Treatment of idiopathic pulmonary fibrosis with empenoxine

Abstract

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

Description

TECHNICAL FIELD

[0001] The present invention relates to the treatment of pulmonary fibrosis (PF), and more particularly to the treatment of idiopathic pulmonary fibrosis (IPF). BACKGROUND

[0003] Ensititide (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 Al.

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

[0005]

[0006] Pulmonary fibrosis is a disease associated with scarring of lung tissue. The scarring causes the lung tissue to harden, which leads to symptoms such as shortness of breath. Pulmonary fibrosis can be caused by a variety of factors including bacterial or viral infection and cigarette smoke. However, the majority of pulmonary fibrosis is idiopathic and has no known cause. Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating disease that affects approximately five million people worldwide.

[0007] Pulmonary fibrosis cannot be cured and there are only limited treatment options. Most therapies focus on slowing the progression of the disease. Known treatments include the anti-fibrotic agents Esbriet (pirfenidone) and Ofev (nintedanib), both of which are administered orally. However, oral treatment of IPF is associated with non-trivial side effects including diarrhoea, making tolerability an issue.

[0008] There is a pressing need to develop further treatments for pulmonary fibrosis, including IPF. In particular, it is desirable to develop treatments with reduced side effects and / or better patient tolerability. SUMMARY

[0010] It has been surprisingly found that ensititide can be administered by inhalation for the treatment of pulmonary fibrosis, in particular idiopathic pulmonary fibrosis. It has also been found that inhaled ensititide avoids side effects such as diarrhoea.

[0011] Accordingly, the present invention provides a compound for use in a method of treating idiopathic pulmonary fibrosis in a patient, the compound being ensititide or a pharmaceutically acceptable salt thereof, wherein the method comprises administering the compound to the patient by inhalation.

[0012] The present application also provides a compound, which is encainide or a pharmaceutically acceptable salt thereof, for use in a method of treating pulmonary fibrosis in a patient by improving lung function or by preventing or reducing a decrease in lung function, wherein the method comprises administering the compound to the patient by inhalation.

[0013] The present application also provides a compound, which is encainide or a pharmaceutically acceptable salt thereof, for use in a method of treating pulmonary fibrosis in a patient by preventing or reducing fibrosis, wherein the method comprises administering the compound to the patient by inhalation.

[0014] The present application also provides a composition comprising (i) a compound which is encainide or a pharmaceutically acceptable salt thereof and (ii) an anti-fibrotic agent.

[0015] BRIEF DESCRIPTION OF DRAWINGS

[0016] Figure 1 The effect of inhaled encainide on blood IL-6 and IL-8 inflammatory biomarkers is shown. DETAILED DESCRIPTION

[0018] The compound can improve lung function in a patient having pulmonary fibrosis. For example, the compound can increase forced vital capacity (FVC) in a patient having pulmonary fibrosis. For example, one month after first administration of the compound, the patient’s FVC can be at least 0.2%, at least 0.5%, at least 1%, or at least 2% higher than the patient’s FVC at the time of first administration of the compound. FVC can be measured by standard spirometry techniques. Typically, as used herein, FVC is measured as described in Standardisation of Spirometry Eur J 2005; 26; 319-338.

[0019] The compound can prevent a decrease in lung function in a patient having pulmonary fibrosis. For example, the compound can prevent (or reduce) a decrease in forced vital capacity (FVC) in a patient having pulmonary fibrosis. Thus, one month after first administration of the compound, the patient’s FVC can be no more than 0.2%, no more than 0.5%, no more than 1%, or no more than 2% less than the patient’s FVC at the time of first administration of the compound.

[0020] The compound can act as an anti-fibrotic. Thus, the compound can prevent or reduce fibrosis, and in particular, the compound can prevent or reduce fibrosis of lung tissue. Thus, the compound can prevent fibrosis or scarring of lung tissue in a patient, or the compound can reduce the amount of fibrotic or scar tissue in the lungs of a patient. The compound can improve lung function by preventing or reducing fibrosis of lung tissue.

[0021] The compound can be used in a method of treating pulmonary fibrosis in a patient by preventing or reducing fibrosis. For example, the method can include treating pulmonary fibrosis in a patient by reducing fibrosis in the patient's lung.

[0022] The compound can cause a decrease in TGF-β concentration in a patient, such as a decrease in lung TGF-β concentration in a patient.

[0023] Pulmonary fibrosis may be caused by infection or external chemical irritants. Pulmonary fibrosis may be fibrosing alveolitis, such as latent fibrosing alveolitis. Pulmonary fibrosis is preferably idiopathic pulmonary fibrosis.

[0024] The fibrosis of the lungs associated with pulmonary fibrosis in a patient can be measured by measuring the decline in the patient's lung function. The decline in lung function can be a decline in the patient's forced vital capacity (FVC). The compound can prevent the patient's FVC from declining by preventing pulmonary fibrosis. The compound can improve the patient's FVC by reducing the fibrosis of lung tissue.

[0025] After administering the compound, the patient's FVC can increase. For example, one month after the first inhalation administration of the compound, the patient's FVC can increase by at least 10 mL or at least 20 mL (compared with the FVC when administering the compound for the first time). One month after the first inhalation administration of the compound, the patient's FVC can reduce by no more than 30 mL or no more than 50 mL (compared with the FVC when administering the compound for the first time).

[0026] 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 may suffer from two or fewer (e.g., one or zero) PF exacerbations per year when treated with the compound, e.g., as a maintenance therapy. The number of PF exacerbations that a patient experiences per year during treatment with the compound can be 1 to 3 fewer than the number of PF exacerbations that the patient experienced per year before treatment with the compound.

[0027] The compound can increase the time to the first PF exacerbation in a patient. Thus, the patient may not have experienced a COPD exacerbation yet, and the compound can increase the time until the patient experiences the first PF exacerbation (i.e., the first PF exacerbation is delayed). Therefore, the compound can reduce the risk of PF exacerbations in patients with pulmonary fibrosis.

[0028] In certain instances, the patient has had one or more PF exacerbations within one year prior to the first administration of the compound. For example, the patient can have had two or more PF exacerbations within one year prior to the first administration of the compound. For example, within the prior year, the patient can have had at least one severe PF exacerbation (i.e., requiring hospitalization). The patient can have had one or more PF exacerbations within six months prior to the first administration of the compound, or one or more PF exacerbations within one month prior to the first administration of the compound.

[0029] The PF exacerbation can be an acute PF exacerbation. For example, the PF exacerbation can be an acute exacerbation of IPF (AE-IPF). AE-IPF is defined as a sudden acceleration of the disease or an idiopathic acute injury superimposed on the diseased lung leading to a significant decline in lung function.

[0030] The patient can have idiopathic pulmonary fibrosis (IPF), and the compound can reduce the frequency and / or severity of acute exacerbations of IPF (AE-IPF) in the patient.

[0031] The patient can be male. The patient can be female. The patient can have an age greater than or equal to 65 years. The patient can have an age less than 65 years. The patient can be taking 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 certain instances, the patient is not receiving a background medication. For example, the patient can not be taking a background medication that is a long-acting muscarinic antagonist (LAMA), a long-acting beta-agonist (LABA), or an inhaled corticosteroid (ICS). The patient can not be receiving a background medication of a muscarinic antagonist or a beta-agonist.

[0032] The compound is encainide or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts are well known to those skilled in the art. Typically, the compound is encainide (i.e., encainide free base).

[0033] The method typically comprises administering the compound to the patient by inhalation. The pharmaceutical composition comprising the compound and one or more pharmaceutically acceptable excipients or diluents is typically administered to the patient by inhalation, such as by a nebulizer, a pressurized metered dose inhaler (pMDI), or a dry powder inhaler (DPI).

[0034] Preferably, the method comprises administering the compound to the patient by inhalation from a nebulizer. The nebulizer aerosolizes a liquid pharmaceutical composition into a gas aerosol that 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 Philips I-neb TM(Philips), Philips SideStream (Philips), Philips SmartDrive (Philips), Philips SmartJect (Philips), Philips SmartNeb (Philips), Philips SmartSet (Philips), Philips SmartSense (Philips), Philips SmartTrack (Philips), Philips SmartTouch (Philips), Philips SmartTouch+ (Philips), Philips SmartVent (Philips), Philips (Philips), Philips InnoSpire Go (Philips), Pari LC Sprint (Pari GmbH), AERx R TM Pulmonary delivery systems (Aradigm Corp) and Pari LC Plus 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.

[0035] 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 of waking) and a second dose of the compound in the evening (for example within 3 hours of going to sleep). Typically, the morning and evening doses are separated by 10 to 14 hours of administration, for example separated by about 12 hours of administration.

[0036] 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. nintedanib free base) is 5 to 7 mg, for example about 6 mg per day. As used herein, the term“about” can denote a variation of ±10% of the stated value. The total daily dose of the compound can be 6.0 mg.

[0037] Typically, the compound is administered twice a day in two separate doses which are the same or similar. The method can comprise administering the compound to the patient twice a day in a first dose of 1 to 10 mg and a second dose of 1 to 10 mg. For example, the method can comprise administering the compound to the 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 can comprise administering the compound to the patient twice a day in a first dose of 2 to 4 mg and a second dose of 2 to 4 mg.

[0038] The method can comprise administering to the patient about 2 mg, about 3 mg, about 4 mg, about 5 mg, or about 6 mg of the compound as the free base by inhalation twice a day. Preferably, the method comprises administering to the patient about 3 mg of the compound as the free base by inhalation twice a day. The method preferably comprises administering to the patient a dose of about 3 mg of the compound by inhalation twice a day (3 mg BID). More preferably, the method comprises administering to the patient a dose of about 3 mg of the compound by nebulizer twice a day. Each dose can be 3.0 mg of the compound as the free base administered by nebulizer.

[0039] 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.

[0040] The compound is preferably administered as a suspension formulation, i.e. a suspension of particles comprising the compound in a diluent. Alternatively, the compound can be delivered as a dry powder, e.g. a dry powder comprising particles comprising the compound and carrier particles such as lactose.

[0041] The method typically comprises administering an inhalable pharmaceutical composition comprising a suspension of particles comprising the compound in a diluent. The particles comprising the compound typically have a particle size distribution with a Dv50 of 0.5 μιη to 5.0 μιη. The particles preferably have a Dv50 of 1.0 μιη to 2.0 μιη.

[0042] Particle size is described herein by reference to Dv50 values, which is the median particle size of the volume distribution. Thus, one half of the volume of particles have a diameter less than the Dv50 value, and one half of the volume of particles have a diameter greater than the Dv50 value. This is a well-known way of describing particle size distributions.

[0043] The technique used to measure the Dv50 values as described herein is typically laser diffraction. The particle size distribution of the 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 laser diffraction of a Malvern Spraytec in combination with a wet dispersion cell. Typically, the instrument parameters for the Malvern Spraytec are as follows:

[0044] • Particle - Standard opaque particles;

[0045] • Refractive index particles - 1.50;

[0046] • Refractive index (imaginary part) - 0.50;

[0047] • Particle density - 1.00;

[0048] • Refractive index of dispersant - 1.33;

[0049] • Controller unit - 1000 RPM;

[0050] • Measurement type - Timed;

[0051] • Initial sampling time - 30 s;

[0052] • Light obscuration - 20% to 30%;

[0053] • Dispersant - 1% polysorbate 20 in deionised water.

[0054] The particles comprising the compound typically comprise encainide (i.e. encainide free base). The particles comprising the compound can comprise at least 90% by weight of encainide free base relative to the total weight of the particles. The particles can comprise at least 99% by weight of encainide. The particles can consist of encainide.

[0055] The concentration of the particles comprising the compound 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.

[0056] The inhalable pharmaceutical composition typically further comprises one or more tonicity adjusting agents, one or more buffers and one or more surfactants. The tonicity adjusting agent is typically sodium chloride.

[0057] Examples of buffers include citrate buffers, phosphate buffers, acetate buffers and bicarbonate buffers. Preferably, the buffer is a phosphate buffer, for example sodium dihydrogen phosphate dihydrate and / or disodium phosphate dihydrate.

[0058] Examples of surfactants include lecithin, oleic acid, polyoxyethylene glycol alkyl ethers (e.g. PEG 300, PEG 600, PEG 1000, Brij 30, Brij 35, Brij 56, Brij 76, and Brij 97), polypropylene glycol (e.g. PPG 2000), glucoside alkyl ethers, polyoxyethylene glycol octylphenol ethers, polyoxyethylene glycol alkylphenol ethers, glycerol alkyl esters, polyoxyethylene glycol sorbitan alkyl esters (polysorbates, e.g. polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80), sorbitan alkyl esters (e.g. sorbitan monolaurate (Span 20), sorbitan monooleate (Span 80), and sorbitan trioleate (Span 85)), cocamide MEA, cocamide DEA, dodecyl dimethyl amine 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, oligomeric lactic acid, dioctyl sodium sulfosuccinate, and polyethoxylated tallow amine (POEA).

[0059] Preferably, the one or more surfactants include a polysorbate and / or a sorbitan alkyl ester. 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).

[0060] For example, the method can comprise administering to the patient an inhalable liquid pharmaceutical composition comprising:

[0061] • water;

[0062] • particles consisting of encainide free base at a concentration of 0.1 to 20 mg / mL;

[0063] • one or more tonicity adjusting agents at a total concentration of 1.0 to 15 mg / mL;

[0064] • one or more buffers at a total concentration of 0.1 to 4 mg / mL; and

[0065] • one or more surfactants in a total concentration of 0.05 to 3 mg / mL.

[0066] The inhalable liquid pharmaceutical composition can comprise:

[0067] • water;

[0068] • particles consisting of encainide free base in a concentration of 0.5 to 6 mg / mL;

[0069] • sodium chloride in a concentration of 5 to 12 mg / mL;

[0070] • sodium phosphate monobasic dihydrate in a concentration of 0.3 to 2 mg / mL;

[0071] • sodium phosphate dibasic dihydrate in a concentration of 0.3 to 2 mg / mL;

[0072] • polysorbate 20 in a concentration of 0.1 to 1.5 mg / mL; and

[0073] • sorbitan monolaurate in a concentration of 0.01 to 0.5 mg / mL.

[0074] Side effects of certain anti-fibrotic treatments are gastrointestinal adverse events, such as diarrhoea. These side effects can prevent patients from taking the compound and can reduce patient compliance. This is particularly true for patients who already have or are predisposed to gastrointestinal conditions such as diarrhoea.

[0075] It has been found that inhaled encainide is not associated with diarrhoea in patients. Therefore, the compound can be used to treat pulmonary fibrosis in patients who have or are predisposed to gastrointestinal conditions. The patient can be predisposed to or have diarrhoea. The patient can have ulcerative colitis, Crohn’s disease, microscopic colitis, celiac disease, irritable bowel syndrome, bile acid malabsorption or diverticulitis.

[0076] 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 can already be taking the second active agent as background therapy for pulmonary fibrosis. Alternatively, treatment with the second active agent can be initiated at approximately the same time as treatment with the compound. The compound and the second active agent can be administered in a fixed combination.

[0077] The second active agent is typically an anti-fibrotic agent, a muscarinic receptor antagonist, a beta-adrenergic receptor agonist or an inhaled corticosteroid. Therefore, the compound can be used in combination with an anti-fibrotic agent, a muscarinic receptor antagonist, a beta-adrenergic receptor agonist or an inhaled corticosteroid.

[0078] Typically, the second active agent is an anti-fibrotic agent. The anti-fibrotic agent can be pirfenidone, nintedanib, or a pharmaceutically acceptable salt thereof. Preferably, the anti-fibrotic agent is pirfenidone.

[0079] The second active agent can be administered by inhalation or orally. Typically, the anti-fibrotic agent is administered orally. For example, the patient can take an oral anti-fibrotic agent such as pirfenidone as a background drug.

[0080] The second active agent can be a long-acting muscarinic receptor antagonist (LAMA) or a long-acting beta-adrenergic receptor agonist (LABA). Examples of LAMA include aclidinium, darolium, tiotropium, glycopyrronium, umeclidinium and pharmaceutically acceptable salts thereof. Examples of LABA include salmeterol, formoterol, indacaterol, vilanterol, olodaterol, abetrol, carmoterol and pharmaceutically acceptable salts thereof. Examples of inhaled corticosteroids include beclomethasone, budesonide, fluticasone propionate, ciclesonide, mometasone, fluticasone furoate and pharmaceutically acceptable salts thereof.

[0081] Alternatively, the compound can be used as a monotherapy. For example, the compound can be used as the sole active agent for treating pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis). In certain embodiments, the compound is not administered in combination with a muscarinic receptor antagonist or a beta-adrenergic receptor agonist.

[0082] The present invention has discovered that encefantine can be used in combination with an anti-fibrotic agent. Accordingly, the present invention also provides a composition comprising (i) a compound which is encefantine or a pharmaceutically acceptable salt thereof and (ii) an anti-fibrotic agent.

[0083] The composition is typically a pharmaceutical composition. The composition may further comprise one or more pharmaceutically acceptable carriers, diluents, or excipients. The one or more pharmaceutically acceptable carriers, diluents, or excipients may be as defined herein. The composition may be administered as described herein. For example, the composition may be administered by inhalation.

[0084] The two active ingredients can be a fixed or free combination. Typically, the two active ingredients are a fixed combination. For example, they can be mixed with each other. The two active ingredients can be present in an inhalable liquid pharmaceutical composition.

[0085] Typically, the anti-fibrotic agent is pirfenidone, nintedanib or a pharmaceutically acceptable salt thereof. Preferably, the anti-fibrotic agent is pirfenidone.

[0086] The composition may be used in a method of treating or preventing pulmonary fibrosis as defined herein.

[0087] The present application also provides an anti-fibrotic agent (e.g. pirfenidone) for use in a method of treating pulmonary fibrosis in a patient, the anti-fibrotic agent being combined with a compound which is emisphere or a pharmaceutically acceptable salt thereof. The method can be as further defined herein.

[0088] The present application also provides a method of preventing or treating pulmonary fibrosis in a patient by improving lung function or by preventing or reducing a decrease in lung function, the method comprising administering to the patient a therapeutically effective amount of a compound by inhalation, the compound being emisphere or a pharmaceutically acceptable salt thereof.

[0089] The present application also provides the use of a compound which is emisphere 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 decrease in lung function, wherein the method comprises administering to the patient the compound by inhalation.

[0090] The present application also provides a method of treating IPF in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound by inhalation, the compound being emisphere or a pharmaceutically acceptable salt thereof.

[0091] The present application also provides the use of a compound which is emisphere or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for a method of treating IPF, wherein the method comprises administering to the patient the compound by inhalation.

[0092] The present application is described in more detail by the following examples. Example

[0093] Example 1 - Effect of emisphere on inflammatory mediators

[0094] Study design

[0095] A clinical study was conducted to determine the efficacy of emisphere in the treatment of COPD compared to placebo. Emisphere was administered by 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 of approximately 800 patients and 5:3 randomization.

[0096] The study population included patients aged 40 to 80 years with moderate to severe COPD (FEV130% to 70% p.n, FEV1 / forced vital capacity (FVC) ratio <0.7, mMRC >2). Randomization was stratified (a) by use of stable background maintenance LAMA or LABA therapy (approximately 50%, yes or no) and (b) by smoking (current or former). Inhaled corticosteroid (ICS) maintenance therapy was allowed in up to 20% of patients according to certain regulations.

[0097] To determine the effect of ondansetron on blood IL-6 and IL-8 changes.

[0098] Formulation

[0099] The study product and placebo were provided in 2.5 mL unit dose form in ampoules and administered via nebulizer. The formulation of the study product (ondansetron suspension formulation) and placebo is shown in Table 1 below.

[0100] Composition Concentration (mg / mL) Ensitentan granules (RPL554) 1.2 (for active substance) or 0 (for placebo) Polysorbate 20 (Tween 20) 0.50 Sorbitan monolaurate (span 20) 0.05 Sodium phosphate monobasic dihydrate 0.744 Sodium phosphate dibasic dihydrate 0.853 Sodium chloride solution 8.60 Water q.s. to 1 mL

[0101] Table 1

[0102] Results

[0103] The effect of inhaled ondansetron on the inflammatory biomarkers interleukin 6 (IL-6) and IL-8 compared to placebo is shown in Figure 1 It was found that inhaled ondansetron reduced IL-6 and IL-8 in patients.

[0104] Conclusion

[0105] It has been found that inhaled ondansetron 3 mg twice daily (BID) resulted in a reduction of IL-6 and IL-8 in patients, which is consistent with the profile of an anti-fibrotic drug.

[0106] Example 2 - Effect of ondansetron in an IPF rodent model

[0107] The anti-fibrotic activity of ondansetron was evaluated using a bleomycin-induced pulmonary fibrosis rodent model.

[0108] Anesthetized rodents were given bleomycin to induce pulmonary fibrosis. Test rodents were then given ondansetron by inhalation for a period of time, after which the rodents were sacrificed. Lung samples were obtained for histological studies to determine fibrosis area.

[0109] It was determined that ondansetron has an anti-fibrotic effect in bleomycin-induced pulmonary fibrosis.

[0110] Example 3 - Effect of ondansetron on bleomycin-induced pulmonary fibrosis

[0111] Study Overview

[0112] An in vivo study was conducted to determine the efficacy of ondansetron in treating bleomycin-induced pulmonary fibrosis in rats compared to controls. Rats were given bleomycin to induce pulmonary fibrosis. One week later, they then received a daily inhaled dose of ondansetron or control for two weeks. At the end of the two weeks, the rats were sacrificed and their airways were analyzed for bronchoalveolar lavage (BAL) differential cell counts and TGF-β concentration.

[0113] BAL differential cell counts provide a total inflammatory cell count, so changes in inflammation after treatment can be observed. TGF-β is a key cytokine in the progression of tissue fibrosis. Macrophages and other immune cells produce TGF-β, which induces fibroblast differentiation into myofibroblasts and increases TGF-β expression. Overexpression of active TGF-β1 in rodent lungs causes severe and progressive tissue fibrosis, including fibroblastic foci and honeycombing. Inhibition of TGF-β1 can be central to the anti-fibrotic action of drugs.

[0114] Study Design

[0115] On day 0, rats were subjected to intratracheal challenge with either 0.9% w / v saline or bleomycin, the latter of which is used to induce lung fibrosis.

[0116] Beginning on day 7, two groups of 12 rats from the bleomycin-challenged group were dosed on a daily basis for two weeks, ending on day 21, with inhaled doses of 3 mg / kg (Experiment 1) or 10 mg / kg (Experiment 2) of ensifentrine. The ensifentrine was dosed as a suspension in the vehicle suspension formulation.

[0117] Two control experiments were also performed. Control 1 subjected 12 rats from the saline-challenged group to daily dosing by inhalation of the vehicle suspension formulation until day 21. Control 2 subjected 12 rats from the bleomycin-challenged group to daily dosing by inhalation of the vehicle suspension formulation until day 21. The experimental setup is summarized in Table 2 below.

[0118]

[0119] Table 2

[0120] At the end of the 21 -day period, rats were sacrificed and BAL differential cell counts and TGF-β concentration data were collected.

[0121] Results

[0122] BAL differential cell counts at day 21 showed a reduction in total inflammatory cell and macrophage infiltration into the airways of rats after treatment with ensifentrine at 3 mg / kg / day (Experiment 1) and 10 mg / kg / day (Experiment 2) compared to the bleomycin control 2.

[0123] TGF-β concentration was also lower in rats at day 21 after treatment compared to the bleomycin control 2.

[0124] Conclusion

[0125] It has been found that inhaled ensifentrine at 3 mg / kg and 10 mg / kg in bleomycin-induced pulmonary fibrosis rats caused a reduction in BAL differentiated cell counts and TGF-β concentration. Thus, it has been found that administration of ensifentrine by inhalation is effective in the treatment of bleomycin-induced pulmonary fibrosis.

[0126] Example 4 - Comparison of ensifentrine and nintedanib

[0127] Study design

[0128] An in vivo study was performed to compare the efficacy of ensifentrine and nintedanib in the treatment of bleomycin-induced pulmonary fibrosis in rats. Following the same initial experimental procedure as in Example 3, a new control experiment (Control 3) was performed administering orally by gavage a daily dose of 100 mg / kg of nintedanib to 12 rats from the bleomycin-challenged group for two weeks (Experiment 3). The experimental design is summarized in Table 3 below.

[0129] On day 21, the rats were sacrificed and their airways were analyzed to calculate the TGF-β concentration. The results were compared with those of Experiments 1 and 2 (Example 3).

[0130]

[0131] Table 3

[0132] Results

[0133] The TGF-β concentration in the lungs of rats treated with ensifentrine (Experiments 1 and 2) was lower than the TGF-β concentration in the lungs of rats treated with nintedanib (Experiment 3).

[0134] Conclusions

[0135] It has been found that inhaled ensifentrine at 3 mg / kg / day or 10 mg / kg / day in bleomycin-induced pulmonary fibrosis rats caused a greater reduction in TGF-β concentration than oral administration of nintedanib at 100 mg / kg / day.

Claims

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

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

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

4. A compound for use according to any preceding claim, wherein the compound improves the patient's lung function, preferably wherein the compound increases the patient's forced vital capacity.

5. The compound for use according to any one of claims 1 to 3, wherein the compound prevents a decrease in lung function in the patient, preferably wherein the compound prevents or reduces a decrease in forced vital capacity in the patient.

6. The compound for use according to any preceding claim, wherein the compound treats the pulmonary fibrosis by preventing or reducing fibrosis, preferably wherein the compound treats the pulmonary fibrosis by reducing fibrosis.

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

8. A compound for use according to any preceding claim, wherein the patient suffers from idiopathic pulmonary fibrosis (IPF) and the compound reduces the frequency and / or severity of acute exacerbations of IPF (AE-IPF) in the patient.

9. A compound for use according to any preceding claim, wherein the method comprises administering the compound to the patient by inhalation from a nebuliser.

10. A compound for use according to any preceding claim, wherein the compound is encefantine.

11. A compound for use according to any preceding claim, wherein the method comprises administering the compound to the patient once, twice or three times daily.

12. A compound for use according to any preceding claim, wherein the method comprises administering the compound to the patient twice daily.

13. A compound for use according to any preceding claim, wherein the method comprises administering to the patient a total daily dose of the compound of 0.1 to 20 mg, preferably 0.5 to 10 mg.

14. The compound for use according to any preceding claim, 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. The compound for use according to any preceding claim, 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 via a nebulizer.

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

17. A compound for use according to any preceding claim, wherein the patient is susceptible to or suffers from diarrhoea.

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

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

20. A compound for use according to any preceding claim, wherein the compound is used in combination with a second active agent which is an anti-fibrotic agent, a muscarinic receptor antagonist, a beta-adrenergic receptor agonist or an inhaled corticosteroid.

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

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

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

24. A composition comprising (i) a compound that is encefantine or a pharmaceutically acceptable salt thereof and (ii) an anti-fibrotic agent.

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

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

27. An anti-fibrotic 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 encefantine or a pharmaceutically acceptable salt thereof.

28. A method for treating idiopathic pulmonary fibrosis in a patient, said method comprising administering to said patient by inhalation a therapeutically effective amount of a compound which is encefantine or a pharmaceutically acceptable salt thereof.

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

30. Use of a compound which is ensifenline or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method of treating idiopathic pulmonary fibrosis in a patient, wherein the method comprises administering the compound to the patient by inhalation.

31. Use of a compound which is Ensefentin or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in a method of treating pulmonary fibrosis in a patient by improving lung function or by preventing or reducing a decrease in lung function, wherein the method comprises administering the compound to the patient by inhalation.

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