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

Abstract

The present invention relates to a compound useful in the treatment of moderate COPD in a patient, which compound is empedentine or a pharmaceutically acceptable salt thereof.

Description

Field of the Invention

[0001] The present invention relates to the treatment of moderate chronic obstructive pulmonary disease (COPD). Background of the Invention

[0003] Ensefentin (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, Enseifentin has bronchodilatory and anti-inflammatory activities and is useful for treating respiratory diseases including chronic obstructive pulmonary disease (COPD). The chemical structure of Enseifentin is shown below.

[0005]

[0006] COPD is a progressive, long-term condition and can be experienced by patients at varying degrees of severity. The symptoms of COPD can range from mild to severe, and different treatment options can be preferred for different degrees of severity of COPD.

[0007] It would be beneficial to develop treatments that are particularly effective for moderate COPD. SUMMARY OF THE INVENTION

[0009] The surprising discovery of the present invention is that, although Enseifentin is effective in treating all forms of COPD, it has been found to be particularly effective in treating moderate COPD. Inhaled administration of Enseifentin has been found to cause a particularly significant increase in FEV1 (forced expiratory volume in 1 second) in patients with moderate COPD.

[0010] There are many drugs that are published for the treatment of COPD. These drugs have different efficacy profiles for different grades and subtypes of COPD.

[0011] Therefore, the present invention provides a compound for use in treating moderate COPD in a patient, the compound being encefantine or a pharmaceutically acceptable salt thereof.

[0012] The present invention also provides a method for treating moderate COPD in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound, which is encefantine or a pharmaceutically acceptable salt thereof.

[0013] The present invention also provides use of a compound in preparing a drug for treating moderate COPD, wherein the compound is encefantine or a pharmaceutically acceptable salt thereof.

[0014] BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 The 12-hour FEV1 curve at week 12 is shown. DETAILED DESCRIPTION OF THE INVENTION

[0017] The Global Initiative for Chronic Obstructive Lung Disease (GOLD) classifies COPD into four different stages. These are mild COPD, moderate COPD, severe COPD, or very severe COPD. The 2022 COPD report is published by the Global Initiative for Chronic Obstructive Disease, Inc, and the entire contents of this document are incorporated herein by reference.

[0018] The above stages of COPD can be classified as follows, where FEV1 is the forced expiratory volume in 1 second and FVC is the forced vital capacity.

[0019] Mild COPD: FEV1 / FVC < 0.7 and FEV1 ≥ 80% predicted

[0020] Moderate COPD: FEV1 / FVC < 0.7 and 50% ≤ FEV1 < 80% predicted

[0021] Severe COPD: FEV1 / FVC < 0.7 and 30% ≤ FEV1 < 50% predicted

[0022] Very severe COPD: FEV1 / FVC < 0.7 and FEV1 < 30% predicted

[0023] In each case, the actual FEV1 of the patient is compared with the predicted FEV1 value based on factors such as the patient's age and height. These predicted values ​​are readily available to 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 (spirometry reference values ​​from a sample of the general American population). AM J Respir Crit Care 1999; 159: 179-187). An example of an equation for calculating the predicted FEV1 (in L) of a patient is as follows, where H is height (cm) and A is age (years):

[0024] ·Male: 0.0430H-0.0290A-2.490

[0025] ·Female: 0.0395H-0.025A-2.600

[0026] FEV1 and FVC used to determine the severity of COPD in patients are measured by spirometry shortly after administration of an adequate dose of at least one short-acting inhaled bronchodilator. Typically, measurements of FEV1 and FVC used to determine COPD disease severity are performed 15 to 30 minutes after administration of albuterol.

[0027] Typically, FEV1 and FVC as used herein are measured as described in Standardisation of Spirometry Eur J 2005; 26; 319-338

[0028] The patient has been determined to have moderate COPD by measuring FEV1 / FVC < 0.7 and 50% ≤ FEV1 < 80% predicted FEV1 values, where FEV1 is the forced expiratory volume in 1 second and FVC is the forced vital capacity measured 15 to 30 minutes after administration of a bronchodilator, optionally where the bronchodilator is albuterol. Determination of the severity of COPD in the patient may be performed at least 1 day prior to the first administration of the compound.

[0029] The patient can be male. The patient can be female. The patient can have an age greater than or equal to 65 years old. The patient can have an age less than 65 years old. The patient can take one or more background medications selected from long-acting muscarinic antagonists (LAMA), long-acting beta-agonists (LABA) and inhaled corticosteroids (ICS). In some cases, the patient does not receive background medications. For example, the patient may not take background medications, which are long-acting muscarinic antagonists (LAMA), long-acting beta-agonists (LABA) or inhaled corticosteroids (ICS).

[0030] The compound is Ensefentin or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts are well known to those skilled in the art. Typically, the compound is Ensefentin (i.e., Ensefentin free base).

[0031] The method generally comprises administering the compound to the patient by inhalation. Pharmaceutical compositions comprising the compound and one or more pharmaceutically acceptable excipients or diluents are generally administered to the patient by inhalation, such as by a nebulizer, a pressurized metered dose inhaler (pMDI) or a dry powder inhaler (DPI).

[0032] Preferably, the method comprises administering the compound to the patient by inhalation from a nebulizer. A nebulizer aerosolizes a liquid pharmaceutical composition into an aerosol which is inhaled into the respiratory tract of the patient. Examples of nebulizers include soft mist nebulizers, vibrating mesh nebulizers, jet nebulizers, and ultrasonic nebulizers. Suitable nebulizer devices include the Philips I-neb TM (Philips)、Philips SideStream(Philips)、 (Philips), Philips InnoSpire Go (Philips), Pari LC Sprint (Pari GmbH), AERxR TM Pulmonary delivery system (Aradigm Corp) and Pari LCPlus reusable nebulizer (Pari GmbH). The nebulizer can be, for example, a PARI PRO Aerosol Delivery System PARI PARI LC Sprint Jet Nebulizer with Compressor. The compound can be inhaled via the nebulizer for 1 to 15 minutes.

[0033] Typically, the method includes 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 once, twice or three times a day by inhalation. Preferably, the method includes administering the compound to the patient by inhalation twice a day. The method may include administering a first dose of the compound in the morning (e.g., within 3 hours after waking up) and administering a second dose of the compound in the evening (e.g., 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.

[0034] 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 comprises administering a total daily dose of 0.5 to 10 mg of the compound. Preferably, the total daily dose of the compound (e.g., Ensefentin free base) is 5 to 7 mg, such as about 6 mg / day. As used herein, the term "about" may represent a variation of ±10% of the value. The total daily dose of the compound may be 6.0 mg.

[0035] Typically, the compound is administered twice a day in two separate doses that are identical or similar. For example, the method may include administering the compound to a patient twice a day in a first dose of 1 to 5 mg and a second dose of 1 to 5 mg. Typically, the method may include administering the compound to a patient twice a day in a first dose of 2 to 4 mg and a second dose of 2 to 4 mg.

[0036] Preferably, the method comprises administering two doses of about 3 mg of Ensefentin free base to the patient daily by inhalation. The method preferably comprises administering to the patient about 3 mg doses of the compound twice daily (3 mg BID) by inhalation. More preferably, the method comprises administering to the patient about 3 mg doses of the compound twice a day by nebulizer. Each dose may be 3.0 mg of free base Ensefentin administered by nebulizer.

[0037] The compound is generally used as a maintenance therapy. Typically, the method comprises administering the compound to the patient at least once a day for at least 8 weeks. The compound may be administered to the patient at least once a day for at least 16 weeks, preferably at least 24 weeks. The compound may be administered to the patient daily for at least 1 year. The method may comprise administering the compound to the patient at least once every 24 hours, preferably at least twice every 24 hours for at least 8 weeks, preferably at least 16 weeks, more preferably at least 24 weeks.

[0038] The compound is preferably administered as a suspension formulation, ie, a suspension of particles containing the compound in a diluent. Alternatively, the compound may be delivered in the form of a dry powder, for example a dry powder comprising particles containing the compound and carrier particles such as lactose.

[0039] The method generally comprises administering an inhalable pharmaceutical composition comprising a suspension of particles of the compound in a diluent. The particles comprising the compound generally have a particle size distribution of Dv50 of 0.5 μm to 5.0 μm. The particles preferably have a Dv50 of 1.0 μm to 2.0 μm.

[0040] Particle size is described herein by reference to the Dv50 value, which is the median particle size of the volume distribution. Thus, half the volume of particles has a diameter less than the Dv50 value, and half the volume of particles has a diameter greater than the Dv50 value. This is a well-known way of describing particle size distribution.

[0041] The technique used to measure the Dv50 value as described herein is generally laser diffraction. The particle size distribution of particles comprising the compound can be measured by laser diffraction using a wet powder dispersion system. For example, the particle size distribution can be measured using the laser diffraction of a Malvern Spraytec in combination with a wet dispersion cell. Typically, the instrument parameters of the Malvern Spraytec are as follows:

[0042] ●Granules-standard opaque grains;

[0043] Refractive index particles -1.50;

[0044] Refractive index (imaginary part) -0.50;

[0045] Particle density - 1.00;

[0046] The refractive index of the dispersant is -1.33;

[0047] Controller unit - 1000RPM;

[0048] Measurement type – timing;

[0049] Initial sampling time - 30s;

[0050] · Shading - 20% to 30%;

[0051] Dispersant - 1% polysorbate 20 in deionized water.

[0052] The particles comprising the compound generally comprise ensephentin (i.e., ensephentin free base). The particles comprising the compound may comprise at least 90% by weight of ensephentin free base relative to the total weight of the particles. The particles may comprise at least 99% by weight of ensephentin. The particles may consist of ensephentin.

[0053] The concentration of particles comprising the compound in the inhalable pharmaceutical composition is generally 0.1 to 5.0 mg / mL, preferably 0.1 to 2.5 mg / mL, more preferably 1.0 to 2.0 mg / mL.

[0054] Inhalable pharmaceutical compositions also typically include one or more tonicity adjusters, one or more buffers, and one or more surfactants. The tonicity adjuster is typically sodium chloride.

[0055] 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.

[0056] 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 such as 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 100). 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), polyvinyl pyrrolidone K25, polyvinyl alcohol, oligomeric lactic acid, sodium dioctyl sulfosuccinate and polyethoxylated tallow amine (POEA).

[0057] Preferably, the one or more surfactants include polysorbates and / or sorbitan alkyl esters. The one or more surfactants may, 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 may, 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).

[0058] For example, the method may comprise administering to a patient an inhalable liquid pharmaceutical composition comprising:

[0059] ·water;

[0060] particles consisting of encephalin free base at a concentration of 0.1 to 20 mg / mL;

[0061] One or more tonicity adjusting agents at a total concentration of 1.0 to 15 mg / mL;

[0062] One or more buffering agents at a total concentration of 0.1 to 4 mg / mL; and

[0063] • One or more surfactants at a total concentration of 0.05 to 3 mg / mL.

[0064] The inhalable liquid pharmaceutical composition may comprise:

[0065] ·water;

[0066] particles consisting of encephalin free base at a concentration of 0.5 to 6 mg / mL;

[0067] Sodium chloride, at a concentration of 5 to 12 mg / mL;

[0068] Sodium dihydrogen phosphate dihydrate at a concentration of 0.3 to 2 mg / mL;

[0069] Sodium hydrogen phosphate dihydrate at a concentration of 0.3 to 2 mg / mL;

[0070] Polysorbate 20 at a concentration of 0.1 to 1.5 mg / mL; and

[0071] Sorbitan monolaurate at a concentration of 0.01 to 0.5 mg / mL.

[0072] 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 the second active agent as a background therapy for COPD. Alternatively, treatment with the second active agent can be started at about the same time as treatment with the compound. The compound and the second active agent can be administered in a fixed combination.

[0073] The second active agent is typically a muscarinic receptor antagonist, a beta-adrenergic receptor agonist, or an inhaled corticosteroid. Thus, the compound can 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).

[0074] Examples of LAMAs include aclidinium, darolium, tiotropium, glycopyrronium, and umeclidinium. Examples of LABAs include salmeterol, formoterol, indacaterol, vilanterol, olodaterol, abetrol, and carmoterol. Examples of inhaled corticosteroids include beclomethasone, budesonide, fluticasone propionate, ciclesonide, mometasone, and fluticasone furoate.

[0075] Patients can take beta-agonists (such as albuterol) as rescue medication.

[0076] The present invention is described in more detail by the following examples. Example

[0077] Study Design

[0078] A clinical study was conducted to determine the efficacy of Ensefentin in the treatment of COPD compared to placebo. Ensefentin was administered twice a day (BID) at a dose of 3 mg via nebulizer for 24 weeks. The study was a multicenter, randomized, double-blind, parallel-group, placebo-controlled trial with approximately 800 patients and 5:3 randomization.

[0079] The study population included patients aged 40 to 80 years with moderate to severe COPD (FEV1 30% to 70% pn, FEV1 / forced vital capacity (FVC) ratio <0.7, mMRC ≥2). Randomization was stratified by (a) use of stable background maintenance LAMA or LABA therapy (approximately 50%, yes or no) and (b) smoking (current or former). Inhaled corticosteroid (ICS) maintenance therapy was allowed in up to 20% of patients under certain provisions.

[0080] The primary endpoint of the study was the mean FEV1 area under the curve (AUC) compared with baseline at week 12 after dosing. 0-12h 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 over 24 weeks.

[0081] method

[0082] COPD severity was derived as follows: mild: 80% <= FEV1, moderate: 50% <= FEV1 < 80% predicted, severe: 30% <= FEV1 < 50% predicted, and very severe: FEV1 < 30% predicted after administration of bronchodilators at screening.

[0083] Baseline FEV1 was the average of two measurements taken ≤40 minutes before the first dose of study drug on the day of administration and just before dosing on the first day.

[0084] Mean FEV1 AUC 0-12h It is defined as the area under the curve of FEV1 over 12 hours divided by 12 hours.

[0085] preparation

[0086] The study product and placebo were provided in 2.5 mL unit dose form in ampoules and administered by nebulizer. The formulations of the study product (Ensefentin suspension formulation) and placebo are shown in Table 1 below.

[0087]

[0088]

[0089] Table 1

[0090] result

[0091] Mean FEV1 (AUC) achieved at week 12 0-12h All subgroups showed an improvement in lung function with ensefentin, which was statistically significant. The results are shown in Table 2.

[0092]

[0093] Table 2

[0094] FEV1 (AUC) at Week 12 in patients with moderate and severe COPD 0-12h The mean mL changes from baseline for and are shown in Table 3 below.

[0095] COPD type <![CDATA[Mean change in baseline FEV1 (AUC) at Week 12 0-12h > Moderate 139mL Severe 45mL

[0096] Table 3

[0097] Significant increases in FEV1 were observed for both moderate and severe COPD. However, particularly significant increases were observed in the treatment of patients with moderate COPD.

[0098] in conclusion

[0099] It has been found that Ensefantin provides statistically significant improvements in lung function in all subgroups of COPD patients in the study. In addition, Ensefantin has been found to be particularly effective in improving lung function in moderate COPD.

Claims

1. A compound for use in a method for treating moderate COPD in a patient, said compound being ensefentin or a pharmaceutically acceptable salt thereof.

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

3. The compound of claim 1 or 2, wherein the method comprises administering the compound to the patient by inhalation through a nebulizer.

4. A compound as claimed in any preceding claim, wherein the compound is encefantine.

5. The compound of any preceding claim, wherein the method comprises administering the compound to the patient once, twice or three times per day.

6. The compound of any preceding claim, wherein the method comprises administering the compound to the patient twice a day.

7. A compound as claimed in any preceding claim, wherein the method comprises administering a total daily dose of 0.5 to 10 mg, preferably 5 to 7 mg, of the compound.

8. The compound of any preceding claim, wherein the method comprises 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.

9. A compound as claimed in any preceding claim, 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 twice a day via a nebulizer.

10. The compound according to any preceding claim, wherein the method comprises administering the compound to a patient at least once a day for at least 8 weeks, preferably at least 16 weeks, more preferably at least 24 weeks.

11. A compound as claimed in any preceding claim, wherein the patient suffers from moderate COPD as determined by measuring FEV1 / FVC≤0.7 and 50%≤FEV1≤80% predicted FEV1 values, wherein FEV1 is the forced expiratory volume in 1 second and FVC is the forced vital capacity measured 15 to 30 minutes after administration of a bronchodilator, optionally wherein the bronchodilator is salbutamol.

12. A compound as claimed in any preceding claim, wherein the method comprises administering an inhalable pharmaceutical composition comprising a suspension of particles of the compound in a diluent.

13. A compound according to any preceding claim, wherein the compound is used in combination with a muscarinic receptor antagonist, a beta-adrenergic receptor agonist or an inhaled corticosteroid.

14. A method for treating moderate COPD in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound which is encefantine or a pharmaceutically acceptable salt thereof.

15. Use of a compound in the preparation of a medicament for treating moderate COPD, wherein the chemical compound is ensefentin or a pharmaceutically acceptable salt thereof.

16. A suspension preparation having the following composition: 。

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