Treatment of idiopathic pulmonary fibrosis with ensifentrine.

Abstract

The present invention relates to a compound for use in a method of treating idiopathic pulmonary fibrosis in a patient, the compound being ensifentrine or a pharmaceutically acceptable salt thereof, wherein the method comprises administering the compound to the patient by inhalation.The present invention relates to a compound for use in a method of treating pulmonary fibrosis in a patient by improving lung function or preventing or reducing a decline in lung function, the compound being ensifentrine or a pharmaceutically acceptable salt thereof, wherein the method comprises administering the compound to the patient by inhalation.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to the treatment of pulmonary fibrosis (PF), and in particular to the treatment of idiopathic pulmonary fibrosis (IPF). [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 (including inhibition of PDE4B) and is described in WO 00 / 58308 A1.

[0003] As a combined phosphodiesterase 3 / 4 (PDE3 / PDE4) inhibitor, ensifentrine has both bronchodilator and anti-inflammatory activities 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] Pulmonary fibrosis is a disease associated with scarring of lung tissue. Scarring causes hardening of lung tissue, which leads to symptoms such as shortness of breath. Pulmonary fibrosis can be caused by many factors, including bacterial or viral infections and cigarette smoke. Most pulmonary fibrosis, however, is idiopathic and has no known cause. Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating disease that affects approximately 5 million people worldwide.

[0006] There is no cure for pulmonary fibrosis, and limited treatment options exist. Most therapies focus on slowing disease progression. Known treatments include the antifibrotic agents Esbriet (pirfenidone) and Ofev (nintedanib), both of which are administered orally. However, oral treatments for IPF are associated with minor side effects (including diarrhea), making tolerability an issue.

[0007] There is a need to develop additional treatments for pulmonary fibrosis, including for IPF. In particular, it would be desirable to develop treatments that have reduced side effects and / or are better tolerated by patients. Summary of the Invention

[0008] It is a surprising discovery of the present invention that ensifentrine can be used to treat pulmonary fibrosis, and in particular idiopathic pulmonary fibrosis, by inhalation administration. Inhaled ensifentrine has also been found to avoid side effects such as diarrhea.

[0009] The present invention therefore provides a compound for use in a method of treating idiopathic pulmonary fibrosis in a patient, the compound being ensifentrine or a pharmaceutically acceptable salt thereof, the method comprising administering the compound to the patient by inhalation.

[0010] Also provided by the present invention is a compound for use in a method of treating pulmonary fibrosis in a patient by improving lung function or preventing or reducing a decline in lung function, the compound being ensifentrine or a pharmaceutically acceptable salt thereof, wherein the method comprises administering the compound to the patient by inhalation.

[0011] The present invention further provides a compound for use in a method of treating pulmonary fibrosis in a patient by preventing or reducing fibrosis, the compound being ensifentrine or a pharmaceutically acceptable salt thereof, the method comprising administering the compound to the patient by inhalation.

[0012] The present invention further provides a composition comprising (i) a compound that is ensifentrine or a pharmaceutically acceptable salt thereof, and (ii) an anti-fibrotic agent. [Brief explanation of the drawings]

[0013] [Figure 1] FIG. 1 shows the effect of inhaled ensifentrine on blood IL-6 and IL-8 inflammatory biomarkers. DETAILED DESCRIPTION OF THE INVENTION

[0014] Detailed Description of the Invention Compound can improve the lung function in patients with pulmonary fibrosis.For example, compound can increase the forced vital capacity (FVC) in patients with pulmonary fibrosis.For example, the FVC of patient after one month of first administration of compound can be at least 0.2%, at least 0.5%, at least 1% or at least 2% greater than the FVC of patient on the day of first administration of compound.FVC can be measured by standard spirometry technology.Typically, the FVC used herein is determined as presented in the paper Standardization of Spirometry, Eur Resp J 2005;26;319-338.

[0015] Compound can prevent the decline in pulmonary function in patients with pulmonary fibrosis.For example, compound can prevent (or reduce) the decline in forced vital capacity (FVC) in patients with pulmonary fibrosis.As such, the FVC of patient after one month of first administration of compound can be 0.2% or less, 0.5% or less, 1% or less or 2% or less than the FVC of patient on the day of first administration of compound.

[0016] The compound can act as an anti-fibrotic agent.As such, the compound can prevent or reduce fibrosis, and in particular, the compound can prevent or reduce fibrosis of lung tissue.The compound can therefore prevent the formation of fibrosis or scarring in lung tissue in patients, or the compound can reduce the amount of fibrosis or scarring in the lungs of patients.The compound can improve lung function by preventing or reducing fibrosis of lung tissue.

[0017] The compounds may be for use in methods of treating pulmonary fibrosis in a patient by preventing or reducing fibrosis. For example, the methods may include treating pulmonary fibrosis in a patient by reducing fibrosis in the patient's lungs.

[0018] The compound may cause a decrease in TGF-β levels in the patient, for example, a decrease in pulmonary TGF-β levels in the patient.

[0019] Pulmonary fibrosis can be caused by infection or external chemical irritants. Pulmonary fibrosis can be fibrosing alveolitis, such as cryptogenic fibrosing alveolitis. Pulmonary fibrosis is preferably idiopathic pulmonary fibrosis.

[0020] The pulmonary fibrosis associated with a patient's pulmonary fibrosis can be measured by determining the decline in the patient's pulmonary function. The decline in pulmonary function can be the decline in the patient's forced vital capacity (FVC). The compound can prevent the decline in the patient's FVC by preventing fibrosis of lung tissue. The compound can improve the patient's FVC by reducing fibrosis of lung tissue.

[0021] The patient's FVC may increase following administration of the compound. For example, the patient's FVC may increase by at least 10 mL or at least 20 mL one month after the first inhalation administration of the compound (compared to the FVC at the time of the first administration of the compound). The patient's FVC may decrease by no more than 30 mL or no more than 50 mL one month after the first inhalation administration of the compound (compared to the FVC at the time of the first administration of the compound).

[0022] The compound can reduce the frequency and / or severity of pulmonary fibrosis (PF) exacerbations in patients. The compound can reduce the frequency of PF exacerbations. For example, a patient can experience two or fewer (e.g., one or zero) PF exacerbations per year while being treated with the compound, for example, as maintenance therapy. The number of PF exacerbations experienced by a patient per year during treatment with the compound can be one to three less than the number of PF exacerbations experienced by a patient per year before treatment with the compound.

[0023] The compound can increase the time to first PF exacerbation in patients.Therefore, the patient may not yet have experienced COPD exacerbation, and the compound can increase the time to first PF exacerbation in patients (i.e., the first PF exacerbation is delayed).The compound can therefore reduce the risk of PF exacerbation in patients with pulmonary fibrosis.

[0024] In some cases, the patient has suffered one or more PF exacerbations in the year prior to the first administration of the compound.For example, the patient may have suffered two or more PF exacerbations in the year prior to the first administration of the compound.For example, the patient may have suffered at least one severe PF exacerbation (i.e., requiring hospital treatment) in the previous year.The patient may have suffered one or more PF exacerbations in the six months prior to the first administration of the compound, or one or more PF exacerbations in the month prior to the first administration of the compound.

[0025] The PF exacerbation can be an acute PF exacerbation. For example, the PF exacerbation can be an acute IPF exacerbation (AE-IPF). AE-IPF is defined as a sudden acceleration of disease or idiopathic acute injury superimposed on a diseased lung, leading to a significant decline in lung function.

[0026] The patient may be suffering from idiopathic pulmonary fibrosis (IPF), and the compound may reduce the frequency and / or severity of acute exacerbations of IPF (AE-IPF) in the patient.

[0027] 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 an antifibrotic agent, 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 an antifibrotic agent, a long-acting muscarinic antagonist (LAMA), a long-acting beta agonist (LABA), or an inhaled corticosteroid (ICS). The patient may not be taking a background medication that is a muscarinic antagonist or a beta agonist.

[0028] 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).

[0029] The method 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 typically administered to a patient by inhalation, for example, by a nebulizer, pressurized metered dose inhaler (pMDI) or dry powder inhaler (DPI).

[0030] 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.

[0031] 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.

[0032] The compound can be used in any suitable therapeutically effective amount. Typically, the daily dose of the compound is 0.1 to 40 mg or 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.

[0033] Typically, the compound is administered twice a day in two separate doses that are the same or similar.The method can include administering the compound to a patient twice a day at a first dose of 1 to 10 mg and a second dose of 1 to 10 mg.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.Typically, 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.

[0034] The method may involve administering to the patient two doses of about 2 mg, about 3 mg, about 4 mg, about 5 mg, or about 6 mg of ensifentrine free base per day by inhalation. 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.

[0035] 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 daily 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.The compound is typically used as maintenance therapy.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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:

[0040] · 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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).

[0046] 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).

[0047] 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:

[0048] 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:

[0049] The side effect of some anti-fibrotic treatments is gastrointestinal adverse events such as diarrhea.These side effects can prevent patients from taking compound and reduce patient compliance.This is especially true for patients who already suffer from or are prone to gastrointestinal disorders such as diarrhea.

[0050] It has been found that inhaled ensifentrine is not associated with diarrhea in patients.Therefore, the compound can be used to treat pulmonary fibrosis in patients suffering from or prone to gastrointestinal disorders.The patient may be prone to or suffering from diarrhea.The patient may be suffering from ulcerative colitis, Crohn's disease, microscopic colitis, celiac disease, irritable bowel syndrome, bile acid malabsorption, or diverticulitis.

[0051] 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 pulmonary fibrosis.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.

[0052] The second active agent is typically an antifibrotic agent, a muscarinic receptor antagonist, a beta-adrenergic receptor agonist, or an inhaled corticosteroid. The compound may therefore be used in combination with an antifibrotic agent, a muscarinic receptor antagonist, a beta-adrenergic receptor agonist, or an inhaled corticosteroid.

[0053] Typically, the second active agent is an antifibrotic agent.Antifibrotic agent can be pirfenidone, nintedanib or its pharmaceutically acceptable salt.Preferably, antifibrotic agent is pirfenidone.

[0054] The second active agent can be administered by inhalation or orally. Typically, the antifibrotic agent is administered orally. For example, the patient may be taking an oral antifibrotic agent such as pirfenidone as a background drug.

[0055] The second active agent can be a long-acting muscarinic receptor antagonist (LAMA), a long-acting beta-adrenergic receptor agonist (LABA), or an inhaled corticosteroid. Examples of LAMAs include aclidinium, darotropium, tiotropium, glycopyrrolate, umeclidinium, and their pharmaceutically acceptable salts. Examples of LABAs include salmeterol, formoterol, indacaterol, vilanterol, olodaterol, abesiterol, carmoterol, and their pharmaceutically acceptable salts. Examples of inhaled corticosteroids include beclomethosone, budesonide, fluticasone propionate, ciclesonide, mometasone, fluticasone furoate, and their pharmaceutically acceptable salts.

[0056] The compounds may alternatively be used as monotherapy. For example, the compounds may be for use in treating pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis) as the sole active agent. In some embodiments, the compounds are not administered in combination with a muscarinic receptor antagonist or a beta-adrenergic receptor agonist.

[0057] It is a discovery of the present invention that ensifentrine can be used in combination with an antifibrotic agent. The present invention therefore also provides a composition comprising (i) a compound that is ensifentrine or a pharmaceutically acceptable salt thereof, and (ii) an antifibrotic agent.

[0058] Composition is typically a pharmaceutical composition.Composition can further comprise one or more pharmaceutically acceptable carriers, diluents or excipients.One or more pharmaceutically acceptable carriers, diluents or excipients can be as defined herein.Composition can be administered as described herein.For example, composition can be administered by inhalation.

[0059] The two active ingredients can be in a fixed or free combination. Typically, the two active ingredients are in a fixed combination. For example, they can be mixed together. The two active ingredients can be present in an inhalable liquid pharmaceutical composition.

[0060] Typically, the antifibrotic agent is pirfenidone, nintedanib, or a pharmaceutically acceptable salt thereof. The antifibrotic agent is preferably pirfenidone.

[0061] The composition may be for use in a method of treating or preventing pulmonary fibrosis as defined herein.

[0062] The present invention also provides an antifibrotic agent (e.g., pirfenidone) for use in a method of treating pulmonary fibrosis in a patient in combination with a compound that is ensifentrine or a pharmaceutically acceptable salt thereof. The method may be as further defined herein.

[0063] The present invention also provides a method of preventing or treating pulmonary fibrosis in a patient by improving lung function or by preventing or reducing a decline in lung function, the method comprising administering to the patient by inhalation a therapeutically effective amount of a compound that is ensifentrine or a pharmaceutically acceptable salt thereof.

[0064] 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 a method of treating pulmonary fibrosis by improving lung function or by preventing or reducing a decline in lung function, wherein the method comprises administering the compound to a patient by inhalation.

[0065] The present invention also provides a method of treating IPF in a patient, the method comprising administering to the patient by inhalation a therapeutically effective amount of a compound that is ensifentrine or a pharmaceutically acceptable salt thereof.

[0066] 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 a method of treating IPF, wherein the method comprises administering the compound to a patient by inhalation.

[0067] The invention will now be described in further detail by the following examples. [Example]

[0068] Example 1 - Effect of Ensifentrine on Inflammatory Mediators 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.

[0069] 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.

[0070] The effect of ensifentrine on changes in blood IL-6 and IL-8 was measured.

[0071] 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.

[0072] [Table 1]

[0073] result The effect of inhaled ensifentrine on the inflammatory biomarkers interleukin 6 (IL-6) and IL-8 compared to placebo is shown in Figure 1. Inhaled ensifentrine was found to reduce blood IL-6 and IL-8 in patients.

[0074] conclusion Inhaled ensifentrine 3 mg twice daily (BID) was found to cause a decrease in blood IL-6 and IL-8 in patients, consistent with the profile of an antifibrotic drug.

[0075] Example 2 - Efficacy of Ensifentrine in a Rodent Model of IPF The antifibrotic activity of ensifentrine is evaluated using a rodent model of bleomycin-induced pulmonary fibrosis.

[0076] Bleomycin is administered to anesthetized rodents to induce pulmonary fibrosis. Ensifentrine is then administered by inhalation to the test rodents for a period of time, and the rodents are subsequently sacrificed. Lung samples are taken for histological study to determine the area of ​​fibrosis.

[0077] Ensifentrine is determined to have antifibrotic effects in bleomycin-induced pulmonary fibrosis.

[0078] Example 3 - Effect of ensifentrine on bleomycin-induced pulmonary fibrosis Research overview An in vivo study was conducted to determine the efficacy of ensifentrine in treating bleomycin-induced pulmonary fibrosis in rats compared with controls. Rats were administered bleomycin to induce pulmonary fibrosis. After one week, they then received daily inhaled doses of ensifentrine or control for a two-week period. At the end of the two weeks, the rats were sacrificed, and their airways were analyzed for differential cell counts and TGF-β concentrations in bronchoalveolar lavage (BAL).

[0079] BAL differential cell counts provide total inflammatory cell counts, allowing us to observe changes in inflammation following treatment. TGF-β is a key cytokine in the development of tissue fibrosis. Macrophages and other immune cells produce TGF-β, which induces the differentiation of fibroblasts into myofibroblasts and increases TGF-β expression. Overexpression of active TGF-β1 in rodent lungs causes severe and progressive tissue fibrosis, including fibroblastic nests and honeycomb formation. Inhibiting TGF-β1 may be central to the antifibrotic effects of drugs.

[0080] Study design On day 0, rats were subjected to an intratracheal challenge with either 0.9% w / v saline or bleomycin, the latter used to induce pulmonary fibrosis.

[0081] Starting on day 7, two groups of 12 rats from the bleomycin-challenged group were administered an inhaled dose of either 3 mg / kg (Experiment 1) or 10 mg / kg (Experiment 2) ensifentrine on a daily basis for 2 weeks, ending on day 21. Ensifentrine was administered as a suspension in vehicle suspension.

[0082] Two control experiments were also conducted. Control 1 involved 12 rats from the saline challenge group receiving daily administration of the vehicle suspension via inhalation for a full 21 days. Control 2 involved 12 rats from the bleomycin challenge group receiving daily administration of the vehicle suspension via inhalation for a full 21 days. The experimental setup is summarized in Table 2 below.

[0083] [Table 2]

[0084] At the end of the 21-day period, rats were sacrificed and BAL differential cell count and TGF-β concentration data were collected.

[0085] result BAL differential cell counts on day 21 showed a reduction in total inflammatory cell and macrophage infiltration into rat airways following treatment with ensifentrine at 3 mg / kg / day (Experiment 1) and 10 mg / kg / day (Experiment 2) compared with bleomycin control 2.

[0086] TGF-β concentrations on day 21 were also lower in rats following ensifentrine treatment compared with those in bleomycin control 2.

[0087] conclusion In rats with bleomycin-induced pulmonary fibrosis, inhaled ensifentrine at 3 mg / kg and 10 mg / kg was found to cause a decrease in BAL differential cell count and TGF-β concentration. Therefore, ensifentrine administered via inhalation was found to be effective in treating bleomycin-induced pulmonary fibrosis.

[0088] Example 4 - Comparison of Ensifentrine and Nintedanib Study design In vivo study was conducted to compare the effectiveness of ensifentrine and nintedanib in treating bleomycin-induced pulmonary fibrosis in rats.Following the same initial experimental procedure as in Example 3, 12 rats from the bleomycin challenge group were administered a daily dose of 100mg / kg of nintedanib via oral gavage for 2 weeks, starting from the 7th day (Experiment 3).A new control experiment was also conducted, in which vehicle suspension was orally administered in aqueous solution (Control 3).The experimental design is summarized in Table 3 below.

[0089] On day 21, the rats were sacrificed, their airways were analyzed, and TGF-β concentrations were calculated. The results were compared with those of Experiments 1 and 2 (Example 3).

[0090] [Table 3]

[0091] result TGF-β concentrations in rat lungs following treatment with ensifentrine (experiments 1 and 2) were lower than TGF-β concentrations following treatment with nintedanib (experiment 3).

[0092] conclusion In rats with bleomycin-induced pulmonary fibrosis, inhaled ensifentrine at 3 mg / kg / day or 10 mg / kg / day was found to cause a greater reduction in TGF-β concentrations than orally administered nintedanib at 100 mg / kg / day.

Claims

1. 1. A compound for use in a method of treating idiopathic pulmonary fibrosis in a patient, the compound being ensifentrine or a pharmaceutically acceptable salt thereof; wherein the method comprises administering the compound to the patient by inhalation.

2. 1. A compound for use in a method of treating pulmonary fibrosis in a patient by improving lung function or preventing or reducing a decline in lung function, the compound being ensifentrine or a pharmaceutically acceptable salt thereof; wherein the method comprises administering the compound to the patient by inhalation.

3. 3. The compound for use according to claim 2, wherein said pulmonary fibrosis is idiopathic pulmonary fibrosis.

4. 10. The compound for use according to any one of the preceding claims, wherein said compound improves lung function in said patient, preferably wherein said compound increases forced vital capacity in said patient.

5. 4. A compound for use according to any one of claims 1 to 3, wherein said compound prevents a decline in lung function in said patient, preferably said compound prevents or reduces a decline in forced vital capacity in said patient.

6. 10. The compound for use according to any one of the preceding claims, wherein said compound treats said pulmonary fibrosis by preventing or reducing fibrosis, preferably said compound treats said pulmonary fibrosis by reducing fibrosis.

7. 10. A compound for use according to any one of the preceding claims, wherein said compound reduces the frequency and / or severity of pulmonary fibrosis exacerbations in said patient suffering from pulmonary fibrosis.

8. 10. The compound for use according to any one of the preceding claims, wherein the patient is suffering from idiopathic pulmonary fibrosis (IPF) and wherein the compound reduces the frequency and / or severity of acute exacerbations of IPF (AE-IPF) in the patient.

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

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

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

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

13. 10. The compound for use according to any one of the preceding claims, wherein said method comprises administering to said patient a total daily dose of said compound of from 0.1 to 20 mg, preferably from 0.5 to 10 mg.

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

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

16. 10. The compound for use according to any one of the preceding claims, wherein the method comprises administering the compound to the patient at least once per day for at least 8 weeks, preferably at least 16 weeks, more preferably at least 24 weeks.

17. 10. A compound for use according to any one of the preceding claims, wherein the patient is prone to or suffers from diarrhea.

18. 18. The compound for use according to claim 17, wherein the patient is suffering from ulcerative colitis, Crohn's disease, microscopic colitis, celiac disease, irritable bowel syndrome, bile acid malabsorption, or diverticulitis.

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

20. 10. The compound for use according to any one of the preceding claims, wherein the compound is used in combination with a second active agent, the second active agent being an antifibrotic agent, a muscarinic receptor antagonist, a beta-adrenergic receptor agonist or an inhaled corticosteroid.

21. 21. The compound for use according to claim 20, wherein the second active agent is an anti-fibrotic agent.

22. 22. The compound for use according to claim 21, wherein the antifibrotic agent is pirfenidone, nintedanib or a pharmaceutically acceptable salt thereof.

23. 23. The compound for use according to claim 21 or claim 22, wherein the antifibrotic agent is administered orally.

24. A composition comprising (i) a compound that is ensifentrine or a pharmaceutically acceptable salt thereof, and (ii) an antifibrotic agent.

25. 25. The composition of claim 24, wherein the anti-fibrotic agent is pirfenidone, nintedanib, or a pharmaceutically acceptable salt thereof.

26. 26. A composition as defined in claim 24 or 25 for use in a method for treating pulmonary fibrosis as defined in any one of claims 1 to 22.

27. 26. An antifibrotic agent as defined in claim 24 or 25 for use in a method of treating pulmonary fibrosis in a patient in combination with a compound which is ensifentrine or a pharmaceutically acceptable salt thereof.

28. 1. A method of treating idiopathic pulmonary fibrosis in a patient, the method comprising administering to the patient by inhalation a therapeutically effective amount of a compound that is ensifentrine or a pharmaceutically acceptable salt thereof.

29. 1. A method for treating pulmonary fibrosis in a patient by improving lung function or preventing or reducing a decline in lung function, the method comprising administering to the patient by inhalation a therapeutically effective amount of a compound that is ensifentrine or a pharmaceutically acceptable salt thereof.

30. 1. Use of a compound that is ensifentrine or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for a method of treating idiopathic pulmonary fibrosis in a patient, the method comprising administering the compound to the patient by inhalation.

31. 1. Use of a compound which is ensifentrine or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for a method of treating pulmonary fibrosis in a patient by improving lung function or by preventing or reducing a decline in lung function, the method comprising administering the compound to the patient by inhalation.

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