Ensifentrine (RPL-554) for reducing the frequency and / or severity of COPD exacerbations

Abstract

The present invention relates to a compound for use in a method for reducing the frequency and / or severity of chronic obstructive pulmonary disease (COPD) exacerbations in a patient suffering from COPD, wherein the compound is ensifentrine or a pharmaceutically acceptable salt thereof. The present invention also relates to a compound for use in a method for treating chronic obstructive pulmonary disease (COPD) in a patient, wherein: the compound is ensifentrine or a pharmaceutically acceptable salt thereof; and the patient is susceptible to COPD exacerbations.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to reducing the frequency and / or severity of chronic obstructive pulmonary disease (COPD) exacerbations in patients with COPD. The present invention also relates to treating COPD in patients prone to COPD exacerbations. [Background technology]

[0002] Background of the Invention 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.

[0003] As a combined PDE3 / PDE4 inhibitor, ensifentrine has both bronchodilator and anti-inflammatory activity and is useful in the treatment of respiratory disorders, including chronic obstructive pulmonary disease (COPD). The chemical structure of ensifentrine is shown below.

[0004] [ka]

[0005] COPD is a progressive, long-term condition that affects many people worldwide. Ongoing symptoms include shortness of breath and coughing. However, many COPD patients also suffer from occasional, temporary worsening of their symptoms (known as COPD exacerbations). COPD exacerbations typically include an increase in shortness of breath (dyspnea), the presence of excess mucus (increased sputum volume), a change in mucus color (sputum purulence), and / or an increase in coughing.

[0006] Certain patient groups are particularly susceptible to COPD exacerbations. This includes patients with additional respiratory conditions, such as asthma, and patients with allergic conditions. Patients susceptible to COPD exacerbations typically have previously experienced a COPD exacerbation.

[0007] COPD exacerbation can be severe and can limit the quality of life of COPD patients.Not all drugs disclosed for treating COPD are equally effective in reducing the severity and / or frequency of COPD exacerbation or the time to the first COPD exacerbation.Therefore, when there is a specific clinical need to deal with COPD exacerbation, it would be advantageous to use a COPD drug that is particularly effective in reducing the severity and / or frequency of COPD exacerbation. Summary of the Invention

[0008] It is a surprising discovery of the present invention that ensifentrine is highly effective in reducing the frequency and / or severity of COPD exacerbations in COPD patients. In particular, ensifentrine has been found to lead to a greater reduction in COPD exacerbations than many known treatments for COPD.

[0009] The present invention thus provides a compound for use in a method of reducing the frequency and / or severity of chronic obstructive pulmonary disease (COPD) exacerbations in a patient with COPD, wherein the compound is ensifentrine or a pharmaceutically acceptable salt thereof. The present invention also provides a compound for use in a method of increasing the time to first COPD exacerbation in a patient with COPD, wherein the compound is ensifentrine or a pharmaceutically acceptable salt thereof.

[0010] Also provided by the present invention is a compound for use in a method of treating chronic obstructive pulmonary disease (COPD) in a patient, wherein: the compound is ensifentrine or a pharmaceutically acceptable salt thereof; and the patient is susceptible to COPD exacerbations.

[0011] The present invention also provides a method for reducing the frequency and / or severity of chronic obstructive pulmonary disease (COPD) exacerbations in a patient suffering from COPD, the method comprising administering to the patient a therapeutically effective amount of a compound, wherein the compound is ensifentrine or a pharmaceutically acceptable salt thereof.

[0012] The present invention further provides a method of treating COPD in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound that is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the patient is prone to COPD exacerbations.

[0013] Further provided by the present invention is the use of a compound in the manufacture of a medicament for use in a method for reducing the frequency and / or severity of chronic obstructive pulmonary disease (COPD) exacerbations in a patient suffering from COPD, wherein the compound is ensifentrine or a pharmaceutically acceptable salt thereof.

[0014] Also provided by the present invention is the use of a compound that is ensifentrine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating COPD, wherein the patient is susceptible to COPD exacerbation. [Brief explanation of the drawings]

[0015] [Figure 1] Figure 1 shows the FEV1 profile over 12 hours at 12 weeks. DETAILED DESCRIPTION OF THE INVENTION

[0016] Detailed Description of the Invention The compound reduces the frequency and / or severity of COPD exacerbations in patients with chronic obstructive pulmonary disease (COPD). The compound can reduce the frequency of COPD exacerbations. For example, a patient may experience two or fewer (e.g., one or zero) COPD exacerbations per year while being treated with the compound, for example, as maintenance therapy. The number of COPD exacerbations experienced by a patient per year during treatment with the compound may be one to three less than the number of COPD exacerbations experienced by a patient per year before treatment with the compound.

[0017] The compound may increase the time to first COPD exacerbation in a patient. Thus, the patient may not yet have experienced a COPD exacerbation, and the compound may increase the time until the patient experiences their first COPD exacerbation (i.e., the first COPD exacerbation is delayed). The compound may therefore reduce the risk of a COPD exacerbation in a COPD patient.

[0018] A COPD exacerbation typically includes one or more of the following symptoms: dyspnea (shortness of breath), increased cough, increased sputum production, sputum purulence, wheezing, sore throat, cold, and fever. Sputum purulence is a change in the color of a naturally expectorated sample from colorless to yellow-green. A COPD exacerbation may last at least 1 day or at least 2 days.

[0019] A COPD exacerbation can include (A) a worsening of two or more of the following major symptoms for at least two consecutive days: dyspnea, sputum volume, and sputum purulence, or (B) a worsening of any one major symptom for at least two consecutive days in combination with any one of the following minor symptoms: sore throat, cold (runny nose and / or nasal congestion), fever without other cause (oral temperature >37.5°C), and increased cough. For example, a COPD exacerbation can include a worsening of two or more major symptoms (dyspnea, sputum volume, and sputum purulence) for at least two consecutive days.

[0020] COPD exacerbation can be a moderate COPD exacerbation or a severe COPD exacerbation. A moderate exacerbation is defined as a worsening symptom of COPD (as defined above) that requires at least 3 days of treatment with oral / systemic corticosteroids and / or antibiotics. A severe exacerbation is defined as a worsening symptom of COPD (as defined above) that requires hospitalization. The compound can reduce the severity of COPD exacerbation in patients, and therefore the compound can be used to prevent severe COPD exacerbations in patients. For example, a patient may not experience any severe COPD exacerbation in the year following the first administration of the compound.

[0021] The compound may increase the time to COPD exacerbation, for example, it may increase the time to exacerbation by two or more months.

[0022] The patient is typically susceptible to COPD exacerbation. Typically, a "patient susceptible to COPD exacerbation" is a patient suffering from one or more comorbidities (other than COPD). The patient typically suffers from one or more diseases or conditions selected from asthma, pulmonary hypertension, bronchiectasis, allergy, lung cancer, chest infection, cystic fibrosis, pulmonary fibrosis, pneumonia, hay fever, allergic rhinitis, bronchitis, emphysema, adult respiratory distress syndrome (ARDS), interstitial lung disease, or tuberculosis, optionally wherein the asthma is allergic asthma, steroid-resistant asthma, severe asthma, or childhood asthma. Patients susceptible to COPD exacerbations may have a chronic bronchitis etiology, may have impaired pulmonary function (such as 30 to 70% of predicted FEV1), or may have COPD symptoms despite the use of long-acting muscarinic receptor antagonist (LAMA) or long-acting beta-adrenergic receptor agonist (LABA) therapy.

[0023] For example, the compound may be for use in treating COPD in patients with both COPD and asthma. The compound may be for use in treating COPD in patients with both COPD and pulmonary hypertension. The compound may be for use in treating COPD in patients with both COPD and bronchiectasis.

[0024] Other risk factors for COPD exacerbations include: high serum immunoglobulin (Ig), previous tuberculosis, severe airflow obstruction, chest infection, and one or more hospitalizations for a COPD exacerbation in the previous year.

[0025] In some cases, the patient has experienced one or more COPD exacerbations in the year prior to the first administration of the compound.For example, the patient may have experienced two or more COPD exacerbations in the year prior to the first administration of the compound.For example, the patient may have suffered at least one severe COPD exacerbation (i.e., requiring hospital treatment) in the previous year.The patient may have experienced one or more COPD exacerbations in the six months prior to the first administration of the compound, or one or more COPD exacerbations in the month prior to the first administration of the compound.

[0026] The patient may be male. The patient may be female. The patient may be 65 years of age or older. The patient may be under 65 years of age. The patient may be taking background medications selected from one or more of a long-acting muscarinic antagonist (LAMA), a long-acting beta agonist (LABA), and an inhaled corticosteroid (ICS).

[0027] The compound is ensifentrine or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts are well known to those skilled in the art. Typically, the compound is ensifentrine (i.e., ensifentrine free base).

[0028] The method typically involves administering the compound to a patient by inhalation. A pharmaceutical composition comprising the compound and one or more pharmaceutically acceptable excipients or diluents is typically administered to a patient by inhalation, for example, by a nebulizer, pressurized metered dose inhaler (pMDI) or dry powder inhaler (DPI).

[0029] Preferably, the method comprises administering the compound to the patient by inhalation from a nebulizer. The nebulizer aerosolizes the liquid pharmaceutical composition into an aerosol that is inhaled into the patient's respiratory tract. Examples of nebulizers include soft mist nebulizers, vibrating mesh nebulizers, jet nebulizers, and ultrasonic nebulizers. Suitable nebulizer devices include Philips I-neb™ (Philips), Philips SideStream (Philips), AeroNeb® (Philips), Philips InnoSpire Go (Philips), Pari LC Sprint (Pari GmbH), AERxR™ Pulmonary Delivery System (Aradigm Corp), and Pari LC Plus Reusable Nebulizer (Pari GmbH). The nebulizer can be, for example, a PARI LC Sprint jet nebulizer with a PARI Vios® PRO Aerosol Delivery System PARI BOY® compressor. The compounds may be inhaled via a nebulizer for 1 to 15 minutes.

[0030] Typically, the method comprises administering the compound to the patient once, twice or three times a day, for example, twice or three times a day.The compound can 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 can comprise administering a first dose of the compound in the morning (for example, within 3 hours after waking up) and a second dose of the compound in the evening (for example, within 3 hours before going to bed).Typically, the morning and evening doses are administered 10 to 14 hours apart, for example, about 12 hours apart.

[0031] The compound can be used in any suitable therapeutically effective amount. Typically, the daily dose of the compound is 0.1 to 20 mg. Typically, the method includes administering a total daily dose of the compound of 0.5 to 10 mg. Preferably, the total daily dose of the compound (e.g., ensifentrine free base) is 5 to 7 mg per day, for example, about 6 mg. As used herein, the term "about" can represent a ±10% variation of the stated value. The total daily dose of the compound can be 6.0 mg.

[0032] Typically, compound is administered twice a day in two separate doses that are the same or similar.For example, the method can include administering compound to patient twice a day with a first dose of 1-5 mg and a second dose of 1-5 mg.Typically, the method can include administering compound to patient twice a day with a first dose of 2-4 mg and a second dose of 2-4 mg.

[0033] Preferably, the method comprises administering to the patient two doses of about 3 mg of ensifentrine free base per day by inhalation. Preferably, the method comprises administering to the patient a dose of about 3 mg of the compound twice a day (3 mg BID) by inhalation. More preferably, the method comprises administering to the patient a dose of about 3 mg of the compound twice a day by nebulizer. Each dose can be 3.0 mg of ensifentrine free base administered by nebulizer.

[0034] The compound is typically used as maintenance therapy.Typically, the method comprises administering the compound to the patient at least once a day for at least 8 weeks.The compound can be administered to the patient at least once a day for at least 16 weeks, preferably at least 24 weeks.The compound can be administered to the patient every day for at least 1 year.The method can 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 at least 16 weeks, more preferably at least 24 weeks.

[0035] 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 example, a dry powder comprising particles comprising the compound and particles of a carrier such as lactose.

[0036] The method typically involves 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 0.5 μm to 5.0 μm. The particles preferably have a Dv50 of 1.0 μm to 2.0 μm.

[0037] Particle size is described herein with reference to the Dv50 value, which is the median particle size for a volume distribution. That is, half of the particle volume has a diameter smaller than the Dv50 value, and half of the particle volume has a diameter larger than the Dv50 value. This is a well-known way of describing particle size distribution.

[0038] The technique used to measure Dv50 value described herein is typically laser diffraction.The particle size distribution of particles comprising compound can be measured by laser diffraction using wet powder dispersion system.For example, particle size distribution can be measured by laser diffraction using Malvern Spraytec connected with wet dispersion cell.Typically, the instrument parameters for Malvern Spraytec are as follows:

[0039] · Particles – standard opaque particles; Refractive index particles - 1.50; · Refractive index (imaginary) -0.50; · Particle density -1.00; · Refractive index of the dispersant - 1.33; Controller unit - 1000RPM; Measurement type - timed; Initial sampling time - 30 seconds; · Shading - 20%-30%; Dispersant - 1% Polysorbate 20 in deionized water.

[0040] The compound-containing particles typically contain ensifentrine (i.e., ensifentrine free base). The particles may contain at least 90% by weight of ensifentrine free base based on the total weight of the particle. The particles may contain at least 99% by weight of ensifentrine. The particles may consist of ensifentrine.

[0041] The concentration of compound-containing particles in the inhalable pharmaceutical composition is typically 0.1 to 5.0 mg / mL, preferably 0.1 to 2.5 mg / mL, more preferably 1.0 to 2.0 mg / mL.

[0042] Inhalable pharmaceutical compositions typically further comprise one or more tonicity adjusters, one or more buffering agents, and one or more surfactants. The tonicity adjuster is typically sodium chloride.

[0043] Examples of buffers include citrate buffers, phosphate buffers, acetate buffers, and bicarbonate buffers. Preferably, the buffer is a phosphate buffer, such as sodium dihydrogen phosphate dihydrate and / or disodium phosphate dihydrate.

[0044] Examples of surfactants are lecithin, oleic acid, polyoxyethylene glycol alkyl ethers (e.g., PEG 300, PEG 600, PEG 1000, Brij 30, Brij 35, Brij 56, Brij 76, and Brij 97), polypropylene glycols (e.g., PPG 2000), glucoside alkyl ethers, polyoxyethylene glycol octylphenol ethers, polyoxyethylene glycol alkylphenol ethers, glycerol alkyl esters, polyoxyethylene glycol sorbitan alkyl esters (polysorbates, e.g., polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80), sorbitan alkyl esters (e.g., sorbitan monolaurate (Span 20), sorbitan monooleate (Span 80), and sorbitan trioleate (Span 80)). 85), cocamide MEA, cocamide DEA, dodecyldimethylamine oxide, block copolymers of polyethylene glycol and polypropylene glycol (poloxamers), block copolymers of polyethylene glycol and polypropylene oxide (e.g., Pluronic surfactants), polyvinylpyrrolidone K25, polyvinyl alcohol, oligolactic acid, sodium dioctyl sulfosuccinate, and polyethoxylated tallowamine (POEA).

[0045] Preferably, the one or more surfactants include polysorbate and / or sorbitan alkyl ester. The one or more surfactants may include, for example, 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 include, for example, sorbitan monolaurate (Span 20), sorbitan monooleate (Span 80), or sorbitan trioleate (Span 85). Preferably, the sterile liquid vehicle includes polysorbate 20 and / or sorbitan monolaurate (Span 20).

[0046] For example, the method is: · Water; Particles consisting of ensifentrine free base in a concentration of 0.1 to 20 mg / mL; · One or more tonicity adjusters at a total concentration of 1.0 to 15 mg / mL; one or more buffering agents at a total concentration of 0.1 to 4 mg / mL; and One or more surfactants at a total concentration of 0.05 to 3 mg / mL The method may include administering to a patient an inhalable liquid pharmaceutical composition comprising:

[0047] The inhalable liquid pharmaceutical composition comprises: · Water; · Particles consisting of ensifentrine free base in a concentration of 0.5 to 6 mg / mL; · Sodium chloride at a concentration of 5 to 12 mg / mL; · Sodium dihydrogen phosphate dihydrate in a concentration of 0.3 to 2 mg / mL; · Disodium phosphate dihydrate at a concentration of 0.3 to 2 mg / mL; Polysorbate 20 at a concentration of 0.1 to 1.5 mg / mL; and Sorbitan monolaurate at a concentration of 0.01 to 0.5 mg / mL may include:

[0048] The compound can be used in combination with a second active agent.The compound and the second active agent can be administered separately or simultaneously.The patient may already be taking the second active agent as background therapy for COPD.Alternatively, the treatment with the second active agent can be started approximately at the same time as the treatment with the compound.The compound and the second active agent can be administered as a fixed combination.

[0049] The second active agent is typically a muscarinic receptor antagonist, a beta-adrenergic receptor agonist, or an inhaled corticosteroid.The compound can therefore be used in combination with a muscarinic receptor antagonist, a beta-adrenergic receptor agonist, or an inhaled corticosteroid.The second active agent can be a long-acting muscarinic receptor antagonist (LAMA) or a long-acting beta-adrenergic receptor agonist (LABA).

[0050] Examples of LAMAs include aclidinium, darotropium, tiotropium, glycopyrrolate, and umeclidinium. Examples of LABAs include salmeterol, formoterol, indacaterol, vilanterol, olodaterol, abesiterol, and carmoterol. Examples of inhaled corticosteroids include beclomethosone, budesonide, fluticasone propionate, ciclesonide, mometasone, and fluticasone furoate.

[0051] The patient may be using a beta agonist (e.g., salbutamol) as a rescue medication.

[0052] The invention will now be described in further detail by the following examples. [Example]

[0053] Study design A clinical study was conducted to determine the efficacy of ensifentrine compared with placebo in treating COPD. Ensifentrine was administered via nebulizer at a dose of 3 mg twice daily (BID) for 24 weeks. The study was a multicenter, randomized, double-blind, parallel-group, placebo-controlled trial with approximately 800 patients and a 5:3 randomization.

[0054] The study population included patients aged 40 to 80 years with moderate to severe COPD (mMRC ≥ 2, FEV1 30%-70% pn, FEV1 / forced vital capacity [FVC] ratio < 0.7). Randomization was stratified by (a) stable background maintenance LAMA or LABA therapy use (approximately 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 conditions.

[0055] The primary endpoint of the study was the change from baseline in mean FEV1 area under the curve (AUC) 0-12 hours post-dose at week 12. Secondary endpoints of the study included: peak FEV1 over 4 hours post-dose at week 12; morning trough FEV1 at week 12; and other endpoints, including frequency of moderate / severe COPD exacerbations and time to first moderate or severe COPD exacerbation over 24 weeks.

[0056] method COPD severity will be derived as follows: mild: 80%<=FEV1, moderate: 50%<=FEV1<80% predicted, severe: 30%<=FEV1<50% predicted and very severe: FEV1<30% predicted, after bronchodilator administration at screening.

[0057] Baseline FEV1 is the average of two measurements taken before study drug on the day of first dosing, i.e., within 40 minutes, and immediately before dosing, on Day 1.

[0058] Mean FEV1AUC0-12h is defined as the area under the curve of FEV1 over 12 hours divided by 12 hours.

[0059] An exacerbation was defined as a worsening of two or more major symptoms (dyspnea, sputum volume, and sputum purulence) for at least two consecutive days, or a worsening of any one major symptom together with any one of the following minor symptoms: sore throat, cold, fever without other cause, and increased cough or wheezing. A COPD exacerbation was considered to be of moderate severity if it required treatment with systemic corticosteroids and / or antibiotics, and severe if it required hospitalization.

[0060] formulation The study drug and placebo were provided in a 2.5 mL unit dose format in ampoules and administered via a nebulizer. The formulations for the study drug (ensifentrine suspension) and placebo are shown in Table 1 below.

[0061] [Table 1]

[0062] result The primary endpoint of mean FEV1 (AUC) 0-12h at 12 weeks was met. All subgroups showed statistically significant improvements in lung function with ensifentrine. Results are shown in Table 2 and Figure 1.

[0063] [Table 2]

[0064] Ensifentrine treatment resulted in an approximately 40% reduction in the relative risk of moderate or severe COPD exacerbations versus placebo (including 52% of patients on background bronchodilator therapy).

[0065] Comparison with other drugs For comparison, the reduction in COPD exacerbation rate achieved with other treatments taken from the literature (long-acting muscarinic antagonists (LAMAs), long-acting beta-agonists (LABAs), inhaled corticosteroids (ICS) and PDE4 inhibitors) is shown in Table 4 below.

[0066] [Table 4]

[0067] Ensifentrine was found to cause a greater reduction in the frequency of COPD exacerbations than other treatments.

[0068] conclusion Ensifentrine was found to provide statistically significant improvements in lung function in all subgroups of COPD patients in the study. Furthermore, ensifentrine was found to be particularly effective in increasing the time to first exacerbation (i.e., reducing the risk of exacerbations) and reducing the frequency of COPD exacerbations.

Claims

1. 1. A compound for use in a method for reducing the frequency and / or severity of chronic obstructive pulmonary disease (COPD) exacerbations in a patient suffering from COPD, wherein the compound is ensifentrine or a pharmaceutically acceptable salt thereof.

2. 2. The compound for use according to claim 1, wherein the method is a method for reducing the frequency of COPD exacerbations.

3. 1. A compound for use in a method of treating chronic obstructive pulmonary disease (COPD) in a patient, comprising: the compound is ensifentrine or a pharmaceutically acceptable salt thereof; and the patient is prone to COPD exacerbations, compound.

4. 10. The compound of any one of the preceding claims, wherein the COPD exacerbations include one or more of: dyspnea, increased cough, increased sputum volume, sputum purulence, wheezing, sore throat, cold, and fever.

5. 10. The compound of any one of the preceding claims, wherein the patient is a patient prone to COPD exacerbation, and wherein the patient prone to COPD exacerbation suffers from one or more diseases or conditions selected from asthma, pulmonary hypertension, bronchiectasis, allergy, lung cancer, chest infection, cystic fibrosis, pulmonary fibrosis, pneumonia, hay fever, allergic rhinitis, bronchitis, emphysema, adult respiratory distress syndrome (ARDS), interstitial lung disease or tuberculosis, optionally wherein the asthma is allergic asthma, steroid-resistant asthma, severe asthma or childhood asthma.

6. 10. The compound of any one of the preceding claims, wherein the patient has suffered one or more COPD exacerbations in the year prior to first administration of the compound, and optionally wherein the patient has suffered two or more COPD exacerbations in the year prior to first administration of the compound.

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

8. 10. A compound for use according to any one of the preceding claims, wherein the method comprises administering the compound to the patient by inhalation through a nebulizer.

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

10. 10. The 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.

11. 10. The compound for use according to any one of the preceding claims, wherein said method comprises administering said compound to said patient twice daily.

12. 10. The 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.

13. 10. The compound for use according to any one of the preceding claims, wherein the method comprises administering the compound to the patient twice daily in a first dose of 2 to 4 mg and a second dose of 2 to 4 mg.

14. 10. The compound for use according to any one of the preceding claims, wherein the method comprises administering to the patient a dose of about 3 mg of the compound twice daily (3 mg BID), preferably wherein the method comprises administering to the patient a dose of about 3 mg of the compound twice daily by nebulizer.

15. 10. The 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 at least 16 weeks, more preferably at least 24 weeks.

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

17. 10. A compound for use according to any one of the preceding claims, wherein the compound is used in combination with a muscarinic receptor antagonist, a beta-adrenergic receptor agonist or an inhaled corticosteroid.

18. 1. A method for reducing the frequency and / or severity of chronic obstructive pulmonary disease (COPD) exacerbations in a patient suffering from COPD, the method comprising administering to the patient a therapeutically effective amount of a compound, the compound being ensifentrine or a pharmaceutically acceptable salt thereof.

19. 1. A method for treating COPD in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound that is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the patient is prone to COPD exacerbations.

20. Use of a compound in the manufacture of a medicament for use in a method for reducing the frequency and / or severity of chronic obstructive pulmonary disease (COPD) exacerbations in a patient suffering from COPD, wherein the compound is ensifentrine or a pharmaceutically acceptable salt thereof.

21. 10. Use of a compound which is ensifentrine or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating COPD, wherein the patient is susceptible to COPD exacerbations.

22. composition: A suspension formulation comprising:

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