Ensifentrine (RPL-554) for the treatment of moderate chronic obstructive pulmonary disease (COPD)

Abstract

The present invention relates to a compound for use in treating moderate COPD in a patient, wherein the compound is ensifentrine or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to the treatment of moderate chronic obstructive pulmonary disease (COPD). [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 and can be experienced by patients with different levels of severity. COPD symptoms can range from mild to severe, and different treatment options may be preferred for different severities of COPD.

[0006] It would be beneficial to develop treatments that are particularly effective for moderate COPD. Summary of the Invention

[0007] It is a surprising discovery of the present invention that while ensifentrine is effective in treating all forms of COPD, it has been found to be particularly effective in treating moderate COPD. Inhaled administration of ensifentrine has been found to cause a particularly significant increase in FEV1 (forced expiratory volume in 1 second) in patients with moderate COPD.

[0008] There are many drugs disclosed for use in treating COPD, with different efficacy profiles for different grades and subtypes of COPD.

[0009] The present invention therefore provides a compound for use in treating moderate COPD in a patient, wherein the compound is ensifentrine or a pharmaceutically acceptable salt thereof.

[0010] The present invention also provides a method of treating moderate 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.

[0011] Further 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 moderate COPD. [Brief explanation of the drawings]

[0012] [Figure 1] Figure 1 shows the FEV1 profile over 12 hours at 12 weeks. DETAILED DESCRIPTION OF THE INVENTION

[0013] Detailed Description of the Invention The Global Initiative for Chronic Obstructive Lung Disease (GOLD) classifies COPD into four distinct stages: mild COPD, moderate COPD, severe COPD, or very severe COPD. The 2022 COPD Report has been published by the Global Initiative for Chronic Obstructive Disease, Inc., and that document is incorporated by reference in its entirety.

[0014] The stages of COPD can be classified as presented below, where FEV1 is forced expiratory volume in 1 second and FVC is forced vital capacity. Mild COPD: FEV1 / FVC<0.7 and FEV1≥80% predicted Moderate COPD: FEV1 / FVC<0.7 and 50%≦FEV1<80% predicted Severe COPD: FEV1 / FVC<0.7 and 30%≦FEV1<50% predicted Most severe COPD: FEV1 / FVC<0.7 and FEV1<30% predicted

[0015] In each case, the actual FEV1 for a patient is compared with the predicted FEV1 value based on factors such as the patient's age and height. These predicted values can be easily obtained by those skilled in the art, for example, from the National Health and Nutrition Examination Survey III (Hankinson JL, Odencrantz JR, Fedan KB. Spirometry reference values from a sample of the general US population. Am J Respir Crit Care. 1999; 159: 179-187). An example of the equation for calculating the predicted FEV1 (in L) for a patient is as follows, where H is height (cm) and A is age (years): Male: 0.0430H-0.0290A-2.490 Women: 0.0395H-0.025A-2.600

[0016] FEV1 and FVC used to determine COPD severity in patients are measured by spirometry immediately after administration of an appropriate dose of at least one short-acting inhaled bronchodilator. Typically, FEV1 and FVC measurements for determining COPD disease severity are performed between 15 and 30 minutes following administration of salbutamol (albuterol).

[0017] Typically, FEV1 and FVC as used herein are determined as presented in the article Standardisation of spirometry, Eur J 2005; 26; 319-338.

[0018] A patient may therefore be determined to have moderate COPD by measuring FEV1 / FVC<0.7 and 50%≦FEV1<80% predicted FEV1 values, where FEV1 is forced expiratory volume in 1 second and FVC is forced vital capacity measured between 15 and 30 minutes after administration of a bronchodilator, optionally where the bronchodilator is salbutamol. Determining the patient's COPD severity may be performed at least one day prior to the first administration of the compound.

[0019] 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 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). In some cases, the patient is not taking a background medication. For example, the patient may not be taking a background medication, and the background medication is a long-acting muscarinic antagonist (LAMA), a long-acting beta agonist (LABA), or an inhaled corticosteroid (ICS).

[0020] 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).

[0021] 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).

[0022] 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.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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:

[0032] · 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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).

[0038] 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).

[0039] 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:

[0040] 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:

[0041] 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.

[0042] 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).

[0043] 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.

[0044] The patient may be using a beta agonist (e.g., salbutamol) as a rescue medication.

[0045] The invention will now be described in further detail by the following examples. [Example]

[0046] 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.

[0047] The study population included patients aged 40–80 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.

[0048] The primary endpoint of the study was the change from baseline in mean area under the FEV1 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 the frequency of moderate / severe COPD exacerbations over 24 weeks.

[0049] 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.

[0050] 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, both taken before dosing on Day 1.

[0051] Mean FEV1AUC0-12h is defined as the area under the curve of FEV1 over 12 hours divided by 12 hours.

[0052] 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.

[0053] [Table 1]

[0054] 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.

[0055] [Table 2]

[0056] The mean mL change from baseline in FEV1(AUC) 0-12h at 12 weeks for patients with moderate and severe COPD, respectively, is shown in Table 3 below.

[0057] [Table 3]

[0058] Significant increases in FEV1 were observed for both moderate and severe COPD, however, particularly pronounced increases were observed in treatment of patients with moderate COPD.

[0059] 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 improving lung function in moderate COPD.

Claims

1. An agent for a method of treating moderate COPD in a patient, wherein the agent contains a compound which is encifentrin or a pharmaceutically acceptable salt thereof as an active ingredient.

2. The agent according to claim 1, wherein the method comprises administering the compound to the patient by inhalation.

3. The agent according to claim 1, wherein the method comprises administering the compound to the patient by inhalation using a nebulizer.

4. The agent according to claim 1, wherein the compound is ensifentrin.

5. The agent according to claim 1, wherein the method comprises administering the compound to the patient once, twice, or three times per day.

6. The agent according to claim 1, wherein the method comprises administering the compound to the patient twice a day.

7. The agent according to claim 1, wherein the method comprises administering a total daily dose of the compound of 0.5 to 10 mg, preferably 5 to 7 mg.

8. The agent according to claim 1, 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.

9. The agent according to claim 1, wherein the method comprises administering a dose of about 3 mg of the compound to the patient twice daily (3 mg BID), preferably wherein the method comprises administering a dose of about 3 mg of the compound to the patient twice daily by nebulizer.

10. The agent according to claim 1, wherein the method comprises administering the compound to the patient at least once a day for at least eight weeks, preferably at least sixteen weeks, and more preferably at least twenty-four weeks.

11. The patient had FEV １ / FVC < 0.7 and 50% ≤ FEV １ <80% forecast FEV １ It was determined that the patient has moderate COPD by measuring the FEV. １ The agent according to claim 1, wherein is the forced expiratory volume in one second, and FVC is the forced vital capacity measured between 15 and 30 minutes after administration of a bronchodilator, wherein optionally the bronchodilator is salbutamol.

12. The agent according to claim 1, wherein the method comprises administering an inhalable pharmaceutical composition comprising a suspension of particles of the compound in a diluent.

13. The agent according to claim 1, wherein the compound is administered in combination with a muscarinic receptor antagonist, a beta-adrenergic receptor agonist, or an inhaled corticosteroid.

14. The use of compounds that are ensifentrin or pharmaceutically acceptable salts thereof in the manufacture of drugs for the treatment of moderate COPD.

15. composition: A suspension formulation having the following properties.

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