Ensifentrine for use in the treatment of allergic diseases

Abstract

The present invention relates to a compound for use in a method of hastening recovery from a disease or condition in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the disease or condition is an allergic disease or condition. The present invention also relates to a compound for use in a method of increasing tolerance to an allergen in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof. The present invention further relates to a compound for use in a method of treating or preventing a disease or condition in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the disease or condition is an allergic disease or condition caused by a parasitic allergen.

Description

[0001] TREATMENT

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to the use of ensifentrine in hastening the recovery from a disease or condition in a patient and the use of ensifentrine in a method of increasing tolerance to an allergen in a patient.

[0004] BACKGROUND OF THE INVENTION

[0005] Ensifentrine (N-(2-{(2E)-9,10-dimethoxy-4-oxo-2-[(2,4,6-trimethylphenyl)imino]- 6,7-dihydro-2H-pyrimido[6,1 -a]isoquinolin-3(4H)-yl}ethyl)urea; also known as RPL554) is a dual PDE3 / PDE4 inhibitor and is described in WO 00 / 58308 A1.

[0006] As a combined PDE3 / PDE4 inhibitor, ensifentrine has both bronchodilatory and anti-inflammatory activity and is useful in the treatment of respiratory disorders. The chemical structure of ensifentrine is shown below.

[0007] Many allergic diseases or conditions are treated with antihistamines, decongestants, corticosteroids and leukotriene inhibitors. These drugs can cause adverse side effects in the patient such as drowsiness, increased blood pressure, nosebleeds, septal perforation, thrush, immunosuppression and psychological interference (e.g. anxiety). Franciosi et al, Clinical and Translational Allergy 2013, 3(Suppl 1 ):O13 discusses the administration of ensifentrine to human patients suffering with allergic asthma, resulting in an increase in FEVi (forced expiratory volume in 1 second). Zuiker (Development and use of biomarkers in clinical development of new therapies for chronic airway disease, Universiteit Leiden, 2016) describes an experiment in which ensifentrine suppressed eosinophil and neutrophil migration into the nasal cavity in human patients suffering with allergic rhinitis.

[0008] Neither Franciosi et al nor Zuiker concerns the effects of ensifentrine on hastening recovery from an allergic disease or increasing tolerance of a patient to an allergen.

[0009] There is a need to develop alternative methods of treating allergic diseases or conditions in patients and for increasing patient tolerance to allergens.

[0010] SUMMARY OF THE INVENTION

[0011] It is a surprising finding of the present invention that ensifentrine may be used in a method of hastening recovery from an allergic disease or condition in a patient. It is a further surprising finding that ensifentrine may be used in a method of increasing tolerance to an allergen in a patient.

[0012] The invention accordingly provides a compound for use in a method of hastening recovery from a disease or condition in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the disease or condition is an allergic disease or condition.

[0013] The invention provides a compound for use in a method of hastening recovery from a disease or condition in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein: the disease or condition is an allergic disease or condition; and hastening recovery from the disease or condition comprises: one or more of: (i) increasing the peak expiratory flow of the patient; (ii) increasing the tidal volume of the patient; (iii) decreasing the breathing rate of the patient; and (iv) reducing inflammation in the patient; and / or one or more of: (v) decreasing the total nasal symptom score by at least 1 relative to the total nasal symptom score of the patient when first administered the compound; and (vi) decreasing the total ocular symptom score by at least 1 relative to the total ocular symptom score of the patient when first administered the compound.

[0014] The invention also provides a compound for use in a method of increasing tolerance to an allergen in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof.

[0015] The invention also provides a compound for use in a method of increasing tolerance to an allergen in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein increasing tolerance to the allergen comprises increasing the threshold exposure to the allergen tolerated by the patient, wherein: the threshold exposure to the allergen tolerated by the patient is the exposure to the allergen below which the patient does not experience one or more of: (i) a decrease in peak expiratory flow of the patient; (ii) a decrease of the tidal volume of the patient; (iii) an increase in the breathing rate of the patient; and (iv) an increase in inflammation in the patient; and / or the threshold exposure to the allergen tolerated by the patient is the exposure to the allergen below which the patient does not experience one or more of: (i) an increase in the total nasal symptom score by at least 1 ; and (ii) an increase in the total ocular symptom score by at least 1 .

[0016] The invention also provides a compound for use in a method of treating or preventing a disease or condition in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the disease or condition is an allergic disease or condition caused by a parasitic allergen.

[0017] Further provided by the invention is a method of hastening recovery from a disease or condition in a patient, the method comprising administering a therapeutically effective amount of a compound to the patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the disease or condition is an allergic disease or condition.

[0018] Further provided by the invention is a method of hastening recovery from a disease or condition in a patient, the method comprising administering a therapeutically effective amount of a compound to the patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the disease or condition is an allergic disease or condition; and hastening recovery from the disease or condition comprises: one or more of: (i) increasing the peak expiratory flow of the patient; (ii) increasing the tidal volume of the patient; (iii) decreasing the breathing rate of the patient; and (iv) reducing inflammation in the patient; and / or one or more of: (v) decreasing the total nasal symptom score by at least 1 relative to the total nasal symptom score of the patient when first administered the compound; and (vi) decreasing the total ocular symptom score by at least 1 relative to the total ocular symptom score of the patient when first administered the compound.

[0019] Further provided by the invention is the use of a compound in the manufacture of a medicament for use in a method of hastening recovery from a disease or condition in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the disease or condition is an allergic disease or condition. Further provided by the invention is the use of a compound in the manufacture of a medicament for use in a method of hastening recovery from a disease or condition in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the disease or condition is an allergic disease or condition; and hastening recovery from the disease or condition comprises: one or more of: (i) increasing the peak expiratory flow of the patient; (ii) increasing the tidal volume of the patient; (iii) decreasing the breathing rate of the patient; and (iv) reducing inflammation in the patient; and / or one or more of: (v) decreasing the total nasal symptom score by at least 1 relative to the total nasal symptom score of the patient when first administered the compound; and (vi) decreasing the total ocular symptom score by at least 1 relative to the total ocular symptom score of the patient when first administered the compound.

[0020] Further provided by the invention is a method of increasing tolerance to an allergen in a patient, the method comprising administering a therapeutically effective amount of a compound to the patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof.

[0021] Further provided by the invention is a method of increasing tolerance to an allergen in a patient, the method comprising administering a therapeutically effective amount of a compound to the patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein increasing tolerance to the allergen comprises increasing the threshold exposure to the allergen tolerated by the patient, wherein: the threshold exposure to the allergen tolerated by the patient is the exposure to the allergen below which the patient does not experience one or more of: (i) a decrease in peak expiratory flow of the patient; (ii) a decrease of the tidal volume of the patient; (iii) an increase in the breathing rate of the patient; and (iv) an increase in inflammation in the patient; and / or the threshold exposure to the allergen tolerated by the patient is the exposure to the allergen below which the patient does not experience one or more of: (i) an increase in the total nasal symptom score by at least 1 ; and (ii) an increase in the total ocular symptom score by at least 1 .

[0022] Further provided by the invention is the use of a compound in the manufacture of a medicament for use in a method of increasing tolerance to an allergen in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof.

[0023] Further provided by the invention is the use of a compound in the manufacture of a medicament for use in a method of increasing tolerance to an allergen in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein increasing tolerance to the allergen comprises increasing the threshold exposure to the allergen tolerated by the patient, wherein: the threshold exposure to the allergen tolerated by the patient is the exposure to the allergen below which the patient does not experience one or more of: (i) a decrease in peak expiratory flow of the patient; (ii) a decrease of the tidal volume of the patient; (iii) an increase in the breathing rate of the patient; and (iv) an increase in inflammation in the patient; and / or the threshold exposure to the allergen tolerated by the patient is the exposure to the allergen below which the patient does not experience one or more of: (i) an increase in the total nasal symptom score by at least 1 ; and (ii) an increase in the total ocular symptom score by at least 1 .

[0024] Further provided by the invention is a method of treating or preventing a disease or condition in a patient, the method comprising administering a therapeutically effective amount of a compound to the patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the disease or condition is an allergic disease or condition caused by a parasitic allergen.

[0025] Further provided by the invention is the use of a compound in the manufacture of a medicament for use in a method of treating or preventing a disease or condition in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the disease or condition is an allergic disease or condition caused by a parasitic allergen.

[0026] DETAILED DESCRIPTION OF THE INVENTION

[0027] The compound may hasten recovery from a disease or condition in a patient, wherein the disease or condition is an allergic disease or condition. As used herein, the term “hastening” refers to facilitating, speeding-up, accelerating or quickening. Typically, hastening recovery comprises accelerating recovery, for instance the amount of time in which the patient has symptoms may be reduced.

[0028] Typically, hastening recovery from the disease or condition comprises one or more of: (i) increasing the peak expiratory flow of the patient; (ii) increasing the tidal volume of the patient; (iii) decreasing the breathing rate (e.g. breaths per minute) of the patient; and (iv) reducing inflammation in the patient. The peak expiratory flow is the maximum speed of expiration (L / min), for instance as measured with a peak flow meter. The tidal volume is the volume of air that moves in (or out) of the lungs with each respiratory cycle, for instance as measured with a respirometer. A change in inflammation in the patient may be determined by comparing the eosinophil and / or neutrophil count in the mucosa (e.g. lungs or nose) to the baseline count.

[0029] Typically, if the allergic disease or condition is an allergic disease or condition affecting the lungs (such as allergic asthma), hastening recovery from the disease or condition comprises one or more of: (i) increasing the peak expiratory flow of the patient; (ii) increasing the tidal volume of the patient; (iii) decreasing the breathing rate of the patient; and (iv) reducing inflammation in the patient (e.g. inflammation of the lungs). Typically, if the allergic disease or condition is an allergic disease or condition affecting the nose (such as a nasal allergy or allergic rhinitis), hastening recovery from the disease or condition comprises reducing inflammation in the patient (e.g. inflammation of the nose).

[0030] Preferably, hastening recovery from the disease or condition comprises one or more of: (i) increasing the peak expiratory flow of the patient by at least 10 % relative to the peak expiratory flow of the patient when first administered the compound, optionally wherein the increase is achieved within 24 hours; (ii) increasing the tidal volume of the patient by at least 10 % relative to the tidal volume of the patient when first administered the compound, optionally wherein the increase is achieved within 24 hours; and (iii) decreasing the breathing rate of the patient by at least 10 % relative to the breathing rate of the patient when first administered the compound, optionally wherein the decrease is achieved within 24 hours.

[0031] The peak expiratory flow of the patient may be increased by at least 20 %, or by at least 30 %, relative to the peak expiratory flow of the patient when first administered the compound, optionally wherein the increase is achieved within 24 hours. The tidal volume of the patient may be increased by at least 20 %, or by at least 50 %, relative to the tidal volume of the patient when first administered the compound, optionally wherein the increase is achieved within 24 hours. The breathing rate of the patient may be decreased by at least 20 %, or by at least 50 %, relative to the breathing rate of the patient when first administered the compound, optionally wherein the decrease is achieved within 24 hours. Respectively, the increase in peak expiratory flow and / or tidal volume and / or the decrease in breathing rate may be achieved within 12 hours, within 6 hours, within 3 hours or within 1 hour of administering the compound. Alternatively, hastening recovery from the disease or condition comprises decreasing the total symptom score (nasal and / or ocular) of the patient. The total symptom score (TSS) is the sum of the ranked-severity of individual symptoms experienced by a patient. For each symptom, the severity is ranked on a scale of 0 to 3 (according to Ellis et al. Allergy Asthma Clin Immunol. 2015 11 (1 ) 16) as follows: (none) 0 = no symptoms evident; (mild) 1 = symptom present but easily tolerated; (moderate) 2 = definite awareness of symptom, bothersome but tolerable; and (severe) 3 = symptom hard to tolerate, interferes with daily activity. The total symptom score therefore acts as a measure of the overall severity of symptoms experienced by a patient. A low TSS means the patient is experiencing few and / or mild symptoms. A high TSS means the patient is experiencing many and / or severe symptoms. Total nasal symptom score (TNSS) is the sum of the ranking of the four nasal symptoms: sneezing, congestion, itching, and rhinorrhoea. Total ocular symptom score (TOSS) is the sum of the ranking of the three ocular symptoms: itching / burning, tearing / watering, and redness. Preferably, the compound decreases TNSS.

[0032] The compound may decrease the TNSS by at least 1 (to a non-negative value) within 48 hours of administering the compound to the patient. For example, if the TNSS score was 12 at the time the compound was administered, the TNSS would be at most 11 after a further 48 hours. Typically, the decrease in TNSS occurs within 24 hours of administering the compound to the patient. The compound may decrease the TNSS by at least 2 (to a non-negative value) within two weeks of administering the compound to the patient. The compound may decrease the TNSS by at least 2 (to a non-negative value) within one week of administering the compound to the patient. The compound may decrease the TNSS by at least 2, by at least 3, by at least 4, by at least 5 or by at least 6 within 4 weeks of administering the compound to the patient. The compound may decrease the TOSS by at least 1 (to a non-negative value) within 48 hours of administering the compound to the patient. For example, if the TOSS score was 9 at the time the compound was administered, the TOSS would be at most 8 after a further 48 hours. Typically, the decrease in TOSS occurs within 24 hours of administering the compound to the patient. The compound may decrease the TOSS by at least 2 (to a non-negative value) within two weeks of administering the compound to the patient. The compound may decrease the TOSS by at least 2 (to a non-negative value) within one week of administering the compound to the patient. The compound may decrease the TOSS by at least 2, by at least 3, by at least 4, by at least 5 or by at least 6 within 4 weeks of administering the compound to the patient.

[0033] The compound may decrease one or more of TNSS or TOSS. For instance, the compound may hasten recovery from the disease or condition by one or more of: (i) decreasing the total nasal symptom score by at least 1 relative to the total nasal symptom score of the patient when first administered the compound, optionally wherein the decrease is achieved within 48 hours; and (ii) decreasing the total ocular symptom score by at least 1 relative to the total ocular symptom score of the patient when first administered the compound, optionally wherein the decrease is achieved within 48 hours.

[0034] The compound may increase the tolerance to an allergen in a patient. As used herein, the term “tolerance" refers to a state of unresponsiveness of a patient’s immune system to an allergen that would otherwise trigger an immune response in the patient. For instance, a high tolerance to an allergen causes little to no response from the patient’s immune system when the patient is exposed to said allergen. A low tolerance to an allergen causes a significant immune response from the patient’s immune system when the patient is exposed to said allergen (e.g. an increase in the TNSS or TOSS of the patient). The patient may be sensitised to the allergen. As used herein, the term “sensitised” refers to the precondition that a patient exposed to an allergen, in the absence of any anti-allergy drug, will experience an immune response as a result of said exposure. The patient may be sensitised to the allergen due to genetic factors (i.e. inherited genes or by mutation in DNA) or may be caused by environmental exposure to the allergen (i.e. isolated one-time exposure or repeated exposure).

[0035] Typically, increasing tolerance to the allergen comprises increasing the threshold exposure to the allergen tolerated by the patient, optionally wherein the threshold exposure to the allergen tolerated by the patient is the exposure to the allergen below which the patient does not experience one or more of: (i) a decrease in peak expiratory flow; (ii) a decrease of the tidal volume; (iii) an increase in the breathing rate; and (iv) an increase in inflammation.

[0036] Typically, if the allergen causes an allergic disease or condition affecting the lungs in the patient (such as allergic asthma), the threshold exposure to the allergen tolerated by the patient is the exposure to the allergen below which the patient does not experience one or more of: (i) a decrease in peak expiratory flow; (ii) a decrease of the tidal volume; (iii) an increase in the breathing rate; and (iv) an increase in inflammation (e.g. inflammation of the lungs).

[0037] Typically, if the allergen causes an allergic disease or condition affecting the nose in the patient, the threshold exposure to the allergen tolerated by the patient is the exposure to the allergen below which the patient does not experience an increase in inflammation in the patient (e.g. inflammation of the nose).

[0038] The threshold exposure to the allergen tolerated by the patient may be the exposure to the allergen below which the patient does not experience a decrease in the peak expiratory flow by 10 % or greater, by 20 % or greater, or by 30 % or greater. The threshold exposure to the allergen tolerated by the patient may be the exposure to the allergen below which the patient does not experience a decrease in the tidal volume by 10 % or greater, by 20 % or greater, or by 50 % or greater. The threshold exposure to the allergen tolerated by the patient may be the exposure to the allergen below which the patient does not experience an increase in the breathing rate by 10 % or greater, by 20 % or greater, or by 50 % or greater. Typically, any changes are measured within a period of 24 hours, 12 hours, 6 hours, 3 hours or 1 hour.

[0039] For instance, the compound may increase tolerance to an allergen in a patient by increasing the threshold exposure to the allergen tolerated by the patient, wherein the threshold exposure is the exposure to the allergen below which the patient does not experience one or more of: (i) a decrease in peak expiratory flow by 10%, optionally within 24 hours; (ii) a decrease of the tidal volume by 10%, optionally within 24 hours; and (iii) an increase in the breathing rate by 10%, optionally within 24 hours.

[0040] Alternatively, increasing tolerance to the allergen may comprise increasing the threshold exposure to the allergen tolerated by the patient below which the patient does not experience an increase in the total symptom score (nasal and / or ocular). The threshold exposure to the allergen tolerated by the patient may be the exposure to the allergen below which the patient does not experience an increase in the TNSS by at least 1 , by at least 2, by at least 3, by at least 4, by at least 5 or by at least 6. The threshold exposure to the allergen tolerated by the patient may be the exposure to the allergen below which the patient does not experience an increase in the TOSS by at least 1 , by at least 2, by at least 3, by at least 4, or by at least 5. Typically, any changes are measured within a period of two weeks, one week, 48 hours and most preferably 24 hours. For instance, the compound may increase tolerance to an allergen in a patient by increasing the threshold exposure to the allergen tolerated by the patient, wherein the threshold exposure is the exposure to the allergen below which the patient does not experience one or more of: (i) an increase in the total nasal symptom score by at least 1 , optionally within 48 hours; and (ii) an increase in the total ocular symptom score by at least 1 , optionally within 48 hours.

[0041] The compound may increase the tolerance to an allergen in the patient, wherein the allergen comprises one or more of a food allergen, an animal allergen, a pharmaceutical allergen, an environmental allergen (including seasonal allergens), a contact allergen and a parasitic allergen. The compound may therefore increase the tolerance to an allergen in the patient, wherein the allergen is a seasonal allergen. Food allergens may include an allergen selected from egg, milk, wheat, nut and seafood. Animal allergens may include an allergen selected from cat dander or hair, dog dander or hair, bee or wasp sting venom, and dust mite excretion. Environmental allergens may include an allergen selected from dust, grass pollen and tree pollen (e.g. seasonal allergens). Parasitic allergens include an allergen selected from a nematode and nematode eggs.

[0042] The compound may increase the tolerance to an allergen in a patient, wherein the patient is suffering from an allergic disease or condition.

[0043] According to the methods of the invention, the allergic disease or condition may be an inflammatory disease or condition or a respiratory disease or condition. Typically, the allergic disease or condition is selected from an allergy, allergic asthma, allergic rhinitis (e.g. seasonal allergic rhinitis and perennial allergic rhinitis), allergic sinusitis, hay fever, bronchitis, atopic dermatitis, allergic conjunctivitis, eczema, urticaria and angioedema. For instance, the allergic disease or condition may be selected from an allergy, allergic asthma, allergic rhinitis, allergic sinusitis and hay fever. The allergic disease or condition may therefore be selected from allergic asthma and allergic rhinitis.

[0044] In some instances, the allergic disease or condition is not associated with cystic fibrosis (CF) in the patient. In some instances, the allergic disease or condition is not allergic rhinosinusitis or allergic chronic rhinosinusitis (CRS). In some instances, the allergic disease or condition is neither associated with CF- rhinosinusitis nor non-CF rhinosinusitis. In some instances, the allergic disease or condition is not allergic sinusitis.

[0045] The allergic disease or condition is typically an allergic condition affecting the nose. For instance, the disease or condition may be selected from allergic rhinitis (e.g. seasonal allergic rhinitis and perennial allergic rhinitis), allergic sinusitis, or a nasal allergy.

[0046] Alternatively, the allergic disease or condition is an allergy. Typically, the allergy is to an allergen comprising one or more of a food allergen, an animal allergen, a pharmaceutical allergen, an environmental allergen (including seasonal allergens), a contact allergen and a parasitic allergen. Food allergens may include an allergen selected from egg, milk, wheat, nut and seafood. Animal allergens may include an allergen selected from cat dander or hair, dog dander or hair, bee or wasp sting venom, and dust mite excretion. Environmental allergens may include an allergen selected from dust, grass pollen and tree pollen (e.g. seasonal allergens). Parasitic allergens include an allergen selected from a nematode and nematode eggs.

[0047] According to the methods of the invention, the allergen may therefore comprise one or more of: a food allergen selected from egg, milk, wheat, nut and seafood; an animal allergen selected from cat dander or hair, dog dander or hair, bee or wasp sting venom, and dust mite excretion; an environmental allergen selected from dust, grass pollen and tree pollen; and a parasitic allergen selected from a nematode and nematode eggs.

[0048] The allergy may be a nasal allergy and the allergen may be a nasal allergen. Typically, nasal allergens may be selected from pollen, dust, house dust, animal dander (e.g. dog dander, cat dander, mouse dander, rat dander, pig dander, hamster dander, horse dander, guinea pig dander, rabbit dander, ferret dander), mould spores, fungus spores, bacteria, cigarette smoke and food particles.

[0049] For instance, the invention provides a compound for use in a method of treating or preventing a disease or condition in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the disease or condition is an allergic disease or condition caused by a parasitic allergen. Typically, the parasitic allergen is selected from helminths (e.g. Ascaris lumbricoides, Strongyloides stercoralis, Trichuris trichi ura, Necator americanus and Ancylostoma duodenalis), helminth eggs, nematodes (e.g. Wuchereria bancrofti, Brugia malayi, Onchocerca volvulus, Ascaris suum), nematode eggs, flukes (Schistosoma haematobium, S. mansoni, S. japonicum) and fluke eggs. For example, the parasitic allergen may be selected from a nematode and nematode eggs. Preferably, the nematode is Ascaris suum (A. suum).

[0050] The compound may inhibit eosinophil migration into the lungs of the patient. Typically, the compound may inhibit eosinophil migration into the lungs of the patient by at least 10 %. For example, an inhibition of eosinophil migration into the lungs by 10 % causes the eosinophil count of the bronchoalveolar lavage (BAL) to be 10 % lower than the eosinophil count if the patient had not been administered the compound. Preferably, the compound may inhibit eosinophil migration into the lungs of the patient by at least 20 %, by at least 30 %, by at least 40 % or by at least 50 %. The eosinophil count may be as determined by (i) centrifuging 100 pL of BAL for 5 minutes using a cytospin at 1500RPM; (ii) preparing the acquired pellet on a glass slide; (iii) staining the slide with Wright stain solution for 5 minutes; (iv) counting the eosinophils under a microscope at 40x power; (v) extrapolating the count on the slide to calculate a total eosinophil count for the lungs. The skilled person would be able to identify and count eosinophils on the stained slide.

[0051] The patient may be susceptible to inflammation of the lungs (e.g. pneumonitis). A patient susceptible to inflammation of the lungs may be suffering from chronic or recurrent chest infections, a lung injury (including following surgery), a weakened or compromised immune system, an autoimmune disease or a chronic cough. Alternatively, a patient susceptible to lung inflammation may be exposed (e.g. through working or living conditions) to a high quantity of irritants e.g. mold spores, grain / hay particles, wood dust, dust, silica gel, excrement particles and feather particles.

[0052] Alternatively, the compound may also inhibit eosinophil migration into the nasal cavity of the patient. Typically, the compound may inhibit eosinophil migration into the nasal cavity of the patient by at least 10 %. For example, an inhibition of eosinophil migration into the nasal cavity by 10 % causes the eosinophil count of the nasal lavage to be 10 % lower than the eosinophil count if the patient had not been administered the compound. Preferably, the compound may inhibit eosinophil migration into the lungs of the patient by at least 20 %, by at least 30 %, by at least 40 % or by at least 50 %. For instance, if the patient is suffering from nasal allergies, the compound may be administered to hasten recovery from the nasal allergies.

[0053] In some instances, the patient does not have cystic fibrosis. In some instances, the patient is not diagnosed with cystic fibrosis. In some instances, the patient is not suffering from undiagnosed cystic fibrosis. In some instances, the patient does not have an underlying condition selected from one or more of cystic fibrosis, chronic obstructive pulmonary disease and bronchiectasis.

[0054] The compound is ensifentrine or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts are well known to the skilled person. Typically, the compound is ensifentrine (i.e. ensifentrine free base).

[0055] The compound is administered before, during or after exposure of the patient to an allergen. Preferably the compound is administered before or after exposure of the patient to an allergen, most preferably before exposure of the patient to an allergen.

[0056] The compound may be administered to the patient orally or nasally. Typically, the method comprises administering the compound to the patient by oral inhalation, nasal inhalation, nasal insufflation or nasal instillation. As used herein, the term “inhalation" refers to the act of introducing an aerosolised substance into the respiratory system via the mouth (oral) or nose (nasal) of the patient by breathing, such as by nebuliser or dry powder inhaler. As used herein, the term “nasal insufflation" refers to the act of introducing a powder or liquid into the nasal cavity of the patient, such as by snorting, by nasal spray or by nasal pump. As used herein, the term “nasal instillation" refers to the act of introducing a liquid into nasal cavity of the patient, such as by nasal drops.

[0057] Typically, the compound is administered by inhalation, optionally by inhalation from a nebuliser, pressurised metered dose inhaler or a dry powder inhaler, preferably by nebuliser.

[0058] Preferably, the compound may be administered nasally to the patient, for instance by nasal inhalation or nasal insufflation (e.g. using a nasal pump). When the condition or disease is an allergic disease or condition affecting the nose, it is preferable that the compound is nasally administered.

[0059] Nebulisers aerosolise a liquid pharmaceutical composition into an aerosol that is inhaled into a patient's respiratory tract through the nose or mouth. Examples of nebulisers include a soft mist nebuliser, a vibrating mesh nebuliser, a jet nebuliser and an ultrasonic wave nebuliser. Suitable nebuliser devices include the Philips I- nebTM (Philips), the Philips SideStream (Philips), the AeroNeb® (Philips), the Philips InnoSpire Go (Philips), the Pari LC Sprint (Pari GmbH), the AERxRTM Pulmonary Delivery System (Aradigm Corp) and the Pari LC Plus Reusable Nebuliser (Pari GmbH). The nebulizer may for instance be a PARI LC Sprint jet nebulizer with a PARI Vios® PRO Aerosol Delivery System PARI BOY® compressor. The compound may be inhaled via the nebuliser for from 1 to 15 minutes.

[0060] Nasal sprays aerosolise a liquid solution, liquid suspension or dry powder pharmaceutical composition such that the composition is deposited in the nasal cavity of the patient. Examples of spray devices include squeezed bottle spray devices, metered dose spray devices, airless spray devices and pressurised nasal spray devices.

[0061] A nasal pump is a device that will deliver a liquid solution or dry powder into the nasal cavity of a patient when a pumping action is operated on the device, Typically, the nasal pump is a nasal spray pump. A nasal spray pump delivers a liquid formulation. Typically, the nasal spray pump is a fixed metered dose nasal spray pump. A fixed metered dose nasal spray pump delivers a measured dose of a liquid formulation into the nose of a patient when a pump action is operated on the device. The compound may be used in any suitable therapeutically effective amount. Typically, the total daily dose of the compound is from 0.05 mg to 10 mg. Typically, the method comprises administering a total daily dose of 0.1 mg to 10 mg. Preferably, the total daily dose of the compound (e.g. ensifentrine free base) is from 0.2 to 6 mg, more preferably from 0.5 to 2.5 mg, for instance from about 1 to about 2 mg per day. As used herein, the term “about” may represent a variation of ± 10% of the stated value. The total daily dose of the compound may be from 1 .0 to 2.0 mg, for instance 1.0 mg. The method may comprise administering a total daily dose of the compound of from 0.1 mg to 10 mg or from 0.5 mg to 2.5 mg.

[0062] The compound may be used for a maintenance therapy, optionally wherein the method comprises administering the compound at least once per day for at least 12 weeks. The compound may be administered to the patient at least once per day for at least 16 weeks, preferably for at least 24 weeks. The compound may be administered daily to the patient for at least 1 year. The method may comprise administering the compound to the patient at least once every 24 hours, preferably at least twice every 24 hours, for at least 12 weeks, preferably for at least 16 weeks, more preferably for at least 24 weeks.

[0063] The compound may be used for acute treatment, optionally wherein the method comprises administering the compound to the patient for a period of no more than 12 weeks, for instance no more than 4 weeks. The compound may be administered to the patient at least once per day for no more than 4 weeks, preferably no more than 2 weeks, more preferably no more than 1 week, most preferably no more than 3 days. For instance, the compound may be administered at least once per day, optionally for from 3 days to 4 weeks, preferably from 3 days to 2 weeks. The compound may be administered to the patent once or twice per day for a period of no more than 2 weeks. The compound may be used for acute treatment, wherein the acute treatment is seasonal (e.g. for treating seasonal allergies). The compound may be administered for no more than 12 weeks in a treatment for seasonal allergies. Seasonal allergies may include an allergic reaction in the patient to one or more allergen selected from dust, grass pollen and tree pollen (e.g. hay fever).

[0064] Typically, the compound is administered to the patient at least once per day. The method may comprise administering the compound to the patient once, twice or three times a day, preferably once or twice per day. The compound may therefore be administered once per day. Typically, if administered more than once per day, the compound is administered at regular intervals. For instance, if the compound is administered twice per day, this may be once in the morning and once in the evening. If the compound is administered three times per day, the compound may be administered once in the morning, once in the afternoon and once in the evening. The compound may be administered twice or three times per day.

[0065] Typically, the compound is administered in the form of a liquid pharmaceutical composition comprising the compound. Typically, the liquid pharmaceutical composition is a suspension of particles comprising the compound in a diluent. The compound may alternatively be delivered as a dry powder, for instance a dry powder comprising particles comprising the compound and particles of a carrier such as lactose.

[0066] The particles of the compound may be particles of ensifentrine (i.e. ensifentrine free base). The ensifentrine may be in the form of ensifentrine crystalline Form I as described in WO 2012 / 020016 A1 . For instance, the pharmaceutical composition may comprise ensifentrine having a powder X-ray diffraction pattern comprising characteristic peaks, in terms of 29, at about 10.1 ° and about 12.9° (as measured using Cu Ka radiation). The powder X-ray diffraction pattern may further comprise characteristic peaks, in terms of 2 6 at about 15.3° and about 17.6°. The powder X-ray diffraction pattern comprises at least 5 characteristic peaks, in terms of 26, selected from about 6.4°, about 10.1 °, about 12.6°, about 12.9°, about 13.6°, about 14.2°, about 14.7°. about 15.3°, about 15.4°, about 15.8°, about 17.0°, about 17.6°, about 18.9°, about 20.9°, about 22.4 °, about 22.8° and about 28.7°.

[0067] The method typically comprises administering a liquid pharmaceutical composition comprising a suspension of particles of the compound in a diluent. The liquid pharmaceutical composition is typically suitable for administration by inhalation, suitable for inhalation by nasal inhalation, or suitable for administration by insufflation.

[0068] The particles comprising the compound may have a particle size distribution with a Dv50 of from 0.5 pm to 5.0 pm. The particles typically have a Dv50 of from 1.0 pm to 2.0 pm.

[0069] Particle sizes are typically described herein by reference to the Dv50 value, which is the median particle size for a volume distribution. Thus, half the volume of the particles have diameters of less than the Dv50 value and half the volume of the particles have diameters of greater than the Dv50 value. This is a well-known manner in which to describe particle size distributions.

[0070] The technique used to measure the Dv50 values as stated herein is typically laser diffraction. For instance, the particle size distribution can be measured by laser diffraction using a Malvern Mastersizer 3000. Typically, the instrument parameters for the Malvern Mastersizer 3000 are as follows:

[0071] • Non-spherical particle mode: Yes

[0072] • Refractive index: 1 .500

[0073] • Absorption index: 0.500

[0074] • Particle density: 1 .00 g / cm3

[0075] • Dispersant name: 0.02% Polysorbate 20 in water • Refractive index: 1 .330

[0076] • Stirrer; 1000 rpm

[0077] • Sample measurement: 10 s

[0078] • Obscuration: 10-20 %

[0079] The particles comprising the compound typically comprise ensifentrine (i.e. ensifentrine free base). The particles may comprise at least 90 wt% ensifentrine free base relative to the total weight of the particles. The particles may comprise at least 99 wt% ensifentrine. The particles may consist of ensifentrine.

[0080] The concentration of particles comprising the compound in the liquid pharmaceutical composition is typically from 0.1 to 5.0 mg / mL, for instance from 0.1 to 2.5 mg / mL or from 1.0 to 2.0 mg / mL.

[0081] The liquid pharmaceutical composition typically further comprises one or more buffers and / or one or more surfactants.

[0082] Examples of buffers include a citrate buffer, a phosphate buffer, an acetate buffer, and a bicarbonate buffer. Preferably, the buffer is a phosphate buffer, for instance sodium dihydrogen phosphate dihydrate and / or disodium phosphate dihydrate.

[0083] Examples of surfactants include lecithin, oleic acid, polyoxyethylene glycol alkyl ethers (for instance PEG 300, PEG 600, PEG 1000, Brij 30, Brij 35, Brij 56, Brij 76 and Brij 97), polypropylene glycol (for instance PPG 2000), glucoside alkyl ethers, polyoxyethylene glycol octylphenol ethers, polyoxyethylene glycol alkylphenol ethers, glycerol alkyl esters, polyoxyethylene glycol sorbitan alkyl esters (polysorbates, for instance polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80), sorbitan alkyl esters (for instance sorbitan monolaurate (Span 20), sorbitan monooleate (Span 80) and sorbitan trioleate (Span 85)), cocam ide MEA, cocam ide DEA, dodecyldimethylamine oxide, block copolymers of polyethylene glycol and polypropylene glycol (poloxamers), block copolymers of polyethylene glycol and polypropylene oxide (for instance Pluronic surfactants), polyvinyl pyrrolidone K25, polyvinyl alcohol, oligolactic acid, sodium dioctyl sulfosuccinate and polyethoxylated tallow amine (POEA).

[0084] Preferably, the one or more surfactants comprise a polysorbate and / or a sorbitan alkyl ester. The one or more surfactants may for instance comprise polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate) or polysorbate 80 (polyoxyethylene (20) sorbitan monooleate). The one or more surfactants may for instance comprise sorbitan monolaurate (Span 20), sorbitan monooleate (Span 80) or sorbitan trioleate (Span 85). Preferably, the liquid vehicle comprises polysorbate 20 and / or sorbitan monolaurate (Span 20).

[0085] For instance, the method may comprise administering to the patient a liquid pharmaceutical composition comprising:

[0086] • a liquid vehicle, such as water;

[0087] • particles consisting of ensifentrine free base at a concentration of from 0.1 to 20 mg / mL;

[0088] • one or more buffers at a total concentration of from 0.1 to 4 mg / mL; and

[0089] • one or more surfactants at a total concentration of from 0.05 to 3 mg / mL.

[0090] The liquid pharmaceutical composition may comprise:

[0091] • water;

[0092] • particles consisting of ensifentrine free base at a concentration of from 0.5 to 6 mg / mL;

[0093] • sodium dihydrogen phosphate dihydrate at a concentration of from 0.3 to 2 mg / mL;

[0094] • disodium phosphate dihydrate at a concentration of from 0.3 to 2 mg / mL; • polysorbate 20 at a concentration of from 0.1 to 1 .5 mg / mL; and

[0095] • sorbitan monolaurate at a concentration of from 0.01 to 0.5 mg / mL.

[0096] For instance, the method may comprise administering to the patient a liquid pharmaceutical composition comprising:

[0097] (i) particles of the compound at a concentration of from 0.1 to 3.0 mg / mL;

[0098] (ii) one or more surfactants at a total concentration of from 0.1 to 1.0 mg / mL;

[0099] (iii) one or more buffers at a total concentration of from 1.0 to 2.0 mg / mL; and

[0100] (iv) water, optionally wherein the liquid pharmaceutical composition further comprises one or more buffers and / or one or more surfactants.

[0101] The liquid pharmaceutical composition may be administered nasally to the patient, for instance by nasal inhalation or nasal insufflation (e.g. using a nasal pump).

[0102] The compound may be used in combination with a second active agent. The compound may be administered simultaneously, sequentially or separately in combination with a second active agent. The patient may already be taking the second active agent as a background therapy for the disease or condition. Alternatively, treatment with the second active agent may start at around the same time as treatment with the compound. The compound and the second active agent may be administered in a fixed combination.

[0103] The second active agent is typically selected from an antihistamine, a nonsteroidal anti-inflammatory drug, a corticosteroid, a muscarinic receptor antagonist, an adrenomimetic and a leukotriene receptor antagonist. For instance, the compound may be administered simultaneously, sequentially or separately in combination with a second active agent, wherein the second active agent is selected from an antihistamine, a non-steroidal anti-inflammatory drug, a corticosteroid, a muscarinic receptor antagonist, an adrenomimetic and a leukotriene receptor antagonist.

[0104] In some instances, the compound is not administered in combination with a further phosphodiesterase inhibitor, such as a PDE3, PDE4 or PDE3 / 4 inhibitor. As such, the compound may be the only phosphodiesterase inhibitor administered to the subject.

[0105] In some instances, the compound is not administered in combination with a drug for treating cystic fibrosis. For instance, the compound may not be administered in combination with a CFTR modulator or a CFTR activator.

[0106] The antihistamine may be selected from brompheniramine, cetirizine, chlorpheniramine, clemastine, diphenhydramine, fexofenadine and loratadine, and pharmaceutically acceptable salts thereof. The non-steroidal anti-inflammatory drug may be selected from ibuprofen, diclofenac, celecoxib, mefenamic acid, etoricoxib, indomethacin and aspirin, and pharmaceutically acceptable salts thereof. The corticosteroid may be selected from betamethasone, dexamethasone, mometasone, beclomethasone, prednisolone, budesonide, hydrocortisone, triamcinolone acetonide, clobetasol propionate, cortisone, cortisone acetate, desoximetasone, fluticasone, methylprednisolone, amcinonide, celestone, ciclesonide, clocortolone, cortobenzolone, desonide and prednazate, and pharmaceutically acceptable salts thereof. The adrenomimetic may be oxymetazoline or a pharmaceutically acceptable salt thereof. The leukotriene receptor antagonist may be selected from montelukast, zafirlukast and zileuton, and pharmaceutically acceptable salts thereof. The muscarinic receptor antagonist may be a long-acting muscarinic receptor antagonist selected from aclidinium, darotropium, tiotropium, glycopyrrolate and umeclidinium, and pharmaceutically acceptable salts thereof. Preferably, the second active agent is selected from an antihistamine, a non-steroidal anti-inflammatory drug and a corticosteroid.

[0107] The compound may alternatively be used as a monotherapy (e.g. the compound may be the sole active pharmaceutical ingredient).

[0108] The invention is described in more detail by the following Examples, which are not intended to limit the scope of the claims. All documents referred to herein are incorporated by reference in their entirety.

[0109] The following are additional aspects of the invention:

[0110] 1 . A compound for use in a method of hastening recovery from a disease or condition in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the disease or condition is an allergic disease or condition.

[0111] 2. A compound for use according to aspect 1 , wherein hastening recovery from the disease or condition comprises one or more of: (i) increasing the peak expiratory flow of the patient; (ii) increasing the tidal volume of the patient; (iii) decreasing the breathing rate of the patient; and (iv) reducing inflammation in the patient.

[0112] 3. A compound for use according to aspect 2, wherein hastening recovery from the disease or condition comprises one or more of:

[0113] (i) increasing the peak expiratory flow of the patient by at least 10 % relative to the peak expiratory flow of the patient when first administered the compound, optionally wherein the increase is achieved within 24 hours; (ii) increasing the tidal volume of the patient by at least 10 % relative to the tidal volume of the patient when first administered the compound, optionally wherein the increase is achieved within 24 hours; and

[0114] (iii) decreasing the breathing rate of the patient by at least 10 % relative to the breathing rate of the patient when first administered the compound, optionally wherein the decrease is achieved within 24 hours.

[0115] 4. A compound for use according to aspect 1 , wherein hastening recovery from the disease or condition comprises one or more of:

[0116] (i) decreasing the total nasal symptom score by at least 1 relative to the total nasal symptom score of the patient when first administered the compound, optionally wherein the decrease is achieved within 48 hours; and

[0117] (ii) decreasing the total ocular symptom score by at least 1 relative to the total ocular symptom score of the patient when first administered the compound, optionally wherein the decrease is achieved within 48 hours.

[0118] 5. A compound for use in a method of increasing tolerance to an allergen in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof.

[0119] 6. A compound for use according to aspect 5, wherein the patient is sensitised to the allergen.

[0120] 7. A compound for use according to aspect 5 or aspect 6, wherein increasing tolerance to the allergen comprises increasing the threshold exposure to the allergen tolerated by the patient, optionally wherein: the threshold exposure to the allergen tolerated by the patient is the exposure to the allergen below which the patient does not experience one or more of: (i) a decrease in peak expiratory flow of the patient; (ii) a decrease of the tidal volume of the patient; (iii) an increase in the breathing rate of the patient; and (iv) an increase in inflammation in the patient; and / or the threshold exposure to the allergen tolerated by the patient is the exposure to the allergen below which the patient does not experience one or more of: (i) an increase in the total nasal symptom score by at least 1 ; and (ii) an increase in the total ocular symptom score by at least 1.

[0121] 8. A compound for use according to any one of aspects 5 to 7, wherein the allergen comprises one or more of a food allergen, an animal allergen, a pharmaceutical allergen, an environmental allergen, a contact allergen and a parasitic allergen.

[0122] 9. A compound for use according to any one of aspects 5 to 8, wherein the patient is suffering from an allergic disease or condition.

[0123] 10. A compound for use according to any one of aspects 1 to 4 and 9, wherein the allergic disease or condition is an inflammatory disease or condition or a respiratory disease or condition.

[0124] 11. A compound for use according to any one of aspects 1 to 4, 9 and 10, wherein the allergic disease or condition is selected from an allergy, allergic asthma, allergic rhinitis, allergic sinusitis, hay fever, bronchitis, atopic dermatitis, allergic conjunctivitis, eczema, urticaria and angioedema.

[0125] 12. A compound for use according to aspect 11 , wherein the allergic disease or condition is allergic asthma or allergic rhinitis.

[0126] 13. A compound for use according to aspect 11 , wherein the allergic disease or condition is an allergy, optionally wherein the allergy is to an allergen comprising one or more of a food allergen, an animal allergen, a pharmaceutical allergen, an environmental allergen, a contact allergen and a parasitic allergen.

[0127] 14. A compound for use according to aspect 8 or aspect 13, wherein allergen comprises one or more of: a food allergen selected from egg, milk, wheat, nut and seafood; an animal allergen selected from cat dander or hair, dog dander or hair, bee or wasp sting venom, and dust mite excretion; an environmental allergen selected from dust, grass pollen and tree pollen; and a parasitic allergen selected from a nematode and nematode eggs.

[0128] 15. A compound for use in a method of treating or preventing a disease or condition in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the disease or condition is an allergic disease or condition caused by a parasitic allergen.

[0129] 16. A compound for use according to aspect 15, wherein the parasitic allergen comprises one or more of a nematode and nematode eggs.

[0130] 17. A compound for use according to any one of the preceding aspects, wherein the allergic disease or condition affects the nose of the patient.

[0131] 18. A compound for use according to any one of the preceding aspects, wherein the method inhibits eosinophil migration into the lungs.

[0132] 19. A compound for use according to any one of the preceding aspects, wherein the patient is susceptible to inflammation of the lungs. 20. A compound for use according to any one of the preceding aspects, wherein the total nasal symptom score (TNSS) of the patient is decreased by the compound, optionally wherein the TNSS is decreased by at least 1 or by at least 2.

[0133] 21 . A compound for use according to any one of the preceding aspects, wherein the compound reduces one or more of sneezing, nasal congestion, nasal itching, and rhinorrhoea in the patient.

[0134] 22. A compound for use according any one of the preceding aspects, wherein the compound is administered before, during or after exposure of the patient to an allergen, preferably wherein the compound is administered before exposure of the patient to an allergen.

[0135] 23. A compound for use according to any one of the preceding aspects, wherein the method comprises administering a total daily dose of the compound of from 0.05 mg to 10 mg or the method comprises administering a dose of the compound of from 0.5 mg to 2.5 mg.

[0136] 24. A compound for use according to any one of the preceding aspects, wherein: the compound is used as a maintenance therapy, optionally wherein the method comprises administering the compound to the patient at least once per day for a period of at least 12 weeks; or the compound is used as an acute treatment, optionally wherein the method comprises administering the compound to the patient for a period of no more than 12 weeks. 25. A compound for use according to any one of the preceding aspects, wherein the compound is administered by inhalation, optionally wherein the compound is administered by inhalation from a nebuliser, pressurised metered dose inhaler or a dry powder inhaler.

[0137] 26. A compound for use according to any one of the preceding aspects, wherein the compound is administered in the form of a liquid pharmaceutical composition comprising the compound, preferably wherein the liquid pharmaceutical composition comprises a suspension of particles comprising the compound in a diluent.

[0138] 27. A compound for use according to aspect 26, wherein the liquid pharmaceutical composition comprises:

[0139] (i) particles of the compound at a concentration of from 0.1 to 3.0 mg / mL;

[0140] (ii) one or more surfactants at a total concentration of from 0.1 to 1.0 mg / mL;

[0141] (iii) one or more buffers at a total concentration of from 1.0 to 2.0 mg / mL; and

[0142] (iv) water, optionally wherein the liquid pharmaceutical composition further comprises one or more buffers and / or one or more surfactants.

[0143] 28. A compound for use according to any one of the preceding aspects, wherein the compound is administered simultaneously, sequentially or separately in combination with a second active agent, wherein the second active agent is selected from an antihistamine, a non-steroidal anti-inflammatory drug a corticosteroid, a muscarinic receptor antagonist, an adrenomimetic or a leukotriene receptor antagonist.

[0144] 29. A method of hastening recovery from a disease or condition in a patient, the method comprising administering a therapeutically effective amount of the compound to the patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the disease or condition is an allergic disease or condition. 30. Use of compound in the manufacture of a medicament for use in a method of hastening recovery from a disease or condition in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the disease or condition is an allergic disease or condition. 31 . A method of increasing tolerance to an allergen in a patient, the method comprising administering a therapeutically effective amount of the compound to the patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof.

[0145] EXAMPLES

[0146] Example 1 - Effect of ensifentrine on methacholine and A. suum induced bronchoconstriction in primates

[0147] A study was conducted to investigate the effect of ensifentrine on methacholine and Ascaris Suum (A. suum) induced bronchoconstriction in primates.

[0148] Materials

[0149] The primates were monkeys of the species Macaca fascicularis (3 to 5 kg). Each monkey demonstrated positive skin tests for A. suum and broncho-responsiveness for both inhaled A. suum and methacholine

[0150] Study design

[0151] Before the experiment, each monkey was anesthetised and secured with an endotracheal tube. Peak expiratory flow, tidal volume and breathing rate, dynamic compliance and resistance, maximum esophageal pressure, and oxygen saturation were recorded.

[0152] At the start of the experiment, the monkeys were administered escalating doses of either:

[0153] (1 ) methacholine (0.1 to 100 mg / mL, nebulised, 5 breaths, via endotracheal tube) at 5-m inute intervals; or

[0154] (2) A. suum (5.46 to 18,200 PNU / mL, nebulised, 1 minute of breathing, via endotracheal tube) at 10-minute intervals. Dose escalation continued until reaching a threshold dose of methacholine or A. suum that caused one or a combination of:

[0155] (a) a 50 % reduction in tidal volume (TV);

[0156] (b) a 50 % increase in breathing rate (breaths per minute, BPM); and at least

[0157] (c) a 100% increase in esophageal pressure (Max Press).

[0158] After the initial dose escalation, the monkeys were allowed to recover to reestablish stable values for airway and hemodynamic variables.

[0159] Following recovery, the monkeys were administered ensifentrine (0.3 mg / mL, nebulised) for 10 minutes. Each animal was then subjected to a challenge of the individualized methacholine or A. suum threshold dose. Each animal therefore served as its own control. Peak expiratory flow, tidal volume and breathing rate, dynamic compliance and resistance, maximum esophageal pressure, and oxygen saturation were recorded.

[0160] In some instances, the monkeys were further administered escalating doses of methacholine or A. suum greater than the threshold dose to determine the new threshold post-administration of ensifentrine.

[0161] This experiment provides a model of the effect of ensifentrine in treating allergic reactions and allergen-induced bronchoconstriction.

[0162] Resu / ts

[0163] Ensifentrine reduced the effects of methacholine and A. suum on peak expiratory flow, tidal volume and breathing rate, dynamic compliance and resistance, maximum esophageal pressure, and oxygen saturation. In the animals subjected to escalating doses of methacholine post-administration of ensifentrine, the threshold dose increased by an average of 1 .13 ± 0.31 log units. In the animals subjected to escalating doses of A. suum post-administration of ensifentrine, the threshold dose increased by an average of 1 .30 ± 0.4 log units. In the animals subjected to A. suum challenge, it was observed that the recovery from flow and volume changes induced by A. suum challenge occurred more rapidly post-administration of ensifentrine. The esophageal pressure responses elicited by A. suum in the absence of ensifentrine were virtually eliminated by ensifentrine. Similar results were observed following methacholine challenge.

[0164] Conclusion

[0165] Ensifentrine has been shown to be effective at treating allergen-induced bronchoconstriction. Ensifentrine was also found to improve resistance to allergens, with higher threshold doses for both methacholine and A. suum following ensifentrine treatment. It was further observed that ensifentrine hastened the recovery of primates from allergen-induced bronchoconstriction.

[0166] Example 2 - The effect of ensifentrine on inflammatory cell infiltration into the lungs

[0167] A study was conducted to investigate the effect of ensifentrine on total cell and eosinophil infiltration into the lungs and blood in monkeys exposed to A. summ, compared to control.

[0168] Materials

[0169] The primates were monkeys of the species Macaca fascicularis (2.8 to 5 kg). Each monkey demonstrated positive skin tests and broncho-responsiveness for A. suum.

[0170] Study design

[0171] Before the experiment, the monkeys were anesthetized (20 mg / kg ketamine i.m., 4.0 mg / kg propofol i.v., 0.2 to 0.4 mg / kg / min propofol i.v.) and instrumented (tracheal tube, esophageal balloon catheter, lead II ECG, i.v. catheter). The monkeys could spontaneously breathe.

[0172] At the start of the experiment (t = 0 min), each monkey was administered saline via nebuliser for 1 minute. At 6 minutes (t = 6 min), each monkey was then administered either (i) saline (nebulised, 10 minutes) or (ii) ensifentrine (0.3 mg / mL, 10 minutes). The monkeys were allowed to rest for 20 minutes while being monitored. Starting at 36 minutes (t = 36 min), each monkey was administered escalating concentrations of A. suum (0.5 to 50,000 PNU / mL, 3 to 10-fold escalations, 1 minute, nebulised, via endotracheal tube) at 5-minute intervals. Dose escalation continued until reaching a threshold concentration of A. suum (PC100) where there was: (1 ) a 100% increase in lung resistance (RL); and

[0173] (2) one or a combination of:

[0174] (a) a 50% reduction in dynamic compliance (Cdyn);

[0175] (b) a 50% increase in breathing rate (breaths per minute); and

[0176] (c) a 50% reduction in tidal volume (TV).

[0177] Following administration of the A. suum threshold concentration (PC100), each monkey was allowed 20 to 30 minutes to recover to normal airway and hemodynamic variables.

[0178] At 6 hours after administration of the A. summ threshold concentration (PC100), bronchoalveolar lavage (BAL) and blood was collected from each monkey. A differential cell count was performed on the BAL and blood.

[0179] This experiment provides a model of the effect of ensifentrine in treating allergen- induced asthma.

[0180] Results

[0181] The ensifentrine-treated monkeys exhibited numerically lower eosinophils than saline-treated animals in both blood (saline = 0.192 106 / mL; ensifentrine = 0.037 106 / mL) and BAL fluid (saline = 4.790 104 / mL; ensifentrine = 3.063 104 / mL).

[0182] Conclusion

[0183] Ensifentrine has been found to be effective at reducing inflammation in allergen- induced asthma. Example 3 - Effect of ensifentrine on inflammatory cell migration into human nasal mucosa following nasal allergen challenge (Reference Example)

[0184] A phase Ila clinical trial was conducted to investigate the effect of nasally inhaled ensifentrine on inflammatory cell migration into the nasal mucosa of patients with allergic rhinitis.

[0185] Materials

[0186] The nasal brush was a Buccal Swab Brush, BlOzym TC. The nasal allergen challenge for each patient was determined in advance by a standardised skin prick test (SPT) consisting of 10 common airborne allergens.

[0187] Study design

[0188] Prior to the experiment, one nostril from each patient was subjected to nasal brushing (NAB). The brush was deposited in a plastic tube containing 2 mL roomtemperature phosphate-buffered saline. The cell suspension was centrifuged, cytospun and stained to produce a baseline differential count (eosinophil and neutrophil).

[0189] At the start of the experiment, each patient was subjected to a nasal allergen challenge (0.125 mL allergen solution, delivered by nasal spray) in the same nostril. Nasal brushing was then performed, as described above, at 7 hours and 24 hours into the experiment to determine the nasal inflammatory cell count. Each patient was then given a three-week wash-out period to recover before continuing.

[0190] Subsequently, each patient was administered a 0.018 mg / Kg dose of ensifentrine (nebulised, nasal inhalation through a facemask covering the mouth and nose, breathing only through the nose) 40 minutes prior to receiving the same nasal allergen challenge as above in the same nostril. Nasal brushing was performed at 7 hours and 24 hours into the experiment to determine nasal inflammatory cell count. The percentage change from baseline eosinophil and neutrophil cell count was calculated for each nasal brush sample.

[0191] Results Ensifentrine (0.018 mg / kg) inhibited inflammatory cell (combined eosinophil and neutrophil) migration into the nasal cavity at 7 and 24 hours after allergen challenge compared to no ensifentrine. Inhibition of inflammatory cell migration was greatest at 7 hours. Conclusion

[0192] Ensifentrine suppresses an immune response to an allergen in a patient. Ensifentrine increases the tolerance to an allergen in a patient.

Claims

CLAIMS1 . A compound for use in a method of hastening recovery from a disease or condition in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein: the disease or condition is an allergic disease or condition; and hastening recovery from the disease or condition comprises: one or more of:(i) increasing the peak expiratory flow of the patient;(ii) increasing the tidal volume of the patient;(iii) decreasing the breathing rate of the patient; and(iv) reducing inflammation in the patient; and / or one or more of:(v) decreasing the total nasal symptom score by at least 1 relative to the total nasal symptom score of the patient when first administered the compound; and(vi) decreasing the total ocular symptom score by at least 1 relative to the total ocular symptom score of the patient when first administered the compound.

2. A compound for use according to claim 1 , wherein hastening recovery from the disease or condition comprises one or more of:(i) increasing the peak expiratory flow of the patient by at least 10 % relative to the peak expiratory flow of the patient when first administered the compound, optionally wherein the increase is achieved within 24 hours;(ii) increasing the tidal volume of the patient by at least 10 % relative to the tidal volume of the patient when first administered the compound, optionally wherein the increase is achieved within 24 hours; and(iii) decreasing the breathing rate of the patient by at least 10 % relative to the breathing rate of the patient when first administered the compound, optionally wherein the decrease is achieved within 24 hours.

3. A compound for use according to claim 1 , wherein:(v) decreasing the total nasal symptom score by at least 1 relative to the total nasal symptom score of the patient when first administered the compound is achieved within 48 hours; and(vi) decreasing the total ocular symptom score by at least 1 relative to the total ocular symptom score of the patient when first administered the compound is achieved within 48 hours.

4. A compound for use in a method of increasing tolerance to an allergen in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein increasing tolerance to the allergen comprises increasing the threshold exposure to the allergen tolerated by the patient, wherein: the threshold exposure to the allergen tolerated by the patient is the exposure to the allergen below which the patient does not experience one or more of: (i) a decrease in peak expiratory flow of the patient; (ii) a decrease of the tidal volume of the patient; (iii) an increase in the breathing rate of the patient; and (iv) an increase in inflammation in the patient; and / or the threshold exposure to the allergen tolerated by the patient is the exposure to the allergen below which the patient does not experience one or more of: (i) an increase in the total nasal symptom score by at least 1 ; and (ii) an increase in the total ocular symptom score by at least 1.

5. A compound for use according to claim 4, wherein the patient is sensitised to the allergen.

6. A compound for use according to claim 4 or claim 5, wherein the allergen comprises one or more of a food allergen, an animal allergen, a pharmaceutical allergen, an environmental allergen, a contact allergen and a parasitic allergen.

7. A compound for use according to any one of claims 4 to 6, wherein the patient is suffering from an allergic disease or condition.

8. A compound for use according to any one of claims 1 to 3 and 7, wherein the allergic disease or condition is an inflammatory disease or condition or a respiratory disease or condition.

9. A compound for use according to any one of claims 1 to 3, 7 and 8, wherein the allergic disease or condition is selected from an allergy, allergic asthma, allergic rhinitis, allergic sinusitis, hay fever, bronchitis, atopic dermatitis, allergic conjunctivitis, eczema, urticaria and angioedema.

10. A compound for use according to claim 9, wherein the allergic disease or condition is allergic asthma or allergic rhinitis.

11. A compound for use according to claim 9, wherein the allergic disease or condition is an allergy, optionally wherein the allergy is to an allergen comprising one or more of a food allergen, an animal allergen, a pharmaceutical allergen, an environmental allergen, a contact allergen and a parasitic allergen.

12. A compound for use according to claim 6 or claim 11 , wherein allergen comprises one or more of: a food allergen selected from egg, milk, wheat, nut and seafood;an animal allergen selected from cat dander or hair, dog dander or hair, bee or wasp sting venom, and dust mite excretion; an environmental allergen selected from dust, grass pollen and tree pollen; and a parasitic allergen selected from a nematode and nematode eggs.

13. A compound for use in a method of treating or preventing a disease or condition in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the disease or condition is an allergic disease or condition caused by a parasitic allergen.

14. A compound for use according to claim 13, wherein the parasitic allergen comprises one or more of a nematode and nematode eggs.

15. A compound for use according to any one of the preceding claims, wherein the allergic disease or condition affects the nose of the patient.

16. A compound for use according to any one of the preceding claims, wherein the method inhibits eosinophil migration into the lungs.

17. A compound for use according to any one of the preceding claims, wherein the patient is susceptible to inflammation of the lungs.

18. A compound for use according to any one of the preceding claims, wherein the total nasal symptom score (TNSS) of the patient is decreased by the compound, optionally wherein the TNSS is decreased by at least 1 or by at least 2.

19. A compound for use according to any one of the preceding claims, wherein the compound reduces one or more of sneezing, nasal congestion, nasal itching, and rhinorrhoea in the patient.

20. A compound for use according any one of the preceding claims, wherein the compound is administered before, during or after exposure of the patient to an allergen, preferably wherein the compound is administered before exposure of the patient to an allergen.21 . A compound for use according to any one of the preceding claims, wherein the method comprises administering a total daily dose of the compound of from 0.05 mg to 10 mg or the method comprises administering a dose of the compound of from 0.5 mg to 2.5 mg.

22. A compound for use according to any one of the preceding claims, wherein: the compound is used as a maintenance therapy, optionally wherein the method comprises administering the compound to the patient at least once per day for a period of at least 12 weeks; or the compound is used as an acute treatment, optionally wherein the method comprises administering the compound to the patient for a period of no more than 12 weeks.

23. A compound for use according to any one of the preceding claims, wherein the compound is administered by inhalation, optionally wherein the compound is administered by inhalation from a nebuliser, pressurised metered dose inhaler or a dry powder inhaler.

24. A compound for use according to any one of the preceding claims, wherein the compound is administered in the form of a liquid pharmaceutical composition comprising the compound, preferably wherein the liquid pharmaceutical composition comprises a suspension of particles comprising the compound in a diluent.

25. A compound for use according claim 24, wherein the liquid pharmaceutical composition comprises:(i) particles of the compound at a concentration of from 0.1 to 3.0 mg / mL;(ii) one or more surfactants at a total concentration of from 0.1 to 1.0 mg / mL;(iii) one or more buffers at a total concentration of from 1.0 to 2.0 mg / mL; and(iv) water, optionally wherein the liquid pharmaceutical composition further comprises one or more buffers and / or one or more surfactants.

26. A compound for use according to any one of the preceding claims, wherein the compound is administered simultaneously, sequentially or separately in combination with a second active agent, wherein the second active agent is selected from an antihistamine, a non-steroidal anti-inflammatory drug a corticosteroid, a muscarinic receptor antagonist, an adrenomimetic or a leukotriene receptor antagonist.

27. A method of hastening recovery from a disease or condition in a patient, the method comprising administering a therapeutically effective amount of the compound to the patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein: the disease or condition is an allergic disease or condition; and hastening recovery from the disease or condition comprises: one or more of:(i) increasing the peak expiratory flow of the patient;(ii) increasing the tidal volume of the patient;(iii) decreasing the breathing rate of the patient; and(iv) reducing inflammation in the patient; and / or one or more of:(v) decreasing the total nasal symptom score by at least 1 relative to the total nasal symptom score of the patient when first administered the compound; and(vi) decreasing the total ocular symptom score by at least 1 relative to the total ocular symptom score of the patient when first administered the compound.

28. Use of compound in the manufacture of a medicament for use in a method of hastening recovery from a disease or condition in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein: the disease or condition is an allergic disease or condition; and hastening recovery from the disease or condition comprises: one or more of:(i) increasing the peak expiratory flow of the patient;(ii) increasing the tidal volume of the patient;(iii) decreasing the breathing rate of the patient; and(iv) reducing inflammation in the patient; and / or one or more of:(v) decreasing the total nasal symptom score by at least 1 relative to the total nasal symptom score of the patient when first administered the compound; and(vi) decreasing the total ocular symptom score by at least 1 relative to the total ocular symptom score of the patient when first administered the compound.

29. A method of increasing tolerance to an allergen in a patient, the method comprising administering a therapeutically effective amount of the compound to the patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein increasing tolerance to the allergen comprises increasing the threshold exposure to the allergen tolerated by the patient, wherein: the threshold exposure to the allergen tolerated by the patient is the exposure to the allergen below which the patient does not experience one or more of: (i) a decrease in peak expiratory flow of the patient; (ii) a decrease of the tidal volume of the patient; (iii) an increase in the breathing rate of the patient; and (iv) an increase in inflammation in the patient; and / or the threshold exposure to the allergen tolerated by the patient is the exposure to the allergen below which the patient does not experience one or more of: (i) an increase in the total nasal symptom score by at least 1 ; and (ii) an increase in the total ocular symptom score by at least 1.

30. Use of a compound in the manufacture of a medicament for use in a method of increasing tolerance to an allergen in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein increasing tolerance to the allergen comprises increasing the threshold exposure to the allergen tolerated by the patient, wherein: the threshold exposure to the allergen tolerated by the patient is the exposure to the allergen below which the patient does not experience one or more of: (i) a decrease in peak expiratory flow of the patient; (ii) a decrease of the tidal volume of the patient; (iii) an increase in the breathing rate of the patient; and (iv) an increase in inflammation in the patient; and / or the threshold exposure to the allergen tolerated by the patient is the exposure to the allergen below which the patient does not experience one or more of: (i) an increase in the total nasal symptom score by at least 1 ; and (ii) an increase in the total ocular symptom score by at least 1.

Images