WO2025093848A1

WO2025093848A1 - Ensifentrine for treating bronchiectasis

Info

Publication number: WO2025093848A1
Application number: PCT/GB2024/051144
Authority: WO
Inventors: Kathleen RICKARD; Tara Renae Rheault
Original assignee: Verona Pharma Ltd
Current assignee: Verona Pharma Ltd
Priority date: 2023-11-01
Filing date: 2024-04-30
Publication date: 2025-05-08
Anticipated expiration: 2026-05-01

Abstract

The present invention relates to a compound for use in a method of preventing or treating bronchiectasis in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the bronchiectasis is non-cystic fibrosis (non-CF) bronchiectasis. The invention also relates to a compound for use in a method of treating bronchiectasis in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the method comprises treating the bronchiectasis by (a) reducing the frequency of cough in the patient and/or (b) reducing sputum production and/or facilitating clearance of mucus from the lungs in the patient.

Description

ENSIFENTRINE FOR TREATING BRONCHIECTASIS

FIELD OF THE INVENTION

The present invention relates to the treatment of bronchiectasis.

BACKGROUND OF THE INVENTION

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

As a combined PDE3/PDE4 inhibitor, ensifentrine has both bronchodilatory and antiinflammatory activity and is useful in the treatment of respiratory disorders including chronic obstructive pulmonary disease (COPD). The chemical structure of ensifentrine is shown below.

Ensifentrine has also been found to modulate cystic fibrosis transmembrane conductance regulator (CFTR, WO 2015/173551 A1 ).

Bronchiectasis is a chronic respiratory disorder characterised by permanent abnormal dilation of the bronchi (i.e. enlargement of the airways in the lung). The prevalence of bronchiectasis has been estimated at over 100 cases per 100,000 population and the disease has a significant clinical and economic burden. The main symptoms of bronchiectasis are chronic cough, sputum production, impaired mucociliary clearance, and bronchial infection. Patients may also suffer breathlessness (dyspnoea), fatigue, coughing up blood (haemoptysis) and chest pain. Bronchiectasis may arise from a large number of different etiologies. Cystic fibrosis is a common cause, with most cystic fibrosis patients ultimately developing severe bronchiectasis. However, a significant proportion of bronchiectasis cases are in patients who do not have cystic fibrosis (referred to as non-CF bronchiectasis). Non- CF causes of bronchiectasis can include infectious diseases such as pneumonia, measles and tuberculosis, although in some patients the cause of non-CF bronchiectasis is unknown. In non-CF bronchiectasis, the primary cause of the enlargement of the airways is damage caused by persistent inflammation, and in particular persistent neutrophilic inflammation.

Bronchiectasis has limited treatment options. There are no drugs yet approved in the USA or Europe specifically for the treatment of this disease, and particularly for the treatment of non-CF bronchiectasis.

There is a significant need to develop treatments for bronchiectasis and non-CF bronchiectasis. In particular, it is desirable to develop treatments which can reduce cough and sputum production in patients. Treatments targeting the neutrophilic inflammation in non-CF bronchiectasis are also needed.

SUMMARY OF THE INVENTION

It is a surprising finding of the present invention that ensifentrine can reduce cough and sputum production in patients with high levels of cough and sputum.

Ensifentrine has also been found to reduce cytokines associated with neutrophilic inflammation such as IL-8 and to reduce airway macrophage infiltration. These activities allow ensifentrine to target the neutrophilic inflammation underlying non-CF bronchiectasis while alleviating the key symptoms of chronic cough and increased sputum production.

The invention accordingly provides a compound for use in a method of preventing or treating bronchiectasis in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the bronchiectasis is non-cystic fibrosis (non-CF) bronchiectasis.

Also provided by the invention is a compound for use in a method of treating bronchiectasis in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the method comprises treating the bronchiectasis by (a) reducing the frequency of cough in the patient and/or (b) reducing sputum production and/or facilitating clearance of mucus from the lungs in the patient.

DETAILED DESCRIPTION OF THE INVENTION

The compound is for use in the treatment of bronchiectasis, and in particular non- cystic fibrosis (non-CF) bronchiectasis. Non-CF bronchiectasis is bronchiectasis in a patient who does not have cystic fibrosis. A patient who does not have cystic fibrosis is a patient who does not have mutations in both alleles of the gene encoding cystic fibrosis transmembrane conductance regulator (CFTR).

The patient has typically been diagnosed as having the bronchiectasis. The patient may for instance have been diagnosed with bronchiectasis based on observation of bronchial dilation using computed tomography.

In one embodiment, the compound is for use in a method of preventing or treating non-CF bronchiectasis. The compound may be for use in treating non-CF bronchiectasis.

The method may comprise treating the bronchiectasis by (a) reducing the frequency of cough in the patient and/or (b) reducing sputum production and/or facilitating clearance of mucus from the lungs in the patient. The method may comprise treating the bronchiectasis by reducing the frequency of cough in the patient. The method may comprise reducing sputum production in the patient. The method may comprise treating the bronchiectasis by reducing the frequency of cough in the patient and reducing sputum production in the patient.

The severity of cough and sputum production in a patient may be assessed using the cough and sputum domain of the EXACT -Respiratory Symptoms (E-RS) scale as described in “E-RS (EXACT-Respiratory Symptoms), User Manual (Version 3.0), October 2014’’. The cough and sputum domain of E-RS includes the questions 2, 3 and 4 of the E-RS and the total score may range from 0 to 11 . Following treatment, the patient typically has a reduced score in the cough and sputum domain of E-RS, for instance a score reduced by at least 1 or at least 2 relative to the score in the cough and sputum domain of E-RS the day before the day on which the compound is first administered. The reduced score is typically achieved following daily administration of the compound for at least 14 days, for instance for at least 8 weeks. The patient may have a cough and sputum domain score of at least 3, at least 4, at least 5 or at least 6 on the day before the day on which the compound is first administered. The patient may have a cough and sputum domain score of at least 8 or at least 9 on the day before the day on which the compound is first administered. The patient typically has a score of at least 5 or at least 6 on the day before the day on which the compound is first administered.

For instance the compound may reduce the score of the patient in the cough and sputum domain of the EXACT -Respiratory Symptoms (E-RS) scale, preferably wherein the score is reduced by at least 1 following administration of the compound. Typically, the patient has a score of at least 5 in the cough and sputum domain of the EXACT -Respiratory Symptoms (E-RS) scale the day before the day on which the compound is first administered to the patient. For instance, the patient may have a score of at least 5 in the cough and sputum domain of the EXACT-Respiratory Symptoms (E-RS) scale the day before the day on which the compound is first administered to the patient and the patient may have a score of no greater than 4 after daily administration of the compound for at least 12 weeks.

Some bronchiectasis patients suffer from bronchiectasis exacerbations. A bronchiectasis exacerbation is an acute worsening of bronchiectasis symptoms which persists for at least two days. Typically, a bronchiectasis exacerbation in a patient comprises worsening of two or more of cough, sputum volume (i.e. increased sputum volume) and sputum purulence (i.e. increased sputum purulence) for at least two days.

The compound may decrease the frequency and/or severity of bronchiectasis exacerbations in the patient. For instance, the compound may decrease the frequency of bronchiectasis exacerbations in the patient. As such, the invention may provide a compound for use in a method of decreasing the frequency and/or severity of bronchiectasis exacerbations in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof. Ensifentrine has been found to have an anti-inflammatory effect which is well suited to the treatment of bronchiectasis, and in particular non-CF bronchiectasis. As such, the compound may treat the bronchiectasis by reducing proinflammatory cytokines and chemokines such as IL-8, IL-6 and TNF-a in the lungs and/or reducing macrophage infiltration into the lungs.

Typically, the compound reduces neutrophilic inflammation in the patient. Preferably, the compound reduces neutrophilic inflammation in the lungs of the patient. For instance, the bronchiectasis may be non-CF bronchiectasis and administration of the compound by inhalation may reduce neutrophilic inflammation in the lungs of the patient.

The compound may reduce the concentration of one or more of IL-6, IL-8 and TNF-a in the blood and/or lungs of the patient. Typically, the concentration of one or more of IL-6, IL-8 and TNF-a is reduced in the blood of the patient. For instance, the compound may reduce the concentration of both IL-6 and IL-8 in the blood of the patient. The compound may reduce the concentration of both IL-6 and IL-8 in the lungs of the patient. The compound may reduce the concentration of TNF-a in the blood and/or lungs of the patient.

The compound may treat non-CF bronchiectasis by reducing neutrophilic inflammation in the patient and by reducing the frequency of cough in the patient.

The bronchiectasis may be idiopathic bronchiectasis. The bronchiectasis is preferably non-CF bronchiectasis. The bronchiectasis is typically non-CF bronchiectasis caused by one or more of: a lung infection; a lung disease; smoking; an inflammatory disease; and an obstruction in the lung.

The lung infection may be selected from a bacterial infection and a viral infection. The bronchiectasis may be caused by an infection with a bacterium selected from Pseudomonas aeruginosa, Haemophilus influenzae, Mycobacterium tuberculosis and Streptococcus pneumoniae. The lung infection may be pneumonia. The inflammatory disease may be selected from ulcerative colitis, Crohn’s disease and rheumatoid arthritis. The obstruction of the lung may be caused by a tumour or aspiration of a foreign body. Typically, the non-CF bronchiectasis is caused by a lung disease selected from chronic obstructive pulmonary disease (COPD), asthma and interstitial lung disease. The non-CF bronchiectasis may be caused by COPD.

The patient may be suffering from COPD. Thus, the patient may be suffering from both COPD and bronchiectasis (for instance COPD and non-CF bronchiectasis).

The bronchiectasis is typically not caused by a congenital disorder. Typically, the patient is not therefore suffering from any of cystic fibrosis, primary ciliary dyskinesia, Williams-Campbell syndrome, Marfan’s syndrome, Mounier-Kuhn syndrome, Alpha-1 antitrypsin deficiency, yellow nail syndrome and Young’s syndrome.

The patient may be male. The patient may be female. The patient may have an age of greater than or equal to 65 years. The patient may have an age of less than 65 years. The patient may be taking a background medication selected from one or more of a long-acting muscarinic antagonist (LAMA), a long-acting beta-agonist (LABA) and an inhaled corticosteroid (ICS).

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).

The method typically comprises administering the compound to the patient by inhalation. A pharmaceutical composition comprising the compound and one or more pharmaceutically acceptable excipients or diluents is typically administered to the patient by inhalation, for instance by nebuliser, pressurised metered dose inhaler (pMDI) or dry powder inhaler (DPI).

Preferably, the method comprises administering the compound to the patient by inhalation from a nebuliser. Nebulisers aerosolise a liquid pharmaceutical composition into an aerosol that is inhaled into a patient's respiratory tract.

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 l-neb™ (Philips), the Philips SideStream (Philips), the AeroNeb® (Philips), the Philips InnoSpire Go (Philips), the Pari LC Sprint (Pari GmbH), the AERxR™ 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.

Typically, the method comprises administering the compound to the patient once, twice or three times per day, for instance twice or three times per day. The compound may be administered to the patient by inhalation once, twice or three times a day. Preferably the method comprises administering the compound to the patient by inhalation twice a day. The method may comprise administering a first dose of the compound in the morning (for instance within 3 hours following waking) and a second dose of the compound in the evening (for instance within 3 hours before bed). Typically, the morning and evening doses are administered from 10 to 14 hours apart, for instance about 12 hours apart.

The compound may be used in any suitable therapeutically effective amount. Typically, the daily dose of the compound is from 0.1 to 20 mg. Typically, the method comprises administering a total daily dose of the compound of from 0.5 to 10 mg. Preferably, the total daily dose of the compound (e.g. ensifentrine free base) is from 5 to 7 mg, for instance about 6 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 6.0 mg.

Typically, the compound is administered twice a day in two separate doses which are the same or similar. For instance, the method may comprise administering the compound to the patient twice a day in a first dose of from 1 to 5 mg and a second dose of from 1 to 5 mg. Typically, the method may comprise administering the compound to the patient twice a day with a first dose of from 2 to 4 mg and a second dose of from 2 to 4 mg.

Preferably, the method comprises administering two doses of about 3 mg ensifentrine free base to the patient per day by inhalation. The method preferably comprises administering a dose of about 3 mg of the compound to the patient twice a day (3 mg BID) by inhalation. More preferably, the method comprises administering by nebuliser a dose of about 3 mg the compound to the patient twice a day. Each dose may be 3.0 mg free base ensifentrine administered by nebulizer. The compound is typically used as a maintenance therapy. Typically, the method comprises administering the compound to the patient at least once per day for at least 8 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 8 weeks, preferably for at least 16 weeks, more preferably for at least 24 weeks.

The compound is preferably administered as a suspension formulation, i.e. 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 method typically comprises administering an inhalable pharmaceutical composition comprising a suspension of particles of the compound in a diluent. The particles comprising the compound typically have a particle size distribution with a Dv50 of from 0.5 pm to 5.0 pm. The particles preferably have a Dv50 of from 1 .0 pm to 2.0 pm.

Particle sizes are 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.

The technique used to measure the Dv50 values as stated herein is typically laser diffraction. The particle size distribution of the particles comprising the compound may be as measured by laser diffraction using a wet powder dispersion system. For instance, the particle size distribution can be measured by laser diffraction using a Malvern Spraytec in conjunction with a wet dispersion cell. Typically, the instrument parameters for the Malvern Spraytec are as follows:

• particle - standard opaque particle;

• refractive index Particle - 1 .50; • refractive index (imaginary) - 0.50;

• density of particle - 1 .00;

• refractive index of dispersant - 1 .33;

• controller unit - 1000RPM;

• measurement type - timed;

• initial sampling time - 30s;

• obscuration - 20% - 30%;

• dispersant - 1 % Polysorbate 20 in deionised water.

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.

The concentration of particles comprising the compound in the inhalable pharmaceutical composition is typically from 0.1 to 5.0 mg/mL, preferably from 0.1 to 2.5 mg/mL, more preferably from 1 .0 to 2.0 mg/mL.

The inhalable pharmaceutical composition typically further comprises one or more tonicity adjusters, one or more buffers and one or more surfactants. The tonicity adjuster is typically sodium chloride.

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.

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)), cocamide MEA, cocamide 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).

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 sterile liquid vehicle comprises polysorbate 20 and/or sorbitan monolaurate (Span 20).

For instance, the method may comprise administering to the patient an inhalable liquid pharmaceutical composition comprising:

• water;

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

• one or more tonicity adjusters at a total concentration of from 1 .0 to 15 mg/mL;

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

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

The inhalable liquid pharmaceutical composition may comprise:

• water;

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

• sodium chloride at a concentration of from 5 to 12 mg/mL;

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

• 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

• sorbitan monolaurate at a concentration of from 0.01 to 0.5 mg/mL. The compound may be used in combination with a second active agent. The compound may be administered separately or simultaneously with the second active agent. The patient may already be taking a second active agent as a background therapy for COPD. 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 is typically selected from an antibiotic, a macrolide, a muscarinic receptor antagonist, a beta-adrenergic receptor agonist and an inhaled corticosteroid. The compound may accordingly be used in combination with muscarinic receptor antagonist or a beta-adrenergic receptor agonist. The second active agent may be a long-acting muscarinic receptor antagonist (LAMA) or a long- acting beta-adrenergic receptor agonist (LABA).

Examples of LAMAs include aclidinium, darotropium, tiotropium, glycopyrrolate and umeclidinium. Examples of LABAs include salmeterol, formoterol, indacaterol, vilanterol, olodaterol, abediterol and carmoterol. Examples of inhaled corticosteroids include beclomethosone, budesonide, fluticasone propionate, ciclesonide, mometasone, fluticasone furoate and pharmaceutically acceptable salts thereof.

The compound may accordingly be for use in the treatment of the bronchiectasis (e.g. non-CF bronchiectasis) in combination with a second active agent selected from an antibiotic, a macrolide, a muscarinic receptor antagonist, a beta-adrenergic receptor agonist and an inhaled corticosteroid. Preferably, the compound is for use in combination with an antibiotic suitable for the treatment of bronchiectasis or a macrolide suitable for the treatment of bronchiectasis. Typically, the second active agent is an antibiotic selected from tobramycin, ciprofloxacin, aztreonam and colistin; or the second active agent is a macrolide selected from azithromycin and erythromycin.

The invention accordingly provides a second active agent as defined herein for use in the treatment of non-CF bronchiectasis in combination with a compound which is ensifentrine or a pharmaceutically acceptable salt thereof.

The compound may alternatively be used as a monotherapy. For instance, the compound may be for use in treating bronchiectasis (e.g. non-CF bronchiectasis) as the sole active agent. In some embodiments, the compound is not administered in combination with a muscarinic receptor antagonist or a beta-adrenergic receptor agonist.

The invention further provides a method of preventing or treating bronchiectasis in a patient, which method comprises administering a therapeutically effective amount of a compound is ensifentrine or a pharmaceutically acceptable salt thereof to the patient, wherein the bronchiectasis is non-cystic fibrosis (non-CF) bronchiectasis.

The invention further provides a method of treating bronchiectasis in a patient, which method comprises administering a therapeutically effective amount of a compound is ensifentrine or a pharmaceutically acceptable salt thereof to the patient, wherein the method comprises treating the bronchiectasis by (a) reducing the frequency of cough in the patient and/or (b) reducing sputum production and/or facilitating clearance of mucus from the lungs in the patient.

The invention further provides a method of decreasing the frequency and/or severity of bronchiectasis exacerbations in a patient suffering from bronchiectasis, which compound is ensifentrine or a pharmaceutically acceptable salt thereof.

The invention further provides use of a compound in the manufacture of a medicament for use in a method of preventing or treating bronchiectasis in a patient, which method comprises administering a therapeutically effective amount of a compound is ensifentrine or a pharmaceutically acceptable salt thereof to the patient, wherein the bronchiectasis is non-cystic fibrosis (non-CF) bronchiectasis.

The invention further provides use of a compound in the manufacture of a medicament for use in a method of treating bronchiectasis in a patient, which method comprises administering a therapeutically effective amount of a compound is ensifentrine or a pharmaceutically acceptable salt thereof to the patient, wherein the method comprises treating the bronchiectasis by (a) reducing the frequency of cough in the patient and/or (b) reducing sputum production and/or facilitating clearance of mucus from the lungs in the patient.

The invention is described in more detail by the following Examples. EXAMPLES

Example 1 - assessment of ensifentrine in COPD patients with high cough/sputum burden

Study design

A clinical study was conducted to determine the efficacy of ensifentrine in treating COPD compared with placebo. Ensifentrine was administered by nebuliser at a dose of 3 mg twice daily (BID) for 24 weeks. The study was a multi-centre, randomized, double-blind, parallel-group, placebo-controlled trial with around 800 patients and 5:3 randomization.

The study population included patients aged 40-80 years with moderate to severe COPD (FEVi 30% - 70% p.n., FEVi/forced vital capacity (FVC) ratio < 0.7, with mMRC > 2). The randomization stratified (a) the use of stable background maintenance LAMA or LABA therapy use (approx. 50%. yes or no) and (b) cigarette smoking (current or former). Inhaled corticosteroid (ICS) maintenance therapy was permitted in up to 20% of patients under certain provisions.

The study assessed: the effect of ensifentrine on blood IL-6 and IL-8; and the effect of ensifentrine on the cough and sputum domain of E-RS score in patients with high baseline cough/sputum scores. Patients with high baseline cough/sputum E-RS scores were defined as subjects with baseline E-RS cough and sputum domain scores greater than the population mean of 3.6 units (as determined using “E-RS (EXACT-Respiratory Symptoms), User Manual (Version 3.0), October 2014”). These high baseline cough/sputum patients provide a model for non-CF bronchiectasis.

Formulation

The investigational product and placebo were provided in 2.5 mL unit dose format in an ampule and administered via a nebuliser. The formulation of the investigational product (ensifentrine suspension formulation) and placebo are shown in Table 1 below.

Table 1

Results

It was found that inhaled ensifentrine 3 mg twice daily (BID) caused reduction in blood IL-6 and IL-8 in patients. At week 12, mean reductions from baseline of 43 pg/L for blood IL-6 and 45 pg/L for blood IL-8 were observed.

The E-RS cough and sputum domain results from the phase 3 clinical studies in subjects with cough and sputum scores greater than or equal to mean at baseline (pooled analysis) are shown in Table 2. In patients with high baseline cough and sputum scores, ensifentrine was found to cause significant improvements in those scores over 6 weeks to 24 weeks, demonstrating activity against sputum production and cough in these patients.

Conclusion

This study confirms that ensifentrine is able to target both the neutrophilic inflammation associated with non-CF bronchiectasis and the primary bronchiectasis symptoms of cough and sputum production.

Table 2 Example 2 - effect of ensifentrine on inflammation in fibrosis mouse model

Study overview

An in vivo study was conducted to determine the effect of ensifentrine on inflammation in bleomycin-induced pulmonary fibrosis in rats. After a week, the rats received a daily inhaled dosage of ensifentrine or a control over a period of two weeks. At the end of the two weeks, the rats were sacrificed and their airways were analysed for Bronchoalveolar lavage (BAL) differential cell counts and TGF- concentration.

The BAL differential cell count provided a total inflammatory cell count so that changes in inflammation following treatment could be observed.

Study design

At day 0, the rats were subjected to an intratracheal challenge of either 0.9 % w/v saline or bleomycin, the latter used to induce pulmonary fibrosis.

Starting on day 7, two groups of 12 rats from the bleomycin challenge group were administered an inhaled dose of ensifentrine at either 3 mg/kg (Experiment 1 ) or 10 mg/kg (Experiment 2) on a daily basis for two weeks, terminating on day 21 . The ensifentrine was administered as a suspension in the vehicle suspension article.

Two control experiments were also conducted. Control 1 subjected 12 rats from the saline challenge group to daily administration of the vehicle suspension article via inhalation for the full 21 days. Control 2 subjected 12 rats from the bleomycin challenge group to daily administration of the vehicle suspension article via inhalation for the full 21 days. The experimental set-up is summarised in Table 3 below.

Table 3

At the end of the 21 -day period, the rats were sacrificed and the BAL differential cell counts and the TGF- concentration data were collected.

Results The BAL differential cell counts at day 21 showed a reduction in total inflammatory cell and macrophage infiltration into the rat airways following treatment with ensifentrine at 3 mg/kg/day (Experiment 1 ) and 10 mg/kg/day (Experiment 2), in comparison to the bleomycin Control 2.

The TGF-P concentration at day 21 was also lower in the rats following ensifentrine treatment compared to those of the bleomycin Control 2.

Conclusion

It has been found that inhaled ensifentrine can reduce macrophage infiltration in the airways in a rat model of pulmonary fibrosis.

Claims

1 . A compound for use in a method of preventing or treating bronchiectasis in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the bronchiectasis is non-cystic fibrosis (non-CF) bronchiectasis.

2. A compound for use according to claim 1 , wherein the method comprises treating the bronchiectasis by (a) reducing the frequency of cough in the patient and/or (b) reducing sputum production and/or facilitating clearance of mucus from the lungs in the patient.

3. A compound for use in a method of treating bronchiectasis in a patient, which compound is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the method comprises treating the bronchiectasis by (a) reducing the frequency of cough in the patient and/or (b) reducing sputum production and/or facilitating clearance of mucus from the lungs in the patient.

4. A compound for use according to any one of the preceding claims, wherein the method comprises treating the bronchiectasis by reducing the frequency of cough in the patient.

5. A compound for use according to any one of the preceding claims, wherein the compound reduces the score of the patient in the cough and sputum domain of the EXACT-Respiratory Symptoms (E-RS) scale, preferably wherein the score is reduced by at least 1 following administration of the compound.

6. A compound for use according to any one of the preceding claims, wherein the patient has a score of at least 5 in the cough and sputum domain of the EXACT- Respiratory Symptoms (E-RS) scale the day before the day on which the compound is first administered to the patient.

7. A compound for use according to any one of the preceding claims, wherein the compound decreases the frequency and/or severity of bronchiectasis exacerbations in the patient.

8. A compound for use according to any one of the preceding claims, wherein the compound reduces neutrophilic inflammation in the patient, preferably wherein the compound reduces neutrophilic inflammation in the lungs of the patient.

9 A compound for use according to any one of the preceding claims, wherein the compound reduces the concentration of one or more of IL-6, IL-8 and TNF-a in the blood and/or lungs of the patient.

10. A compound for use according to any one of the preceding claims, wherein the bronchiectasis is idiopathic bronchiectasis.

11. A compound for use according to any one of claims 1 to 9, wherein the bronchiectasis is non-CF bronchiectasis caused by one or more of: a lung infection; a lung disease; smoking; an inflammatory disease; and an obstruction of the lung.

12. A compound for use according to claim 11 , wherein the non-CF bronchiectasis is caused by a lung disease selected from chronic obstructive pulmonary disease (COPD), asthma and interstitial lung disease, preferably wherein the lung disease is COPD.

13. A compound for use according to any one of the preceding claims, wherein the patient is suffering from COPD.

14. A compound for use according to any one of the preceding claims, wherein the bronchiectasis is not caused by a congenital disorder, preferably wherein the patient is not suffering from any of cystic fibrosis, primary ciliary dyskinesia, Williams- Campbell syndrome, Marfan’s syndrome, Mounier-Kuhn syndrome, Alpha-1 antitrypsin deficiency, yellow nail syndrome and Young’s syndrome.

15. A compound for use according to any one of the preceding claims, wherein the method comprises administering the compound to the patient by inhalation.

16. A compound for use according to any one of the preceding claims, wherein the method comprises administering the compound to the patient by inhalation by nebuliser.

17. A compound for use according to any one of the preceding claims, wherein the compound is ensifentrine.

18. A compound for use according to any one of the preceding claims, wherein the method comprises administering the compound to the patient once, twice or three times per day.

19. A compound for use according to any one of the preceding claims, wherein the method comprises administering the compound to the patient twice a day.

20. 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 0.5 to 10 mg, preferably from 5 to 7 mg.

21 . A compound for use according to any one of the preceding claims, wherein the method comprises administering the compound to the patient twice a day in a first dose of from 2 to 4 mg and a second dose of from 2 to 4 mg.

22. A compound for use according to any one of the preceding claims, wherein the method comprises administering a dose of about 3 mg the compound to the patient twice a day (3 mg BID), preferably wherein the method comprises administering by nebuliser a dose of about 3 mg the compound to the patient twice a day.

23. A compound for use according to any one of the preceding claims, wherein the method comprises administering the compound to the patient at least once per day for at least 8 weeks, preferably for at least 16 weeks, more preferably for at least 24 weeks.

24. A compound for use according to any one of the preceding claims, wherein the method comprising administering an inhalable pharmaceutical composition comprising a suspension of particles of the compound in a diluent.

25. A compound for use according to any one of the preceding claims, wherein the compound is for use in combination with a second active agent selected from an antibiotic, a macrolide, a muscarinic receptor antagonist, a beta-adrenergic receptor agonist and an inhaled corticosteroid.

26. A compound for use according to claim 25, wherein: the second active agent is an antibiotic selected from tobramycin, ciprofloxacin, aztreonam and colistin; or the second active agent is a macrolide selected from azithromycin and erythromycin.

27. A second active agent as defined in claim 25 or claim 26 for use in the treatment of non-CF bronchiectasis in combination with a compound which is ensifentrine or a pharmaceutically acceptable salt thereof.

28. A method of preventing or treating bronchiectasis in a patient, which method comprises administering a therapeutically effective amount of a compound is ensifentrine or a pharmaceutically acceptable salt thereof to the patient, wherein the bronchiectasis is non-cystic fibrosis (non-CF) bronchiectasis.

29. A method of treating bronchiectasis in a patient, which method comprises administering a therapeutically effective amount of a compound is ensifentrine or a pharmaceutically acceptable salt thereof to the patient, wherein the method comprises treating the bronchiectasis by (a) reducing the frequency of cough in the patient and/or (b) reducing sputum production and/or facilitating clearance of mucus from the lungs in the patient.

30. Use of a compound in the manufacture of a medicament for use in a method of preventing or treating bronchiectasis in a patient, which method comprises administering a therapeutically effective amount of a compound is ensifentrine or a pharmaceutically acceptable salt thereof to the patient, wherein the bronchiectasis is non-cystic fibrosis (non-CF) bronchiectasis.

31 . Use of a compound in the manufacture of a medicament for use in a method of treating bronchiectasis in a patient, which method comprises administering a therapeutically effective amount of a compound is ensifentrine or a pharmaceutically acceptable salt thereof to the patient, wherein the method comprises treating the bronchiectasis by (a) reducing the frequency of cough in the patient and/or (b) reducing sputum production and/or facilitating clearance of mucus from the lungs in the patient.