Ensifentrine (RPL-554) for increasing trough lung function

Abstract

The present invention relates to a compound for use in a method for increasing trough lung function in a patient suffering from chronic obstructive pulmonary disease (COPD), wherein the compound is ensifentrine or a pharmaceutically acceptable salt thereof. The present invention also relates to a compound for use in 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 sleep disorders.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to increasing trough lung function in patients with chronic obstructive pulmonary disease (COPD). The present invention also relates to the treatment of COPD in patients susceptible to sleep disorders. [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 cough. Treatment for COPD typically involves maintenance therapy, in which patients receive medications regularly (e.g., once or twice daily) to improve lung function and ameliorate COPD symptoms.

[0006] Lung function in COPD patients typically follows a cycle during maintenance therapy. Lung function in COPD can be measured by determining the patient's forced expiratory volume in one second (FEV1). During the period following administration of the drug, improved lung function is achieved, reaching a peak improvement after a period of drug administration. The patient's lung function then declines toward trough lung function, i.e., the lowest point in the lung function cycle during maintenance therapy. Trough lung function generally occurs immediately before the next dose of maintenance therapy medication. For example, for twice-daily (morning and evening) maintenance therapy, trough lung function generally occurs immediately before the morning dose of medication (morning trough lung function) and the evening dose of medication (evening trough lung function).

[0007] The trough lung function achieved during maintenance therapy can have a significant impact on the symptoms and / or quality of life of COPD patients. Trough lung function effectively represents the worst lung function during maintenance therapy. For twice-daily administration, morning trough lung function often coincides with the time of day when the patient is asleep. This means that a patient may have poor lung function for part of the night, which can disrupt their sleep (e.g., due to limited oxygen absorption) and cause fatigue, thereby reducing their quality of life. This is particularly true in COPD patients who already have disturbed sleep, for example, due to sleep disorders and sleep-disturbing comorbidities.

[0008] If trough lung function can be improved, then COPD symptoms can be improved more consistently, and quality of life can also be improved. Improvements in morning trough lung function can be particularly beneficial in those patients who are already susceptible to sleep disruption.

[0009] There are many drugs disclosed for use in treating COPD. However, they are not all equally effective in improving trough lung function, and especially morning trough lung function. In order to optimize the therapeutic effect of pharmacological intervention, it would be clinically advantageous to administer a specific drug that is particularly effective in improving trough lung function to patients who have a particular therapeutic need. Summary of the Invention

[0010] It is a discovery of the present invention that ensifentrine, when used as a maintenance therapy, is particularly effective in increasing trough lung function in patients with COPD. In particular, ensifentrine can improve morning trough lung function in COPD patients, which is particularly beneficial for COPD patients who are prone to sleep disruption, for example, due to the presence of comorbid conditions that affect sleep.

[0011] The present invention therefore provides a compound for use in a method of increasing trough lung function in a patient suffering from chronic obstructive pulmonary disease (COPD), wherein the compound is ensifentrine or a pharmaceutically acceptable salt thereof.

[0012] Also provided by the present invention is a compound for use in 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 a sleep disorder.

[0013] The present invention also provides a method for increasing trough lung function 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 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 sleep disorders.

[0015] Further provided by the present invention is the use of a compound in the manufacture of a medicament for use in a method of increasing trough pulmonary function in a patient, wherein the compound is ensifentrine or a pharmaceutically acceptable salt thereof.

[0016] 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 sleep disorders. [Brief explanation of the drawings]

[0017] [Figure 1] Figure 1 shows the FEV1 profile over 12 hours at 12 weeks. DETAILED DESCRIPTION OF THE INVENTION

[0018] Detailed Description of the Invention Patients typically receive the compound as a maintenance therapy. The compound can be administered to patients once, twice or three times a day. The compound is preferably administered twice a day as a maintenance therapy.

[0019] Increases in trough lung function in patients with COPD are typically determined by measuring trough FEV1, i.e., the increase in the patient's FEV1 immediately prior to administration of a compound as part of maintenance therapy. Improvements in trough lung function can result, for example, from changes in maintenance therapy medications.

[0020] The method can include increasing morning trough lung function (i.e., trough lung function following sleep). Morning trough lung function can be measured by determining the patient's FEV1 immediately before the morning administration of a compound as part of maintenance therapy. For example, FEV1 can be measured less than 1 hour before the morning administration of the compound. Morning trough FEV1 can be measured between 11.5 hours and 12 hours following the previous evening dose.

[0021] Typically, FEV1 and FVC (forced vital capacity) as used herein are determined as presented in the article Standardisation of spirometry, Eur J 2005; 26; 319-338.

[0022] Improvement in trough lung function can improve sleep in COPD patients.This is particularly important in patients who are prone to sleep disorders.Patients who are prone to sleep disorders typically suffer from conditions that directly affect their ability to sleep (such as insomnia or sleep apnea), or conditions that indirectly make it more difficult to sleep (such as skin conditions such as psoriasis, which irritate the skin and make it more difficult for patients to fall asleep or stay asleep).

[0023] " Patients susceptible to sleep disorders " are typically patients suffering from one or more diseases or conditions selected from obesity, insomnia, sleep apnea, narcolepsy, restless legs syndrome, REM sleep behavior disorder, circadian rhythm sleep disorder parasomnia, depression, anxiety, psoriasis, dermatitis, eczema or urticaria.For example, compound can be used to treat COPD in patients suffering from COPD and sleep apnea.Compound can be used to treat COPD in patients suffering from COPD and skin conditions such as psoriasis, dermatitis, eczema or urticaria.

[0024] Improved trough lung function can greatly assist COPD patients in exercising, i.e., in a preferred embodiment, the patient suffers from obesity.

[0025] 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).

[0026] 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).

[0027] 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).

[0028] 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.

[0029] 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.

[0030] The compound may 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" may represent a ±10% variation of the stated value. The total daily dose of the compound may be 6.0 mg.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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:

[0038] · 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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).

[0044] 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).

[0045] 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:

[0046] 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 at 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:

[0047] 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.

[0048] 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).

[0049] 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.

[0050] The patient may be using a beta agonist (e.g., salbutamol) as a rescue medication.

[0051] The invention will now be described in further detail by the following examples. [Example]

[0052] 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.

[0053] 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.

[0054] 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 nadir FEV1 at week 12; and other endpoints, including the frequency of moderate / severe COPD exacerbations over 24 weeks.

[0055] 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.

[0056] 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, before dosing.

[0057] Mean FEV1AUC0-12h is defined as the area under the curve of FEV1 over 12 hours divided by 12 hours.

[0058] Morning trough FEV1 at week 12 will be defined as the FEV1 assessed from 11.5 to 12 hours following the previous evening dose.

[0059] 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.

[0060] [Table 1]

[0061] 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.

[0062] [Table 2]

[0063] The effect of ensifentrine on morning trough FEV1 at 12 weeks is shown in Table 3.

[0064] [Table 3]

[0065] Morning trough FEV1 showed a statistically significant effect at 12 weeks, confirming the twice-daily dosing interval.

[0066] 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 trough lung function, particularly by increasing morning trough FEV1.

Claims

1. An agent for a method of increasing trough lung function in patients suffering from chronic obstructive pulmonary disease (COPD), wherein the agent contains a compound which is ensifentrin or a pharmaceutically acceptable salt thereof as an active ingredient.

2. The agent according to claim 1, wherein the compound is administered as maintenance therapy.

3. The agent according to claim 1, wherein the compound is administered twice daily as maintenance therapy.

4. The agent according to claim 1, wherein the method includes increasing morning trough lung function.

5. An agent for a method of treating chronic obstructive pulmonary disease (COPD) in patients, wherein: The agent contains a compound which is ensifentrin or a pharmaceutically acceptable salt thereof; and The patient is prone to sleep disorders. Agent.

6. The agent according to claim 1 or 5, wherein the patient is prone to sleep disorders, and the patient is suffering from one or more diseases or conditions selected from insomnia, sleep apnea, narcolepsy, restless legs syndrome, REM sleep behavior disorder, circadian rhythm sleep disorder, parasomnia, depression, anxiety, psoriasis, dermatitis, eczema, or urticaria.

7. The agent according to claim 1 or 5, wherein the method comprises administering the compound to the patient by inhalation.

8. The agent according to claim 1 or 5, wherein the method comprises administering the compound to the patient by inhalation using a nebulizer.

9. The agent according to claim 1 or 5, wherein the compound is ensifentrin.

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

11. The agent according to claim 1 or 5, wherein the method comprises administering the compound to the patient twice a day.

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

13. The agent according to claim 1 or 5, 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. The agent according to claim 1 or 5, 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.

15. The agent according to claim 1 or 5, wherein the method comprises 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, and more preferably at least 24 weeks.

16. The agent according to claim 1 or 5, wherein the method comprises administering an inhalable pharmaceutical composition comprising a suspension of particles of the compound in a diluent.

17. The agent according to claim 1 or 5, wherein the compound is administered in combination with a muscarinic receptor antagonist, a beta-adrenergic receptor agonist, or an inhaled corticosteroid.

18. Use of a compound in the manufacture of a drug for a method of increasing trough lung function in a patient, wherein the compound is ensifentrin or a pharmaceutically acceptable salt thereof.

19. The use of a compound that is ensifentrin or a pharmaceutically acceptable salt thereof in the manufacture of a drug for a method of treating COPD, wherein the patient is prone to sleep disturbances.

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

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