Enceftine (RPL-554) for reducing frequency and / or severity of COPD worsening

Abstract

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

Description

Field of the Invention

[0001] The present invention relates to reducing the frequency and / or severity of chronic obstructive pulmonary disease (COPD) exacerbations in patients suffering from COPD. The present invention also relates to treating COPD in patients predisposed to COPD exacerbations. Background of the Invention

[0003] 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 WO00 / 58308A1.

[0004] As a combined PDE3 / PDE4 inhibitor, ensifentrine has bronchodilatory and anti-inflammatory activity and can be used to treat respiratory diseases including chronic obstructive pulmonary disease (COPD). The chemical structure of ensifentrine is shown below.

[0005]

[0006] COPD is a progressive long-term condition that affects a large number of people worldwide. Persistent symptoms include dyspnea and cough. However, many COPD patients also suffer from occasional, temporary exacerbations of their symptoms (termed COPD exacerbations). COPD exacerbations typically include an increase in dyspnea (shortness of breath), the presence of excessive mucus (increased sputum volume), a change in mucus color (purulent sputum), and / or an increase in cough.

[0007] Certain patient groups are particularly predisposed to COPD exacerbations. This includes patients with other respiratory conditions such as asthma and patients with allergic conditions. Patients predisposed to COPD exacerbations have typically previously experienced a COPD exacerbation.

[0008] COPD exacerbations can be severe and can limit the quality of life of COPD patients. Not all drugs disclosed for the treatment of COPD are equally effective in reducing the severity and / or frequency of COPD exacerbations or the time to the first COPD exacerbation. Therefore, when continuing to address this particular clinical aspect of exacerbations, it would be advantageous to use a COPD drug that is particularly effective in reducing the severity and / or frequency of COPD exacerbations. Summary of the Invention

[0010] The surprising finding of the present invention is that ensifentrine is highly effective in reducing the frequency and / or severity of COPD exacerbations in COPD patients. In particular, it has been found that ensifentrine results in a more significant reduction in COPD exacerbations compared to many known COPD treatments.

[0011] Accordingly, the present invention provides a compound for use in a method of reducing the frequency and / or severity of exacerbations of chronic obstructive pulmonary disease (COPD) in a patient suffering from 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 suffering from COPD, wherein the compound is ensifentrine or a pharmaceutically acceptable salt thereof.

[0012] The present invention also provides 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.

[0013] The present invention also provides a method of reducing the frequency and / or severity of exacerbations of chronic obstructive pulmonary disease (COPD) 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.

[0014] The present invention also provides a method of treating COPD in a patient, 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, and wherein the patient is susceptible to COPD exacerbations.

[0015] The present invention also provides the use of a compound in the manufacture of a medicament for use in a method of reducing the frequency and / or severity of exacerbations of chronic obstructive pulmonary disease (COPD) in a patient suffering from COPD, wherein the compound is ensifentrine or a pharmaceutically acceptable salt thereof.

[0016] The present invention also provides the use of a compound in the manufacture of a medicament for treating COPD, wherein the compound is ensifentrine or a pharmaceutically acceptable salt thereof, and wherein the patient is susceptible to COPD exacerbations.

[0017] BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 Shows the FEV1 curve at 12 hours at week 12. DETAILED DESCRIPTION OF THE INVENTION

[0020] The compound reduces the frequency and / or severity of exacerbations of chronic obstructive pulmonary disease (COPD) in a patient suffering from COPD. The compound can reduce the frequency of COPD exacerbations. For example, when treating with the compound, such as as maintenance therapy, a patient may have two or fewer (e.g., one or zero) COPD exacerbations per year. The number of COPD exacerbations experienced by a patient per year during treatment with the compound can be 1 to 3 less than the number of COPD exacerbations experienced by the patient per year prior to treatment with the compound.

[0021] The compound can increase the time to the first COPD exacerbation in a patient. Thus, the patient may not have experienced a COPD exacerbation, and the compound can increase the time until the patient experiences the first COPD exacerbation (i.e., the first COPD exacerbation is delayed). Accordingly, the compound can reduce the risk of COPD exacerbation in COPD patients.

[0022] COPD exacerbations typically include one or more of dyspnea (shortness of breath), increased cough, increased sputum volume, purulent sputum, wheezing, sore throat, cold, and fever. Purulent sputum is a color change of a spontaneously expectorated sample from non - colored to yellow - green. A COPD exacerbation can last at least one day or at least two days.

[0023] A COPD exacerbation can include (A) worsening of two or more of the following major symptoms: dyspnea, sputum volume, and purulent sputum over at least two consecutive days; or (B) worsening of any one of the major symptoms together with any one of the following minor symptoms: sore throat, cold (nasal discharge and / or nasal congestion), fever without other cause (oral temperature > 37.5 °C), and increased cough over at least two consecutive days. For example, a COPD exacerbation may include worsening of two or more major symptoms (dyspnea, sputum volume, and purulent sputum) lasting at least two days.

[0024] A COPD exacerbation can be a moderate COPD exacerbation or a severe COPD exacerbation. A moderate exacerbation is defined as exacerbation symptoms of COPD (as defined above) that require treatment with oral / systemic corticosteroids and / or antibiotics for at least three days. A severe exacerbation is defined as exacerbation symptoms of COPD (as defined above) that require hospitalization. The compound can reduce the severity of COPD exacerbation in a patient, and thus the compound can be used to prevent severe COPD exacerbations in patients. For example, in the year following the first administration of the compound, the patient may not experience a severe COPD exacerbation.

[0025] The compound can prolong the time to a COPD exacerbation. For example, it can increase the time to exacerbation by two or more months.

[0026] Patients are generally susceptible to COPD exacerbations. Typically, "patients susceptible to COPD exacerbations" are patients who have one or more comorbidities (other than COPD). The patients generally have one or more diseases or disease states 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 where the asthma is allergic asthma, steroid-resistant asthma, severe asthma or pediatric asthma. Despite treatment with long-acting muscarinic receptor antagonists (LAMA) or long-acting β-adrenergic receptor agonists (LABA), patients susceptible to COPD exacerbations may have a chronic bronchitis etiology, may have impaired lung function (e.g., 30 to 70% predicted FEV1) or may have COPD symptoms.

[0027] For example, the compound can be used to treat COPD in patients with COPD and asthma. The compound can be used to treat COPD in patients with COPD and pulmonary hypertension. The compound can be used to treat COPD in patients with COPD and bronchiectasis.

[0028] Other risk factors for COPD exacerbations include: high serum immunoglobulin (Ig), previous tuberculosis, severe airflow obstruction, chest infection and one or more hospitalizations for COPD exacerbations in the previous year.

[0029] In some cases, the patient has had one or more COPD exacerbations within one year prior to the first administration of the compound. For example, within the year prior to the first administration of the compound, the patient may have had two or more COPD exacerbations. For example, in the previous year, the patient may have had at least one severe COPD exacerbation (i.e., requiring hospital treatment). The patient may have had one or more COPD exacerbations within six months prior to the first administration of the compound, or within one month prior to the first administration of the compound.

[0030] The patient can be male. The patient can be female. The patient can have an age greater than or equal to 65 years. The patient can have an age less than 65 years. The patient can be taking background medications selected from one or more of long-acting muscarinic antagonists (LAMA), long-acting β-agonists (LABA) and inhaled corticosteroids (ICS).

[0031] The compound is ensifentrine or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts are well known to those skilled in the art. Generally, the compound is ensifentrine (i.e., ensifentrine free base).

[0032] The method generally includes administering the compound to a patient by inhalation. A pharmaceutical composition comprising the compound and one or more pharmaceutically acceptable excipients or diluents is generally administered to the patient by inhalation, such as by a nebulizer, pressurized metered-dose inhaler (pMDI), or dry powder inhaler (DPI).

[0033] Preferably, the method includes administering the compound to the patient by inhalation from a nebulizer. The nebulizer aerosolizes the liquid pharmaceutical composition into an aerosol, which 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 TM (Philips), Philips SideStream (Philips), (Philips), Philips InnoSpire Go (Philips), Pari LC Sprint (Pari GmbH), AERxR TM Lung Delivery System (Aradigm Corp), and Pari LCPlus reusable nebulizer (Pari GmbH). The nebulizer can be, for example, a Pari LC Sprint jet nebulizer with a PARI PRO aerosol delivery system PARI compressor. The compound can be inhaled via the nebulizer for 1 to 15 minutes.

[0034] Generally, the method includes administering the compound to the patient once, twice, or three times a day, such as 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 includes administering the compound to the patient by inhalation twice a day. The method can include administering a first dose of the compound in the morning (e.g., within 3 hours after waking up) and a second dose of the compound in the evening (e.g., within 3 hours before going to bed). Generally, the morning and evening doses are administered with an interval of 10 to 14 hours, such as an interval of about 12 hours.

[0035] The compound can be used in any suitable therapeutically effective amount. Generally, the daily dose of the compound is 0.1 to 20 mg. Generally, the method includes administering a total daily dose of 0.5 to 10 mg of the compound. Preferably, the total daily dose of the compound (e.g., ensifentrine free base) is 5 to 7 mg, such as about 6 mg / day. As used herein, the term "about" can represent a variation of ±10% of the stated value. The total daily dose of the compound can be 6.0 mg.

[0036] Typically, the compound is administered twice a day in two separate doses that are the same or similar. For example, the method can include administering the compound to a patient twice a day at a first dose of 1 to 5 mg and a second dose of 1 to 5 mg. Generally, the method can include administering the compound to a patient twice a day at a first dose of 2 to 4 mg and a second dose of 2 to 4 mg.

[0037] Preferably, the method includes administering to the patient two doses of approximately 3 mg of ensifentrine free base by inhalation per day. The method preferably includes administering to the patient a dose of approximately 3 mg of the compound by inhalation twice a day (3 mg BID). More preferably, the method includes administering to the patient a dose of approximately 3 mg of the compound twice a day by nebulizer. Each dose can be 3.0 mg of free base ensifentrine administered by nebulizer.

[0038] The compound is generally used as maintenance therapy. Typically, the method includes 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 daily for at least 1 year. The method can include 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.

[0039] The compound is preferably administered as a suspension formulation, i.e., a suspension of particles containing the compound in a diluent. Alternatively, the compound can be delivered in dry powder form, such as a dry powder containing particles containing the compound and carrier particles such as lactose.

[0040] The method generally includes administering an inhalable pharmaceutical composition that is a suspension of particles containing the compound in a diluent. The particles containing the compound generally 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.

[0041] Particle size is described herein by reference to the Dv50 value, which is the median particle size of the volume distribution. Thus, half of the volume of the particles has a diameter less than the Dv50 value, and half of the volume of the particles has a diameter greater than the Dv50 value. This is a well-known way to describe a particle size distribution.

[0042] The technique generally used to measure the Dv50 value as described herein is laser diffraction. The particle size distribution of the particles containing the compound can be measured by laser diffraction using a wet powder dispersion system. For example, the particle size distribution can be measured using laser diffraction of Malvern Spraytec in combination with a wet dispersion cell. Typically, the instrument parameters for Malvern Spraytec are as follows:

[0043] · Particles - Standard opaque particles;

[0044] · Refractive index of particles - 1.50;

[0045] · Refractive index (imaginary part) - 0.50;

[0046] · Particle density - 1.00;

[0047] · Refractive index of dispersant - 1.33;

[0048] · Controller unit - 1000 RPM;

[0049] · Measurement type - Timed;

[0050] · Initial sampling time - 30 s;

[0051] · Light shielding - 20% to 30%;

[0052] · Dispersant - Aqueous deionized solution of 1% polysorbate 20.

[0053] Particles containing the compound usually contain encefinetine (i.e., encefinetine free base). The particles containing the compound may contain at least 90% by weight of encefinetine free base relative to the total weight of the particles. The particles may contain at least 99% by weight of encefinetine. The particles may consist of encefinetine.

[0054] The concentration of particles containing the compound in the inhalable pharmaceutical composition is usually 0.1 to 5.0 mg / mL, preferably 0.1 to 2.5 mg / mL, more preferably 1.0 to 2.0 mg / mL.

[0055] The inhalable pharmaceutical composition usually further contains one or more tonicity regulators, one or more buffers, and one or more surfactants. The tonicity regulator is usually sodium chloride.

[0056] Examples of buffers include citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer. Preferably, the buffer is a phosphate buffer, such as sodium dihydrogen phosphate dihydrate and / or disodium phosphate dihydrate.

[0057] Examples of surfactants include 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 glycol (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 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 tallow amine (POEA).

[0058] Preferably, the one or more surfactants include polysorbates and / or sorbitan alkyl esters. The one or more surfactants can for example include 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 can for example include sorbitan monolaurate (Span 20), sorbitan monooleate (Span 80), or sorbitan trioleate (Span 85). Preferably, the sterile liquid medium includes polysorbate 20 and / or sorbitan monolaurate (Span 20).

[0059] For example, the method can include administering to a patient an inhalable liquid pharmaceutical composition comprising:

[0060] · water;

[0061] · particles consisting of ensifentrine free base at a concentration of 0.1 to 20 mg / mL;

[0062] · one or more tonicity modifiers at a total concentration of 1.0 to 15 mg / mL;

[0063] · one or more buffers at a total concentration of 0.1 to 4 mg / mL; and

[0064] ·One or more surfactants, with a total concentration of 0.05 to 3 mg / mL.

[0065] An inhalable liquid pharmaceutical composition may comprise:

[0066] ● Water;

[0067] · Particles composed of ensifentrine free base at a concentration of 0.5 to 6 mg / mL;

[0068] · Sodium chloride, with a concentration of 5 to 12 mg / mL;

[0069] · Sodium dihydrogen phosphate dihydrate, with a concentration of 0.3 to 2 mg / mL;

[0070] ● Disodium hydrogen phosphate dihydrate, with a concentration of 0.3 to 2 mg / mL;

[0071] · Polysorbate 20, with a concentration of 0.1 to 1.5 mg / mL; and

[0072] · Sorbitan monolaurate, with a concentration of 0.01 to 0.5 mg / mL.

[0073] The compound can be used in combination with a second active agent. The compound can be administered separately or simultaneously with the second active agent. The patient may already be taking a second active agent as background therapy for COPD. Alternatively, treatment with the second active agent can be initiated at approximately the same time as treatment with the compound. The compound and the second active agent can be administered in a fixed combination.

[0074] The second active agent is typically a muscarinic receptor antagonist, a β-adrenergic receptor agonist, or an inhaled corticosteroid. Thus, the compound can be used in combination with a muscarinic receptor antagonist, a β-adrenergic receptor agonist, or an inhaled corticosteroid. The second active agent can be a long-acting muscarinic receptor antagonist (LAMA) or a long-acting β-adrenergic receptor agonist (LABA).

[0075] Examples of LAMA include aclidinium, darodonium, tiotropium, glycopyrronium, and umeclidinium. Examples of LABA include salmeterol, formoterol, indacaterol, vilanterol, olodaterol, arformoterol, and carmoterol. Examples of inhaled corticosteroids include beclomethasone, budesonide, fluticasone propionate, ciclesonide, mometasone, and fluticasone furoate.

[0076] The patient can use a β-agonist (such as salbutamol) as a rescue medication.

[0077] The present invention is described in more detail by the following examples. Examples

[0078] Study design

[0079] A clinical study was conducted to determine the efficacy of ensifentrine in the treatment of COPD compared to placebo. 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.

[0080] The study population included patients aged 40 to 80 years with moderate to severe COPD (FEV1 30% to 70% p.n., FEV1 / forced vital capacity [FVC] ratio < 0.7, mMRC ≥ 2). Randomization was stratified (a) by use of stable background maintenance LAMA or LABA therapy (approx. 50%, yes or no) and (b) by smoking (current or previous). Inhaled corticosteroid (ICS) maintenance therapy was permitted in up to 20% of patients according to certain provisions.

[0081] At week 12 after dosing, the primary endpoint of the study was the change in the area under the curve (AUC) of mean FEV1 compared to baseline. 0-12h The secondary endpoints of the study included: peak FEV1 at 4 hours at week 12 after dosing; morning trough FEV1 at week 12; and other endpoints including the frequency of moderate / severe COPD exacerbations within 24 weeks and the time to first moderate or severe COPD exacerbation.

[0082] Methods

[0083] COPD severity was determined as follows: mild: 80% <= FEV1, moderate: 50% <= FEV1 < 80% predicted, severe: 30% <= FEV1 < 50% predicted, and very severe: FEV1 < 30% predicted, after administration of a bronchodilator at screening.

[0084] Baseline FEV1 was the mean of two measurements taken before the study drug on the day of the first dosing, i.e., <= 40 minutes and taken immediately before dosing on the first day.

[0085] Mean FEV1 AUC 0-12h Was defined as the area under the curve of FEV1 over 12 hours divided by 12 hours.

[0086] An exacerbation was defined as worsening of two or more major symptoms (dyspnea, sputum volume, and sputum purulence) or 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 for at least 2 consecutive days. A COPD exacerbation was considered moderately severe if treatment with systemic corticosteroids and / or antibiotics was required and severe if hospitalization was required.

[0087] Formulation

[0088] The study product and placebo were provided in 2.5 mL unit doses in ampoules and administered via a nebulizer. The formulations of the study product (ensifentrine suspension formulation) and placebo are shown in Table 1 below.

[0089] Composition Concentration (mg / mL) Encefinatin Granules (RPL554) 1.2 (for active substance) or 0 (for placebo) Polysorbate 20 (Tween20) 0.50 Sorbitan monolaurate (span20) 0.05 Sodium dihydrogen phosphate dihydrate 0.744 Disodium hydrogen phosphate dihydrate 0.853 Sodium chloride solution 8.60 Water To 1 mL q.s.

[0090] Table 1

[0091] Results

[0092] The primary endpoint of mean FEV1 (AUC) was reached at Week 12. All subgroups showed an improvement in lung function with ensifentrine, which was statistically significant. The results are shown in Table 2. 0-12h The treatment with ensifentrine led to a relative risk reduction of approximately 40% for moderate or severe COPD exacerbations compared to placebo (including 52% of patients on background bronchodilators).

[0093]

[0094]

[0095] Table 2

[0096] Treatment with ensifentrine resulted in a relative risk reduction of approximately 40% for moderate or severe COPD exacerbations compared to placebo (including 52% of patients on background bronchodilators).

[0097] Comparison with other drugs

[0098] For comparison, the reduction in the rate of COPD exacerbations obtained with other treatments (long-acting muscarinic antagonists (LAMA), long-acting β-agonists (LABA), inhaled corticosteroids (ICS), and PDE4 inhibitors) is shown in Table 4 below.

[0099]

[0100]

[0101] Table 4

[0102] Ensifentrine was found to cause a greater reduction in the frequency of COPD exacerbations compared to other treatments.

[0103] Conclusion

[0104] It has been found that in the study, ensifentrine provided a statistically significant improvement in lung function in all subgroups of COPD patients. In addition, ensifentrine has been found to be particularly effective in increasing the time to first exacerbation (i.e., reducing the risk of exacerbation) and reducing the frequency of COPD exacerbations.

Claims

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

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

3. 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 prone to COPD exacerbations.

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

5. The compound according to any one of the preceding claims, wherein the patient is a patient prone to COPD exacerbations and the patient prone to COPD exacerbations has one or more diseases or disease states 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 pediatric asthma.

6. The compound according to any one of the preceding claims, wherein the patient has had one or more COPD exacerbations within one year prior to the first administration of the compound, optionally wherein the patient has had two or more COPD exacerbations within one year prior to the first administration of the compound.

7. The compound according to any one of the preceding claims, wherein the method comprises administering the compound to the patient by inhalation.

8. The compound according to any one of the preceding claims, wherein the method comprises administering the compound to the patient by nebulizer inhalation.

9. The compound according to any one of the preceding claims, wherein the compound is ensifentrine.

10. The compound according to any one of the preceding claims, wherein the method comprises administering the compound to the patient once, twice or three times a day.

11. The compound according to any one of the preceding claims, wherein the method comprises administering the compound to the patient twice a day.

12. The compound according to any one of the preceding claims, wherein the method comprises administering a total daily dose of 0.5 to 10 mg, preferably 5 to 7 mg of the compound.

13. The compound according to any one of the preceding claims, wherein the method comprises administering the compound to the patient twice a day at a first dose of 2 to 4 mg and a second dose of 2 to 4 mg.

14. The compound 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 a day (3 mg BID), preferably wherein the method comprises administering to the patient a dose of about 3 mg of the compound by nebulizer twice a day.

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

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

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

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

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

22. A suspension formulation having the following composition:

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