicine, tricine, TAPS, TAPSO, MES, citrate, acetate, borate, citrate / phosphate, bicarbonate, glutarate, succinate, citrate, acetate, and combinations thereof.

[0168] It goes without saying that the excipients to be combined with the target oxytocin receptor agonist may be selected considering (i) the physicochemical properties, including the stability of the therapeutic agent, (ii) the pharmacokinetic profile and / or release profile required for the therapeutic agent, (iii) the dosage form, and (iv) the route of administration.

[0169] The pharmaceutical composition may be of any kind. For example, the pharmaceutical composition may be a solid oral dosage form such as a tablet, a liquid dosage form for intranasal delivery, a suspension or suppository for intravenous routes, an aerosol for administration via the pulmonary route, etc. The pharmaceutical composition may also be a lyophilized powder that is dissolved or suspended in a suitable vehicle before administration via the intranasal route, for example.

[0170] As mentioned above, the preferred route of administration is the intranasal route.

[0171] Therefore, in certain embodiments, the pharmaceutical composition of the present invention is suitable for intranasal administration, for example, as a nasal spray or a dry powder aerosol formulation.

[0172] For example, a pharmaceutical composition intended for intranasal delivery may be in the form of a liquid composition containing the target oxytocin receptor agonist dissolved in a suitable aqueous buffer. Suitable buffers include phosphates, citrates, acetic acid, acetates, aspartates, and combinations thereof. The liquid composition may contain one or more additional pharmaceutical excipients such as preservatives, antioxidants, surfactants, solvents, isotonic agents, pH adjusters (e.g., HCl or NaOH), and wetting agents. The pH of the composition may be adjusted between pH 4.5 and pH 6.0. Divalent ions such as Ca2+, Mg2+, Zn2+, etc., may be added for stabilization purposes or to promote absorption in vivo.

[0173] Liquid oxytocin compositions for intranasal administration are sold in Europe under the trade name Syntocinon®. Syntocinon® is an aqueous buffered formulation of oxytocin containing a combination of buffering agents (e.g., phosphates, citric acid, acetates), sodium chloride, sorbitol, glycerol, and preservatives (chlorobutanol, methylparaben, and propylparaben) in water.

[0174] The prior art also provides several examples of intranasal compositions that may be used to carry out the present invention. For example, one can refer to International Publication No. 2012042371, which describes a liquid composition of an oxytocin receptor agonist (e.g., carbetocin) containing phosphate and citrate as buffers and NaCl as an isotonic agent in water at pH 5.5. The composition may further contain antioxidants such as methionine or EDTA. These compositions are described as being suitable for intranasal administration.

[0175] Other examples can be found in WO2016112205, which refers to a liquid composition for intranasal administration containing oxytocin and magnesium salts. This international application specifically describes a buffered aqueous composition of oxytocin containing buffers such as magnesium salts (e.g., MgCl), acetates, and citrates in water at pH 4.5.

[0176] Additional oxytocin preparations are described, for example, by Avanti et al. (AAPS J. June 2011; 13(2): pp. 284-2890 and Int J Pharm. February 28, 2013; 444(1-2): pp. 139-45). Avanti et al. describe stable aqueous solutions of oxytocin obtained using citrate or aspartate and divalent metal cations such as Ca2+, Mg2+, and Zn2+ (Int J Pharm. February 28, 2013; 444(1-2): pp. 139-45).

[0177] The intranasal composition of the present invention may be administered as a single dose or in divided doses of, for example, one, two, three, four, five, or six sub-dose (e.g., puffs) delivered to one or both nostrils.

[0178] Intranasal compositions of oxytocin receptor agonists can be delivered by any means, for example, using any suitable nasal pump device or apparatus. Such devices are well known to those skilled in the art, and various models are available on the market. In some embodiments, the nasal device or apparatus includes a reservoir bottle attached to a pump actuator. In some embodiments, the nasal device or apparatus includes a reservoir bottle attached to an aerosol generator. Devices for intranasal delivery are preferably designed to deliver multiple doses of oxytocin receptor agonist compositions. For example, a nasal pump device may include a reservoir bottle attached to a pump actuator, where the reservoir bottle holds multiple doses of the liquid formulation, and the pump actuator is metered to deliver a specified volume, which is a portion of the liquid formulation held in the reservoir bottle. In some embodiments, the pump actuator is metered to deliver about 5 μL to about 200 μL, preferably about 25 μL to about 170 μL, for example, about 40 μL to about 150 μL of the liquid formulation per spray. The nasal pump device may be equipped with a filter to prevent backflow in order to reduce or prevent contamination (e.g., bacteria) of the reservoir bottle.

[0179] For example, a device for intranasal delivery may include a multi-dose pump, such as the one described in U.S. Patent No. 5,988,449, which includes a microbial filter and an automatic shut-off mechanism within the pump actuator.

[0180] • Specific embodiments of the present invention: Treatment of dysphagia in subjects suffering from Prader-Willi syndrome and related disorders In certain embodiments, the present invention relates to the use of oxytocin receptor agonists in the treatment or prevention of dysphagia in subjects suffering from Prader-Willi syndrome (PWS) or Prader-Willi-like syndrome.

[0181] Prader-Willi syndrome (PWS) is a complex hereditary neurodevelopmental disorder resulting from a lack of expression of a paternally inherited imprinted gene on chromosomes 15q11-q13, causing hypothalamic dysfunction. The estimated incidence is 1 in 15,000 to 1 in 27,000 live births. The lack of gene expression can be caused by chromosomal deletions, maternal disomy, or imprinting defects.

[0182] The clinical features of PWS include severe neonatal hypotension with feeding difficulties that explain growth retardation (FTT) frequently occurring in the neonatal and infancy periods (0 to 9 months), overall developmental delay with hypogonadism / hypogamosis (2 to 6 years), onset of bulimia nervosa (6 to 12 years) which can lead to morbid obesity if left uncontrolled, and subsequent persistent food cravings that are close to addiction and satiety, hypothalamic and pituitary dysfunction (short stature associated with growth hormone deficiency, hypogonadism, hypothyroidism, and rarely, central adrenal insufficiency), behavioral problems including learning disabilities, cognitive deficits, and social skills deficits, as well as psychiatric phenotypes from age 13 into adulthood (Gunay-Aygun et al., Pediatrics. 2001;108(5):E92).

[0183] PWS is classically described as having two distinct nutritional stages. In Stage 1, subjects exhibit poor feeding and severe hypotension, often accompanied by growth retardation (FTT). Next, Stage 2, which begins around 2-4 years of age, is characterized by rapid weight gain and the onset and progression of bulimia, which leads to the development of obesity, developmental delay, and behavioral disorders. The transition from poor feeding / FTT to obesity / bulimia is not fully understood and, as shown by Miller et al. (Am J Med Genet A. May 2011; 155A(5): pp. 1040-1049), results from a complex progression involving several nutritional stages. Miller et al. describe it as follows: - In Phase 1, the infant is hypotonic but not obese, and subphase 1a is characterized by feeding difficulties with or without FTT (median age at completion: 9 months). Following this stage, subphase 1b follows, in which the infant grows steadily along the growth curve and gains weight at a normal rate (median age at onset: 9 months). - Phase 2 is associated with weight gain; in subphase 2a, weight gain occurs without significant changes in appetite or calorie intake (median age of onset: 2.0 years), while in subphase 2b, weight gain is associated with an accompanying increase in interest in food (median age of onset: 4.5 years). Phase 3 is characterized by bulimia, typically accompanied by food searching and a lack of satiety (median age of onset: 8 years). - In Phase 4, individuals who were previously in Phase 3 lose their insatiable appetite and become able to feel full.

[0184] As used herein, Prader-Willi-like syndrome or Prader-Willi-like disorder refers to any hereditary neurodevelopmental disorder that replicates most of the clinical phenotypes of PWS.

[0185] Prader-Willi-like disorders include Schaf-Yan syndrome (pathogenic mutations in the MAGEL2 gene) and microdeletions in the SNORD116 gene cluster. Deletions or mutations in the following genes, SNURF-SNRPN, MKRN3 gene, NDN gene and several snoRNA sequences, NPAP1 gene, and C15orf2 gene are also included.

[0186] Other Prader-Willi-like disorders are described by Rocha and Paiva (2014, Genetics and Molecular Research 13(1): pp. 2290-2298) and include chromosomal abnormalities such as Xq duplication, 1p36 monosomy, 6q deletion, 10q26 deletion, 12q subtelomere deletion (Niyazov et al., 2007), chromosomal abnormalities associated with Angelman syndrome, 2pter deletion, and deletions related to the SIM1 gene.

[0187] In some embodiments, oxytocin receptor agonists, preferably oxytocin or carbetocin, are used to alleviate, prevent, or treat dysphagia symptoms in subjects with PWS or PWS-like disorders, the symptoms being selected from the group consisting of aspiration including silent aspiration, intrusion, oropharyngeal motility disorders, esophageal motility disorders, pharyngeal residue, reflux, dissynchronization with the respiratory cycle, propulsion disorders, and combinations thereof.

[0188] In preferred embodiments, an oxytocin receptor agonist, preferably oxytocin or carbetocin, is used to treat oropharyngeal motor disorders and / or esophageal motor disorders and / or respiratory-swallowing dissyncope and / or propulsion disorders in subjects with PWS of PW-like syndrome.

[0189] In another embodiment, an oxytocin receptor agonist, preferably oxytocin or carbetocin, is used to treat or prevent one or more dysphagia complications selected from the group consisting of respiratory infections, including aspiration pneumonia, asphyxiation, and combinations thereof, in subjects with PWS or PWS-like disorder.

[0190] In a preferred embodiment, the subject being treated is not a neonatal or infant receiving only liquid nutrition. Preferably, the subject is in the process of transitioning to a diversified diet or is already on a diversified diet, i.e., able to eat both solid and liquid foods.

[0191] In certain embodiments, the subjects having PWS or PWS-like syndrome are at least 6 months old, preferably at least 9 months old, and most preferably at least 12 months old. Furthermore, the subjects having PWS or PWS-like syndrome may be up to 20 years old, preferably at least 15 years old.

[0192] In some embodiments, the subjects had not received oxytocin treatment within the first six months of life.

[0193] In other embodiments, the subject having PWS is in trophic stage 1b, 2, 3, or 4 as described above, particularly in trophic stage 1b, 2, or 3, and more preferably in trophic stage 2 or 3.

[0194] In another embodiment, subjects with PWS or PWS-like syndrome also suffer from bulimia nervosa.

[0195] As described above, preferred OT receptor agonists are oxytocin, carbetocin, and pharmaceutically acceptable thereof. More preferably, the OT receptor agonist is oxytocin or a pharmaceutically acceptable salt thereof.

[0196] Oxytocin receptor agonists are preferably administered once or several times a day (e.g., two or three times a day) via the intranasal route. Preferably, OT receptor agonists are administered once a day. The daily pharmaceutical dose of OT receptor agonists is up to 100 IU, preferably 2 to 50 IU.

[0197] The appropriate daily dose of oxytocin for subjects aged 2 to 15 years is typically 2 IU to 48 IU, preferably 2 IU to 32 IU, 4 IU to 20 IU, for example, 6 IU to 16 IU. Oxytocin may be administered once daily, for example, in the morning, preferably before meals.

[0198] The daily dose of carbetocin is typically 3 to 30 mg. Carbetocin may be administered three times a day, preferably before meals.

[0199] OT receptor agonists, such as oxytocin or carbetocin, can typically be administered in the form of a buffered aqueous composition, i.e., a nasal spray.

[0200] Further aspects and advantages of the present invention are disclosed in the following experimental section, but these should be considered illustrative and not to limit the scope of the application. [Examples]

[0201] (Example 1) Case report Patient 1 was a 6-year-old with Prader-Willi syndrome, caused by maternal uniparental disomy, which was diagnosed shortly after birth.

[0202] He presented with clinical symptoms of dysphagia, including significant difficulty swallowing water, but not solid foods, and had dental problems possibly associated with acid reflux and acid reflux episodes. Videofluoroscopic swallowing study (VFSS) revealed abnormalities, including prolonged esophageal transit time, decreased peristalsis, and abnormal closure of the upper esophageal sphincter.

[0203] He received 8 IU of intranasal OXT daily for three weeks.

[0204] Treatment with oxytocin was well-tolerated and resulted in improvements in VFSS, including complete normalization of peristalsis and improved esophageal transit with normal upper esophageal sphincter closure.

[0205] Patient 2 was 14 years old. He had a neurodevelopmental disorder and exhibited hypothalamic dysfunction. He presented with clinical symptoms of dysphagia and frequently experienced episodes of rumination and bad breath.

[0206] VFSS was an abnormality that included slow pharyngeal transit with pharyngeal residue, as well as slow esophageal transit with esophageal reflux and stasis.

[0207] He received 16 IU of OXT intranasally daily for three weeks. This treatment was well-tolerated and improved the clinical symptoms of dysphagia, with normalization of oropharyngeal initiation and synchronization, and normalization of esophageal transit. Following treatment, the VFSS showed no stasis or reflux.

[0208] (Example 2) The effect of intranasal oxytocin on dysphagia associated with oropharyngeal and esophageal motility disorders in children and adolescents with Prader-Willi syndrome: A Phase 3 trial (DYSMOT) The purpose of this study is to investigate the effectiveness of intranasal oral ophthalmology (OT) therapy for dysphagia associated with oropharyngeal esophageal motility disorders (OPOD) in children aged 2 to 18 years with Prader-Willi syndrome (PWS) using systematic videofluoroscopic swallowing studies (VFSS).

[0209] [Table 1-1]

[0210] [Table 1-2]

[0211] [Table 1-3]

[0212] [Table 1-4]

[0213] [Table 1-5]

[0214] [Table 1-6]

[0215] - Test design This prospective, multicenter, randomized, double-blind, phase 3 clinical trial is planned to include approximately 36 PWS patients aged 2–18 years from five centers in France. The trial will consist of three parts.

[0216] Part 1 is a placebo-controlled, double-blind period to evaluate the effect of intranasal OT treatment and placebo on OPOD-related dysphagia, assessed by videofluoroscopy of swallowing and esophageal transit in male and female children and adolescents with PWS. Groups 1 and 3 will receive OT, and group 2 will receive placebo. Patients will be randomly assigned to one of the three treatment groups in a 1:1:1 ratio. Randomization will be stratified by age group (2 to under 8 years, 8 to 15 years, and over 15 years).

[0217] In the second part, a separate double-blind period, Group 1 (patients treated with OT in Part 1) received a 12-week placebo to evaluate changes after discontinuation of treatment, while Group 2 (patients treated with placebo in Part 1) received OT, and Group 3 (patients treated with OT in Part 1) continued OT treatment to evaluate maintenance of efficacy.

[0218] In the third phase, a 24-week open-label period of intranasal OT treatment, all patients will receive OT to evaluate the maintenance of long-term safety and efficacy.

[0219] The experimental treatment will be administered intranasally daily for 48 weeks. The dosage of OT will be adjusted according to the age at the start of the study: 8 IU for children aged 2 to under 8 years, 16 IU for children aged 8 to 15 years, and 24 IU for adolescents over 15 years.

[0220] A phone call will be scheduled between one of the researchers and parents of PWS patients within the specified age range. The researcher will answer any questions regarding the objectives, constraints, and foreseeable risks. After some time to consider, parents who agree to their child participate in the trial will contact the researcher to arrange enrollment.

[0221] At the baseline visit (V1), parents sign informed consent and eligibility criteria are confirmed. Eligible patients are then enrolled and randomized. The VFSS is conducted along with other study procedures, and patients are randomly assigned to one of three treatment groups before the first dose of the study treatment.

[0222] If the VFSS is performed in accordance with routine considerations and meets quality and acquisition requirements within four weeks prior to its incorporation into the trial, the VFSS can be used as a baseline and will not be performed in V1.

[0223] In the first two parts of the trial, the investigational treatment (OT or placebo) will be administered daily for 12 weeks via the intranasal route.

[0224] The progression of all parameters is recorded, and the duration of the first and second treatments within each group is compared to evaluate the effects of OT and placebo, the effect of discontinuing treatment, and the maintenance of efficacy.

[0225] The long-term safety profile of intranasal administration of OT is evaluated during the open-label period, as is the long-term efficacy.

[0226] - Trial intervention The investigational drug (IMP) for this trial is intranasal oral ointment (OT). Since this is a double-blind study, a corresponding intranasal placebo solution will also be provided. To maintain blinding of the trial, both the IMP and its corresponding placebo will be provided in identical packaging.

[0227] The main characteristics of IMP and its corresponding placebo are shown in Table 2 below.

[0228] [Table 2]

[0229] The experimental treatment was administered daily via the intranasal route for 12 weeks in Part 1 and Part 2 (OT or placebo), and for 24 weeks in the open-label period (OT only) (Figure 1).

[0230] In V1, the trial treatment is administered by the parent / caregiver or patient under the supervision of a medical team member. Staff members also instruct the parent / caregiver and / or patient on when and how to administer the medication, including how to fill the treatment pump and how to deal with delays or missed doses. Instructions on how to position the device for administration are detailed in a specific trial log completed by the parent / caregiver.

[0231] The diary should be filled out daily to track treatment compliance and administration timing in Parts 1 and 2. In the open-label section, only treatment-related issues such as delayed administration, missed administration, or overdose should be recorded each time a new OT vial is opened / used (every 28 days). The diary should include instructions for use and reminders regarding how to deal with delayed, missed, or overdosed doses.

[0232] The final dose of each period of the study treatment should be administered the day before the visit. For V2, V3, and V4, parents should return the study treatment bottles provided during the period prior to the study, as facility staff need to collect and manage them. For V1, V2, and V3, parents will be provided with the study treatment for the next period of the study, with the first dose administered at the hospital upon the visit.

[0233] The dosage is adjusted according to age, following the guidelines shown in Table 3 below.

[0234] [Table 3]

Claims

1. A composition comprising oxytocin or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of dysphagia in subjects at least 1 year of age suffering from a hereditary neurodevelopmental disorder with hypothalamic dysfunction.

2. The composition according to claim 1, wherein the dysphagia is characterized by impaired esophageal motility.

3. The composition according to claim 1 or 2, wherein the hereditary neurodevelopmental disorder is selected from the group consisting of Prader-Willi syndrome and Prader-Willi-like syndrome, Fragile X syndrome, DiGeorge / 22q11.2 deletion syndrome, Down syndrome, Rett syndrome, Noonan syndrome, CHARGE syndrome, Kabuki syndrome, Troyer syndrome, Christianson syndrome, Smith-Magenis syndrome, Alstrom syndrome, symptomatic obesity, familial autonomic dysfunction, and Williams syndrome.

4. The composition according to any one of claims 1 to 3, wherein the target is an infant, child, or teenager.

5. Swallowing difficulties are characterized by the following clinical signs: - Esophageal stasis, - Esophageal residue, - Abnormal closure of the esophageal sphincter, - Esophageal dilation, - Inhalation, including intrusion and asymptomatic inhalation - Prolonged or slow esophageal passage, - Reduced peristalsis, and - Esophageal reflux The composition according to any one of claims 1 to 4, characterized by at least one of the clinical signs, wherein the clinical signs are evaluable by videofluoroscopy.

6. The subjects exhibit the following characteristics: slow esophageal transit, poor esophageal clearance, esophageal reflux, reduced peristalsis, and combinations thereof. The composition according to any one of claims 1 to 5, exhibiting esophageal motility disorders characterized by one or more of the following.

7. The composition according to any one of claims 1 to 6, wherein oxytocin or a pharmaceutically acceptable salt thereof is used to improve or normalize esophageal motility in a subject.

8. The target conditions are: esophageal bolus obstruction, pulmonary aspiration, recurrent lung infections, aspiration pneumonia, suffocation, reflux, nasal reflux, and rumination. A composition according to any one of claims 1 to 7, which has experienced, is currently experiencing, or is at risk of experiencing one or more of the following.

9. The composition according to any one of claims 1 to 8, wherein the neurodevelopmental disorder is Prader-Willi syndrome or Prader-Willi-like disorder.

10. The composition according to claim 9, wherein the subject suffers from asymptomatic dysphagia.

11. A composition according to any one of claims 1 to 10, administered via an intranasal route.

12. The composition according to claim 11, wherein the oxytocin or a pharmaceutically acceptable salt thereof is administered in a daily dose of 2 IU to 48 IU.

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