treatment

Abstract

The present invention 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 method comprises nasally administering the compound to the patient; and the disease or condition is an inflammatory disease or condition or a respiratory disease or condition. The present invention also relates to a compound for use in a method of treating or preventing a disease or condition in a patient by reducing, or inhibiting an increase in, nasal airway resistance in the 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 reducing, or inhibiting an increase in, nasal airway resistance in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof.

Description

[0001] TREATMENT

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to the nasal administration of ensifentrine and the use of ensifentrine for decreasing, or inhibiting an increase in, nasal airway resistance.

[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 inflammatory and respiratory diseases and conditions. The chemical structure of ensifentrine is shown below.

[0007] Ensifentrine is administered by oral inhalation from a liquid composition with a nebuliser. For example, Ohtuvayre™ is a liquid pharmaceutical composition comprising ensifentrine for use in treating chronic obstructive pulmonary disease (COPD). Ohtuvayre™ is taken as a breathing treatment by oral inhalation and may be used with a standard jet nebulizer with a mouthpiece connected to an air compressor.

[0008] Many inflammatory and respiratory diseases and conditions cause symptoms in the nose such as swelling of the soft tissue lining, an increase in mucus production and / or an increase in congestion. This can cause an increase in the nasal airway resistance (NAR) of the nose, leading to difficulties in breathing and increased discomfort.

[0009] Airway resistance (the quantified measure of the ability for air to flow through a given airway of an animal or human) is influenced by multiple mechanisms, including nasal ciliary function, bronchodilation and inflammatory immune response. For instance, normal ciliary function efficiently removes mucus from the airways, minimising airway resistance. Bronchodilation of an airway also increases the volume of air that may flow through in a set time, thereby reducing resistance. However, the responsiveness of a given airway (e.g. a nasal passage) to a drug for lowering airway resistance may differ from that of another airway (e.g. the airways of the lower lungs).

[0010] Rheault et al (Anti-inflammatory pharmacology of ensifentrine, CHEST J. 2020; 158(4) A2284) describes experiments in which ensifentrine is administered by inhalation via nebuliser to OVA-sensitised guinea-pigs both pre- and post-OVA challenge. Pre-administration of ensifentrine was found to inhibit total cell and eosinophil migration into the nasal cavity.

[0011] Zuiker (Development and use of biomarkers in clinical development of new therapies for chronic airway disease, Universiteit Leiden, 2016) describes an experiment in which nebulised ensifentrine (inhaled through the nose) suppressed eosinophil and neutrophil migration into the nasal cavity in human patients suffering with allergic rhinitis. Neither Rheault et al nor Zuiker discusses the effect of ensifentrine on nasal airway resistance (NAR). Further, there is no discussion of the effect of the local application of ensifentrine (e.g. by nasal insufflation or nasal instillation) on an immune response.

[0012] There is a need to develop alternative methods for administering ensifentrine and to develop further treatments for inflammatory and respiratory diseases causing symptoms in the nose.

[0013] SUMMARY OF THE INVENTION

[0014] It is a surprising finding of the present invention that nasally administered ensifentrine is highly effective at treating inflammatory and respiratory diseases or conditions. In particular, it has been found that administration of ensifentrine by nasal insufflation or nasal instillation is particularly effective at treating inflammatory and respiratory diseases. It is a further surprising finding that ensifentrine is highly effective at reducing the nasal airway resistance in the nose of a patient.

[0015] The invention accordingly 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 method comprises nasally administering the compound to the patient; and the disease or condition is an inflammatory disease or condition or a respiratory disease or condition.

[0016] In particular, 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 method comprises nasally administering the compound to the patient by nasal insufflation or nasal instillation; the disease or condition is an inflammatory disease or condition or a respiratory disease or condition; and the compound is administered to the patient in the form of a liquid pharmaceutical composition comprising the compound.

[0017] The invention also provides a compound for use in a method of treating or preventing a disease or condition in a patient by reducing, or inhibiting an increase in, nasal airway resistance in the patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof.

[0018] The invention further provides a compound for use in a method of reducing, or inhibiting an increase in, nasal airway resistance in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof.

[0019] Further provided by the invention is a method of treating or preventing a disease or condition in a patient, wherein the method comprises nasally administering a therapeutically effective amount of a compound to the patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof; and wherein the disease or condition is an inflammatory disease or condition or a respiratory disease or condition.

[0020] Further provided by the invention is a method of treating or preventing a disease or condition in a patient, wherein the method comprises nasally administering a therapeutically effective amount of a compound to the patient by nasal insufflation or nasal instillation, which compound is ensifentrine or a pharmaceutically acceptable salt thereof; wherein the disease or condition is an inflammatory disease or condition or a respiratory disease or condition; and the compound is administered to the patient in the form of a liquid pharmaceutical composition comprising the compound.

[0021] 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 method comprises nasally administering the compound to the patient; and the disease or condition is an inflammatory disease or condition or a respiratory disease or condition.

[0022] 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 method comprises nasally administering the compound to the patient by nasal insufflation or nasal instillation; the disease or condition is an inflammatory disease or condition or a respiratory disease or condition; and the compound is administered to the patient in the form of a liquid pharmaceutical composition comprising the compound.

[0023] Further provided by the invention is a method of treating or preventing a disease or condition in a patient by reducing, or inhibiting an increase in, nasal airway resistance in the patient, wherein the method comprises administering a therapeutically effective amount of a compound to the patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof.

[0024] 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 by reducing, or inhibiting an increase in, nasal airway resistance in the patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof.

[0025] BRIEF DESCRIPTION OF THE FIGURES

[0026] Fig. 1A shows the dose response effect of ensifentrine (0.1 and 0.3 mg / mL, inhaled for 10 mins) on nasal airway resistance (NAR) in guinea pigs compared with placebo.

[0027] Fig. 1 B shows the dose response effect of ensifentrine (0.1 and 0.3 mg / mL, inhaled for 10 mins) on lower respiratory pressure (LRP) in guinea pigs compared with placebo.

[0028] Fig. 2A shows the dose response effect of ensifentrine (0.1 , 0.3 and 1 mg / mL, inhaled for 10 mins) on total cell migration into the nasal cavity in guinea pigs compared with placebo.

[0029] Fig. 2B shows the dose response effect of ensifentrine (0.1 , 0.3 and 1 mg / mL, inhaled for 10 mins) on eosinophil migration into the nasal cavity in guinea pigs compared with placebo.

[0030] Fig. 3 shows the duration of effect of ensifentrine (0.3 mg / mL, inhaled for 10 mins) on nasal airway resistance (NAR) in guinea pigs compared with placebo.

[0031] Fig. 4A shows the duration of effect of ensifentrine (0.3 mg / mL, inhaled for 10 mins) on total cell migration into the nasal cavity in guinea pigs compared with placebo.

[0032] Fig. 4B shows the duration of effect of ensifentrine (0.3 mg / mL, inhaled for 10 mins) on eosinophil migration into the nasal cavity in guinea pigs compared with placebo. Fig. 5 shows the dose response effect of locally applied ensifentrine on suppressing total cell and eosinophil migration into nasal mucosa of guinea pigs.

[0033] DETAILED DESCRIPTION OF THE INVENTION

[0034] The compound may reduce, or inhibit an increase in, the nasal airway resistance (NAR) of the patient. Typically, the compound may reduce the NAR of the patient by 10%, compared to the NAR prior to administration of the compound (for instance the NAR of the patient within one week prior to administration of the compound). Preferably the compound may reduce the NAR of the patient by about 20%, for instance by about 30%, by about 40% or by about 50%, compared to the NAR prior to administration of the compound.

[0035] Typically, the compound may inhibit an increase in the nasal airway resistance of the patient by 10%. For example, an inhibition of the increase in the nasal airway resistance by 10% causes the NAR of the patient to be 10% lower than the NAR if the patient had not been administered the same compound. Preferably, the compound may inhibit an increase in the NAR of a patient by about 20%, for instance by about 30%, about 40% or by about 50%. Preferably, the compound inhibits an increase in the nasal airway resistance of the patient.

[0036] Nasal airway resistance is a quantified measure of the ability for air to flow through the nasal cavity of an animal or human. As used herein, the term “nasal cavity” refers to the space inside the nose above the bone that forms the roof of the mouth, curving down at the back to join the throat and inclusive of the nostrils. By way of example, a high nasal airway resistance restricts airflow and makes breathing through the nose difficult. In contrast, a low nasal airway resistance readily allows airflow and makes breathing through the nose easy. Accordingly, nasal airway resistance is a quantified measure of nasal inflammation, nasal congestion and / or nasal obstruction within the nose of an animal or human. Nasal airway resistance is calculated by rhinomanometry i.e. by dividing the pressure (Pa) in the nasal cavity, measured with a pressure detector, by the airflow through the nasal cavity (cm3 / s), measured by tachometer, within one breath (i.e. inhalation). For humans, this value is typically calculated from the airflow when the pressure in the nasal cavity is at the set value of 150 Pa. Nasal airway resistance as defined herein may be as measured by rhinomanometry, optionally as defined herein.

[0037] As used herein, the nasal airway resistance may be an average nasal airway resistance. For instance, the average nasal airway resistance of a patient following treatment with the compound (for instance within one week following treatment with the compound) may be lower than the average nasal airway resistance of the patient (a) prior to treatment with the compound (for instance within one week prior to treatment, e.g. reducing NAR) or (b) compared with a patient untreated with the compound (e.g. preventing an increase in NAR). The average NAR may be the average of two or three measurements of NAR in a patient within one week (or within one day).

[0038] As used herein, the nasal airway resistance of the patient can be associated with the total nasal symptom score (TNSS) 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 seventy is ranked on a scale of 0 to 3 (for instance 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 TSS therefore acts as a measure of the overall seventy of symptoms experienced by a patient. TNSS is the sum of the ranking of the four nasal symptoms: sneezing, congestion, itching, and rhinorrhoea. A low TNSS means the patient is experiencing few and / or mild symptoms and typically has a low nasal airway resistance. A high TNSS means the patient is experiencing many and / or severe symptoms and typically has a high nasal airway resistance. Preferably, the compound decreases TNSS in the patient. For instance, the TNSS of the patient may be decreased by at least 1 , at least 2, at least 3 or at least 4 following administration of the compound. The compound may decrease the TNSS by at least 1 (to a non-negative value), optionally within 48 hours of administering the compound to the patient. The compound may decrease the TOSS by at least 2 (to a non-negative value), optionally within two weeks of administering the compound to the patient.

[0039] Total ocular symptom score (TOSS) is the sum of the ranking of the three ocular symptoms: itching / burning, tearing / watering, and redness.

[0040] Provided herein is a method of reducing, or inhibiting an increase in, nasal airway resistance in a patient, wherein the method comprises administering a therapeutically effective amount of a compound to the patient, wherein the compound is ensifentrine or a pharmaceutically acceptable salt thereof. Provided herein is the use of a compound in in the manufacture of a medicament for use in a method of reducing, or inhibiting an increase in, nasal airway resistance in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof.

[0041] The compound may reduce one or more of sneezing, congestion, itching, and rhinorrhoea in the patient. For instance, the compound may reduce congestion and / or rhinorrhoea in the patient.

[0042] The compound may 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 10%. For example, an inhibition of eosinophil migration into the nasal cavity by 10% causes the eosinophil count of the nasal cavity to be 10% lower than the eosinophil count if the patient had not been administered the same compound. Preferably, the compound may inhibit eosinophil migration into the nasal cavity of the patient by about 20%, by about 30%, by about 40% or by about 50%. The eosinophil count may be as determined by (i) centrifuging 100 pL of saline-collected nasal lavage 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 nasal cavity. The skilled person would be able to identify and count eosinophils on the stained slide.

[0043] 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).

[0044] The compound may be for use in method of treating or preventing an inflammatory disease or condition or a respiratory disease or condition in a patient, wherein: the method comprises nasally administering the compound to the patient. For instance, the method may comprise treating an inflammatory disease or condition in a patient by nasally administering the compound. The compound may be for use in a method of treating or preventing an inflammatory disease or condition or a respiratory disease or condition in a patient, wherein: the method comprises nasally administering the compound to the patient by nasal insufflation or nasal instillation; and the compound is administered to the patient in the form of a liquid pharmaceutical composition comprising the compound.

[0045] Typically, the inflammatory disease or condition or respiratory disease or condition causes symptoms in the nasal cavity of the patient. Such symptoms may include nasal inflammation, nasal congestion or nasal obstruction. Typically, the method comprises causing a reduction in the symptoms of the inflammatory disease or condition or respiratory disease or condition in the nasal cavity of the patient. The inflammatory disease or condition or respiratory disease or condition may be an inflammatory disease or condition.

[0046] The compound may be for use in a method of treating or preventing a disease or condition in a patient by reducing, or inhibiting an increase in, nasal airway resistance in the patient. Preferably, the disease or condition is an inflammatory disease or condition or a respiratory disease or condition. 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.

[0047] Nasal insufflation and nasal instillation are distinguished from nasal inhalation in that the compound is deposited directly into the nasal mucosa (the moist, mucous membrane that lines the inside of the nasal cavity) and a lower proportion of the compound is inhaled into the lower respiratory airways. In contrast, the purpose of nasal inhalation is typically to achieve deposition of the compound in the lower respiratory airways while minimising deposition on the nasal mucosa. As used herein, “nasal mucosa” refers to the mucous membrane that lines the inside of the nasal cavity. As used herein “lower respiratory airways” refers to the air passages at or below the throat, comprising the trachea, bronchi, bronchioles and alveoli. Administering the compound to a patient by nasal insufflation or nasal instillation typically comprises depositing at least 50 wt.% of the compound to the nasal mucosa of the patient relative to the total weight of the ensifentrine administered to the patient, preferably at least 60 wt.%, further preferably 75 wt.%, most preferably 95 wt.%. Thus, administering a liquid pharmaceutical composition comprising the compound to a patient by nasal insufflation or nasal instillation typically comprises depositing at least 50 wt.% of the compound to the nasal mucosa of the patient relative to the total weight of the ensifentrine in the formulation administered to the patient, preferably at least 60 wt.%, further preferably 75 wt.%, most preferably 95 wt.%. In this embodiment, the “formulation administered to the patient” refers to the total volume of the formulation administered to the patient e.g. the total volume of the formulation administered into the patient’s nostril by insufflation (e.g. by nasal spray).

[0048] Similarly, administering the compound to the patient by nasal insufflation or nasal instillation typically comprises administering less than 50 wt.% of the compound to the lower respiratory airways relative to the total weight of the ensifentrine administered to the patient, preferably less than 40 wt.%, further preferably less than 25 wt.%, most preferably less than 5 wt.%. Thus, administering a liquid pharmaceutical composition comprising the compound to a patient by nasal insufflation or nasal instillation typically comprises administering less than 50 wt.% of the compound to the lower respiratory airways of the patient relative to the total weight of the ensifentrine in the formulation administered to the patient, preferably less than 40 wt.%, further preferably less than 25 wt.%, most preferably less than 5 wt.%.

[0049] Preferably, the compound is administered to the patient nasally. Preferably, the compound is administered to the patient by nasal inhalation, nasal insufflation or nasal instillation, for instance by nasal inhalation or nasal insufflation. The compound may be administered to the patient by nasal inhalation. In some instances, the compound is only administered nasally. In some instances, the compound is not simultaneously administered orally (i.e. the compound is not substantially administered orally at the same time as the compound is being administered nasally). Further preferably, the compound is administered to the patient by nasal insufflation or by nasal instillation, optionally wherein and the compound is administered to the patient in the form of a liquid pharmaceutical composition comprising the compound (e.g. a liquid nasal spray or nasal drops). Most preferably, the compound is administered to the patient by nasal insufflation. For instance, the compound may be administered to the patient by nasal insufflation with a nasal spray, for instance a liquid nasal spray.

[0050] When using a nebuliser, the compound may be administered to the patient by a nebuliser with a face mask (i.e. an attachment covering the mouth and the nose), or by nasal nebuliser (i.e. with a nasal attachment). For instance, the compound may be administered by nasal nebuliser.

[0051] 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.

[0052] Alternatively, the compound may be administered by nasal spray. Preferably, the compound is administered by nasal spray (i.e. a form of nasal insufflation). 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.

[0053] Alternatively, the compound may be administered by nasal pump. A nasal pump is a device that will deliver a liquid formulation 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, preferably 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.

[0054] The compound may be administered as a dry powder to the nose, for instance via a dry powder inhaler or via insufflation of a dry powder.

[0055] The methods of the invention typically comprise administering the compound to the patient by nasal inhalation or nasal insufflation. Typically, the compound is administered by nasal spray, nasal nebuliser, or nasal pump, preferably by nasal nebuliser or nasal pump. The compound may be administered by nasal spray. The compound may alternatively be administered by nasal pump. Typically, the nasal pump is a nasal spray pump, preferably a fixed metered dose nasal spray pump.

[0056] Typically, the disease or condition is selected from rhinitis, nasal congestion, rhinorrhoea, sinusitis, hay fever, nasal allergies, asthma, bronchitis, emphysema, bronchiectasis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), cystic fibrosis, lung fibrosis, pulmonary fibrosis, interstitial lung disease, dermatitis, psoriasis, ocular inflammation or cerebral ischaemia. The disease or condition may be selected from rhinitis, nasal congestion, rhinorrhoea, sinusitis, and hay fever and nasal allergies. For instance, the disease or condition may be selected from rhinitis, nasal congestion, rhinorrhoea, sinusitis, and hay fever. Preferably, the disease or condition is selected from rhinitis, rhinorrhoea and sinusitis. For instance, the method may comprise treating rhinitis (e.g. allergic rhinitis) by nasally administering the compound, for instance by nasal spray.

[0057] In some instances, the disease or condition is not associated with cystic fibrosis (CF) in the patient. In some instances, the disease or condition is not rhinosinusitis or chronic rhinosinusitis (CRS). In some instances, the disease or condition is neither CF-rhinosinusitis nor non-CF rhinosinusitis. In some instances, the disease or condition is not sinusitis. In some instances, the disease or condition is not caused by allergies.

[0058] Typically, the rhinitis is allergic rhinitis (e.g. seasonal allergic rhinitis and perennial allergic rhinitis), non-allergic rhinitis, mixed rhinitis, viral rhinitis or bacterial rhinitis for instance allergic rhinitis, mixed rhinitis, viral rhinitis or bacterial rhinitis. Preferably, the disease or condition is allergic rhinitis.

[0059] Typically, the sinusitis is chronic sinusitis or acute sinusitis, for instance acute sinusitis. Typically, the asthma is allergic asthma, paediatric asthma, steroid resistant asthma or severe asthma. The asthma may be allergic asthma.

[0060] Typically, nasal allergies include an allergic reaction nasal cavity of the patient to one or more allergens 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. The patient may be susceptible to nasal inflammation, nasal congestion or nasal obstruction. Preferably, the patient is susceptible to nasal inflammation or nasal congestion, for instance nasal inflammation. A patient susceptible to nasal inflammation, nasal congestion or nasal obstruction may be a patient suffering from a deviated septum, nasal polyps, chronic sinusitis, swollen adenoid glands, nasal injury (including following nasal surgery), persistent rhinitis or rebound congestion following cessation of a decongestant medication. The patient may have a high baseline nasal airway resistance prior to first administration of the compound and optionally a correspondingly high TNSS. The patient may also have a high TOSS. For instance, the patient may have a baseline TNSS of at least 8 and optionally a TOSS of at least 5. Following treatment with the compound, the patient may for instance have a TMS of 6 or less, 5 or less, or 4 or less.

[0061] 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.

[0062] The method may treat or prevent the disease or condition by (a) reducing and / or inhibiting nasal inflammation and / or (b) inhibiting eosinophil and / or neutrophil migration into the nasal cavity of the patient. For instance, the method may treat the disease or condition by reducing nasal inflammation. In doing so, the compound may reduce nasal airway resistance in the patient, and reduce the presence of daily symptoms. The method may for instance treat rhinitis, rhinorrhoea or sinusitis by reducing nasal inflammation.

[0063] 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 mg to 2.0 mg, for instance about 1 .0 mg.

[0064] The method may comprise administering by nasal insufflation (e.g. by nasal spray) a total daily dose of the compound of from 0.1 mg to 10 mg or from 0.5 mg to 2.5 mg.

[0065] As used here, the doses are typically delivered doses of the compound (for instance the amount of the compound delivered to the nasal cavity of the patient). The total daily delivered dose of the compound may be from 0.5 mg to 2.0 mg, for instance about 1 .0 mg.

[0066] 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 by nasal spray twice or three times per day.

[0067] The compound may be used for a maintenance therapy. If used for maintenance therapy, the method typically comprises administering the compound at least once per day (for instance nasally) 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.

[0068] The compound may be used for acute treatment. If used for acute treatment, the method typically 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 as a nasal spray 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).

[0069] Preferably, the compound is to be used for a maintenance therapy.

[0070] 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. 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°.

[0071] 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. The method may comprise nasally administering a liquid pharmaceutical composition comprising a suspension of particles of the compound in a diluent, optionally in the form of a nasal spray. Preferably the method comprises administering a liquid pharmaceutical composition comprising a suspension of particles of the compound in a diluent in the form of a nasal spray.

[0072] 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.

[0073] 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.

[0074] 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:

[0075] • Non-spherical particle mode: Yes

[0076] • Refractive index: 1.500

[0077] • Absorption index: 0.500

[0078] • Particle density: 1 .00 g / cm3

[0079] • Dispersant name: 0.02% Polysorbate 20 in water

[0080] • Refractive index: 1.330

[0081] • Stirrer; 1000 rpm

[0082] • Sample measurement: 10 s

[0083] • Obscuration: 10-20 %

[0084] 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.

[0085] 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.

[0086] The liquid pharmaceutical composition typically further comprises one or more buffers and / or one or more surfactants. 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.

[0087] 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).

[0088] 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).

[0089] For instance, the method may comprise administering to the patient a liquid pharmaceutical composition comprising: • a liquid vehicle, such as water;

[0090] • particles consisting of ensifentrine free base at a concentration of from 0.1 to 20 mg / mL;

[0091] • one or more buffers at a total concentration of from 0.1 to 4 mg / mL; and

[0092] • one or more surfactants at a total concentration of from 0.05 to 3 mg / mL.

[0093] The liquid pharmaceutical composition may comprise:

[0094] • water;

[0095] • particles consisting of ensifentrine free base at a concentration of from 0.5 to 6 mg / mL;

[0096] • sodium dihydrogen phosphate dihydrate at a concentration of from 0.3 to 2 mg / mL;

[0097] • disodium phosphate dihydrate at a concentration of from 0.3 to 2 mg / mL;

[0098] • polysorbate 20 at a concentration of from 0.1 to 1 .5 mg / mL; and

[0099] • sorbitan monolaurate at a concentration of from 0.01 to 0.5 mg / mL.

[0100] For instance, the method may comprise administering to the patient a liquid pharmaceutical composition comprising:

[0101] (i) particles of the compound at a concentration of from 0.1 to 3.0 mg / mL;

[0102] (ii) one or more surfactants at a total concentration of from 0.1 to 1.0 mg / mL;

[0103] (iii) one or more buffers at a total concentration of from 1.0 to 2.0 mg / mL; and

[0104] (iv) water, optionally wherein the liquid pharmaceutical composition further comprises one or more buffers and / or one or more surfactants.

[0105] 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). Preferably, the compound is administered to the patient by nasal insufflation. For instance, the compound may be administered to the patient by nasal insufflation with a nasal spray, for instance a liquid nasal spray. 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. The second active agent may be administered orally or nasally. Typically, the second active agent is administered nasally.

[0106] The second active agent is typically a nasal decongestant, an antihistamine, a non-steroidal anti-inflammatory drug, a corticosteroid, a muscarinic receptor antagonist, an adrenomimetic or a leukotriene receptor antagonist. The compound may accordingly be used separately, sequentially or simultaneously in combination with a nasal decongestant, an antihistamine, a non-steroidal antiinflammatory drug, a corticosteroid, an adrenomimetic or a leukotriene receptor antagonist.

[0107] 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.

[0108] 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.

[0109] Nasal decongestants relieve nasal congestion in the upper respiratory tract. The nasal decongestant may be selected from pseudoephedrine, xylometazoline, ephedrine, naphazoline, phenylpropanolamine, synephrine and propylhexedrine, and pharmaceutically acceptable salts thereof. 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, glycopyrrol ate and umeclidinium, and pharmaceutically acceptable salts thereof. Preferably, the second active agent is selected from a nasal decongestant, an antihistamine, a non-steroidal anti-inflammatory drug and a corticosteroid.

[0110] The compound may alternatively be used as a monotherapy (e.g. the compound may be the sole active pharmaceutical ingredient). For instance, the method may comprise nasally administering the compound as a monotherapy.

[0111] 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.

[0112] The following are additional aspects of the invention: 1 . 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 method comprises nasally administering the compound to the patient; and the disease or condition is an inflammatory disease or condition or a respiratory disease or condition.

[0113] 2. A compound for use in a method of treating or preventing a disease or condition in a patient by reducing, or inhibiting an increase in, nasal airway resistance in the patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof.

[0114] 3. A compound for use according to aspect 2, wherein the disease or condition is an inflammatory disease or condition or a respiratory disease or condition.

[0115] 4. A compound for use according to aspect 2 or aspect 3, wherein the method comprises administering the compound to the patient by oral inhalation, nasal inhalation, nasal insufflation or nasal instillation.

[0116] 5. A compound for use according to any one of the preceding aspects, wherein the method comprises administering the compound to the patient by nasal inhalation or nasal insufflation, optionally wherein the method comprises administering the compound to the patient by nasal spray, nasal nebuliser, or nasal pump.

[0117] 6. A compound for use according to any one of the preceding aspects, wherein the disease or condition is selected from rhinitis, nasal congestion, rhinorrhoea, sinusitis, hay fever, nasal allergies, asthma, bronchitis, emphysema, bronchiectasis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), cystic fibrosis, lung fibrosis, pulmonary fibrosis, interstitial lung disease, dermatitis, psoriasis, ocular inflammation or cerebral ischaemia.

[0118] 7. A compound for use according to aspect 6, wherein: the rhinitis is allergic rhinitis, non-allergic rhinitis, mixed rhinitis, viral rhinitis or bacterial rhinitis; the sinusitis is chronic sinusitis or acute sinusitis; or the asthma is allergic asthma, paediatric asthma, steroid resistant asthma or severe asthma.

[0119] 8. The compound for use according to any one of the preceding aspects, wherein the disease or condition is selected from rhinitis, nasal congestion, rhinorrhoea, sinusitis, hay fever and nasal allergies, preferably wherein the disease or condition is rhinitis or allergic rhinitis.

[0120] 9. A compound for use according to any one of the preceding aspects, wherein the patient is susceptible to nasal inflammation, nasal congestion or nasal obstruction.

[0121] 10. A compound for use according to any one of the preceding aspects, wherein the method treats or prevents the disease or condition by (a) reducing and / or inhibiting nasal inflammation and / or (b) inhibiting eosinophil and / or neutrophil migration into the nasal cavity of the patient.

[0122] 11. 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. 12. 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.

[0123] 13. A compound for use according any one of the preceding aspects, wherein the compound is administered to the patient at least once per day, optionally wherein the compound is administered to the patient once, twice or three times a day.

[0124] 14. 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.

[0125] 15. A compound for use according to any one of the preceding aspects, wherein the method comprises administering a dose of the compound of from 0.5 mg to 2 mg.

[0126] 16. 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.

[0127] 17. A compound for use according to any one of aspects 1 to 15, wherein 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. 18. 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.

[0128] 19. A compound for use according to aspect 18, wherein the liquid pharmaceutical composition comprises a suspension of particles comprising the compound in a diluent.

[0129] 20. A compound for use according to aspect 18 or aspect 19, wherein the liquid pharmaceutical composition comprises:

[0130] (i) particles of the compound at a concentration of from 0.1 to 3.0 mg / mL;

[0131] (ii) one or more surfactants at a total concentration of from 0.1 to 1.0 mg / mL;

[0132] (iii) one or more buffers at a total concentration of from 1.0 to 2.0 mg / mL; and

[0133] (iv) water, optionally wherein the liquid pharmaceutical composition further comprises one or more buffers and / or one or more surfactants.

[0134] 21 . 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 a nasal decongestant, an antihistamine, a non-steroidal antiinflammatory drug, a corticosteroid, an adrenomimetic, a leukotriene receptor antagonist and a muscarinic receptor antagonist.

[0135] 22. A compound for use in a method of reducing, or inhibiting an increase in, nasal airway resistance in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof.

[0136] 23. A method of treating or preventing a disease or condition in a patient, wherein the method comprises nasally administering a therapeutically effective amount of a compound to the patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof; and wherein the disease or condition is an inflammatory disease or condition or a respiratory disease or condition.

[0137] 24. 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 method comprises nasally administering the compound to the patient; and the disease or condition is an inflammatory disease or condition or a respiratory disease or condition.

[0138] 25. A method of treating or preventing a disease or condition in a patient by reducing, or inhibiting an increase in, nasal airway resistance in the patient, wherein the method comprises administering a therapeutically effective amount of a compound to the patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof.

[0139] 26. 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 by reducing, or inhibiting an increase in, nasal airway resistance in the patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof.

[0140] EXAMPLES

[0141] Example 1 - Effect of ensifentrine on nasal airway resistance (NAR) and lower respiratory pressure (LRP)

[0142] A study was conducted to determine the effect of inhaled ensifentrine on the nasal airway resistance (NAR) and the lower respiratory pressure (LRP) of OVA- sensitised guinea pigs compared with placebo.

[0143] Materials

[0144] The guinea pigs were male, Dunkin Hartley guinea pigs weighing from 300 to 350 g each. The guinea pigs were sensitised to ovalbumin (OVA) prior to experimentation. On days 1 and 7, each guinea pig received a 1 % OVA aerosol for 15 minutes at 1.2 L / min. On days 14, 15 and 16, the guinea pigs received a booster sensitisation of 0.1 % OVA pL / nostril. The experiments took place on day 24.

[0145] Study design

[0146] At the start of the experiment (t = 0 min), each guinea pig was administered either (i) ensifentrine in pH 3.5 citrate-phosphate buffer (0.1 or 0.3 mg / mL: vapour inhalation at 300cc / min / guinea pig oxygen flow rate: 10 minutes) or (ii) pH 3.5 citrate-phosphate buffer (vapour inhalation at 300cc / min / guinea pig oxygen flow rate: 10 minutes) prior to surgery. At 10 minutes (t = 10 min), the guinea pigs were anaesthetized with an intraperitoneal injection of pentobarbital (60 mg / Kg). Two tracheal tubes were then inserted in each guinea pig, one towards the lungs and the other towards the nasopharynx from two cuts made in the trachea. Each tube was connected at the external end to an external ventilation pump, allowing pulsetile air to pass to the lungs (72 stokes / min at 10ml / kg) and the nasal cavity (8ml / stoke, 72 stokes / min). The mouth was then sealed with cotton soaked with epoxy glue. Each guinea pig was allowed 10 minutes of surgical recovery before challenge.

[0147] At 45 minutes (t = 45 min), an ovalbumin challenge was administered. A 0.5 ml, 2% ovalbumin challenge was delivered through the nasal catheter into the nasal cavity. Concurrently, 2% ovalbumin vapor was delivered through the lung tube via nebuliser. The ventilation pumps were then reconnected, the nasal airway resistance and lower respiratory pressure were recorded, and the animal was further observed for 60 minutes using a polygraph.

[0148] Results

[0149] Ensifentrine (0.1 and 0.3 mg / mL) dose dependently inhibited NAR in the guinea pigs compared with placebo (Figure 1A). The 0.1 mg / mL dose inhibited the increase in NAR by around 40 % relative to control. The 0.3 mg / mL dose inhibited the increase in NAR by around 65 % relative to control. Ensifentrine (0.1 and 0.3 mg / mL) also dose dependently inhibited LRP compared with placebo (Figure 1 B). The percentage decrease in NAR compared with placebo was greater than the percentage decrease in LRP compared with placebo for both the 0.1 and 0.3 mg / mL ensifentrine doses.

[0150] Conclusion

[0151] Ensifentrine is effective at reducing both nasal airway resistance and lower respiratory pressure. Ensifentrine was observed to have a greater effect on lowering nasal airway resistance than lowering lower respiratory pressure. Example 2 - Effect of ensifentrine on total cell and eosinophil infiltration into the nasal cavities (Reference example)

[0152] Following the study of Example 1 , a further study was conducted to investigate the effect of inhaled ensifentrine on total cell and eosinophil migration into the nasal cavity of OVA-sensitised guinea pigs compared with placebo. A further group was included in which the Guinea pigs were administered 1 mg / mL ensifentrine in pH 3.5 citrate-phosphate buffer (vapour inhalation at 300cc / min / guinea pig oxygen flow rate: 10 minutes) at the start of the experiment (t = 0 min).

[0153] Study design

[0154] Following the 60 minute polygraph time (Example 1 ) (t = 105 min), 2 mL of saline was passed through the nasal cavity from the trachea in each guinea pig, and the lavage was collected from the nostrils.

[0155] A total cell count was performed by mixing 50 pL lavage with 50 pL 0.1 % methylene blue and using a haemocytometer at 40x power. A differential cell count was also performed by centrifuging 100 pL of nasal lavage for 5 minutes using a cytospin at 1500RPM. After spinning, a sample was prepared on a glass slide and was stained with Wright stain solution for 5 minutes. The eosinophil cells were then counted under a microscope at 40x power.

[0156] Resu / ts

[0157] Ensifentrine (0.1 , 0.3 and 1 mg / mL) significantly and dose dependently inhibited the total cell migration and eosinophil migration into the nasal cavity compared with placebo (Figures 2A and 2B). Conclusion

[0158] Ensifentrine is effective at inhibiting total cell and eosinophil migration into the nasal cavity.

[0159] Example 3 - Duration of effect of ensifentrine on nasal airway resistance (NAR)

[0160] A study was conducted to determine the effect of pre-dosing ensifentrine on the nasal airway resistance following exposure of OVA-sensitised guinea pigs to OVA at different durations of time between administration of ensifentrine and exposure to OVA.

[0161] Study design

[0162] The study of Example 1 was repeated using ensifentrine in pH 3.5 citratephosphate buffer (0.3 mg / mL) or pH 3.5 citrate-phosphate buffer, further involving a time break of 45 (t = 45 min), 90 (t = 90 min) and 180 (t = 180 min) minutes between administration of ensifentrine and administration of the OVA challenge. The nasal airway resistance was calculated as in Example 1 . The nasal airway resistance of the control group was measured at 45 min (t = 45 min).

[0163] Results

[0164] An increase in nasal airway resistance was inhibited at 45, 90 and 180 minutes post-ensifentrine (0.3 mg / mL) administration by over 50% compared with placebo (Figure 3). Conclusion

[0165] Ensifentrine was found to have a long-term effect in preventing an increase in nasal airway resistance.

[0166] Example 4 - Duration of effect of ensifentrine on total cell and eosinophil infiltration into the nasal cavity

[0167] Following Example 3, a study was conducted to determine the effect of ensifentrine on total cell and eosinophil migration into the nasal cavity following exposure of OVA-sensitised guinea pigs to OVA at different durations of time between administration of ensifentrine and exposure to OVA.

[0168] Study design

[0169] The study of Example 2 was repeated using ensifentrine in pH 3.5 citratephosphate buffer (0.3 mg / mL) or pH 3.5 citrate-phosphate buffer, further involving a time break of 45 (t = 45 min), 90 (t = 90 min) and 180 (t = 180 min) minutes between administration of ensifentrine and administration of the OVA challenge. After monitoring each animal for a further 60 minutes, a total cell count and differential cell count (eosinophil) was then performed as in Example 2. Nasal lavage was therefore collected at t = 105 min, t = 130 min and t = 240 min respectively. The total cell count and differential cell count for the control group were measured at 105 min (t = 105 min).

[0170] Results

[0171] Ensifentrine inhibited total cell and eosinophil migration into the nasal cavity at 105, 130 and 240 minutes compared with placebo (Figures 4A and 4B). Conclusion

[0172] Ensifentrine has a long duration of action for inhibiting total cell and eosinophil migration into the nasal cavity.

[0173] Example 5 - Repeated dosing effect of ensifentrine on inhibition of total cell and eosinophil infiltration in the nasal cavity

[0174] The effect of daily repeat-dosing of ensifentrine on total cell and eosinophil migration into the nasal cavities of OVA-sensitised guinea pigs was investigated.

[0175] Study design

[0176] The study of Example 2 was repeated. However, ensifentrine in pH 3.5 citratephosphate buffer (0.3 mg / mL) was administered for 10 minutes of inhalation daily before the challenge was administered on day 2 or day 4. The total cells and eosinophils were then counted as in Example 2.

[0177] Results

[0178] Total cell migration into the nasal cavity of the guinea pigs was significantly reduced after 2 or 4 days of repeated dosing compared with placebo. Eosinophil migration into the nasal cavity of the guinea pigs was significantly reduced after 4 days of repeated dosing compared with placebo.

[0179] Conclusion

[0180] Repeat dosing of ensifentrine reduces total and eosinophil cell migration into the nasal cavity. Example 6 - Effect of ensifentrine on inflammatory cell migration into human nasal mucosa following nasal allergen challenge (Reference example)

[0181] 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.

[0182] Materials

[0183] 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.

[0184] Study design

[0185] 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).

[0186] At the start of the experiment, each patient was subjected to a nasal allergen challenge (0.125 mL allergen solution, delivered by nasal pump) 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.

[0187] 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.

[0188] The percentage change from baseline eosinophil and neutrophil cell count was calculated for each nasal brush sample.

[0189] Results

[0190] 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.

[0191] Conclusion

[0192] Nasal administration of ensifentrine causes an anti-inflammatory effect in the nose.

[0193] Example 7 - Effect of locally applied ensifentrine on total cell and eosinophil migration into the nasal mucosa

[0194] A study was conducted to determine the effect of locally administered ensifentrine on suppressing total cell and eosinophil migration into the nasal mucosa of guinea pigs.

[0195] Study design

[0196] Male albino guinea-pigs (250-300 g) were sensitized to ovalbumin (OVA): on day 1 , ovalbumin was prepared (2 mg / mL) with alum (10 mg / mL) and 1 mL of this mixture was injected into each guinea pig via an intraperitoneal route (ovalbumin dose: 8 mg / Kg). This procedure was repeated 8 days later as a booster injection. On day 15, each guinea-pig tested positive to being sensitised to ovalbumin following of ovalbumin solution being injected into intradermal sites (2 mg / mL, 100 ml).

[0197] On day 18, the guinea-pigs were randomized into groups (n = no. guinea pigs). Each group received a nasal ovalbumin challenge (75 mL of 2 mg / mL ovalbumin into each nostril). Each group also received an administration regime of ensifentrine (ensifentrine solution in DMSO applied locally to the nasal mucosa by micropipette) or vehicle control as set out below.

[0198] • Group 1 : ensifentrine (0.5 mg / mL; -12 h, -1 h pre- and 9 h post-OVA challenge; n = 4)

[0199] • Group 2: ensifentrine (0.1 mg / mL; -12 h, -1 h pre- and 9 h post-OVA challenge; n = 4)

[0200] • Group 3: vehicle control -12 h, -1 h pre- and 9 h post- OVA challenge; n = 4)

[0201] After a total of 24 hours post-challenge, 1 mL saline was passed through each nostril of each guinea pig to collect nasal lavage (total 2 mL). A total cell count was performed. Total cells were counted by mixing the nasal lavage (50 pL) with 0.1 % methylene blue (50 pL) and using a haemocytometer at 40x power. A differential cell count was also performed. Eosinophils were counted by subjecting a 100 pL sample of nasal lavage to a cytospin at 2000RPM for 2 minutes and staining with eosin / haematoxylin, counting under a microscope at 40x power. Results

[0202] Ensifentrine applied locally to the nasal mucosa suppressed both total cell and eosinophil recruitment into the nasal mucosa (Figure 5).

[0203] Conclusion

[0204] Local application of ensifentrine to the nasal mucosa suppresses total cell and eosinophil recruitment into the nasal mucosa.

Claims

CLAIMS1 . A compound for use in a method of treating or preventing a disease or condition in a patient by reducing, or inhibiting an increase in, nasal airway resistance in the patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof.

2. A compound for use according to claim 1 , wherein the disease or condition is an inflammatory disease or condition or a respiratory disease or condition.

3. A compound for use according to claim 1 or claim 2, wherein the method comprises administering the compound to the patient by oral inhalation, nasal inhalation, nasal insufflation or nasal instillation, preferably nasal insufflation or nasal instillation, most preferably nasal insufflation.

4. A compound for use according to any one of the preceding claims, wherein the method comprises administering the compound to the patient by nasal inhalation or nasal insufflation, optionally wherein the method comprises administering the compound to the patient by nasal spray, nasal nebuliser, or nasal pump.

5. 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.

6. 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 method comprises nasally administering the compound to the patient by nasal insufflation or nasal instillation;the disease or condition is an inflammatory disease or condition or a respiratory disease or condition; and the compound is administered to the patient in the form of a liquid pharmaceutical composition comprising the compound.

7. A compound for use according to claim 5 or claim 6, wherein the liquid pharmaceutical composition comprises a suspension of particles comprising the compound in a diluent.

8. A compound for use according to any one of claims 5 to 7, 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.

9. A compound for use according to any one of the preceding claims, wherein the disease or condition is selected from rhinitis, nasal congestion, rhinorrhoea, sinusitis, hay fever, nasal allergies, asthma, bronchitis, emphysema, bronchiectasis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), cystic fibrosis, lung fibrosis, pulmonary fibrosis, interstitial lung disease, dermatitis, psoriasis, ocular inflammation or cerebral ischaemia.

10. A compound for use according to claim 9, wherein: the rhinitis is allergic rhinitis, non-allergic rhinitis, mixed rhinitis, viral rhinitis or bacterial rhinitis; the sinusitis is chronic sinusitis or acute sinusitis; orthe asthma is allergic asthma, paediatric asthma, steroid resistant asthma or severe asthma.11 . The compound for use according to any one of the preceding claims, wherein the disease or condition is selected from rhinitis, nasal congestion, rhinorrhoea, sinusitis, hay fever and nasal allergies, preferably wherein the disease or condition is rhinitis or allergic rhinitis.

12. A compound for use according to any one of the preceding claims, wherein the patient is susceptible to nasal inflammation, nasal congestion or nasal obstruction.

13. A compound for use according to any one of the preceding claims, wherein the method treats or prevents the disease or condition by (a) reducing and / or inhibiting nasal inflammation and / or (b) inhibiting eosinophil and / or neutrophil migration into the nasal cavity of the patient.

14. 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.

15. 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.

16. A compound for use according any one of the preceding claims, wherein the compound is administered to the patient at least once per day, optionally wherein the compound is administered to the patient once, twice or three times a day.

17. 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.

18. A compound for use according to any one of the preceding claims, wherein the method comprises administering a dose of the compound of from 0.5 mg to 2 mg.

19. 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.

20. A compound for use according to any one of claims 1 to 18, wherein 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.21 . 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 a nasal decongestant, an antihistamine, a non-steroidal antiinflammatory drug, a corticosteroid, an adrenomimetic, a leukotriene receptor antagonist and a muscarinic receptor antagonist.

22. A compound for use in a method of reducing, or inhibiting an increase in, nasal airway resistance in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof.

23. A method of treating or preventing a disease or condition in a patient, wherein the method comprises nasally administering a therapeutically effective amount of a compound to the patient by nasal insufflation or nasal instillation, which compound is ensifentrine or a pharmaceutically acceptable salt thereof; wherein the disease or condition is an inflammatory disease or condition or a respiratory disease or condition; and the compound is administered to the patient in the form of a liquid pharmaceutical composition comprising the compound.

24. 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 method comprises nasally administering the compound to the patient by nasal insufflation or nasal instillation; the disease or condition is an inflammatory disease or condition or a respiratory disease or condition; and the compound is administered to the patient in the form of a liquid pharmaceutical composition comprising the compound.

25. A method of treating or preventing a disease or condition in a patient by reducing, or inhibiting an increase in, nasal airway resistance in the patient, wherein the method comprises administering a therapeutically effective amount of a compound to the patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof.

26. 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 by reducing, or inhibiting an increase in, nasal airway resistance in the patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof.

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