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] The present invention relates to the therapeutic management of dysphagia, particularly in subjects with autonomic nervous system dysfunction. [Background technology]

[0002] Swallowing in adults and children is a complex mechanism based on coordinated actions 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 depends on major muscle groups innervated by a subset of cranial nerves.

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

[0004] Only the oral stage requires conscious effort: once in the pharynx, the bolus passes involuntary into the stomach (Maynard et al., Annual Review of Neuroscience, 2020, 4:316-36).

[0005] Dysphagia is a medical term that indicates a disorder of the swallowing process, i.e., a malfunction in one or more stages of the swallowing process. Dysphagia can be characterized by several symptoms, such as coughing before and after swallowing, choking, hoarseness, regurgitation, persistent saliva drooling, aspiration, food impaction, and improper chewing. Patients with dysphagia often complain of a sensation of food sticking or getting stuck in the throat or chest, and / or discomfort in the chest or throat. Sometimes dysphagia can be asymptomatic (i.e., not identifiable by a physician without instrumentation) while still causing serious health complications.

[0006] Indeed, malnutrition and dehydration, aspiration pneumonia, deterioration of general condition, chronic lung disease, choking, and even death can occur as a result of dysphagia.

[0007] Today, dysphagia is a major health concern given its incidence in the population and associated morbidity.

[0008] In this regard, it has recently been shown that dysphagia has a high prevalence in patients with dysfunction of the autonomic nervous system, e.g. in patients with certain neurodegenerative diseases or in patients suffering from certain neurodevelopmental disorders such as Prader-Willi syndrome.

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

[0010] Between birth and 9 months, infants with PWS exhibit feeding problems and anorexia, accompanied by severe hypotonia. Conversely, after 2 years, young children with PWS then exhibit early excessive weight gain leading to severe obesity with hyperphagia and satiety deficiency.

[0011] At all ages, the phenotype also includes endocrine disorders (growth hormone deficiency, hypogonadism, hypothyroidism), learning disabilities, and behavioral and psychiatric disorders. Patients with PWS also show several clinical symptoms that are evidence of autonomic nervous system (ANS) dysfunction, such as oropharyngeal and intestinal motility disorders, abnormal thermoregulation, altered sleep control, insensitivity to hypoxia and hypercapnia, altered pain sensation, and reduced salivation (Haqq et al., 2012, clinical obesity 1, pp. 175-183).

[0012] Although feeding problems in infants are well documented, swallowing problems in children and adults with PWS have not been evaluated until recently, despite the high incidence of pulmonary infections and sudden death in this population.

[0013] Recent studies have shown that asymptomatic (silent) dysphagia is highly prevalent in children and adults with PWS. This study, performed by videofluoroscopy of swallowing (VFS), showed that children and adults with PWS have impaired pharyngeal and esophageal swallowing, with impaired timing of swallowing, clearance, and coordination of swallowing with the respiratory cycle. 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] As of today, there are few options to manage 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 manipulatives, postural / positional techniques, biofeedback, and oral motor training. In some cases, anti-reflux and prokinetic drugs may also be administered. However, these approaches are not curative and may not be feasible for patients with cognitive or intellectual disabilities. Unfortunately, when a patient's swallowing safety and efficiency does not reach an adequate functional level, or when swallowing function does not adequately support nutrition and hydration, tube feeding, e.g., nasogastric tube or gastrostomy, is the only remaining option.

[0015] Currently, there is a need for new therapies 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

Patent Document 3

Patent document 4

Patent document 5

Patent document 6

Patent document 7

Non-licensed literature

[0017]

Non-licensed literature 1

Non-licensed Document 2

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

[0018] The present 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, the dysphagia is characterized by oropharyngeal and / or esophageal motility disorders. The dysphagia may involve solids and / or liquids, preferably both. In a preferred embodiment, 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 a genetic neurodevelopmental disorder, preferably selected from the group consisting of Prader-Willi and Prader-Willi-like syndromes, 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, Alström syndrome, syndromic obesity, familial dysautonomia, 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 a preferred embodiment, the subject is at least 6 months old and is in the transitional period of dietary diversification or is already under dietary diversification.Preferably, the subject is at least 1 year old.For example, the subject can be an infant, a child, or a teenager.In addition, the subject can be an adult.

[0022] In some embodiments, the dysphagia is characterized by the following clinical signs: - Pharyngeal or esophageal congestion - Pharyngeal residue, - Abnormal closure of the esophageal sphincter, especially the upper esophageal sphincter - esophageal dilatation, preferably upper esophageal dilatation or megaesophagus - Propulsion disorder - Delayed initiation of swallowing - Desynchronization with the respiratory cycle - Invasion, including asymptomatic inhalation; - Decreased peristalsis, - Prolonged esophageal transit, and - Nasopharyngeal or esophageal reflux and wherein said clinical signs are optionally assessable by videofluoroscopy.

[0023] In some further embodiments, the subject has experienced, is experiencing, or is at risk of experiencing one or more of the following disorders: esophageal bolus obstruction, pulmonary aspiration, recurrent pulmonary infections, aspiration pneumonia, choking, regurgitation, nasal regurgitation, and rumination.

[0024] The oxytocin receptor agonists of interest are oxytocin, carbetocin, [Thr 4 ]OT, HO[Thr 4 ]OT, [Thr 4 , Gly 7 ]OT, HO[Thr 4 , Gly 7 ]OT, lipo-oxytocin-1 (LOT-1), demoxytocin, merotocin, demoxytocin, lipo-oxytocin-1 (LOT-1), TC OT 39, and WAY-267464, LIT-001. Preferred oxytocin receptor agonists include oxytocin, carbetocin, and combinations thereof.

[0025] Another object of the present invention is the use of oxytocin in the treatment of dysphagia in a subject suffering from a neurodevelopmental disorder. The neurodevelopmental disorder is preferably Prader-Willi syndrome or a Prader-Willi-like disorder. The subject is preferably at least 6 months old and in a transitional period of dietary diversification or is already under a diversified diet. The subject may suffer from asymptomatic dysphagia. Oxytocin may be administered by intranasal route, preferably in a daily dosage of 2 IU to 48 IU. [Brief description of the drawings]

[0026] [Figure 1] FIG. 1 illustrates the different steps of the clinical study (see Examples section). [Diagram 2] FIG. 1 shows the videofluoroscopic scoring chart for swallowing and esophageal transit used during the clinical trial. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] As explained 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 problems, poor appetite, and failure to thrive, and a later stage in which children or adults exhibit excessive weight gain leading to obesity with hyperphagia and lack of satiety. Subjects with PWS also exhibit several clinical symptoms highly suggestive of dysfunction of the autonomic nervous system (ANS), including oropharyngeal, esophageal, and intestinal motility disorders, abnormalities in thermoregulation, altered sleep control, insensitivity to hypoxia and hypercapnia, altered pain sensation, and reduced salivation.

[0028] A higher incidence of pulmonary infections and sudden death has been reported in the PWS population compared with healthy controls and patients with similar intellectual disabilities.

[0029] Recent studies demonstrate that adults and children with PWS suffer from subclinical dysphagia characterized by esophageal stasis, pharyngeal residue, high risk of silent aspiration, and disturbances in the coordination of the respiratory cycle and swallowing.

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

[0031] Oxytocin (OT) is a naturally occurring hypothalamic hormone. It has peripheral hormonal actions and acts as a neurotransmitter and neuromodulator in the brain via OT receptors. OT plays an important role in regulating social interactions and maternal-infant 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 being evaluated in several clinical trials, for example, for the treatment of social disorders in patients with autism, or for the treatment of binge eating and obsessive-compulsive disorder in adult PWS patients. Applicants recently completed a Phase II clinical trial showing that intranasal administration of OT was well tolerated and significantly improved feeding and social skills in infants with PWS less than 6 months of age (Tauber et al., 2017, Pediatrics, 139, 2 e2 0162976).

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

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

[0034] In particular, the Applicant has shown that in a 6-year-old patient with Prader-Willi syndrome and severe clinical symptoms of dysphagia, daily administration of oxytocin over a period of 3 weeks is able to completely normalize peristalsis and closure of the upper esophageal sphincter, improving esophageal transit.

[0035] Interestingly, applicants also demonstrated the efficacy of daily administration of oxytocin 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] Additionally, Applicants are conducting a clinical trial aimed at evaluating the effect of chronic administration of oxytocin (OT) on swallowing disorders in children and adolescents with PWS, ages 2 to 14 years.

[0037] Based on these data, Applicants believe that oxytocin may improve swallowing patterns in subjects with PWS and other patients with autonomic nervous system dysfunction by improving oropharyngeal esophageal motility.

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

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

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

[0041] In a further aspect, the present invention relates to the use of an oxytocin receptor agonist in the manufacture of a medicament for the treatment or prevention of dysphagia, particularly in a subject suffering from autonomic nervous system dysfunction, such as a subject with a neurodevelopmental disorder, such as a subject suffering from PWS.

[0042] In a particular aspect, the present invention relates to the use of an oxytocin receptor agonist or a pharmaceutical composition thereof for treating oral and / or pharyngeal and / or esophageal motility disorders and / or swallowing-respiratory desynchronization in a subject with dysphagia.

[0043] In a further aspect, the present invention relates to the use of an oxytocin receptor agonist or a pharmaceutical composition thereof for treating or reducing the occurrence of symptoms of dysphagia selected from the group consisting of pharyngeal retention, nasal and / or esophageal reflux, aspiration, intrusion, propulsion disorders and combinations thereof.

[0044] In another aspect, the present invention relates to the use of an oxytocin receptor agonist or a pharmaceutical composition thereof for preventing respiratory infections, including aspiration pneumonia, and / or asphyxiation in a subject with dysphagia, preferably in a subject with a neurodevelopmental disorder, such as autonomic nervous system dysfunction, e.g. PWS.

[0045] As described in further detail below, the subject is preferably on a diversified diet or is on a diet diversified diet and is at least 6 months of age.

[0046] A preferred subgroup of subjects with dysphagia are patients with neurodevelopmental disorders, in particular genetic 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 "treating dysphagia" includes curing, delaying, alleviating, or slowing the progression of dysphagia, or curing, delaying, alleviating, or slowing the progression of one or more associated symptoms and / or disorders, as well as 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 can be used to reduce or alleviate one or several symptoms of dysphagia in a subject, such as silent aspiration, oropharyngeal and esophageal motility disorders, propulsion disorders, desynchronization with the respiratory cycle, esophageal and / or nasopharyngeal reflux, prolonged esophagogastric transit, and / or aspiration involving esophageal or pharyngeal residue, etc.

[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, the term also refers to minimizing the risk (or probability) of a patient developing said symptoms or complications compared to a patient not receiving a compound of the present invention. For example, in the context of the present invention, oxytocin receptor agonists can be used to prevent or minimize the risk of experiencing respiratory infections, such as aspiration pneumonia, or choking in subjects with dysphagia, who may also suffer from a neurodevelopmental disorder. As a further example, oxytocin receptor agonists can be used to delay the onset or slow the progression of dysphagia in subjects with neurodegenerative disorders.

[0050] As used herein, "therapeutically effective amount" refers to an amount of an 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 "pharmacologically acceptable" refers to compositions, compounds, salts, etc., that are suitable for contact with the tissues of a subject or can be administered to a subject, within the scope of sound medical judgment, without undue toxicity or other complications commensurate with a reasonable benefit / risk ratio.

[0052] Swallowing problems The term "dysphagia" as used herein refers to any swallowing disorder, ie, a dysfunction at one or more stages of the swallowing process, ie, the oral, pharyngeal, and / or esophageal stages.

[0053] As explained in the background section, swallowing in adults and children is a complex mechanism based on the coordinated actions of the mouth, pharynx, and esophagus. The swallowing mechanism includes three phases: the oral phase, the pharyngeal phase, and the esophageal phase.

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

[0055] In a preferred embodiment, the subject suffers from oropharyngeal esophageal dysphagia.

[0056] Oropharyngeal dysphagia generally refers to disorders that affect the oropharynx and the uppermost part of the esophagus (around the upper esophageal sphincter), while esophageal dysphagia refers to disorders that affect the esophagus (including the lower esophageal sphincter). Oropharyngeal esophageal dysphagia refers to disorders that affect both the oropharynx and the esophagus.

[0057] In fact, disorders 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 (preparatory) phase: poor lip closure and impaired tongue movement can result in loss of food from the oral cavity and problems with mastication, as well as problems with bolus formation and transit through the oral cavity due to reduced tongue strength, which can lead to delayed introduction into the oropharynx; - At the pharyngeal stage: reduced tongue elevation resulting in intrapharyngeal pooling, poor oral bolus control and reduced posterior tongue thrust leading to delayed initiation of pharyngeal swallowing, nasal regurgitation due to dysregulated pharyngeal contraction or insufficient closure of the nasopharyngeal region, food penetration into the subepiglottic space or (subclinical) aspiration due to impaired timing and coordination, post-swallow residues in the valleculae and pyriform sinuses due to reduced activity of the submandibular muscles, reduced tongue base retraction, or reduced pharyngeal contraction (pharyngeal dysmotility). - At the esophageal stage: Residue above the upper esophageal sphincter due to restricted sphincter opening, residue or retention in the proximal esophagus due to motility problems.

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

[0059] In certain embodiments, a subject with dysphagia may exhibit one or several dysfunctions in oral and pharyngeal propulsion, initiation and synchronization, and / or esophageal motility, as listed in the chart shown in FIG.

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

[0061] Dysphagic subjects may complain of a sensation of food sticking or getting stuck in the throat or chest, and / or discomfort in the chest or throat. Subjects may suffer from visible or directly observable symptoms such as coughing before or after swallowing, choking, hoarseness, regurgitation, persistent drooling of saliva, improper chewing, shortness of breath, sore throat, and heartburn.

[0062] However, in some subjects, dysphagia may be asymptomatic, i.e., the dysphagia does not show visible symptoms in the subject and the subject does not feel any sensations associated with the dysphagia. For example, the subject may not experience any sensation of food sticking or blocking in the throat or esophagus and / or may not recognize the presence of aspiration or intrusion even when severe aspiration / intrusion occurs. This may be due to concomitant cognitive problems, as in the case of subjects with Prader-Willi syndrome, or sensory impairments, such as impaired perception of pain.

[0063] "Aspiration" as used herein describes a swallowing disorder in which food, liquid, or saliva that should go into the stomach instead goes into the airways or lungs. When this occurs, the subject still breathes, but typically coughs to clear the 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] "Choking" as used herein describes a swallowing disorder in which food becomes lodged in the airway, blocking airflow. Sometimes the Heimlich maneuver is required to expel food that has become lodged in the airway.

[0065] In some embodiments of the present invention, the subject with dysphagia has chest or throat discomfort including sensation of food sticking, and / or has one or more of the swallowing disorders selected from the group consisting of coughing before or after swallowing, choking, hoarseness, regurgitation including rumination, persistent drooling of saliva, inadequate chewing, awareness of aspiration or intrusion, and heartburn.

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

[0067] In the context of the present invention, the term "dysphagia" generally refers to "functional dysphagia", which means that from an etiological point of view, the dysphagia is not explained by a structural, mucosal, or tissue lesion or abnormality such as a head and neck tumor, Zenker's diverticulum, luminal stenosis, surgical resection of the oropharynx / larynx, radiation injury, anterior cervical spine surgery, or extrinsic compression (e.g. goiter, cervical osteophytes, or vascular compression of the esophagus as in the case of Lusorian dysphagia), etc. In particular, the term "dysphagia" in the context of the present invention does not encompass Lusorian dysphagia or aortic dysphagia.

[0068] In the context of the present invention, the term "dysphagia" similarly does not encompass dysphagia caused by diseases that affect connective tissue, such as autoimmune connective tissue diseases, e.g. scleroderma.

[0069] The exact mechanism of functional dysphagia is unclear but may be related to inappropriate sensory and motor disorders in the swallowing apparatus or dysfunction of the central integration center.

[0070] Further, 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 apparatus, including the esophagus and its sphincters (both upper and lower).

[0071] However, in certain embodiments, the subject may show some mild congenital abnormalities in the swallowing apparatus, such as ogee or high palate, or mild facial asymmetry, compared with healthy subjects.Furthermore, the subject's long-term dysphagia may cause changes in one or several parts of the swallowing apparatus.For example, a PWS subject who continues to have difficulty swallowing for a long period of time may develop megaesophagus.

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

[0073] Dysfunction of the ANS can contribute to dysphagia by, for example, impairing oropharyngeal and esophageal motility, synchronization between the swallowing and respiratory cycles, sensory awareness, and integration and control of information in central integration centers.

[0074] In certain embodiments, the subject's swallowing disorder is at least partially due to a disorder caused by ANS dysfunction, preferably selected from the group consisting of oropharyngeal and / or esophageal motility disorders, desynchronization between the respiratory and swallowing cycles, sensory disorders in the swallowing apparatus and central integration centers, and combinations thereof.

[0075] As used herein, "motility disorder" refers to abnormalities in the coordination of contraction / relaxation and muscle activity of the oral cavity, and / or pharynx, and / or esophagus. The term "motility disorder" may include abnormalities in pharyngeal and / or esophageal peristalsis, particularly reduced esophageal peristalsis.

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

[0077] Dysphagia can be diagnosed and investigated by several techniques, including esophageal manometry, videofluoroscopy (VFS) or radiographic contrast x-ray (barium x-ray), fiberoptic endoscopic evaluation of swallowing (FEES), pH monitoring, endoscopic examinations such as pharyngoscopy or esophagoscopy, esophagogastric transit, and imaging studies.

[0078] Of note, videofluoroscopy (VFS) is the gold standard 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 suffering from Prader-Willi syndrome, as illustrated in the Examples.

[0079] Indeed, VFS makes it possible to characterize the main signs of oropharyngeal dysfunction, in particular pharyngeal swallowing delay, aspiration, nasopharyngeal reflux, esophageal motility disorders, and pharyngeal residue.

[0080] To quantify dysphagia in a subject by VFS, for example, the videofluoroscopic scoring chart of swallowing and esophageal transit shown in FIG. 2 may be used.

[0081] In some other or additional embodiments, the dysphagia is characterized by one or more clinical signs such as: - oropharyngeal and / or esophageal motility disorders, especially pharyngeal and / or esophageal stasis - Abnormal closure of the esophageal sphincter, especially the upper esophageal sphincter, - esophageal dilatation, preferably upper esophageal dilatation or megaesophagus - Propulsion disorders, - Desynchronization with the respiratory cycle, - Esophageal and / or nasopharyngeal reflux disease, - Aspiration, including silent aspiration - Intrusion, e.g., food entering the larynx - Prolonged esophagogastric transit, e.g., esophageal transit, and / or - Esophageal or pharyngeal residue.

[0082] Such clinical signs are preferably evidenced 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: - Oropharyngeal and esophageal motility disorders, especially pharyngeal and / or esophageal stasis - Desynchronization with the respiratory cycle, - nasopharyngeal and / or esophageal reflux, - Aspiration, including silent aspiration - Intrusion, e.g., laryngeal intrusion of food, and - Esophageal or pharyngeal residue.

[0084] Such clinical symptoms may be evidenced by VFS.

[0085] In certain embodiments of the invention, the dysphagia may be characterized by motility disorders affecting the oral cavity, and / or the pharynx and / or the esophagus. For example, the dysphagia may be characterized by both oropharyngeal and esophageal motility disorders, such motility disorders being preferably evidenced by VFS and / or manometric testing.

[0086] In another embodiment, dysphagia may be characterized by, for example, slow pharyngeal transit with pharyngeal residue, for example, slow esophageal transit with esophageal residue, esophageal reflux, abnormal upper esophageal sphincter closure, delayed oropharyngeal opening and entrainment, and combinations thereof. Needless to say, administering an oxytocin receptor agonist to said patient allows at least one of the above clinical symptoms to be alleviated or even treated.

[0087] For example, the oxytocin receptor agonist may reduce, prevent or treat a dysphagia symptom selected from the group consisting of aspiration including silent aspiration, oropharyngeal motility disorder, esophageal motility disorder, esophageal stasis, impaired closure of the upper esophageal sphincter, pharyngeal residue, reflux, desynchronization with the respiratory cycle, propulsion disorder, and combinations thereof.

[0088] For example, oxytocin receptor agonists can be used to improve or normalize esophageal motility, oral and pharyngeal propulsion and / or oropharyngeal opening and synchronization in subjects with dysphagia.As shown in case reports, oxytocin receptor agonists can 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 when asymptomatic, dysphagia can lead to serious health problems and complications, particularly due to aspiration, and especially silent aspiration.

[0090] In some embodiments, the subject with dysphagia is experiencing or is at risk of experiencing a dysphagia complication selected from the group consisting of esophageal bolus obstruction, chronic respiratory infections including recurrent pulmonary infections, exacerbations of chronic obstructive pulmonary disease (COPD) and aspiration pneumonia, choking, sudden death, and combinations thereof.

[0091] Dysphagia, especially when associated with silent aspiration, may 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 failure to thrive in children.

[0093] Administration of an oxytocin receptor agonist in a subject can treat or prevent one or several of the complications listed above, particularly respiratory infections, including aspiration pneumonia, and choking.

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

[0095] The autonomic nervous system (ANS), formerly the vegetative nervous system, is a division of the peripheral nervous system that supplies smooth muscles and glands and influences the function of internal organs. The autonomic nervous system is a control system that operates primarily involuntarily, regulating 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) integrative centers, e.g., at the level of the brainstem (including the solitary tract), hypothalamus, and limbic system, and 3) efferent control pathways to muscles or glands.

[0096] The 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 in dynamic balance at rest and in response to stress.

[0097] ANS dysfunction refers to an alteration in the function of the autonomic nervous system that can cause dysregulation of one or several bodily functions. ANS dysfunction can lead to a variety of serious problems manifesting in multiple organ systems, such as tachycardia, sleep disorders, swallowing disorders, hypotension, orthostatic hypotension, and others.

[0098] In certain embodiments, the subject with dysphagia suffers from a disease classified as a disorder of the autonomic nervous system, also known as dysautonomia.

[0099] Dysautonomia refers to disorders that can affect all or part of the ANS. Dysautonomia can cause a variety of problems, such as blood pressure problems, breathing problems, or swallowing problems, and can be inherited, caused by injury, or by conditions such as diabetes, neurodegenerative diseases such as Parkinson's disease, autoimmune diseases, alcoholism, Riley-Day syndrome, etc., also known as familial dysautonomia.

[0100] In a more particular aspect, the subject with dysphagia suffers from an autonomic nervous system disorder, particularly selected from neurodegenerative diseases.

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

[0102] Preferred neurodegenerative diseases include, but are not limited to, amyotrophic lateral sclerosis, muscular dystrophy, multiple sclerosis, Parkinson's disease, Alzheimer's disease, dementia with Lewy bodies, 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 found in conditions that are not, or have not yet been, classified as autonomic disorders.

[0104] Dysregulation of the autonomic nervous system has been demonstrated in a variety of 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, which can be observed not only during the perinatal period but also after.This fact underlies the fact that the genetic network related to the feeding, feeding and swallowing (SFS) mechanism of infants and the transition to feeding and swallowing in children / adults is vulnerable to genetic mutations and environmental damage.Applicants believe that ANS dysregulation or dysfunction may contribute to the dysphagia observed in neurodevelopmental disorders, for example, by impairing the motility of the oropharyngeal and esophageal passage, the synchronization between the swallowing and respiratory cycles, the sensation in the swallowing apparatus or central integration center.

[0106] Thus, in some aspects of the invention, the subject with dysphagia suffers from a neurodevelopmental disorder. Thus, the dysphagia may be a symptom or complication of a neurodevelopmental disorder in the subject.

[0107] As used herein, neurodevelopmental disorders refer to a group of disorders with severely affected behavioral features caused by alterations 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 neurons and the construction of neural networks, both of which are required for i) the perception and integration of sensory information, ii) the construction and coordination of adaptive responses, iii) the control of effectors (i.e., motor and endocrine responses), and iv) the construction and maintenance of functional neuronal networks involved in learning and memory processes. Neurodevelopmental disorders cause brain dysfunction, such as impairments in the sensory or motor systems, speech, language, or more generally oral changes, many cognitive disorders (e.g., in learning, memory, organization, and / or planning abilities), or a combination thereof.

[0108] Without wishing to be bound by any theory, hypothalamic dysfunction may contribute to the subject's dysphagia.

[0109] In some more particular embodiments, the subject suffers from a neurodevelopmental disorder associated with or related to hypothalamic dysfunction.

[0110] Such neurodevelopmental disorders are described below and include, for example, Prader-Willi syndrome and Prader-Willi-like syndromes, and fetal alcohol spectrum disorder (FSAD).

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

[0112] In some embodiments, the subject suffers from a non-genetic neurodevelopmental disorder, i.e., a neurodevelopmental disorder with no identified genetic cause. In such cases, the neurodevelopmental disorder may be caused by environmental abuse, e.g., exposure to alcohol, drugs, pesticides, and other harmful substances in utero. In some other embodiments, the neurodevelopmental disorder is idiopathic or congenital with no clear cause, and is suspected to be caused by a combination of genetic and / or environmental and / or epigenetic factors.

[0113] Non-genetic neurodevelopmental disorders associated with dysphagia 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 genetic neurodevelopmental disorder, i.e., a neurodevelopmental disorder caused by, for example, aneuploidy, disomy, chromosomal deletion, genetic mutations and / or epigenetic changes affecting genomic imprinting.

[0115] Inherited neurodevelopmental disorders with dysphagia patterns include, but are not limited to, Prader-Willi and Prader-Willi-like syndromes, 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, Alström syndrome, syndromic obesity, familial dysautonomia, and Williams syndrome. Dysphagia can also be observed in patients with inherited neurodevelopmental disorders such as Pierre Robin syndrome, optic septal dysplasia (SOD), ROHHAD (rapid-onset obesity, hypothalamic dysfunction, hypoventilation, dysautonomia) syndrome, etc.

[0116] In a preferred embodiment, the subject with dysphagia suffers from Prader-Willi syndrome (PWS) or a PWS-like disorder. Details regarding this subgroup of patients are described in more detail below.

[0117] ·subject The term "subject" or "patient" refers to any mammal, and includes human and veterinary subjects.

[0118] A subject suffering from dysphagia can be of any age and of any gender. The subject is preferably a human.

[0119] For example, the subject may be an infant, a child, a juvenile, an adolescent, or an adult, including an elderly person.

[0120] Of note, feeding in infants is very different from feeding and swallowing in children and adults. This is because the immaturity of the oropharyngeal region, or more precisely, the high position of the larynx and hyoid bone, allows the immature epiglottis to hook behind the soft palate, creating separate pathways for simultaneous nasal breathing and swallowing of liquids. Thus, feeding in infants is a continuous behavior that does not stop for breathing as in adults. Initially, feeding is controlled by brainstem reflexes, which disappear with age. During the first year, the neck grows, the hyoid bone and larynx drop, the epiglottis flattens, and the soft palate matures, facilitating the transition to eating solid foods between 4 and 6 months of age. A complete swallowing mechanism then develops through gradual changes in recruitment of the oropharyngeal muscles and growth of the pharynx (Maynard et al., Annual Review of Neuroscience, 2020, 4:316-36).

[0121] In a preferred embodiment, the subject is in a food diversification transition or is already on a diversified diet, i.e., can eat both solid and liquid foods. More preferably, the subject is not on an exclusively liquid diet.

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

[0123] Thus, the dysphagic subject is preferably at least 6 months of age, such as at least 9 months of age or at least 1 year of age.

[0124] The feeding-swallowing mechanism is an innate, reflex-driven behavior that subsequently becomes voluntary during infancy. The rooting reflex disappears in normal infants at about 7 months of age. After 12 months of age, the feeding / swallowing reflex is completely lost and swallowing becomes a voluntary movement.

[0125] In other words, during the first 12 months of life, children undergo morphological and functional changes that lead to a different swallowing mechanism.

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

[0127] In some embodiments, the subject is under 50 years of age, eg, under 40 years of age, under 30 years of age, or under 20 years of age.

[0128] In certain embodiments, the subject is under 18 years of age, preferably at most 16 years of age.

[0129] Typically, the subject with dysphagia is a child aged between 1 and 16 years, preferably between 2 and 15 years.

[0130] As mentioned above, the subject may suffer from a neurodegenerative or neurodevelopmental disorder, preferably a genetic neurodevelopmental disorder such as PWS or Prader-Willi-like syndrome.

[0131] In some embodiments, the subject suffers from a cognitive 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 subject has not been treated with oxytocin during infancy, particularly within the first six months of life.

[0135] Targeted Oxytocin Receptor Agonists The term "agonist" refers to any compound that interacts with a target to cause or promote increased activation of said target in a selective manner. In the context of the present invention, the target is the "oxytocin receptor", preferably the "human oxytocin receptor".

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

[0137] [ka]

[0138] Alternatively, the oxytocin receptor agonist may be any compound capable of activating the oxytocin receptor, preferably in a selective manner. The compound may be of any type. It preferably has a maximum potency of 3000 g.mol -1 The ligands may be selected from chemical agents such as antibodies and fragments thereof, and nucleic acid ligands such as aptamers.

[0139] As used herein, "aptamer" (also referred to as nucleic acid aptamer) refers to a synthetic single-stranded polynucleotide that typically contains 20-150 nucleotides in length and can bind to a target molecule with high affinity. Aptamers are characterized by a three-dimensional conformation that can play an important role in the interaction with the target molecule.

[0140] The term "antibody" as used herein refers to an immunoglobulin or a fragment or derivative thereof, and includes any polypeptide comprising an antigen-binding domain, whether produced in vitro or in vivo. The term includes, but is not limited to, polyclonal, monoclonal, monospecific, multispecific (e.g., bispecific), humanized, single-chain, chimeric, synthetic, recombinant, hybrid, mutated, 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 assessing whether a given molecule is an agonist of the oxytocin receptor.

[0142] For example, see Manning et al. (J. Neuroendocrinol, 2012, 24(4):609-628), who refer to a binding and functional assay in a cell line expressing the hOT receptor based on the accumulation of cyclic AMP. As another example, agonist activity on the OT receptor can be measured by the method described in WO2009 / 122285. In this method, agonist activity of compounds on 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 regulates the expression of firefly luciferase. Cells are exposed to serial dilutions of compounds diluted 10-fold per dose for 5 hours, after which the cells are lysed, luciferase activity is measured, and compound potency and EC50 values ​​are determined by nonlinear regression. Oxytocin (OT) is used as an internal control for each experiment, and compounds are tested in at least three independent experiments.

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

[0144] In some embodiments, the oxytocin receptor agonist is selective for the oxytocin receptor, more precisely the human OT receptor, meaning that it does not significantly bind to and / or activate other receptors.

[0145] In some other embodiments, the oxytocin receptor agonist may also bind to and even activate other receptors, such as the V1a, V1b and V2 receptors, but preferably with a lower potency than for the oxytocin receptor (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).

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

[0147] In a preferred embodiment, the oxytocin receptor agonist is a synthetic chemical molecule. It is a peptide or a non-peptide molecule, preferably with a maximum of 3000 g.mol -1 or up to 2000 g.mol -1 It 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, in particular an analogue of oxytocin, i.e. a compound with a chemical structure close to that of oxytocin. An analogue of oxytocin may differ from oxytocin by one or several amino acid modifications (e.g. by one, two, three, four or five modifications selected from insertions, deletions or substitutions, including non-natural amino acids) or by one or several chemical modifications.

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

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

[0152] [ka]

[0153] Wherein, in the formula: Each of W and X is independently CH2 and S, with the proviso that W and X are not both CH2; A is an amino acid selected from the group consisting of alanine, the side chain of which is substituted with a 5- or 6-membered heteroaromatic ring; tyrosine; and phenylalanine, the phenyl ring of which is substituted with 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 substituted at the α-carbon with a C4-6 cycloalkyl; C is an amino acid selected from the group consisting of proline, the side chain of which is optionally substituted with hydroxyl, C1-4 alkoxy, halogen or azide, and proline, the side chain of which is optionally interrupted with a heteroatom, the optionally interrupted side chain being optionally substituted with C1-4 alkyl; D is an amino acid selected from the group consisting of leucine; homoleucine; isoleucine; and glycine substituted at the α-carbon with a C4-6 cycloalkyl; 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, where the phenyl ring is substituted with 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 ]OT, lipo-oxytocin-1 (LOT-1), demoxitocin, merotocin (development code name FE-202767), pharma- ceutically acceptable salts thereof, and combinations thereof.

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

[0156] Route of administration, regimen, and formulation The oxytocin receptor agonist may be administered by any conventional route, including, but not limited to, oral, buccal, sublingual, intravenous, intramuscular, intranasal, pulmonary (eg, by inhalation), or subcutaneous routes.

[0157] Indeed, depending on the agonist used, the person skilled in the art will be able to determine the best route to use, especially in terms of its bioavailability and its stability.

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

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

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

[0161] The daily amount of oxytocin receptor agonist administered to a subject will generally be 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, depending on the agonist potency.

[0162] By convention, for purposes of labeling of oxytocin-containing medications, the dosage of oxytocin is expressed in international units, where 1 IU is equivalent to approximately 1,667 μg of oxytocin (which is equivalent to saying that 1 mg of oxytocin is 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 (ie 166.7 μg), preferably between 1 IU (1,667 μg) and 50 IU (83.35 μg).

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

[0165] By way of further example, carbetocin may be administered in a daily dose of up to 30 mg per day, typically between 3 mg and 30 mg per day.

[0166] Oxytocin receptor agonist can be administered once a day, every two days, or several times a day, for example, twice, three or four times a day.OT receptor agonist can be administered with or without food, preferably without food, for example, before a meal.Oxytocin receptor agonist can be administered for a period of one week to several weeks, or one month to several months, typically as long as necessary.

[0167] Oxytocin receptor agonist is typically formulated into pharmaceutical composition to be administered to subject.Oxytocin receptor agonist can be formulated in any suitable pharmaceutical composition according to standard methods such as described in Remington: The Science and Practice of Pharmacy (Lippincott Williams & Wilkins; 21st Edition, 2005).Pharmaceutically acceptable excipients that can be used are particularly described in Handbook of Pharmaceuticals Excipients, American Pharmaceutical Association (Pharmaceutical Press; 6th Revised Edition, 2009).Typically, therapeutic agent is mixed with one or several excipients to obtain desired pharmaceutical form. Examples of suitable excipients include, but are not limited to, solvents such as water or water / ethanol mixtures, fillers, carriers, diluents, binders, anti-caking agents, plasticizers, disintegrants, lubricants, flavors, buffers, stabilizers, colorants, dyes, antioxidants, anti-adherents, softeners, preservatives, surfactants, waxes, emulsifiers, humectants, isotonicity 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, mono- or disaccharides such as lactose, glucose, sucrose, and the like, 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, corn starch; gums, such as tragacanth, acacia, gelatin; hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose; polyvinylpyrrolidone, copovidone, polyethylene glycol, and combinations thereof.Examples of lubricants include, but are not limited to, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, zinc stearate, or fatty acids and their derivatives, such as stearic acid, or polyalkylene glycols, such as PEG. Glidants may be selected from colloidal silica, silicon dioxide, talc, and the like. Examples of disintegrants include, but are not limited to, crospovidone, croscarmellose salts, such as croscarmellose sodium, starch, and their derivatives. Examples of surfactants include, but are not limited to, simethicone, triethanolamine, polysorbates and their derivatives, such as Tween® 20 or Tween® 40, poloxamers, fatty alcohols, such as lauryl alcohol, cetyl alcohol, and the like, phospholipids, alkyl sulfates, such as sodium dodecyl sulfate (SDS), and the like. Examples of stabilizers particularly useful for lyophilization include sugars such as mannitol, sucrose, dextrose, trehalose, and the like, 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 of these substances. Preservatives include, but are not limited to, parabens, chlorobutanol, benzalkonium chloride, benzoic acid, sorbic acid, and salts thereof. Antioxidants include ascorbic acid, ascorbyl palmitate, tocopherol, and combinations thereof.Examples of buffers include phosphate, tris(hydroxymethyl)aminomethane hydrochloride (TRIS.HCl), 4-morpholinepropanesulfonic 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 excipients to be combined with the subject oxytocin receptor agonist may be selected taking into consideration (i) the physicochemical properties, including stability, of the therapeutic agent, (ii) the pharmacokinetic and / or release profile desired for the therapeutic agent, (iii) the dosage form, and (iv) the route of administration.

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

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

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

[0172] For example, a subject pharmaceutical composition for intranasal delivery may be in the form of a liquid composition comprising a subject oxytocin receptor agonist dissolved in a suitable aqueous buffer. Suitable buffers include phosphate, citric acid, acetic acid, acetate, aspartate, and combinations thereof. The liquid composition may contain one or several additional pharmaceutical excipients, such as preservatives, antioxidants, surfactants, solvents, isotonicity agents, pH adjusters (e.g., HCl or NaOH), and wetting agents. The pH of the composition may be adjusted to between pH 4.5 and pH 6.0. Divalent ions, such as Ca2+, Mg2+, Zn2+, and the like, may be added for stabilization or to facilitate absorption in vivo.

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

[0174] The prior art also provides some examples of intranasal compositions that can be used to implement the present invention. For example, reference can be made to WO2012042371, which describes a liquid composition of an oxytocin receptor agonist (e.g., carbetocin) containing phosphate and citric acid as buffering agents and NaCl as isotonic agent in water at pH 5.5. The composition may further contain an antioxidant such as methionine or EDTA. These compositions are described as being suitable for intranasal administration.

[0175] Another example can be found in WO2016112205, which refers to a liquid composition for intranasal administration comprising oxytocin and a magnesium salt. This international application specifically describes a buffered aqueous composition of oxytocin comprising buffering agents such as magnesium salts (e.g. MgCl), acetate and citrate in water at pH 4.5.

[0176] Additional oxytocin formulations are described, for example, in Avanti et al. (AAPS J. 2011 June;13(2):284-90 and Int J Pharm. 2013 Feb. 28;444(1-2):139-45). Avanti et al. describe stable aqueous solutions of oxytocin obtained using citrate or aspartate salts and divalent metal cations such as Ca2+, Mg2+, Zn2+, etc. (Int J Pharm 2013 Feb. 28;444(1-2):139-45).

[0177] The intranasal compositions of the present invention may be administered as a single dose or divided into, for example, 1, 2, 3, 4, 5 or 6 sub-doses (eg, puffs) delivered to one or both nostrils.

[0178] The intranasal composition of oxytocin receptor agonist may 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. The device for intranasal delivery is preferably designed to deliver multiple doses of the oxytocin receptor agonist composition. For example, the 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 designated volume that 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 include a filter to prevent backflow 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 that includes a microbial filter and an automatic shut-off mechanism in the pump actuator, such as described in US Pat. No. 5,988,449.

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

[0181] Prader-Willi syndrome (PWS) is a complex genetic neurodevelopmental disorder resulting from the absence of expression of paternally inherited imprinted genes on chromosome 15q11-q13, resulting in hypothalamic dysfunction. Estimated incidence ranges from 1 in 15,000 to 1 in 27,000 live births. The absence of gene expression can be due to chromosomal deletions, maternal disomy, or imprinting defects.

[0182] Clinical features of PWS include severe neonatal hypotonia with feeding problems accounting for frequent failure to thrive (FTT) during the neonatal and infancy period (0 to 9 months), global developmental delay with hypogonadism / hypogonadism (2 to 6 years), onset of hyperphagia that can lead to morbid obesity if not managed (6 to 12 years) followed by a persistent preoccupation with food that borders on addiction and lack of satiety, hypothalamic and pituitary insufficiency (short stature associated with growth hormone deficiency, hypogonadism, hypothyroidism, and rarely central adrenal insufficiency), behavioral problems including learning disabilities, cognitive deficits, and deficits in social skills, as well as a psychiatric phenotype from age 13 to adulthood (Gunay-Aygun et al., Pediatrics. 2001;108(5):E92).

[0183] PWS has classically been described as having two distinct nutritional stages. In stage 1, subjects exhibit poor feeding and severe hypotonia, often accompanied by failure to thrive (FTT). Stage 2, which begins at approximately 2-4 years of age, is then characterized by rapid weight gain, onset and escalation of hyperphagia, which leads to the development of obesity, developmental delay, and behavioral disorders. The transition from poor feeding / FTT to obesity / hyperphagia is not fully understood and occurs as a result of a complex evolution involving several nutritional stages, as shown by Miller et al. (Am J Med Genet A. 2011 May;155A(5):1040-1049). Miller et al. state: - In phase 1, infants are hypotonic but not obese, and subphase 1a is characterized by feeding difficulties with or without FTT (median age at completion: 9 months). This stage is followed by subphase 1b (median age at onset: 9 months) in which infants grow steadily along the growth curve and gain weight at a normal rate. - Phase 2 is associated with weight gain; in sub-phase 2a, weight gain occurs without significant changes in appetite or caloric intake (median age at onset 2.0 years), whereas in sub-phase 2b, weight gain is associated with a concomitant increased interest in food (median age at onset: 4.5 years); - Phase 3 is characterized by binge eating, typically accompanied by food seeking and lack of satiety (median age at onset: 8 years). - In Phase 4, individuals previously in Phase 3 lose their insatiable appetite and are able to feel full.

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

[0185] Prader-Willi-like disorders include Scharf-Yang syndrome (pathogenic mutations in the MAGEL2 gene) and microdeletions in the SNORD116 gene cluster. Deletions or mutations in the following genes have also been implicated: SNURF-SNRPN, MKRN3, NDN and several snoRNAs, NPAP1, and C15orf2.

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

[0187] In some embodiments, an oxytocin receptor agonist, preferably oxytocin or carbetocin, is used to reduce, prevent, or treat dysphagia symptoms in a subject with PWS or a PWS-like disorder, said symptoms being selected from the group consisting of aspiration including silent aspiration, intrusion, oropharyngeal motility disorders, esophageal motility disorders, pharyngeal residue, reflux, desynchronization with the respiratory cycle, propulsion disorders, and combinations thereof.

[0188] In a preferred embodiment, an oxytocin receptor agonist, preferably oxytocin or carbetocin, is used to treat oropharyngeal motility disorders, and / or esophageal motility disorders, and / or respiratory swallowing desynchronization and / or propulsion disorders in subjects with PWS with 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, choking, and combinations thereof in a subject with PWS or a PWS-like disorder.

[0190] In a preferred embodiment, the subject to be treated is not a newborn or infant who is fed only liquid nutrition. Preferably, the subject is in the food diversification transition or is already under a diversified diet, i.e., can eat both solid and liquid foods.

[0191] In certain embodiments, the subject with PWS or PWS-like syndrome is at least 6 months of age, preferably at least 9 months of age, and most preferably at least 12 months of age. Further, the subject with PWS or PWS-like syndrome may be up to 20 years of age, preferably at least 15 years of age.

[0192] In some embodiments, the subject has not been treated with oxytocin within the first 6 months of life.

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

[0194] In another embodiment, the subject with PWS or a PWS-like syndrome also suffers from binge eating disorder.

[0195] As mentioned above, preferred OT receptor agonists are oxytocin, carbetocin, and pharma- ceutically acceptable versions thereof. More preferably, the OT receptor agonist is oxytocin or a pharmaceutical salt thereof.

[0196] The oxytocin receptor agonist is preferably administered once a day or several times a day (for example, twice or three times a day) by intranasal route.Preferably, the OT receptor agonist is administered once a day.The daily pharmaceutical dose of the OT receptor agonist is up to 100IU, preferably 2IU to 50IU.

[0197] A suitable daily dose of oxytocin for a subject 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 a day, for example in the morning, preferably before a meal.

[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, may be administered, typically in the form of a buffered aqueous composition, ie, in the form of a nasal spray.

[0200] Further aspects and advantages of the present invention are disclosed in the following experimental section, which should be considered as illustrative and not limiting the scope of the present application. EXAMPLES

[0201] Example 1 Case report Patient 1 was a 6-year-old boy with Prader-Willi syndrome due to maternal uniparental disomy diagnosed shortly after birth.

[0202] He presented with clinical symptoms of dysphagia with great difficulty swallowing water but not solid foods, acid reflux, and dental problems possibly related to acid reflux episodes.A videofluoroscopic swallowing study (VFSS) was abnormal, showing prolonged esophageal transit time and decreased peristalsis, and abnormal closure of the upper esophageal sphincter.

[0203] He received 8 IU of intranasal OXT daily for 3 weeks.

[0204] Treatment with oxytocin was well tolerated and was associated with improvement 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 presented with hypothalamic involvement. He presented with clinical symptoms of dysphagia and frequent episodes of rumination and halitosis.

[0206] The VFSS was abnormal, including slow pharyngeal transit with pharyngeal residue, and slow esophageal transit with esophageal reflux and stasis.

[0207] He received 16 IU of intranasal OXT daily for 3 weeks. This treatment was well tolerated and resulted in clinical improvement of dysphagia with normalization of oropharyngeal opening and synchrony and esophageal transit. After treatment, VFSS showed no stasis or reflux.

[0208] Example 2 Effect of intranasal oxytocin on dysphagia associated with oropharyngeal esophageal motility disorders in children and adolescents with Prader-Willi syndrome: A phase 3 trial (DYSMOT) The aim of this study was to investigate the effect of intranasal OT treatment on 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] - Study Design This prospective, multicenter, randomized, double-blind, phase 3 clinical trial is planned to include approximately 36 PWS patients aged 2 to 18 years from five centers in France. The study will include three parts:

[0216] The first part is a placebo-controlled, double-blind period to evaluate the effect of 12 weeks of intranasal OT treatment versus placebo on OPOD-associated dysphagia, as 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 three treatment groups in a 1:1:1 ratio. Randomization will be stratified by age group (2 to <8 years, 8 to 15 years, and >15 years).

[0217] In the second part, a separate double-blind period, group 1 (patients treated with OT in the first part) will receive placebo for 12 weeks to assess changes after treatment cessation, while group 2 (patients treated with placebo in the first part) will receive OT and group 3 (patients treated with OT in the first part) will continue OT treatment to assess maintenance of efficacy.

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

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

[0220] A telephone conference will be scheduled between one of the researchers and the parents of PWS patients in the above age range. The researcher will answer any questions regarding the objectives, limitations, and foreseeable risks. After some consideration, the parents who accept that their child will participate in the study will contact the researcher to coordinate inclusion in the study.

[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 performed along with other study procedures, and patients are randomly assigned to one of the three treatment arms before the first dose of study treatment.

[0222] If the VFSS was performed according to routine considerations and met quality and acquisition requirements within 4 weeks prior to inclusion in the study, the VFSS may be used as the baseline and will not be performed in V1.

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

[0224] All parameters will be tracked over time and compared between the first and second treatment periods within each group to assess the effects of OT vs. placebo, the effect of discontinuation of treatment, and maintenance of efficacy.

[0225] The long-term safety profile of intranasal OT will be evaluated during an open-label period, as will its long-term efficacy.

[0226] - Study intervention The investigational medicinal product (IMP) for this study is intranasal OT. As this is a double-blind study, a matching intranasal placebo solution will also be provided. To maintain the blinding of the study, both the IMP and its matching placebo will be provided in identical packaging.

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

[0228] [Table 2]

[0229] Study treatments will be administered daily via the intranasal route for 12 weeks in parts 1 and 2 (OT or placebo) and for 24 weeks in the open-label period (OT only) (Figure 1).

[0230] In V1, the study treatment will be administered by the parent / caregiver or patient under the supervision of a medical team member. A staff member will also instruct the parent / caregiver and / or patient on how and when to administer the medication, including how to fill the treatment pump and how to handle late or missed doses. Instructions on how to position the device for administration will be detailed in a specific study diary to be completed by the parent / caregiver.

[0231] A diary should be completed daily to track treatment compliance and dosing times in Parts 1 and 2. In the open-label portion, only treatment problems such as late doses, missed doses, or overdoses should be recorded each time a new OT vial is opened / used (every 28 days). The diary will include reminders with instructions for use and instructions on how to handle late, missed, or overdosed doses.

[0232] The last dose of each period of study treatment should be administered the day before the visit. In V2, V3, and V4, parents should return the study treatment bottles provided in the previous period of the study as they will need to be collected and managed by site staff. In V1, V2, and V3, parents will be provided with study treatment for the next part of the study, and the first dose will be administered in the hospital at the visit.

[0233] Dosage is adjusted according to age, following the guidelines provided in Table 3 below.

[0234] [Table 3]

Claims

1. A composition for use in the treatment or prevention of swallowing disorders in a subject who is at least 1 year old and suffers from a neurodevelopmental disorder, the composition comprising an oxytocin receptor agonist.

2. The composition of claim 1, wherein the swallowing disorder is characterized by esophageal motility disorder.

3. The composition of claim 1 or 2, wherein the subject is suffering from hypothalamic dysfunction.

4. The composition of any one of claims 1 to 3, wherein the subject suffers from a genetic neurodevelopmental disorder.

5. The composition of claim 4, wherein the genetic 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, syndromic obesity, familial dysautonomia, and Williams syndrome.

6. 3. The composition of claim 1 or 2, wherein the subject suffers from a neurodevelopmental disorder selected from the group consisting of autism spectrum disorder, cerebral palsy, fetal alcohol spectrum disorder, and intellectual disability.

7. 7. The composition of any one of claims 1 to 6, wherein the subject is an infant, a child or a teenager.

8. Clinical signs of dysphagia include: - Esophageal congestion, - Esophageal residue, - Abnormal closure of the esophageal sphincter, - Esophageal dilation, - Invasion, including asymptomatic inhalation - Prolonged or slow esophageal transit, - Decreased peristalsis, and - Esophageal reflux 8. The composition of claim 1, wherein the clinical signs are assessable by videofluoroscopy.

9. The subject is diagnosed with a condition characterized by the following: slow esophageal transit, poor esophageal clearance, esophageal reflux, reduced peristalsis, and combinations thereof. The composition according to any one of claims 1 to 8, which exhibits esophageal motility disorders characterized by one or several of the following:

10. A composition described in any one of claims 1 to 9, wherein the oxytocin receptor agonist is used to improve or normalize esophageal motility in a subject.

11. Subjects with the following disorders: esophageal bolus obstruction, pulmonary aspiration, recurrent pulmonary infections, aspiration pneumonia, choking, regurgitation, nasal reflux, and rumination. The composition of any one of claims 1 to 10, wherein the patient has experienced, is experiencing, or is at risk of experiencing, one or more of:

12. The oxytocin receptor agonist is selected from the group consisting of oxytocin, carbetocin, [Thr 4 ]OT, HO[Thr 4 ]OT, [Thr 4 , Gly 7 ]OT, HO[Thr 4 , Gly 7 ]OT, lipo-oxytocin-1 (LOT-1), demoxytocin, merotocin, demoxytocin, lipo-oxytocin-1 (LOT-1), TC OT 39, WAY-267464, and LIT-001.

13. The composition of any one of claims 1 to 12, wherein the oxytocin receptor agonist is oxytocin or a pharma- ceutically acceptable salt thereof.

14. 14. The composition of claim 13, wherein the neurodevelopmental disorder is Prader-Willi syndrome or a Prader-Willi-like disorder.

15. 15. The composition of claim 13 or 14, wherein the subject suffers from asymptomatic dysphagia.

16. The composition of any one of claims 13 to 15, wherein the oxytocin receptor agonist is administered by an intranasal route.

17. The composition of claim 16, wherein the oxytocin receptor agonist is administered in a daily dosage of 2 IU to 48 IU.

Images