Ensifentrine for the treatment of bronchiectasis

Abstract

This invention relates to a compound used in a method for preventing or treating bronchiectasis in a patient, said compound being encefenstein or a pharmaceutically acceptable salt thereof, wherein said bronchiectasis is noncystic fibrotic (non-CF) bronchiectasis. The invention also relates to a compound used in a method for treating bronchiectasis in a patient, said compound being encefenstein or a pharmaceutically acceptable salt thereof, wherein said method comprises treating bronchiectasis by (a) reducing the frequency of coughing in the patient and / or (b) reducing sputum production in the patient and / or promoting mucus clearance from the lungs.

Description

Technical Field

[0001] This invention relates to the treatment of bronchiectasis. Background Technology

[0002] Ensefentin ( N -(2-{(2 E )-9,10-dimethoxy-4-oxo-2-[(2,4,6-trimethylphenyl)imino]-6,7-dihydro-2 H -pyrimidino[6,1- a Isoquinoline-3(4) H RPL554 (also known as RPL554) is a dual PDE3 / PDE4 inhibitor and is described in WO 00 / 58308A1.

[0003] As a combined PDE3 / PDE4 inhibitor, enstatin possesses both bronchodilatory and anti-inflammatory activities and can be used to treat respiratory disorders, including chronic obstructive pulmonary disease (COPD). The chemical structure of enstatin is shown below.

[0004] Encerfentin was also found to regulate the transmembrane conduction modulator of cystic fibrosis (CFTR, WO 2015 / 173551 A1).

[0005] Bronchiectasis is a chronic respiratory disorder characterized by permanent abnormal dilation of the bronchi (i.e., dilation of the airways in the lungs). The prevalence of bronchiectasis is estimated to be over 100 cases per 100,000 population, and the disease carries a significant clinical and economic burden. The main symptoms of bronchiectasis are chronic cough, sputum production, impaired mucociliary clearance, and bronchial infections. Patients may also experience wheezing (dyspnea), fatigue, hemoptysis (coughing up blood), and chest pain.

[0006] Bronchiectasis can be caused by a wide range of different etiologies. Cystic fibrosis is a common cause, with the majority of patients with cystic fibrosis eventually developing severe bronchiectasis. However, a significant proportion of bronchiectasis cases occur in patients without cystic fibrosis (referred to as non-CF bronchiectasis). Non-CF causes of bronchiectasis can include infectious diseases such as pneumonia, measles, and tuberculosis, although in some patients the cause of non-CF bronchiectasis is unknown. In non-CF bronchiectasis, the primary cause of airway dilation is damage resulting from persistent inflammation, and particularly persistent neutrophilic inflammation.

[0007] Bronchiectasis has limited treatment options. No drugs have been approved in the United States or Europe specifically for the treatment of this condition, and particularly for the treatment of non-CF bronchiectasis.

[0008] There is a strong need to develop treatments for bronchiectasis and non-CF bronchiectasis. In particular, there is a need to develop treatments that can reduce cough and sputum production in patients. There is also a need for treatments that target neutrophilic inflammation in non-CF bronchiectasis. Summary of the Invention

[0009] A striking finding of this invention is that encefentin can reduce cough and sputum production in patients with high levels of cough and sputum. It was also found that encefentin reduces cytokines associated with neutrophilic inflammation, such as IL-8, and reduces airway macrophage infiltration. These activities allow encefentin to target neutrophilic inflammation in non-CF bronchiectasis while alleviating key symptoms of chronic cough and increased sputum production.

[0010] Therefore, the present invention provides a compound for a method of preventing or treating bronchiectasis in a patient, said compound being encefentin or a pharmaceutically acceptable salt thereof, wherein said bronchiectasis is noncystic fibrotic (non-CF) bronchiectasis.

[0011] The present invention also provides a compound in a method for treating bronchiectasis in a patient, said compound being encefentin or a pharmaceutically acceptable salt thereof, said method comprising treating bronchiectasis by (a) reducing the frequency of coughing in the patient and / or (b) reducing sputum production in the patient and / or promoting mucus clearance from the lungs. Detailed Implementation

[0012] This compound is used to treat bronchiectasis, and particularly non-cystic fibrosis (non-CF) bronchiectasis. Non-CF bronchiectasis is bronchiectasis in patients without cystic fibrosis. Patients without cystic fibrosis are those without mutations in either allele of the gene encoding the cystic fibrosis transmembrane conduction regulator (CFTR).

[0013] Patients are often diagnosed with bronchiectasis. For example, a patient may have already been diagnosed with bronchiectasis based on the presence of bronchiectasis observed using a computed tomography scan.

[0014] In one embodiment, the compound is used in a method for preventing or treating non-CF bronchiectasis. The compound can be used to treat non-CF bronchiectasis.

[0015] This method may include treating bronchiectasis by (a) reducing the frequency of a patient's cough and / or (b) reducing the patient's sputum production and / or promoting mucus clearance from the lungs. This method may include treating bronchiectasis by reducing the frequency of a patient's cough. This method may include reducing the patient's sputum production. This method may include treating bronchiectasis by reducing the frequency of a patient's cough and reducing the patient's sputum production.

[0016] The severity of a patient's cough and sputum production can be assessed using methods such as... "E-RS (EXACT - Respiratory Symptoms)," User Manual (Version 3.0), October 2014 The cough and sputum volume domains of the EXACT-Respiratory Symptoms (E-RS) scale, as described in the description, are used for assessment. The E-RS cough and sputum volume domains include E-RS questions 2, 3, and 4, and the total score ranges from 0 to 11. Following treatment, patients typically have a reduced score in the E-RS cough and sputum volume domains, for example, a reduction of at least 1 or at least 2 points relative to the score in the E-RS cough and sputum volume domains on the day prior to the first administration of the compound. This reduction is usually achieved after daily administration of the compound for at least 14 days, for example, at least 8 weeks. On the day prior to the first administration of the compound, the patient's cough and sputum volume domain score may be at least 3, at least 4, at least 5, or at least 6. On the day prior to the first administration of the compound, the patient's cough and sputum volume domain score may be at least 8 or at least 9. On the day prior to the first administration of the compound, the patient typically has a score of at least 5 or at least 6.

[0017] For example, the compound can reduce a patient's score in the cough and sputum volume category of the EXACT-Respiratory Symptoms (E-RS) scale, preferably wherein the score decreases by at least 1 after administration of the compound. Typically, the patient's score in the cough and sputum volume category of the EXACT-Respiratory Symptoms (E-RS) scale is at least 5 the day before the first administration of the compound. For example, the patient's score in the cough and sputum volume category of the EXACT-Respiratory Symptoms (E-RS) scale may be at least 5 the day before the first administration of the compound, and after daily administration of the compound for at least 12 weeks, the patient may have a score of no more than 4.

[0018] Some patients with bronchiectasis experience bronchiectasis exacerbations. A bronchiectasis exacerbation is an acute worsening of bronchiectasis symptoms that lasts for at least two days. Typically, a bronchiectasis exacerbation in a patient includes two or more of the following: cough, sputum volume (i.e., increased sputum volume), and purulent sputum (i.e., increased purulent sputum) that persist for at least two days.

[0019] This compound can reduce the frequency and / or severity of bronchiectasis exacerbations in patients. For example, this compound can reduce the frequency of bronchiectasis exacerbations in patients. Therefore, the present invention can provide a compound in a method for reducing the frequency and / or severity of bronchiectasis exacerbations in patients, said compound being encefentin or a pharmaceutically acceptable salt thereof.

[0020] Encerfentin has been found to have anti-inflammatory effects, making it highly suitable for the treatment of bronchiectasis, particularly non-CF bronchiectasis. Therefore, this compound can treat bronchiectasis by reducing pro-inflammatory cytokines and chemokines such as IL-8, IL-6, and TNF-α in the lungs and / or reducing macrophage infiltration into the lungs.

[0021] Typically, this compound reduces neutrophil inflammation in patients. Preferably, the compound reduces neutrophil inflammation in the lungs of patients. For example, the bronchodilator can be a non-CF bronchodilator, and the compound can be administered by inhalation to reduce neutrophil inflammation in the lungs of patients.

[0022] This compound can reduce the concentration of one or more of IL-6, IL-8, and TNF-α in a patient's blood and / or lungs. Typically, the concentration of one or more of IL-6, IL-8, and TNF-α is reduced in a patient's blood. For example, this compound can reduce the concentration of both IL-6 and IL-8 in a patient's blood. This compound can reduce the concentration of both IL-6 and IL-8 in a patient's lungs. This compound can reduce the concentration of TNF-α in a patient's blood and / or lungs.

[0023] This compound can treat non-CF bronchiectasis by reducing neutrophil inflammation in patients and by reducing the frequency of coughing in patients.

[0024] Bronchiectasis can be idiopathic. Non-CF bronchiectasis is preferred. Non-CF bronchiectasis is typically caused by one or more of the following: lung infections; lung diseases; smoking; inflammatory diseases; and obstruction in the lungs.

[0025] Lung infections can be caused by bacterial or viral infections. Bronchiectasis can be caused by bacterial infections such as Pseudomonas aeruginosa, Haemophilus influenzae, Mycobacterium tuberculosis, and Streptococcus pneumoniae. Lung infections can include pneumonia. Inflammatory diseases can include ulcerative colitis, Crohn's disease, and rheumatoid arthritis. Lung obstruction may be caused by the aspiration of tumors or foreign bodies.

[0026] Non-CF bronchiectasis is typically caused by lung diseases selected from chronic obstructive pulmonary disease (COPD), asthma, and interstitial lung disease. Non-CF bronchiectasis can be caused by COPD.

[0027] The patient may have COPD. Therefore, the patient may have both COPD and bronchiectasis (e.g., COPD and non-CF bronchiectasis).

[0028] Bronchiectasis is not usually caused by a congenital condition. Therefore, patients typically do not have any of the following conditions: cystic fibrosis, primary ciliary dyskinesia, Wiechen syndrome, Marfan syndrome, Moulier-Kuhn syndrome, alpha-1 antitrypsin deficiency, yellow nail syndrome, or Young's syndrome.

[0029] The patient can be male. The patient can be female. The patient can be 65 years of age or older. The patient can be under 65 years of age. The patient may be taking one or more background medications selected from long-acting muscarinic antagonists (LAMA), long-acting beta-agonists (LABA), and inhaled corticosteroids (ICS).

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

[0031] This method typically involves administering the compound to a patient via inhalation. Pharmaceutical compositions comprising the compound and one or more pharmaceutically acceptable excipients or diluents are typically administered to a patient via inhalation, for example, through a nebulizer, a pressurized metered dose inhaler (pMDI), or a dry powder inhaler (DPI).

[0032] Preferably, the method involves administering the compound to a patient via inhalation from a nebulizer. The nebulizer atomizes the liquid pharmaceutical composition into an aerosol, which 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. TM (Philips), Philips SideStream (Philips), AeroNeb ® (Philips), Philips InnoSpire Go (Philips), Pari LC Sprint (Pari GmbH), AERxR TM Pulmonary Delivery System (AradigmCorp) and Pari LC Plus Reusable Nebuliser (Pari GmbH). The sprayer can be, for example, equipped with PARIVIOS. ® PRO Aerosol Delivery System PARI BOY ® The PARI LC Sprint sprayer features a compressor. The compound can be inhaled via the sprayer for 1-15 minutes.

[0033] Typically, this method involves administering the compound to the patient once, twice, or three times daily, for example, twice or three times daily. The compound can be administered to the patient by inhalation once, twice, or three times daily. Preferably, the method involves administering the compound to the patient twice daily by inhalation. The method may include administering a first dose of the compound in the morning (e.g., within 3 hours of waking) and a second dose of the compound in the evening (e.g., within 3 hours of bedtime). Typically, the morning and evening doses are administered 10-14 hours apart, for example, approximately 12 hours apart.

[0034] The compound can be used at any suitable therapeutically effective amount. Typically, the daily dose of the compound is 0.1–20 mg. Generally, the method involves administering a total daily dose of 0.5–10 mg of the compound. Preferably, the total daily dose of the compound (e.g., encefentin free base) is 5–7 mg, for example, about 6 mg / day. As used herein, the term “about” can indicate a variation of ±10% of the stated value. The total daily dose of the compound can be 6.0 mg.

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

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

[0037] This compound is typically used as maintenance therapy. Generally, the method involves administering the compound to the patient at least once daily for at least 8 weeks. Alternatively, the compound can be administered to the patient at least once daily for at least 16 weeks, preferably at least 24 weeks. It can also be administered daily for at least 1 year. The method may also include 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, i.e., a suspension of particles containing the compound in a diluent. Alternatively, the compound may be delivered as a dry powder, such as a dry powder comprising particles containing the compound and a carrier (e.g., lactose).

[0039] This method typically involves administering an inhalable pharmaceutical composition comprising a suspension of particles of the compound in a diluent. The particles containing the compound typically have a Dv50 size distribution of 0.5 μm to 5.0 μm. Preferably, the particles have a Dv50 of 1.0 μm to 2.0 μm.

[0040] Particle size is described in this paper by referring to the Dv50 value, which is the median particle size of the volume distribution. Therefore, particles of half the volume have a diameter smaller than the Dv50 value, and particles of half the volume have a diameter larger than the Dv50 value. This is a well-known way of describing particle size distribution.

[0041] The technique used to measure Dv50 values, as described in this article, is typically laser diffraction. The particle size distribution of particles containing the compound can be measured by laser diffraction, for example, using a wet powder dispersion system. For instance, particle size distribution can be measured by laser diffraction using a Malvern Spraytec instrument in conjunction with a wet dispersion cell. Typically, the instrument parameters for a Malvern Spraytec are as follows: ●Particles—Standard opaque particles; ●Refractive index particles—1.50; ●Refractive index (imaginary part) — 0.50; ●Particle density—1.00; ● The refractive index of the dispersant is 1.33; ●Controller unit—1000 RPM; ●Measurement type—Timed; ●Initial sampling time—30 seconds; ● Shading rate—20% to 30%; ● Dispersant—1% polysorbate 20 in deionized water.

[0042] Particles containing the compound typically contain encefentin (i.e., encefentin free base). The particles may contain at least 90% by weight of encefentin free base relative to the total weight of the particles. Particles may contain at least 99% by weight of encefentin. Particles may consist of encefentin.

[0043] The concentration of the compound particles in an inhalable pharmaceutical composition is typically 0.1-5.0 mg / mL, preferably 0.1-2.5 mg / mL, and more preferably 1.0-2.0 mg / mL.

[0044] Inhalable drug compositions typically also contain one or more tension modifiers, one or more buffers, and one or more surfactants. Tension modifiers are typically sodium chloride.

[0045] 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 hydrogen phosphate dihydrate.

[0046] 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, glyceryl alkyl esters, polyoxyethylene glycol sorbitol alkyl esters (polysorbates, such as polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80), sorbitol alkyl esters (e.g., sorbitol monolaurate (Span 20), sorbitol monooleate (Span 80) and sorbitol trioleate (Span 20)). 85), cocamide MEA, cocamide DEA, dodecyl dimethylamine oxide, block copolymers of polyethylene glycol and polypropylene glycol (poloxam), block copolymers of polyethylene glycol and polypropylene oxide (e.g., Pluronic surfactant), polyvinylpyrrolidone K25, polyvinyl alcohol, oligolactic acid, sodium dioctyl sulfosuccinate, and polyethoxylated tallow amine (POEA).

[0047] Preferably, one or more surfactants comprise polysorbate and / or sorbitol alkyl ester. One or more surfactants may, for example, comprise polysorbate 20 (polyoxyethylene (20) sorbitol monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitol monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitol monostearate), or polysorbate 80 (polyoxyethylene (20) sorbitol monooleate). One or more surfactants may, for example, comprise sorbitol monolaurate (Span 20), sorbitol monooleate (Span 80), or sorbitol trioleate (Span 85). Preferably, the sterile liquid medium comprises polysorbate 20 and / or sorbitol monolaurate (Span 20).

[0048] For example, the method may include administering an inhalable liquid drug composition to a patient, comprising: ●Water; ●Particles composed of encefentin free base at concentrations of 0.1-20 mg / mL; ● One or more tension modifiers with a total concentration of 1.0-15 mg / mL; ● One or more buffers with a total concentration of 0.1-4 mg / mL; and ● One or more surfactants with a total concentration of 0.05-3 mg / mL.

[0049] Inhalable liquid drug compositions may include: ●Water; ●Particles composed of encefentin free base at a concentration of 0.5-6 mg / mL; ●Sodium chloride at a concentration of 5-12 mg / mL; ● Sodium dihydrogen phosphate dihydrate at a concentration of 0.3-2 mg / mL; ● Sodium hydrogen phosphate dihydrate at a concentration of 0.3-2 mg / mL; ● Polysorbate 20 at a concentration of 0.1-1.5 mg / mL; and ●Sorbitol monolaurate at a concentration of 0.01-0.5 mg / mL.

[0050] This compound can be used in combination with a second activator. The compound can be administered separately or simultaneously with the second activator. The patient may already be taking the second activator as background therapy for COPD. Alternatively, treatment with the second activator can begin around the same time as treatment with this compound. The compound and the second activator can be administered in a fixed combination.

[0051] The second active agent is typically selected from antibiotics, macrolides, muscarinic receptor antagonists, β-adrenergic receptor agonists, and inhaled corticosteroids. Therefore, this compound can be used in combination with muscarinic receptor antagonists or β-adrenergic receptor agonists. The second active agent can be a long-acting muscarinic receptor antagonist (LAMA) or a long-acting β-adrenergic receptor agonist (LABA).

[0052] Examples of LAMAs include acilinium, darotropium, tiotropium, glycopyrrolate, and umeclidinium. Examples of LABAs include salmeterol, formoterol, indacaterol, vilanterol, olodaterol, abeterol, and carmocaterol. Examples of inhaled corticosteroids include beclomethasone, budesonide, fluticasone propionate, cicsolone, mometasone, fluticasone furoate, and their pharmaceutically acceptable salts.

[0053] Therefore, this compound can be used in combination with a second active agent selected from antibiotics, macrolides, muscarinic receptor antagonists, β-adrenergic receptor agonists, and inhaled corticosteroids to treat bronchiectasis (e.g., non-CF bronchiectasis). Preferably, the compound is used in combination with an antibiotic or macrolide suitable for treating bronchiectasis. Typically, the second active agent is an antibiotic selected from tobramycin, ciprofloxacin, aztreonam, and colistin; or a macrolide selected from azithromycin and erythromycin.

[0054] Therefore, the present invention provides a second active agent as defined herein, which, in combination with the compound encefentin or a pharmaceutically acceptable salt thereof, is used to treat non-CF bronchiectasis.

[0055] Alternatively, the compound can be used as a monotherapy. For example, the compound can be used as the sole active agent to treat bronchiectasis (e.g., non-CF bronchiectasis). In some embodiments, the compound is not administered in combination with muscarinic receptor antagonists or beta-adrenergic receptor agonists.

[0056] The present invention also provides a method for preventing or treating bronchiectasis in a patient, the method comprising administering to the patient a therapeutically effective amount of the compound encefentin or a pharmaceutically acceptable salt thereof, wherein the bronchiectasis is noncystic fibrotic (non-CF) bronchiectasis.

[0057] The present invention also provides a method for treating bronchiectasis in a patient, the method comprising administering to the patient a therapeutically effective amount of the compound encefentin or a pharmaceutically acceptable salt thereof, wherein the method comprises treating bronchiectasis by (a) reducing the frequency of coughing in the patient and / or (b) reducing sputum production in the patient and / or promoting the clearance of mucus from the lungs.

[0058] The present invention also provides a method for reducing the frequency and / or severity of bronchiectasis exacerbations in patients with bronchiectasis, wherein the compound is encefentin or a pharmaceutically acceptable salt thereof.

[0059] The present invention also provides the use of the compound in a medicament in a method for preventing or treating bronchiectasis in a patient, the method comprising administering to a patient a therapeutically effective amount of the compound encefentin or a pharmaceutically acceptable salt thereof, wherein the bronchiectasis is noncystic fibrotic (non-CF) bronchiectasis.

[0060] The present invention also provides the use of the compound in a medicament in a method for treating bronchiectasis in a patient, the method comprising administering to a patient a therapeutically effective amount of the compound encefentin or a pharmaceutically acceptable salt thereof, wherein the method comprises treating bronchiectasis by (a) reducing the frequency of coughing in the patient and / or (b) reducing sputum production in the patient and / or promoting the clearance of mucus from the lungs.

[0061] The invention is described in more detail through the following embodiments. Example

[0062] Example 1 – Evaluation of enstatin in COPD patients with high cough / sputum burden Research Design A clinical study was conducted to determine the efficacy of enstatin compared to placebo in the treatment of COPD. Enstatin was administered via nebulizer at a dose of 3 mg twice daily (BID) for 24 weeks. This study was a multicenter, randomized, double-blind, parallel-group, placebo-controlled trial with approximately 800 patients and a 5:3 randomization.

[0063] The study cohort included patients aged 40–80 years with moderate to severe COPD (FEV1 30%–70% pn, FEV1 / forced vital capacity (FVC) ratio <0.7, with mMRC ≥2). Randomization was assigned to (a) patients using stable background maintenance LAMA or LABA therapy (approximately 50%, yes or no) and (b) smokers (current or former). Under certain provisions, up to 20% of patients were permitted inhaled corticosteroid (ICS) maintenance therapy.

[0064] This study evaluated: the effects of enstatin on serum IL-6 and IL-8; and the effects of enstatin on cough and sputum volume ranges in patients with high baseline cough / sputum scores. Patients with high baseline cough / sputum E-RS scores were defined as subjects with baseline E-RS cough and sputum volume range scores greater than the population mean of 3.6 units (e.g., using...). "E-RS (EXACT - Respiratory Symptoms), User Manual (Version 3.0), October 2014" (As determined). These patients with high baseline cough / sputum provide a model of non-CF bronchiectasis.

[0065] formula The study product and placebo were administered in 2.5 mL units in ampoules via a nebulizer. The formulations of the study product (encefentin suspension) and placebo are shown in Table 1 below. Table 1 result Inhalation of 3 mg enstatin twice daily (BID) resulted in a decrease in serum IL-6 and IL-8 in patients. At week 12, a mean decrease of 43 pg / L in serum IL-6 and a mean decrease of 45 pg / L in serum IL-8 from baseline were observed.

[0066] E-RS cough and sputum volume range results (pooled analysis) from phase 3 clinical studies in subjects with cough and sputum scores greater than or equal to baseline mean are shown in Table 2. In patients with high baseline cough and sputum scores, enstatin was found to induce significant improvements in those scores over 6 to 24 weeks, demonstrating its activity against sputum production and cough in these patients.

[0067] in conclusion This study confirms that enstatin can target both neutrophilic inflammation associated with non-CF bronchiectasis and primary bronchiectasis symptoms (cough and sputum production). Table 2 Example 2 – Effects of enstatin on inflammation in a mouse model of fibrosis Research Review In vivo studies were conducted to determine the effect of encefentin on inflammation in bleomycin-induced pulmonary fibrosis in rats. One week later, rats received either daily inhaled doses of encefentin or a control for two weeks. At the end of the two weeks, rats were sacrificed, and differential cell counts and TGF-β concentrations in their airways were analyzed via bronchoalveolar lavage (BAL).

[0068] BAL differential cell count provides a total inflammatory cell count, allowing observation of changes in inflammation after treatment.

[0069] Research Design On day 0, rats were subjected to intratracheal challenge with 0.9% w / v saline or bleomycin, the latter being used to induce pulmonary fibrosis.

[0070] Starting on day 7, 12 rats from two groups from the bleomycin challenge group were administered encefentin at an inhaled dose of 3 mg / kg (Experiment 1) or 10 mg / kg (Experiment 2) daily for two weeks, ending on day 21. Encefentin was administered as a suspension in the media suspension product.

[0071] Two control experiments were also conducted. Control 1 involved 12 rats from the saline challenge group who received daily administration of the carrier suspension for a full 21 days. Control 2 involved 12 rats from the bleomycin challenge group who received daily administration of the carrier suspension for a full 21 days. The experimental setup is summarized in Table 3 below. Table 3 At the end of the 21-day period, rats were sacrificed and BAL differential cell counts and TGF-β concentration data were collected.

[0072] result Compared with bleomycin control 2, differential cell counts on day 21 in BAL showed a reduction in total inflammatory cells and macrophage infiltration in the airways of rats after treatment with encefentin at 3 mg / kg / day (Experiment 1) and 10 mg / kg / day (Experiment 2).

[0073] Compared with bleomycin control 2, rats also had lower TGF-β concentrations on day 21 after encefentin treatment.

[0074] in conclusion It has been found that in rat models of pulmonary fibrosis, inhaled encefentanil can reduce macrophage infiltration in the airways.

Claims

1. A compound in a method for preventing or treating bronchiectasis in a patient, said compound being encefentin or a pharmaceutically acceptable salt thereof. The bronchiectasis mentioned therein is noncystic fibrotic (non-CF) bronchiectasis.

2. The compound for use according to claim 1, wherein the method comprises treating the bronchiectasis by (a) reducing the frequency of the patient's cough and / or (b) reducing the patient's sputum production and / or promoting the clearance of mucus from the lungs.

3. A compound in a method for treating bronchiectasis in a patient, said compound being encefentin or a pharmaceutically acceptable salt thereof. The method described therein includes treating the bronchiectasis by (a) reducing the frequency of the patient's cough and / or (b) reducing the patient's sputum production and / or promoting the clearance of mucus from the lungs.

4. The compound for use according to any one of the preceding claims, wherein the method comprises treating the bronchiectasis by reducing the frequency of the patient's cough.

5. The compound for use according to any one of the preceding claims, wherein the compound reduces the patient score in the cough and sputum volume domain of the EXACT-Respiratory Symptoms (E-RS) scale, preferably wherein the score is reduced by at least 1 after administration of the compound.

6. The compound for use according to any one of the preceding claims, wherein on the day prior to the first administration of the compound to the patient, the patient scored at least 5 in the cough and sputum volume category of the EXACT-Respiratory Symptoms (E-RS) scale.

7. The compound for use according to any one of the preceding claims, wherein the compound reduces the frequency and / or severity of bronchiectasis exacerbations in the patient.

8. The compound for use according to any one of the preceding claims, wherein the compound reduces neutrophilic inflammation in the patient, preferably wherein the compound reduces neutrophilic inflammation in the lungs of the patient.

9. The compound for use according to any one of the preceding claims, wherein the compound reduces the concentration of one or more of IL-6, IL-8 and TNF-α in the patient's blood and / or lungs.

10. The compound for use according to any one of the preceding claims, wherein the bronchiectasis is idiopathic bronchiectasis.

11. The compound for use according to any one of claims 1-9, wherein the bronchiectasis is non-CF bronchiectasis caused by one or more of the following: lung infection; lung disease; smoking; inflammatory disease; and pulmonary obstruction.

12. The compound for use according to claim 11, wherein the non-CF bronchiectasis is caused by a lung disease selected from chronic obstructive pulmonary disease (COPD), asthma, and interstitial lung disease, preferably wherein the lung disease is COPD.

13. The compound for use according to any one of the preceding claims, wherein the patient suffers from COPD.

14. The compound for use according to any one of the preceding claims, wherein the bronchiectasis is not caused by a congenital condition, preferably wherein the patient does not suffer from any of cystic fibrosis, primary ciliary dyskinesia, Wiechen syndrome, Marfan syndrome, Moulier-Kuhn syndrome, α-1 antitrypsin deficiency, yellow nail syndrome, and Young's syndrome.

15. The compound for use according to any one of the preceding claims, wherein the method comprises administering the compound to the patient by inhalation.

16. The compound for use according to any one of the preceding claims, wherein the method comprises administering the compound to the patient by inhalation via a nebulizer.

17. The compound for use according to any one of the preceding claims, wherein the compound is encefentin.

18. 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 daily.

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

20. The compound for use according to any one of the preceding claims, wherein the method comprises administering a total daily dose of 0.5-10 mg, preferably 5-7 mg, of the compound.

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

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

23. 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 daily for at least 8 weeks, preferably at least 16 weeks, more preferably at least 24 weeks.

24. The 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.

25. The compound for use according to any one of the preceding claims, wherein the compound is used in combination with a second active agent selected from antibiotics, macrolides, muscarinic receptor antagonists, β-adrenergic receptor agonists, and inhaled corticosteroids.

26. The compound for use according to claim 25, wherein the second active agent is an antibiotic selected from tobramycin, ciprofloxacin, aztreonam and colistin; or the second active agent is a macrolide selected from azithromycin and erythromycin.

27. The second active agent as defined in claim 25 or claim 26, in combination with a compound of encefentin or a pharmaceutically acceptable salt thereof, for the treatment of non-CF bronchiectasis.

28. A method for preventing or treating bronchiectasis in a patient, the method comprising administering to the patient a therapeutically effective amount of the compound encefentin or a pharmaceutically acceptable salt thereof, wherein the bronchiectasis is noncystic fibrotic (non-CF) bronchiectasis.

29. A method of treating a patient with bronchiectasis, the method comprising administering to the patient a therapeutically effective amount of the compound encefentin or a pharmaceutically acceptable salt thereof, wherein the method comprises treating the bronchiectasis by (a) reducing the frequency of the patient's cough and / or (b) reducing the patient's sputum production and / or promoting the clearance of mucus from the lungs.

30. Use of the compound in a medicament in a method for preventing or treating bronchiectasis in a patient, the method comprising administering to the patient a therapeutically effective amount of the compound encefentin or a pharmaceutically acceptable salt thereof, wherein the bronchiectasis is noncystic fibrotic (non-CF) bronchiectasis.

31. Use of the compound in a medicament in a method for treating bronchiectasis in a patient, the method comprising administering to the patient a therapeutically effective amount of the compound encefentin or a pharmaceutically acceptable salt thereof, wherein the method comprises treating the bronchiectasis by (a) reducing the frequency of cough in the patient and / or (b) reducing sputum production in the patient and / or promoting the clearance of mucus from the lungs.

Images