Treatment of non-cystic fibrosis bronchiectasis

Abstract

The present invention relates to the use of colistin to reduce the frequency of pulmonary exacerbations in patients suffering from non-cystic fibrosis bronchiectasis (NCFB), said patients being infected with Pseudomonas aeruginosa.

Description

[Technical field]

[0001] The field of the invention relates to the use of the known antibiotic colistin for the clinical treatment of bronchiectasis associated with bacterial infection. [Background technology]

[0002] Non-cystic fibrosis bronchiectasis (NCFB) is a severe, chronic disease characterized by irreversible dilatation of the airways and thickening of the bronchial walls, chronic inflammation, recurrent infections, and progressive airway obstruction. In contrast to cystic fibrosis bronchiectasis (CFB), which is a distinct genetic disease, NCFB is a terminal condition with multiple causes.

[0003] Non-cystic fibrosis bronchiectasis (NCFB) is an increasingly common and important health problem associated with a significant mortality rate. It is more prevalent in the elderly and in women. Furthermore, the incidence of NCFB has increased during the last decades due to early diagnosis by high-resolution computed tomography (HRCT).

[0004] The main causes of NCFB include infections and non-infectious diseases such as immunodeficiency, impaired mucociliary clearance, bronchial obstruction, chronic obstructive pulmonary disease (COPD), idiopathic inflammatory diseases, and autoimmune diseases. The most common cause in the literature is post-infection, but the underlying cause has not been identified.

[0005] The comorbidity of NCFB and COPD is frequent but often underestimated. Other comorbid conditions are more common in patients with NCFB compared to those with CFB.

[0006] Inhaled antibiotics are effective in P. aeruginosa-infected CFB patients, but their efficacy in NCFB has not been proven. Indeed, many pathogens are involved in the colonization of patients with bronchiectasis. The main pathogens are gram-negative, including Haemophilus influenzae, Moraxella catarrhalis, and Pseudomonas aeruginosa; the latter are associated with increased morbidity and mortality. Gram-positive bacteria, such as Streptococcus pneumoniae and Staphylococcus aureus, are rare. Furthermore, P. aeruginosa strains are more often resistant in NCFB than in CFB.

[0007] Currently, there are no approved inhaled antibiotic therapies for patients with NCFB. Treatment with inhaled ciprofloxacin has been studied for several years, with conflicting results. Specifically, ORBIT-4 and RESPIRE-1 showed clinical benefit (prolonged time to first exacerbation and reduced exacerbation rate in the treatment group compared to the placebo group), whereas ORBIT-3 and RESPIRE-2 failed to meet their primary endpoints.

[0008] Tobramycin has also been proposed for the treatment of NCFB. A review of most clinical trials on NCFB is published in (Amorim A., Rev. Port. Pneumol., 2013, 19(6):266-275).

[0009] Despite some clinical evidence in the last few years, conclusive results are still not available. Guidelines for the treatment of bronchiectasis have been published by the European Respiratory Society. Their recommendations (Polverino E, Goeminne PC, McDonnell MJ, et al. European Respiratory Society guidelines for the management of adult bronchiectasis.Eur Respir J 2017; 50:1700629 [https: / / doi.org / 10.1183 / 13993003.00629-2017]) disclose a complex analysis of clinical symptoms related to bronchiectasis. Treatment of bronchiectasis with a nebulizer spraying colistin 1MU twice daily from an I-neb has been investigated, but no statistically significant improvement in time to first exacerbation was observed compared to placebo.

[0010] A recent review article summarizes the latest clinical trial results (Grimwood, K.; Chang, AB, A new dawn: inhaled antibiotics for patients with bronchiectasis, The Lancet Respiratory Medicine, published online January 15, 2019 http: / / dx.doi.org / 10.1016 / S2213-2600(18)30456-9 . However, to date, no treatment has been shown to cure or reverse the progression of the disease, despite the publication of guidelines by the British Thoracic Society in 2010 for the management of patients with NCFB. Pasteur MC et al..British Thoracic Society Bronchiectasis non-CF Guideline Group.British Thoracic Society guideline for non-CF bronchiectasis.Thorax.2010;65(Suppl.1):i1-58. .The guidance recommends that NCFB patients infected with P. aeruginosa be treated with chronic inhaled antipseudomonal antibiotics, namely gentamicin, tobramycin, and colistimethate sodium.

[0011] Colistin is a polymyxin antibiotic produced by certain strains of Bacillus polymixa. It consists of a cationic cyclic heptapeptide whose tripeptide side chain is acylated at the N-terminus with a fatty acid via an α-amide bond (Reviews of Anti-Infective Agents CID 2005; 40:1033-41).

[0012] There are two clinical uses of colistin: colistin sulfate (administered orally for intestinal decontamination and topically as a powder for the treatment of bacterial skin infections) and colistimethate sodium (CMS) (also known as colistimethane sulfate, pentasodium colistimethane sulfate, or colistin sulfonylmethate) for parenteral therapy (intravenous, intramuscular, aerosolized, or intrathecal / intracerebroventricular).

[0013] Colistin sodium (CMS) is a sulfomethylated form of colistin. CMS is easily hydrolyzed to form the sulfomethylated derivative and the active colistin sulfate. Therefore, CMS is considered a prodrug of colistin, and "colistin" usually refers to a mixture of polymyxins E1 and E2. Chemical Abstracts assigns colistin the number 1066-17-7. According to the European Pharmacopoeia, colistin contains more than 77% polymyxins E1, E2, E3, E1i, and E1-7MOA, with less than 10% each of the minor components polymyxins E3, E1-i, and E1-MOA. The term "polymyxin E" is sometimes used interchangeably with "colistin."

[0014] Colistin has recently played an important role in the treatment of various types of infections (e.g., pneumonia, bacteremia, urinary tract infections) caused by Gram-negative pathogens expressing a multidrug-resistant phenotype (e.g., non-fermenting Gram-negative pathogens and carbapenem-resistant Enterobacteriaceae).

[0015] Colitimethate sodium is effective against gram-negative bacteria such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae.

[0016] Inhaled colistimethate sodium has been approved for the management of pulmonary infections caused by Pseudomonas aeruginosa in patients with cystic fibrosis (CF). Approval was granted on the basis of bibliographic submission. Acute pulmonary exacerbations occur frequently in CF and are associated with progressive morbidity and mortality. Approximately 25% of CF patients do not recover lung function after a pulmonary exacerbation, highlighting the need for optimal and aggressive treatment of such events.

[0017] The following colistimethate formulations are available: - Dry powder for inhalation using the Colobreeze TurboSpin inhaler. Each capsule is equivalent to 1,662,500 international units or 125 mg of colistimethate sodium. This formulation is only licensed for chronic pulmonary infections in children 6 years of age and older.

[0018] - Colistimethin® Powder for injection for solution for inhalation using a nebulizer. Each vial contains 1 or 2 million international units of colistimethinate sodium (dose equivalent not specified).

[0019] - Each vial of Promyxin® Nebulizer Powder contains 1 million International Units, equivalent to 80 mg of colistimethate sodium.

[0020] However, currently, no colistimethate formulations are licensed for the treatment of non-cystic fibrosis bronchiectasis (NICE Advice 2014, "Non-cystic fibrosis bronchiectasis: colistimethate sodium", Evidence summary, 6 January 2014). Furthermore, according to the Summary of Product Characteristics, colistimethate sodium is very commonly associated with adverse respiratory effects, including cough, dyspnea, bronchospasm, and sore throat, affecting at least one in ten people. The Summary of Product Characteristics for Promyxin® states that there have been reports of Pseudomonas aeruginosa acquiring resistance to colistimethate sodium during clinical use.

[0021] A phase II clinical trial published in 2014 (Reference: Haworth, C. et al. Am. J. Respir. Crit. Care Med., 2014, 189(8), 975-982) disclosed the use of nebulized colistimethate in NCFB (PPCTP / 001).

[0022] PPCTP / 001 enrolled patients with bronchiectasis who had at least two positive respiratory cultures for P. aeruginosa in the past 12 months and had completed a course of anti-P. aeruginosa antibiotics for treatment of an exacerbation within 3 weeks. P. aeruginosa also had to be cultured from a sputum sample collected at the screening visit. Participants were randomly assigned to receive colistimethate sodium (1 MIU [33 mg CBA], n = 73) or placebo (0.45% saline, n = 71) administered twice daily via an I-neb nebulizer for up to 6 months. The primary outcome was time to exacerbation. Secondary outcomes included time to exacerbation based on adherence recorded by I-neb, P. aeruginosa density, quality of life, and safety parameters.

[0023] However, in this trial, the median time to first progression after treatment was not statistically different from the placebo group.

[0024] Other clinical studies have been conducted in the past decades to evaluate the efficacy of inhaled colistin against NCFB. None of these studies, except for Haworth, C. et al. (ibid.), appear to have been randomized trials. Thus, the conclusions drawn do not appear to be supported by adequate power analyses.

[0025] Blanco-Aparicio et al., 2019, Chron. Resp. Dis_16:1-9, describe the results of a 12-month prospective clinical trial in which patients (n=67) received inhaled colistin after systemic antibiotic eradication therapy.

[0026] Lopez Gil Otero et al. in Rev. Esp.Quimioter.2019, 32(3):217-223 is an observational study of 44 patients treated with CMS for 6 or 12 months. The authors report that after colistin treatment, there was a reduction in emergency admissions and hospital stays compared to the previous period.

[0027] Dhar R. et al. Thorax 2010, 65:553 reported a retrospective study in which colomycin was inhaled at 1-2 megaunits twice daily using a standard "jet nebulizer" for a mean treatment period of 21.2 months, and in a sample of 19 patients, the frequency of exacerbations was reduced compared to before colomycin administration.

[0028] Therefore, there is a strong need for clinical studies in the field of NCFB treatment that can provide results with adequate statistical power. Summary of the Invention [Problem to be solved by the invention]

[0029] The desired treatment for NCFB should not only alleviate the clinical symptoms of bronchiectasis, such as the frequency and severity of pulmonary exacerbations, but also minimize side effects and reduce systemic toxicity. [Means for solving the problem]

[0030] The present invention relates to colistimethate sodium (CMS) administered at a dose of at least 20 mg colistin base activity (CBA) per day to reduce the frequency of pulmonary exacerbations in patients suffering from non-cystic fibrosis bronchiectasis (NCFB) with Pseudomonas aeruginosa infection, wherein said exacerbation is characterized by the simultaneous presence, for at least 24 hours, of at least three of the following eight symptoms or signs: - Increased coughing; - Increased sputum volume and / or viscosity; - increased purulent sputum; - New or increased hemoptysis; - Increased wheezing; - Increasing difficulty in breathing; - Increased fatigue and lethargy; - Episodes of fever (temperature above 38°C) and is defined as when a subject is clinically determined to require and be prescribed systemic antibiotic therapy.

[0031] The amount of CMS comprises 20 mg to 60 mg of CBA per day, more preferably 10 to 30 mg of CBA administered twice daily, said pulmonary exacerbation being as defined above.

[0032] A further object of the present invention is a composition for inhalation, nebulization or aerosol spray comprising colistimethate sodium (CMS) in an amount of at least 30-35 mg CBA / mL to 60-70 mg CBA / mL in a sterile aqueous solution suitable for inhalation, for use in reducing the frequency of pulmonary exacerbations in patients suffering from non-cystic fibrosis bronchiectasis (NCFB) with Pseudomonas aeruginosa infection.

[0033] A further embodiment of the present invention relates to a kit for use in reducing the frequency of pulmonary exacerbations in patients suffering from non-cystic fibrosis bronchiectasis (NCFB) with Pseudomonas aeruginosa infection, comprising: - at least one single-dose vial containing colistimethate sodium (CMS) in powder form containing 30-35 mg CBA to 60-70 mg CBA; - Sterile saline solution, and - A leaflet with instructions for the treatment of NCFB.

[0034] Preferably, the kit further comprises a suitable nebulizer system.

[0035] The present invention also relates to a method of reducing the frequency of pulmonary exacerbations in a patient suffering from non-cystic fibrosis bronchiectasis (NCFB) with Pseudomonas aeruginosa infection, said method comprising: - administering to said patient a daily dose of at least 20 mg of the CBA colistimethate sodium (CMS) by inhalation; and - Reducing the frequency of said pulmonary exacerbations in said patient.

[0036] The invention will be better understood from the accompanying drawings, in which: [Brief description of the drawings]

[0037] [Figure 1] Schematic showing the features of a device suitable for CMS inhalation. [Diagram 2] Schematic showing the features of a device suitable for CMS inhalation. [Diagram 3] Kaplan-Meier curves for time to first NCFB pulmonary exacerbation (mITT population). Placebo: dotted line, CMS: continuous line. [Figure 4] Change from baseline in SGRQ total score by visit (mITT population). Visit 2: t=0 CMS treatment, Visit 3: 28 days ± 1 week, Visit 4: 3 months ± 1 week; Visit 5: 6 months ± 1 week, Visit 6: 9 months ± 1 week, Visit 7: 12 months ± 1 week (end of treatment: EOT). [Diagram 5] Change from baseline in P. aeruginosa density by visit (mITT population). Visit 2: t=0 CMS treatment / placebo, Visit 3: day 28 ± 1 week, Visit 4: 3 months ± 1 week; Visit 5: 6 months ± 1 week, Visit 6: 9 months ± 1 week, Visit 7: 12 months ± 1 week (end of treatment: EOT). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038] definition As used herein, the term "colistin" includes colistin sulfate (usually administered orally for intestinal decontamination and topically as a powder for the treatment of bacterial skin infections) and colistimethate sodium (CMS).

[0039] As used herein, the term colistimethate sodium includes colistimethane sulfate, colistimethane sulfate pentasodium, and colistin sulfonylmethate. CMS is the sulfomethylated form of colistin. To be an effective antibacterial agent, the sulfomethyl group of CMS must be hydrolyzed to liberate the free amino group to give colistin sulfate, the active form of the drug. Thus, CMS is considered to be a prodrug of colistin.

[0040] The active ingredient in "colistin" is chemically a mixture of polymyxins E1 and E2. Chemical Abstracts gives colistin the number 1066-17-7. According to the European Pharmacopoeia, colistin contains more than 77% polymyxins E1, E2, E3, E1i and E1-7MOA, with less than 10% each of the minor components polymyxins E3, E1-i and E1-MOA.

[0041] According to the EMA (European Medicines Agency), the dosage of this antibiotic should always be expressed in IU (International Units) of colistimethate sodium. However, if the dosage and administration method are different, the following conversion table (Table 1) should be used (Reference: "European Medicines Agency completes review of polymyxin-based medicines" December 16, 2014):

[0042] [Table 1]

[0043] CMS is approved for parenteral use (intravenous, intramuscular, inhaled, aerosolized, intrathecal / intracerebroventricular) for the management of chronic Pseudomonas pulmonary infections in adults and children.

[0044] CMS is sold under the following trade names: - Colobreeze® dry powder for inhalation. Each capsule contains 1,662,500 international units, equivalent to 125 mg of colistimethate sodium. This formulation is only licensed for chronic pulmonary infections in children aged 6 years and older. - Colistimethin® Powder for injection for solution for inhalation using a nebulizer. Each vial contains 1 or 2 million international units of colistimethinate sodium (dose equivalent not specified). - Promixin® / Tadim®: Powder (1 million international units).

[0045] As used herein, the term "about" is intended to refer to a range when a point value is given, which range includes at least plus or minus 2% of the given value.

[0046] As used herein, the term "pulmonary exacerbation" in a patient refers to the simultaneous presence of at least three of the following eight symptoms / signs for at least 24 hours: - Increased coughing; - Increased sputum volume and / or viscosity; - increased purulent sputum; - New or increased hemoptysis; - Increased wheezing; - Increasing difficulty in breathing; -Increased fatigue / lethargy; - Episodes of fever (temperature above 38°C) and when a subject is clinically determined to require and be prescribed systemic antibiotic therapy. A new pulmonary exacerbation was considered to have occurred only if there was at least 14 days between the end of the systemic antibiotic course and the onset of the new qualifying symptom. (Note: Pulmonary exacerbations are reported as adverse events or serious AEs [SAEs].)

[0047] A "severe" pulmonary exacerbation is defined herein as a pulmonary exacerbation requiring intravenous antibiotics and / or hospitalization.

[0048] As used herein, the term "inhalation" refers to the administration of a substance through the respiratory tract, usually by oral or nasal inhalation, in the form of a nebulized liquid, gas, aerosol, or fine powder, for localized and / or systemic effect.

[0049] As used herein, the term "inhalation device" refers to devices such as: Respironics I-neb® AAD (with 0.3 mL or 0.5 mL chambers), Pari eFlow® rapid, Pari LC Sprint with Pari Boy® SX compressor. AAD stands for Adaptive Aerosol Delivery System, which is designed to continually adapt to changes in a patient's breathing pattern and pulse aerosol only during the inhalation portion of the breathing cycle. This eliminates waste of aerosol during exhalation and allows for precise delivery of aerosol (dosage).

[0050] The characteristics of these devices are summarized in Figures 1 and 2.

[0051] Modified Intention to Treat (mITT). The mITT population includes all subjects who provided informed consent, were randomized, and received at least one dose or partial dose of IMP.

[0052] By "clinically stable patient" is meant a patient who has not required a change in pulmonary therapy for NCFB within at least 30 days prior to initiation of inhaled CMS therapy according to the present invention.

[0053] By macrolide, Applicants mean any one of the following antibiotics: azithromycin, erythromycin, clarithromycin.

[0054] (Detailed Description) According to a main aspect, the present invention relates to colistimethate sodium (CMS) administered by inhalation at a dose of at least 20 mg colistin base activity (CBA) per day for use in reducing the frequency of pulmonary exacerbations in patients suffering from non-cystic fibrosis bronchiectasis (NCFB) and Pseudomonas aeruginosa infection, said administration being preferably "chronic", where "chronic" contemplates administration of CBA for at least 12 months.

[0055] Preferably, the inhaled colistin is delivered by an adaptive aerosol delivery system. Characteristic features of the I-neb AAD system include: (1) precise dosing, (2) feedback to the patient, (3) recording of information on device use and performance, and (4) data transmission via the internet for remote monitoring of patient adherence to medication and device performance. Furthermore, as is known, the AAD system allows the drug to be inhaled only during the inspiration phase.

[0056] The use of CMS to reduce the frequency of exacerbations in NCFB has not been proven until this Phase III clinical trial (Promis I). In fact, the Phase II trial failed to achieve its primary endpoint, which was the number of days from the start of CMS treatment to the first exacerbation. (Haworth, C. et al. Am.J. Respir.Crit.Care Med., 2014, 189(8), 975-982) discloses the use of colistimethate nebulizer in NCFB (PPCTP / 001).

[0057] Non-cystic fibrosis bronchiectasis (NCFB) is a severe chronic disease characterized by irreversible dilatation of the airways and thickening of the bronchial walls, chronic inflammation, recurrent infections, and progressive airway obstruction. In contrast to cystic fibrosis bronchiectasis (CFB), a well-defined genetic disorder, NCFB is a heterogeneous disease caused by many different pathologies.

[0058] However, a treatment that has shown clinical benefit with CFB may not necessarily show the same benefit with NCFB (Barker et al., "Aztreonam for inhalation solution in patients with non-cystic fibrosis bronchiectasis (AIR-BX1 and AIR-BX2): two randomised double blind, placebo-controlled phase 3 trials.". Lancet Respir Med, 2014, 2:738-749). Therefore, it is not appropriate to draw a direct correlation between CFB and NCFB treatment.

[0059] CMS is approved for the treatment of chronic lung infections caused by Pseudomonas aeruginosa in adult and pediatric CFB patients.

[0060] However, given the previous clinical studies of NCFB summarized above, it was not expected that colistin would reduce the frequency of exacerbations in patients with NCFB.

[0061] Non-cystic fibrosis bronchiectasis (NCFB) is an increasingly common and important health problem associated with a significant mortality rate, with a higher incidence in older adults and women, and its incidence has increased during the last decades due to improved diagnostic tools.

[0062] There are several main causes of NCFB, including infections, bronchial obstruction, allergic bronchopulmonary aspergillosis, immunodeficiency states, connective tissue disorders, idiopathic inflammatory diseases, autoimmune diseases, etc. The most common cause in the literature is post-infectious due to exaggerated and uncontrolled inflammation progressing to small airway obstruction, damage and destruction of the bronchial wall, and ultimately bronchiectasis, but no specific underlying cause has been identified so far.

[0063] Indeed, repeated respiratory infections (bacterial, viral, or fungal) in susceptible individuals lead to chronic airway inflammation, progressive obstruction of small airways, and destruction of the bronchial walls, typical of non-cystic fibrosis bronchiectasis (NCFB). Once established, the airways of NCFB patients are chronically infected with bacteria, and often experience repeated exacerbations. This explanation established the "vicious circle" hypothesis proposed by Cole (Cole PJ, "Inflammation: a two-edged sword--the model of bronchiectasis.", European Journal of Respiratory diseases.Supplement, 1986, 147:6-15 1986). This hypothesis involves a cycle of events: a weakened lung defense allows bacterial infection of the airway mucosa, stimulating a neutrophilic inflammatory response that becomes chronic if the bacteria cannot be eradicated; the host inflammatory response causes tissue damage, e.g. via proteinase enzymes and reactive oxygen species, overwhelming the body's ability to neutralize them; tissue damage further weakens the lung defenses, allowing the bacteria to persist.

[0064] Other comorbidities were more frequent in NCFB patients compared to CFB patients. In fact, COPD (41.4%), asthma (32.8%), and gastroesophageal reflux (18.3%) were the most common predisposing factors for NCFB.

[0065] Inhaled antibiotics are effective in P. aeruginosa-infected CFB patients, but their efficacy in NCFB has not yet been clearly proven. Indeed, many pathogens are involved in the colonization of patients with bronchiectasis. The main gram-negative pathogens include: Haemophilus influenzae, Moraxella catarrhalis, and Pseudomonas aeruginosa. The latter are associated with increased morbidity and mortality. Moreover, in NCFB patients, P. aeruginosa may acquire antibiotic resistance more frequently than in CFB patients.

[0066] Effective treatment according to the present invention involves delivering a CMS amount by inhalation of at least 20 mg CBA to 60 CBA (2 MIU to 6 MIU) per day. More preferably, CMS is administered twice daily in an amount equivalent to 10-30 mg CBA. Even more preferably, the CMS amount is provided by inhalation in a dose of at least 10 mg CBA twice daily, which corresponds to about 0.3 mL of a CMS solution containing 30-35 mg CBA / mL.

[0067] Preferably, NCFB patients suitable for treatment according to the present invention are those who are clinically stable on NCFB, i.e., have not required a change in pulmonary therapy for NCFB within at least 30 days prior to initiation of inhaled CMS therapy.

[0068] Inhalation by respiratory tract, preferably by oral route, is accomplished by an adaptive aerosol delivery system inhalation device, such as the I-neb AAD device. This device is activated by a disk provided with the I-neb and is used after appropriate training (including written instructions) that also instructs on CMS preparation for I-neb. When subjects self-administer the investigational drug, especially the CMS, using the I-neb device, the date, time, and amount of administration are stored on the device, providing a complete and faithful therapeutic record.

[0069] Other suitable devices for CMS nebulization and / or inhalation are depicted, for example, in FIGS.

[0070] The preferred duration of CMS treatment according to the present invention is at least 12 months.

[0071] As mentioned above, the dosage of CMS can be expressed in different ways. The European Medicines Agency provides a conversion table (Table 1) for defining international units and colistimethate and colistin activity. According to this table, 1 MIU corresponds to approximately 80 mg of colistimethate sodium (mass) and approximately 34 mg of colistin base activity (CBA). In the present invention, it is referred to as colistin base activity (CBA).

[0072] A further embodiment according to the present invention relates to a sterile saline composition comprising colistimethate sodium (CMS) suitable for administration of CMS in an amount equivalent to at least 20 mg CBA / day by inhalation, nebulization or aerosol spray for use in reducing the frequency of pulmonary exacerbations in patients suffering from non-cystic fibrosis bronchiectasis (NCFB) with Pseudomonas aeruginosa infection.

[0073] Preferably, compositions for inhalation are prepared at the time of use from a suitable amount of powdered CMS. Suitable compositions contain CMS in an amount of at least 30-35 mg CBA / mL to 60-70 mg CBA / mL and are administered twice daily. According to a preferred embodiment, CMS is prepared in a concentration of at least 30-35 mg CBA in 1 mL of solution suitable for inhalation, about one third (0.3 mL) being delivered by inhalation using a suitable inhalation device, with each inhalation delivering about 10 mg CBA.

[0074] Sterile saline solutions commonly used to disperse powdered colistimethate sodium preferably contain sodium chloride (NaCl) at a concentration of 0.4% to 0.9% w / v in sterile water for injection (WFI) or a suitable physiological sterile buffer. The preferred final NaCl concentration in an inhalation solution containing CMS for use in therapy according to the present invention is 0.4% to 0.5% w / v, more preferably 0.45% w / v.

[0075] As noted above, the CMS compositions are preferably prepared extemporaneously, i.e., at the moment of use, or, if stored at 2-8° C., within 24 hours.

[0076] According to a preferred embodiment, patients who were successfully treated with inhaled CMS therapy had a form of NCFB characterized by at least two NCFB pulmonary exacerbations requiring oral or inhaled antibiotics or one NCFB pulmonary exacerbation requiring intravenous antibiotics in the 12 months prior to inhaled CMS therapy.

[0077] More preferably, the patient is at least 80% adherent to medication.

[0078] The present invention also relates to a kit for reducing the frequency of pulmonary exacerbations in patients suffering from non-cystic fibrosis bronchiectasis (NCFB) with Pseudomonas aeruginosa infection, the kit comprising a vial having a powdered amount of colistimethate sodium (CMS) equivalent to at least 30-35 mg of CBA, an aqueous sterile solution, and a leaflet with instructions for treatment of NCFB by inhalation, which instructs the patient to resuspend the powder in about 1 mL of saline, transfer to a nebulizer chamber, and deliver about 0.3 mL of the prepared CMS composition for long-term treatment, where long-term means at least 12 months.

[0079] The kit may further include a suitable nebulizer system, as described above.

[0080] The kit according to the present invention comprises an aqueous sterile saline solution in which sodium chloride is present at a concentration of 0.4% to 0.9% w / v, more preferably at a concentration of 0.4% to 0.5% w / v, and even more preferably at a concentration of about 0.45% w / v.

[0081] To reduce the frequency of pulmonary exacerbations in patients with non-cystic fibrosis bronchiectasis (NCFB) with Pseudomonas aeruginosa infection, the instruction leaflet recommends the use of an amount of CMS containing at least 20 mg of CBA per day, preferably 20-60 mg of CBA per day, and more preferably at least 10 mg of CBA, by inhalation twice daily for at least 12 months.

[0082] The reduction in frequency of pulmonary exacerbations in patients with non-cystic fibrosis bronchiectasis (NCFB) with Pseudomonas aeruginosa infection is accompanied by an increase in the time from initiation of treatment to first pulmonary exacerbation of at least 180 days, more preferably 185 days, and even more preferably 190, 200, 205, 206, 207 or 208 days, of all medians.

[0083] As stated above, a pulmonary exacerbation is defined as the simultaneous presence of at least three of the following eight symptoms / signs for at least 24 hours: - Increased coughing; - Increased sputum volume and / or viscosity; - increased purulent sputum; - New or increased hemoptysis; - Increased wheezing; - Increasing difficulty in breathing; -Increased fatigue / lethargy; - Episodes of fever (body temperature above 38°C), and is defined as when a subject is clinically determined to require and be prescribed systemic antibiotic therapy.

[0084] A sensitivity analysis was performed using an alternative definition of NCFB pulmonary exacerbation in the mITT population based on the definition published by the ERS in 2017 (Hill AT, Haworth CS, Aliberti S, et al. Pulmonary exacerbation in adults with bronchiectasis: a consensus definition for clinical research. Eur Respir J. 2017;49(6):1700051. doi:10.1183 / 13993003.00051-2017. ).

[0085] This alternative definition was that of ERS, but because of limitations in data collection, the actual definition used in the analysis was modified based on a) the presence of three or more specific precipitating symptoms (with or without exacerbations), b) antibiotic use (with or without changes in NCFB therapy), and c) duration of at least 2 days (instead of duration of at least 48 hours).

[0086] Of note, the results of the sensitivity analyses support the results of the primary analysis by the above criteria.

[0087] A new pulmonary exacerbation was considered to have occurred only if there was at least 14 days between the end of the systemic antibiotic course and the onset of the new qualifying symptom. (Note: pulmonary exacerbations are reported as adverse events or serious AEs [SAEs].)

[0088] A "severe" pulmonary exacerbation is defined herein as one requiring intravenous antibiotics and / or hospitalization; Post-study results regarding P. aeruginosa density confirmed that P. aeruginosa density declined rapidly and remained suppressed in patients treated with colistimethate sodium, with no data to suggest the emergence of colistimethate resistance in either the active or placebo groups.

[0089] According to a further embodiment, the present invention relates to a method of treatment for reducing the frequency of pulmonary exacerbations in patients suffering from non-cystic fibrosis bronchiectasis (NCFB) with Pseudomonas aeruginosa infection, said method comprising: - administering to said patient by inhalation colistimethate sodium (CMS) in a dose equivalent to at least 20 mg CBA / day to reduce said frequency of said pulmonary exacerbations in said patient.

[0090] Preferably, the treatment method is based on the administration of a daily CMS dose containing 20-60 mg of CBA.

[0091] More preferably, the method of the present invention provides for the administration of CMS in an amount equivalent to about 10 mg of CBA to about 30 mg of CBA twice daily.

[0092] In a more preferred embodiment, the dose of CMS administered to the patient by inhalation is at least 10 mg of CBA twice daily.

[0093] A method of reducing the frequency of pulmonary exacerbations in a patient suffering from non-cystic fibrosis bronchiectasis (NCFB) with Pseudomonas aeruginosa infection, comprising: administering to said patient by inhalation, nebulization or aerosol spray a composition comprising at least 1 MIU / mL / day of colistimethate sodium (CMS) (equivalent to about 33-34 mg CBA / mL and 80 mg / mL colistimethate sodium); delivering to said patient a volume of about 0.3 mL of said composition, thereby reducing said frequency of said pulmonary exacerbations in said patient. Preferably, said CMS is in saline, said saline being a sterile aqueous solution comprising 0.4%-0.9% w / v sodium chloride. More preferably, said sterile saline comprises 0.4%-0.5% w / v sodium chloride, more preferably 0.45% w / v sodium chloride.

[0094] More preferably, the CMS is a powder that is dissolved prior to use in a sterile aqueous solution suitable for inhalation, the powder corresponding to the amount of CMS for each inhalation, containing from about 30-35 mg CBA to about 60-70 mg CBA for each dose, preferably resuspended in 1 mL of sterile aqueous solution.More preferably, the amount of CMS corresponds to at least 30-35 mg CBA, preferably 33-34 mg CBA, dissolved in 1 mL of sterile aqueous solution suitable for inhalation, of which about 0.3 mL is inhaled, corresponding to about 10 mg CBA delivered during each inhalation, preferably twice daily.

[0095] Preferably, the sterile aqueous solution is a saline solution containing 0.4-0.9% w / v sodium chloride, optionally diluted with water for injection.

[0096] Preferably, NCFB patients treated according to the invention have not received antibiotic treatment with oral macrolides and / or colistin within at least 30 days prior to initiating treatment with CSM.

[0097] Preferably, administration of the above preferred amounts of CMS is chronic, continuing for at least 12 months.

[0098] According to a preferred embodiment, the method of the present invention comprises administering about 10 mg of CBA by inhalation twice daily, wherein about 30-35 mg of CBA, preferably about 33-34 mg of CBA (corresponding to about 1 MIU), is preferably dissolved in 1 mL of sterile saline, and about 0.3 mL is delivered by I-neb twice daily.

[0099] According to the data detailed in the experimental section, treatment with the present invention reduces the annualized exacerbation rate in patients receiving CMS I-neb versus placebo (0.58 vs. 0.95 per patient per year, rate ratio (RR) 0.61 95% confidence interval 0.46-0.82, p=0.00101).

[0100] CMS treatment reduced the annual incidence of pulmonary exacerbations by 39% compared to placebo, which is both clinically and statistically highly significant. These data are supported by results from other preplanned analyses of the primary endpoint, including a sensitivity analysis using an alternative definition of pulmonary exacerbation (Hill AT, Haworth CS, Aliberti S, et al. Pulmonary exacerbation in adults with bronchiectasis: a consensus definition for clinical research. Eur Respir J. 2017;49(6):1700051. doi:10.1183 / 13993003.00051-2017). Analysis of adherence to treatment (≥80% adherence) also showed a statistically significant (p=0.00080) lower mean annual exacerbation rate at the 5% level in the CMS group (LS mean 0.494) compared to the placebo group (LS mean 0.873).

[0101] Other outcomes (secondary efficacy variables) from this study were: Time to first exacerbation and severe NCFB pulmonary exacerbations The time to first progression was prolonged in the CMS I-neb group (HR 0.59, 95% CI 0.43-0.81, p=0.00074; HR=hazard ratio).

[0102] The time from first dose of IMP to first NCFB pulmonary exacerbation was statistically significantly longer in the CMS group than in the placebo group. The median time to first NCFB pulmonary exacerbation was 208 days in the placebo group and was not reached in the CMS group because less than half of the subjects (n=68, 38.6%) experienced a pulmonary exacerbation during the study.

[0103] Survival distributions were compared between the two treatment groups using the log rank test and were assessed as statistically significant (p = 0.00074). Supportive analyses were performed using Cox proportional hazards regression models for the modified intention to treat (mITT) population.

[0104] The time to first NCFB pulmonary exacerbation was statistically significantly longer in the CMS group than in the placebo group (see Figure 3).

[0105] The risk of a first exacerbation was significantly lower in the CMS group compared with the placebo group (hazard ratio, 0.590; 95% CI, 0.432, 0.806), resulting in a 41% reduction in the risk of a first exacerbation event in the CMS group compared with the placebo group.

[0106] CMS inhaled via I-neb demonstrated superiority over placebo in reducing the annualized rate of severe NCFB exacerbations (p=0.003). The LS mean annualized rate of severe NCFB exacerbations was 0.116 in the CMS group and 0.283 in the placebo group. The LS mean incidence rate ratio for CMS to placebo was 0.409 (95% confidence interval, 0.227, 0.738; p=0.003), a statistically significant 59% reduction in severe exacerbations in the CMS-treated group compared with placebo.

[0107] Severe NCFB pulmonary exacerbations occurred in 19 / 176 patients (10.8%) in the CMS group compared with 36 / 197 patients (18.3%) in the placebo group. The median, 25th, and 75th percentiles of time to first severe NCFB pulmonary exacerbation were not reached in either group. Survival distributions were compared between the two treatment groups, and the difference was assessed as statistically significant (p=0.03318). Quality of life (QoL) as measured by the Saint George's Respiratory Questionnaire (SGRQ) was assessed as 0.001. The treatment difference in SGRQ total score by LS mean across all time points was -3.378, p=0.01766, indicating a statistically significant improvement in QOL over the study period. At the end of CMS treatment, the treatment difference in SGRQ total score by LS mean was 4.552, p=0.0055, indicating a clinically meaningful and statistically significant improvement in QOL at the end of the study compared to baseline (see Figure 4).

[0108] Changes in Pseudomonas aeruginosa density After 1 month, P. aeruginosa density was statistically significantly reduced in the CMS group compared to the placebo group (LS mean difference = -1.620, p < 0.00001). After 12 months, P. aeruginosa density was reduced from baseline to a greater extent in the CMS group (mean CFB -0.86) compared to the placebo group (mean CFB -0.08) (see Figure 5).

[0109] Adverse events The proportion of patients experiencing adverse events was similar in each group. Bronchospasm was clinically observed in only 0.6% of CMS-treated patients, and the incidence of Pseudomonas aeruginosa resistance to colistin sulfate was low at 1%.

[0110] Thus, CMS with I-neb via an adapted aerosol delivery system significantly reduced annual exacerbation and P. aeruginosa infection rates and was safe and well tolerated.

[0111] The above results were achieved by statistical analyses with over 80% power to detect a treatment difference of 30%.

[0112] Macrolide treatment Baseline stable macrolide use was similar in the CMS (24.4%) and placebo (26.9%) groups. Of note, concomitant stable oral macrolide use was included as an effect in the model but was not statistically significant (p=0.44506), suggesting that there was no notable difference in the mean annualized rate of pulmonary exacerbations in NCFB between subjects who were and were not concomitantly using a stable oral macrolide.

[0113] Group The mean age of subjects was 64.2 years in both the CMS and placebo groups, and two-thirds were women (123 [69.9%] in the CMS group and 126 [64.0%] in the placebo group).

[0114] Most subjects were white (167 [94.9%] in the CMS group and 189 [95.9%] in the placebo group). Demographic characteristics, including height, weight, and obesity level, were similar in both groups. More than two-thirds of subjects were never smokers: 124 of 176 (70.5%) in the CMS group and 142 of 197 (72.1%) in the placebo group. Only three (0.8%) were current smokers: 0 / 176 in the CMS group and 3 / 197 in the placebo group. The remaining 27.9% (52 / 176 in the CMS group and 52 / 197 in the placebo group) were former smokers.

[0115] Preferred Embodiments 1. A method for reducing the frequency of pulmonary exacerbations in a patient suffering from non-cystic fibrosis bronchiectasis (NCFB) with Pseudomonas aeruginosa infection, said method comprising: - administering to said patient a daily dose of at least 20 mg of the CBA colistimethate sodium (CMS) by inhalation; and - Reducing the frequency of said pulmonary exacerbations in said patient. 2. The method according to the former embodiment, wherein said dose comprises from 20 mg CBA / day to 60 mg CBA / day. 3. The method according to the previous embodiment, wherein the inhaled colistin is provided by an adaptive aerosol delivery system. 4. The method according to the above embodiment, wherein the patient is clinically stable. 5. The method according to the previous embodiment, wherein the patient had at least two NCFB pulmonary exacerbations requiring oral or inhaled antibiotics, or one NCFB pulmonary exacerbation requiring intravenous antibiotics, in the 12 months prior to CMS treatment. 6. The method according to the previous embodiment, wherein said patient has one or more of the following co-morbidities: COPD, asthma, gastroesophageal reflux. 7. The method according to the previous embodiment, wherein said dose is 10 mg to 30 mg of CBA twice daily. 8. The method according to the former embodiment, wherein said dose is 10 mg of CBA twice daily. 9. A method for reducing the frequency of pulmonary exacerbations in a patient suffering from non-cystic fibrosis bronchiectasis (NCFB) with Pseudomonas aeruginosa infection, said method comprising: - preparing a colistimethate sodium (CMS) composition comprising 30-35 mg of CBA to 60-70 mg of CBA dissolved in 1 mL of saline; - delivering to the patient a volume of about 0.3 mL of the composition by inhalation, nebulization or aerosol spray; and - Reducing the frequency of said pulmonary exacerbations in said patient. 10. The method according to the previous embodiment, wherein the composition comprising CMS is saline. 11. The method according to the previous embodiment, wherein the saline is a sterile aqueous solution containing 0.4% to 0.9% w / v sodium chloride. 12. The method according to the previous embodiment, wherein the sterile aqueous solution comprises 0.45% w / v sodium chloride. 13. The method according to the previous embodiment, wherein the CMS is in the form of a powder that is dissolved prior to use in a sterile aqueous solution suitable for inhalation. 14. The method according to the previous embodiment, wherein the powder corresponds to a dose of 30-35 mg of CBA to 60-70 mg of CBA. 15. The method according to the previous embodiment, wherein the sterile aqueous solution is saline. 16. The method according to the previous embodiment, wherein the saline solution contains 0.4-0.9% w / v sodium chloride. 17. The method according to the previous embodiment, wherein the CMS is administered for at least 12 months. 18. A method according to any of the preceding embodiments, comprising: - administering to said patient a dose of at least 10 mg of the CBA colistimethate sodium (CMS) by inhalation twice daily for at least 12 months; and - Reducing the frequency of said pulmonary exacerbations in said patient. EXAMPLES

[0116] The PROMIS I clinical trial is available at clinicaltrials.gov (https: / / clinicaltrials.gov / ct2 / show / NCT03093974?term=Zambon&cond=Non-cystic+Fibrosis+Bronchiectasis&draw=2&rank=2).

[0117] Abbreviation AAD: Adaptive Aerosol Delivery ADR: Adverse Drug Reaction AE: Adverse event CBA: Colistin base activity (EMA indications) as shown in the table below CF: Cystic fibrosis CFU: colony forming unit CI: Confidence interval COPD: chronic obstructive pulmonary disease HRCT: High-resolution computed tomography IMP: Investigational Drug (CMS) IU: International Unit MIU: Million International Units NCFB: Non-cystic fibrosis bronchiectasis SAE: serious adverse event

[0118] Group 377 patients were randomized (177 to I-neb CMS and 200 to placebo).

[0119] Participation criteria Subjects were considered eligible if they met the following criteria: 1. Individuals who are able and willing to give informed consent after receiving a detailed explanation of the protocol participation and providing signed consent; 2. Men and women aged 18 years or older; 3. Those who have been diagnosed with NCFB by computed tomography (CT) or high-resolution CT (HRCT) and have this documented in the subject's notes, and for whom this is the main disease being treated; 4. Those who had ≥2 NCFB pulmonary exacerbations requiring oral or inhaled antibiotics or ≥1 NCFB pulmonary exacerbation requiring intravenous antibiotics in the 12 months prior to the screening examination (Visit 1) and had no NCFB pulmonary exacerbations with or without treatment between Visit 1 and Visit 2; 5. Subjects with a history of Pseudomonas aeruginosa infection; 6. Clinically stable and not requiring changes in pulmonary therapy for at least 30 days prior to Screening (Visit 1); 7. Pre-bronchodilator FEV1 ≥ 25% of predicted; 8. Subjects have a positive sputum culture for Pseudomonas aeruginosa from the screening test (Visit 1) or an appropriate sample collected during the screening period.

[0120] Exclusion criteria Subjects were excluded if they met any of the following criteria: 1. Individuals with known bronchiectasis as a result of cystic fibrosis (CF); 2. Subjects with a history of hypogammaglobulinemia requiring treatment with immune globulin (unless fully supplemented and deemed immune competent by the investigator); 3. Those with myasthenia gravis or porphyria; 4. Subjects with serious cardiovascular disease, including severe uncontrolled hypertension, ischemic heart disease, arrhythmias, or other conditions that, in the opinion of the investigator, may confound the evaluation of safety; 5. Subjects who had undergone major surgery in the 3 months prior to the screening examination (Visit 1) or were scheduled for inpatient major surgery during the study period; 6. Subjects receiving treatment for allergic bronchopulmonary aspergillosis (ABPA); 7. Massive hemoptysis (>300 mL or requiring transfusion) within the 4 weeks prior to the screening test (Visit 1) or between Visits 1 and 2; 8. Anyone with respiratory insufficiency that, in the opinion of the investigator, compromises patient safety or confounds the evaluation of the safety or efficacy of the study; 9. Those with currently active malignant tumors (excluding nonmetastatic basal cell carcinoma or squamous cell carcinoma of the skin); 10. Taking immunosuppressants (e.g., azathioprine, cyclosporine, tacrolimus, sirolimus, mycophenolate, rituximab) and / or anti-cytokine drugs (e.g., anti-IL-6 drugs, anti-tumor alpha necrosis factor preparations) during the year prior to the screening test (Visit 1); 11. Anyone with a history of human immunodeficiency virus (HIV); 12. Persons receiving treatment for nontuberculous mycobacterial (NTM) lung disease or tuberculosis; 13. Persons with known or suspected allergy or intolerance to colistimethate sodium (intravenous or inhaled) or other polymyxins (including those who have previously experienced bronchial hyperresponsiveness after inhalation of colistimethate sodium); 14. Received prednisone at a dose of more than 15 mg per day (or an equivalent dose of other corticosteroids) for a long period (≥30 days) within 6 months of Screening Examination 1 (Visit 1); 15. New maintenance therapy with oral macrolides (e.g., azithromycin / erythromycin / clarithromycin) was started within 30 days of screening (Visit 1) or between Visits 1 and 2 (Visit 2: t of treatment = 0); 16. Use of intravenous or intramuscular, oral, or inhaled antipseudoantibiotics (except chronic oral administration of stable doses of macrolides) within 30 days prior to the screening examination (Visit 1) and between Visits 1 and 2; 17. Pregnant or breastfeeding, planning to become pregnant within the next year, or of childbearing potential, and unwilling to use reliable contraception for at least 1 month prior to randomization and throughout study participation; 18. Subjects who have significant abnormalities in clinical evaluation and / or laboratory tests (physical examination, vital signs, hematology, clinical chemistry, clinically relevant renal dysfunction (defined as serum creatinine ≥ 2.0 times the upper limit of normal), electrocardiogram) at screening (Visit 1) and throughout the study period that would jeopardize the subject's safe participation in the study; 19. Participation in another clinical trial intervention within 30 days prior to the screening visit (Visit 1).

[0121] Efficacy Data Primary endpoint To determine whether the use of inhaled colistimethate sodium reduces the frequency of pulmonary exacerbations compared with placebo in NCFB patients chronically infected with P. aeruginosa, we tested the following hypotheses: - Null hypothesis A: There is no difference between inhaled colistimethate sodium and inhaled placebo in terms of its effect on pulmonary exacerbation rate.

[0122] For the effectiveness of inhaled colistimethate sodium to be considered proven, the null hypothesis must be rejected.

[0123] A supportive analysis was performed using an alternative definition of NCFB pulmonary exacerbation. Exacerbation reclassification was performed in a blinded manner (before database lock). The alternative definition of pulmonary exacerbation was a worsening of three or more of the following major symptoms for ≥48 hours: - Cough - Sputum volume and viscosity - purulent sputum - Shortness of breath and / or exercise tolerance (dyspnea) - Fatigue and / or lethargy - Hemoptysis and If the physician determines that a change in bronchiectasis treatment is necessary when other potential causes of clinical deterioration have been ruled out.

[0124] Mean annual pulmonary exacerbation rate The number of NCFB pulmonary exacerbations during the treatment period was analyzed using a Poisson regression model accounting for overdispersion with treatment, pooling facility, and use of oral stable macrolide combination therapy as fixed effects and including the logarithm of the study period as an offset.

[0125] Number and proportion of subjects with NCFB pulmonary exacerbations, number of pulmonary exacerbations, and follow-up time (in years) were summarized by treatment group. Adjusted annual means and adjusted rate ratios for exacerbation rates in each treatment group, with their 95% CIs, were estimated by model.

[0126] For the analysis, two pulmonary exacerbations were considered as one episode if the second pulmonary exacerbation began <14 days after the end of antibiotic treatment (oral or intravenous) for the first pulmonary exacerbation.

[0127] If the null hypothesis is rejected, secondary analyses will further explore the proportionality of hazards. Details of the analyses will be provided in the SAP.

[0128] Corresponding two-sided p values ​​of <0.05 were considered statistically significant.

[0129] Secondary endpoints Summary statistics and analyses of secondary efficacy / pharmacoeconomic endpoints were performed for mITT (primary analysis) and PP as follows:

[0130] Time to first exacerbation Time to first NCFB pulmonary exacerbation and time to first severe NCFB pulmonary exacerbation were calculated as the number of days from the date of first dose of IMP to the date of first pulmonary exacerbation (i.e., date of first pulmonary exacerbation – date of first dose + 1). Log-rank test was used to compare treatment groups. Subjects who completed the study without an NCFB pulmonary exacerbation or who discontinued early without an exacerbation were considered censored at last follow-up.

[0131] Annualized number of exacerbation-free days Annualized progression-free days were also presented by treatment group. Appropriate nonparametric tests were used to account for the effect of prognostic covariates.

[0132] Severe NCFB pulmonary exacerbations (including pneumonia episodes) The numbers and percentages of subjects defined as having pneumonia and severe pulmonary exacerbations requiring intravenous antibiotics and / or hospitalization (hospitalization ≥ 24 hours), the number of pneumonia / severe pulmonary exacerbations, and the annual mean pneumonia / severe pulmonary exacerbation rates are also shown by treatment group.

[0133] Quality of life SGRQ total scores and domain scores (symptoms, activity, and impact scores) were summarized at each visit by treatment group using descriptive statistics. Changes from baseline (Visit 2) were also summarized for each post-baseline visit by treatment group. Scores were calculated according to the SGRQ manual

[20] .

[0134] Duplicate entries and missing data are dealt with as described in the manual.

[0135] SGRQ total scores were analyzed using a linear mixed model for repeated measures with treatment, visit, interaction between treatment and visit, use of stable concomitant therapy with oral macrolides, and pooled center as fixed effects, and baseline values ​​as covariates. An unstructured covariance matrix was assumed, and Kenward-Roger adjustments were used for degrees of freedom. Least-squares means in each treatment group, least-squares mean differences between treatments, their 95% CIs, and associated p-values ​​at each visit were estimated by the model.

[0136] The QOL-B questionnaire total scores were summarized and analyzed in the same way as the SGRQ total scores. The scoring algorithm and methods for handling multiple imputation and missing data were performed according to the questionnaire instructions [21, 22].

[0137] Pseudomonas aeruginosa density P. aeruginosa densities, determined by the mean change in log10 CFU / g sputum from baseline (visit 2) to day 28 (visit 3), and to visits 5 and 7, were compared between treatment groups by analysis of covariance models that included treatment, pooling facility, and use of oral macrolide stable combination therapy as fixed effects and baseline values ​​as covariates. Least-squares means in each treatment group, least-squares mean differences between treatments, their 95% CIs, and associated p-values ​​were estimated.

[0138] Sensitivity analyses may be performed to assess the robustness of the conclusions.

[0139] Summary statistics for P. aeruginosa density (log10 CFU / g sputum) and change from baseline (Visit 2) will be provided by treatment group at each study visit.

[0140] treatment One MIU of CMS powder (Xellia Pharm. Aps, Copenhagen, DK) corresponds approximately to 80 mg colistimethate sodium / 33 mg colistin base activity (CBA) according to Table 1 and was administered twice daily with I-neb, a pulmonary administration device powered by an ultrasonic (vibrating mesh) nebulizer system designed to aerosolize liquid medications approved for use in the I-neb AAD system, e.g., as described in US 6,367,470.

[0141] I-Neb (Nebulizer device) Subjects will administer IMP twice daily using the I-neb AAD device, activated by the disk provided with the I-neb. Subjects will receive appropriate training in the use of the I-neb device (including written instructions) and in the preparation of IMP for use with the I-neb. Subjects will administer their first IMP administration at Visit 2 under the supervision of site personnel and will be informed that the amount of IMP used will be recorded by the device. If subjects self-administer IMP with the I-neb device, the time of day when IMP was administered, the time of administration, and the amount of IMP will be stored on the device.

[0142] During the study, the investigator will continually assess medication adherence on-site by downloading data from I-neb to a sponsor-provided data analysis device installed on a laptop. In addition, medication accountability (see Section 11.4) will be conducted to assess the amount of IMP used and not used by the subject. Data will remain in I-neb so that they can be fully analyzed at the end of the study.

[0143] After the end of treatment, i.e. visit 7, device usage data from the I-neb is downloaded to a laptop according to instructions provided to the site personnel. The data can then be sent electronically to the CRO or Philips as instructed. Alternatively, the device can be kept and returned to Almac with the returned IMP. Almac then sends the device to Philips (the I-neb manufacturer), who downloads the data and sends it to the CRO. As the I-neb system records all information regarding the taking of the IMP, these data are used to determine overall medication adherence.

[0144] Pseudomonas aeruginosa Analysis Quantitative analysis of P. aeruginosa density is expressed as the number of colony forming units (CFU) per gram of sputum.

[0145] In addition to P. aeruginosa density analysis (see Section 9.1.5), sputum specimens obtained at each visit should be assessed for susceptibility to colistin sulfate using the minimum inhibitory concentration (MIC) method. Specimens obtained during pulmonary exacerbations should also be susceptible to a panel of additional antimicrobial agents.

[0146] If resistance to colistin sulfate is detected and / or any isolate shows a significant increase in MIC (i.e., a >4-fold change in the colistimethate sodium MIC), genotypic testing of the P. aeruginosa isolate can be performed to determine whether the change in MIC is due to microbiologic relapse or reinfection.

[0147] Results: P. aeruginosa densities declined rapidly and remained suppressed in the colistimethate sodium treatment group compared with the placebo group, and there were no data to suggest the emergence of colistimethate resistance. JPEG2024527021000002.jpg48170

[0148] Biometrics Primary efficacy variables: The primary variable in this study was the mean annualized NCFB pulmonary exacerbation rate (frequency of pulmonary exacerbations) over a 12-month period.

[0149] Secondary efficacy variables: - Time from first dose of IMP to first pulmonary exacerbation (days); - Annualized number of days without pulmonary exacerbations; - number of severe pulmonary exacerbations (defined as those requiring intravenous antibiotics and / or hospitalization); - Time from first dose of IMP to first severe pulmonary exacerbation (days); - QoL was measured by the total scores of the SGRQ and QOL-B questionnaires, as well as the change in SGRQ and QOL-B from baseline to each post-baseline visit; - Number of days missed work due to pulmonary exacerbations; - Pseudomonas aeruginosa density as determined by the mean change in log10 CFU / g sputum from baseline (Visit 2) to Day 28 of treatment (Visit 3), and to Visits 5 and 7.

[0150] Safety Variables - Incidence of TEAEs - Absolute percent change in predicted FEV1 from baseline (Visit 2) to the end of treatment (Visit 7); - the number of subjects who experienced clinical or spirometrically determined bronchospasm after IMP administration at the start and end of treatment; - Determine P. aeruginosa resistance to colistin sulfate by in-vitro susceptibility testing in sputum from screening / randomization (Visit 1 / 2) through Visits 3, 5, and end of treatment (Visit 7), as well as sputum from pneumonia exacerbation visits and clinic visits; - appearance of other bacterial colonies in sputum and emergence of resistant bacteria from screening (visit 1) to the end of treatment (visit 7); - Hematology, clinical chemistry, renal function tests; - Physical examination and vital signs data; - 12-lead ECG

[0151] result The mITT approach was used to generate summaries of baseline subject characteristics and to analyze all primary and secondary efficacy endpoints.

[0152] The annual incidence of exacerbations was lower in the CMS I-neb group than in the placebo group (0.58 vs. 0.95 per patient per year; incidence rate ratio (RR = relative risk) 0.61, 95% confidence interval 0.46-0.82, p=0.00101).

[0153] The LS mean incidence rate ratio for CMS to placebo was 0.612 (95% CI 0.457, 0.820, p = 0.00101), a statistically significant 39% reduction in pulmonary exacerbation rates in subjects treated with CMS compared with placebo (similar results [LS mean incidence rate ratio = 0.591, 95% CI (0.438-0.796), p = 0.0006] were obtained in a post-hoc analysis combining low-recruitment countries). These data were supported in the PP population analysis, whose results were similar to the primary analysis; the LS mean NCFB pulmonary exacerbation rates were 0.491 in the CMS group and 0.842 in the placebo group, with a LS mean rate ratio for CMS to placebo of 0.583 (95% CI, 0.413, 0.822, p = 0.00212), a reduction of 42%.

[0154] Thus, this study demonstrates that inhaled CMS using an I-neb AAD nebulizer is superior to placebo in reducing the annual rate of NCFB pulmonary exacerbations.

[0155] The results are highly statistically relevant.

[0156] Results of a sensitivity analysis using alternative definitions of pulmonary exacerbations (Hill AT, Haworth CS, Aliberti S, et al. Pulmonary exacerbation in adults with bronchiectasis: a consensus definition for clinical research. Eur Respir J. 2017;49(6):1700051:10.1183 / 13993003.00051-2017) support the results of the primary analysis: the LS mean annualized NCFB pulmonary exacerbation rates were 0.538 in the CMS group and 0.838 in the placebo group, with a LS mean rate ratio of CMS to placebo of 0.642 (95% CI, 0.470, 0.877), corresponding to a statistically significantly lower 36% reduction in the CMS group compared with the placebo group (p=0.00540).

[0157] Other secondary efficacy variables are discussed in the following paragraphs.

[0158] Time to first exacerbation The time to first progression was prolonged in the CMS I-neb group (HR 0.59, 95% CI 0.43-0.81, p=0.00074; HR=Hazard Ratio) (see Figure 3).

[0159] The time from first dose of IMP to first NCFB pulmonary exacerbation was statistically significantly longer in the CMS group than in the placebo group. The median time to first NCFB pulmonary exacerbation was 208 days in the placebo group and was not reached in the CMS group because less than half of the subjects (n=68, 38.6%) experienced a pulmonary exacerbation during the study.

[0160] Survival distributions were compared between the two treatment groups using the log rank test and were assessed as statistically significant (p = 0.00074). Supportive analyses were performed using Cox proportional hazards regression models for the modified intention to treat (mITT) population.

[0161] The risk of a first exacerbation was significantly lower in the CMS group compared with the placebo group (hazard ratio, 0.590; 95% CI, 0.432, 0.806), resulting in a 41% reduction in the risk of a first exacerbation event in the CMS group compared with the placebo group.

[0162] Severe NCFB pulmonary exacerbation CMS inhaled via I-neb demonstrated superiority over placebo in reducing the annualized rate of severe NCFB exacerbations (p=0.003). The LS mean annualized rate of severe NCFB exacerbations was 0.116 in the CMS group and 0.283 in the placebo group. The LS mean incidence rate ratio for CMS to placebo was 0.409 (95% confidence interval, 0.227, 0.738; p=0.003), a statistically significant 59% reduction in severe exacerbations in the CMS-treated group compared with placebo.

[0163] Time to severe NCFB pulmonary exacerbation Severe NCFB pulmonary exacerbations occurred in 19 / 176 (10.8%) patients in the CMS group compared with 36 / 197 (18.3%) in the placebo group. The median, 25th, and 75th percentiles of time to first severe NCFB pulmonary exacerbation were not reached in either group. Survival distributions were compared between the two treatment groups, and the difference was assessed as statistically significant (p=0.03318).

[0164] QoL measured by the Saint George's Respiratory Questionnaire (SGRQ) The overall treatment difference in SGRQ total score by LS mean across all time points was -3.378, p=0.01766, indicating a statistically significant improvement in QOL over the study period (see Figure 4). At the end of CMS treatment, the treatment difference in SGRQ total score by LS mean was 4.552, p=0.0055, indicating a clinically meaningful and statistically significant improvement in QOL at the end of the study compared to baseline.

[0165] Changes in Pseudomonas aeruginosa density After 1 month, P. aeruginosa density was statistically significantly reduced in the CMS group compared to the placebo group (LS mean difference = -1.620, p < 0.00001). After 12 months, P. aeruginosa density was reduced from baseline in the CMS group (mean CFB -0.86) compared to the placebo group (mean CFB -0.08) (see Figure 5).

[0166] Adverse events The proportion of patients experiencing adverse events was similar in each group. Bronchospasm and antibiotic resistance were uncommon (2.8% and 1%, respectively). Notably, bronchospasm was clinically observed in only 0.6% of patients treated with CMS, and the incidence of Pseudomonas aeruginosa resistance to colistin sulfate was low at 1%.

[0167] Conclusions: CMS with I-neb significantly reduced annualized and severe exacerbation rates in patients with bronchiectasis and P. aeruginosa. Treatment was safe and well tolerated.

[0168] Baseline stable macrolide use was similar in the CMS (24.4%) and placebo (26.9%) groups. Of note, concomitant stable oral macrolide use was included as an effect in the model but was not statistically significant (p=0.44506), suggesting that there was no notable difference in the mean annualized rate of pulmonary exacerbations in NCFB between subjects who were and were not concomitantly using a stable oral macrolide.

[0169] The above results were achieved by statistical analyses with over 80% power to detect a treatment difference of 30%.

[0170] Group The mean age of subjects was 64.2 years in both the CMS and placebo groups, and two-thirds were women (123 [69.9%] in the CMS group and 126 [64.0%] in the placebo group).

[0171] Most subjects were white (167 [94.9%] in the CMS group and 189 [95.9%] in the placebo group). Demographic characteristics, including height, weight, and obesity level, were similar in both groups. More than two-thirds of subjects were never smokers: 124 of 176 (70.5%) in the CMS group and 142 of 197 (72.1%) in the placebo group. Only three (0.8%) were current smokers: 0 / 176 in the CMS group and 3 / 197 in the placebo group. The remaining 27.9% (52 / 176 in the CMS group and 52 / 197 in the placebo group) were former smokers.

Claims

1. A pharmaceutical composition containing sodium colistimethate (CMS) for use in a method of reducing the frequency of pulmonary exacerbation in patients suffering from non-cystic fibrosis bronchiectasis (NCFB) accompanied by Pseudomonas aeruginosa infection, said method comprising administering CMS by inhalation at a dose of at least 20 mg of colistin base activity (CBA) per day, wherein said exacerbation is - an increase in cough; - an increase in sputum volume and / or viscosity; - an increase in purulent sputum; - new or increased hemoptysis; - an increase in wheezing; - an increase in dyspnea; - an increase in fatigue and malaise; - episodes of fever (body temperature of 38°C or higher) wherein at least three of the eight symptoms or signs are present simultaneously for at least 24 hours, and the pharmaceutical composition is defined as when the subject is clinically determined or prescribed to require systemic antibiotic therapy.

2. The pharmaceutical composition according to claim 1, wherein administration by inhalation is provided by an adaptive aerosol delivery system.

3. The pharmaceutical composition according to claim 1 or 2, wherein the patient is clinically stable.

4. The pharmaceutical composition according to claim 1 or 2, wherein the patient had at least two NCFB pulmonary exacerbations requiring oral antibiotics or inhaled antibiotics, or one NCFB pulmonary exacerbation requiring intravenous antibiotics, in the 12 months prior to CMS treatment.

5. The pharmaceutical composition according to claim 1 or 2, wherein the patient has one or more of the co-existing diseases COPD, asthma, and gastroesophageal reflux.

6. The pharmaceutical composition according to claim 1 or 2, wherein the method comprises administering CMS at a dose of 20 mg to 60 mg of CBA per day.

7. The pharmaceutical composition according to claim 1 or 2, administered for at least 12 months.

8. A pharmaceutical composition for inhalation, nebulization or aerosol spray containing an amount of sodium colistimethate (CMS) in the range of at least 30 - 35 mg CBA / mL to 60 - 70 mg CBA / mL in a sterile aqueous solution for use in a method of reducing the frequency of pulmonary exacerbation in patients suffering from non-cystic fibrosis bronchiectasis (NCFB) accompanied by Pseudomonas aeruginosa infection.

9. The pharmaceutical composition according to claim 8, wherein the sterile aqueous solution is physiological saline containing 0.4% - 0.9% w / v sodium chloride.

10. The pharmaceutical composition according to claim 9, comprising 0.45% w / v sodium chloride.

11. The pharmaceutical composition according to claim 8 or 9, wherein CMS is provided in powder form and dissolved in a sterile aqueous solution before use.

12. The pharmaceutical composition according to claim 11, wherein the CMS in powder form is provided in an amount containing CBA in the range of 30 - 35 mg of CBA to 60 - 70 mg of CBA.

13. The pharmaceutical composition according to claim 11, wherein the sterile aqueous solution is physiological saline containing 0.4% - 0.9% w / v sodium chloride.

14. The pharmaceutical composition according to claim 13, wherein the physiological saline contains 0.45% w / v sodium chloride.

15. A kit for use in a method for reducing the frequency of pulmonary exacerbation in a patient suffering from non - cystic fibrosis bronchiectasis (NCFB) accompanied by Pseudomonas aeruginosa infection, - at least one single - dose vial containing sodium colistimethate (CMS) powder containing CBA in the range of 30 - 35 mg to 60 - 70 mg of CBA, - a sterile aqueous solution, and - a leaflet describing instructions regarding the treatment of NCFB comprising, wherein the exacerbation is as defined in claim 1. A kit.

16. The kit according to claim 15, provided together with an adaptive aerosol delivery system.

17. The kit according to claim 15 or 16, wherein the sterile aqueous solution contains 0.4% - 0.9% w / v sodium chloride.

18. The kit according to claim 17, wherein the sterile aqueous solution contains 0.45% w / v sodium chloride.

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