Treatment of non-cystic fibrosis bronchiectasis (NCFB)

Abstract

Described is a method for improving the condition of a patient suffering from Non-Cystic Fibrosis Bronchiectasis (NCFB), comprising administering to the patient by inhalation from 2.5 million international units (MIU) to 6 MIU of colistimethate sodium (CMS) once a day for a period of at least 28 days. Other embodiments are also disclosed.

Description

[0001] Treatment of Non-Cystic Fibrosis Bronchiectasis (NCFB)

[0002] Related Applications

[0003] This application claims the benefit under US law and priority under the Paris Convention of (1) US application serial no. 63 / 736,624, titled “Treatment of Non-Cystic Fibrosis Bronchiectasis (NCFB)” and filed December 20, 2024, and (2) US application serial no. 63 / 806,037, also titled “Treatment of Non-Cystic Fibrosis Bronchiectasis (NCFB)” and filed May 15, 2025. The contents of both of the aforementioned application are incorporated herein by reference.

[0004] Background

[0005] Cystic fibrosis (CF) is a genetic disease affecting multiple organ systems. The respiratory system is affected by complications resulting from impaired mucociliary clearance in the airways and is the primary cause of morbidity in the current era. This impaired host defense against inhaled debris and microbes results in persistent lower airway bacterial infections, the most common of which are Staphylococcus aureus and Pseudomonas aeruginosa (P. aeruginosa). P. aeruginosa is linked to greater airway inflammation and overall decline in health. Because of this, strategies to administer anti- pseudomonal antibacterials to the airways have been a cornerstone of CF clinical care for many years.

[0006] Non-cystic fibrosis bronchiectasis (NCFB) is a severe chronic illness characterized by irreversible dilation of airways and thickening of bronchial walls, chronic inflammation, repeated infections, and progressive obstruction of the airways. In contrast to cystic fibrosis bronchiectasis (CFB), which is a well-defined genetic disorder, NCFB is a terminal pathologic condition from a number of causes.

[0007] Colistin is a multicomponent antibacterial material composed mainly of colistin A (polymyxin El) and colistin B (polymxyin E2). Colistin is produced by selected strains of the spore-forming soil bacterium Paenihacillus polymyxa and belongs to the polymyxin class of naturally occurring, cyclic polypeptide antibacterials with activity against gram-negative pathogens. Colistimethate sodium (CMS), also known as polymyxin E, is a microbiologically inactive prodrug of colistin, which becomes active when hydrolyzed to the cationic colistin base.

[0008] Colistin was evaluated for antibacterial activity against an extensive collection of gram -negative pathogens collected as part of the SENTRY Antimicrobial Surveillance Program between 2006 and 2009, which included 9,130 clinical isolates of P. aeruginosa.

[0009] Although parenteral preparations of CMS are approved by the FDA for the treatment of acute or chronic infections due to sensitive strains of certain gram-negative bacilli, including P. aeruginosa, there are no inhaled CMS formulations currently approved by the FDA. The therapeutic value of inhaled CMS in the treatment of cystic fibrosis (CF) that is accompanied by P. aeruginosa infection is supported by clinical experience. In patients with CF, inhaled CMS combines the advantage of targeted delivery of high concentrations to the site of action while limiting systemic toxicity associated with the parenteral route.

[0010] In the US, although inhaled tobramycin and aztreonam are approved for the management of CF patients with P. aeruginosa, there is no approved inhaled CMS product.

[0011] CMS [1 MIU (~80 mg CMS equivalent to ~34 mg colistin base activity) and 2 MIU (-160 mg CMS equivalent to -68 mg colistin base activity)] was developed to reduce the toxic side effects of colistin sulfate and colistin base. CMS is administered parenterally since it is less toxic than colistin sulfate. CMS is a nonactive prodrug of colistin; following parenteral administration, CMS undergoes hydrolysis to generate colistin, which also circulates in the body.

[0012] CMS belongs to a different class of antibacterial (polymyxin) than other inhaled antibacterials (aminoglycoside, monobactam, and quinolone) approved for treatment of CF accompanied by P. aeruginosa infection, and acts via a different mechanism of action. Consequently, CMS does not exhibit cross-resistance with these other classes. The lower rate of resistance to CMS compared to other antibacterials targeted to P. aeruginosa therefore renders CMS an invaluable treatment option.

[0013] In the EU, CMS under the brand name ColiFin / Colfmair (PARI Pharma GmbH 2014) was first approved in 2010 through the decentralized / mutual recognition procedures as a generic / hybrid to the reference product, Colomycin (1 MIU Powder for Nebulizer Solution) (Teva UK Eimited 2019).

[0014] The efficacy and safety data for CMS encompass a range of published clinical studies, including randomized controlled trials, observational studies and meta-analyses, demonstrating that treatment with aerosolized CMS attenuates the decline in lung function, decreases P. aeruginosa sputum density and improves respiratory symptom clinical scores.

[0015] As mentioned, non-cystic fibrosis bronchiectasis (NCFB) is a severe chronic illness characterized by irreversible dilation of airways and thickening of bronchial walls, chronic inflammation, repeated infections, and progressive obstruction of the airways. NCFB is an important health issue that is increasingly common and related to a considerably high mortality. It has higher incidence in older patients and females. Furthermore, the incidence of NCFB during the last decades is increasing due to early diagnosis with the use of high -resolution computed tomography (HRCT).

[0016] The main causes of NCFB include infections, and non -infectious conditions such as immune deficiencies, mucociliary clearance defects, bronchial obstruction, chronic obstructive pulmonary disease (COPD), idiopathic inflammatory disorders, and autoimmune diseases. The most common cause in the literature is post-infectious, although no underlying cause is identified. There is frequent, and often underestimated, coexistence of NCFB with chronic obstructive pulmonary disease (COPD). Other co-morbidities are more frequent in NCFB patients as compared to CFB ones.

[0017] As noted, inhaled antibiotics are effective for CFB patients with P. aeruginosa infection, but their efficacy in NCFB has not been demonstrated. In fact, a number of pathogens are involved in the colonization of patients with bronchiectasis.

[0018] At present, there are no approved inhaled antibiotic therapies for NCFB patients. Treatment with inhaled ciprofloxacin has been investigated, with contradictory results.

[0019] Nontuberculous mycobacterial (NTM) lung disease is a disorder characterized by infection of mycobacteria, particularly mycobacterial species that do not cause tuberculosis or leprosy. Nontuberculous mycobacteria are acquired from the environment, and are often found in the water and soil. These organisms commonly affect people with an underlying lung disease such as COPD, bronchiectasis, cystic fibrosis, asthma, primary ciliary dyskinesia, and alpha- 1 -antitrypsin disease; but individuals with no prior history of lung disease can also be affected. The most common symptoms include a persistent cough, fatigue, weight loss, night sweats, and occasionally shortness of breath and coughing up of blood (hemoptysis). Affected individuals may experience recurrent respiratory infections, which can cause progressive damage to the lungs.

[0020] Brief Description

[0021] There is provided, in accordance with an embodiment of the invention, a method for improving the condition of a patient suffering from Non-Cystic Fibrosis Bronchiectasis (NCFB), comprising administering to the patient by inhalation from 2 million international units (MIU) to 6 million international units of colistimethate sodium (CMS) once a day for a period of at least 28 days, wherein improving the condition comprises reducing the frequency of pulmonary exacerbation relative to the frequency of pulmonary exacerbation prior to treatment, wherein pulmonary exacerbation is defined as (a) either (i) being diagnosed as requiring systemic (oral, intravenous or intramuscular) antibiotic treatment or (ii) exhibiting concurrently at least 3 of the following 8 symptoms or signs for at least 24 hours: increased cough, increased sputum volume and / or consistency, increased sputum purulence, new or increased haemoptysis, increased wheezing, increased dysphonea, increased fatigue or malaise, and episodes of fever (temperature >38°C), and (b) being treated with a systemic antibiotic.

[0022] There is also provided, in accordance with an embodiment of the invention, a method for improving the condition of a patient suffering from Non-Cystic Fibrosis Bronchiectasis (NCFB), comprising administering to the patient by inhalation from 2 million international units (MIU) to 6 million international units of colistimethate sodium (CMS) once a day for a period of at least 28 days, wherein improving the condition comprises reducing the frequency of pulmonary exacerbation relative to the frequency of pulmonary exacerbation prior to treatment, wherein pulmonary exacerbation is defined as (a) being diagnosed as requiring systemic (oral, intravenous or intramuscular) antibiotic treatment and (b) being treated with a systemic antibiotic.

[0023] There is also provided, in accordance with an embodiment of the invention, a method for improving the condition of a patient suffering from Non-Cystic Fibrosis Bronchiectasis (NCFB), comprising administering to the patient by inhalation from 2 million international units (MIU) to 6 million international units of colistimethate sodium (CMS) once a day for a period of at least 28 days, wherein improving the condition comprises reducing the frequency of pulmonary exacerbation relative to the frequency of pulmonary exacerbation prior to treatment, wherein pulmonary exacerbation is defined as (a) (i) being diagnosed as requiring systemic (oral, intravenous or intramuscular) antibiotic treatment and (ii) exhibiting concurrently at least 3 of the following 8 symptoms or signs for at least 24 hours: increased cough, increased sputum volume and / or consistency, increased sputum purulence, new or increased haemoptysis, increased wheezing, increased dyspnoea, increased fatigue or malaise, and episodes of fever (temperature >38°C), and (b) being treated with a systemic antibiotic.

[0024] In some embodiments, the amount of CMS administered once daily is at least 2 MIU. In some embodiments, the amount of CMS administered once daily is at least 2.5 MIU. In some embodiments, the amount of CMS administered once daily is at least 3 MIU. In some embodiments, the amount of CMS administered once daily is at least 3.5 MIU. In some embodiments, the amount of CMS administered once daily is at least 3.6 MIU. In some embodiments, the amount of CMS administered once daily is at least 4 MIU. In some embodiments, the amount of CMS administered once daily is at least 4.5 MIU. In some embodiments, the amount of CMS administered once daily is at least 5 MIU. In some embodiments, the amount of CMS administered once daily is at least 5.5 MIU. In some embodiments, the amount of CMS administered once daily is 6 MIU. In some embodiments, the amount of CMS administered once daily 2 MIU. In some embodiments, the amount of CMS administered once daily is

[0025] 2.5 MIU. In some embodiments, the amount of CMS administered once daily is 3 MIU. In some embodiments, the amount of CMS administered once daily is 3.5 MIU. In some embodiments, the amount of CMS administered once daily is 3.6 MIU. In some embodiments, the amount of CMS administered once daily is 4 MIU. In some embodiments, the amount of CMS administered once daily is

[0026] 4.5 MIU. In some embodiments, the amount of CMS administered once daily is 5 MIU. In some embodiments, the amount of CMS administered once daily is 5.5 MIU.

[0027] In some embodiments, a short-acting bronchodilator is administered by inhalation 15 to 30 minutes before commencement of the administration of CMS.

[0028] In some embodiments, the patient also has a pulmonary Pseudomonas aeruginosa infection. In some embodiments, the patient also has a nontuberculous mycobacterium (NTM) infection. In some embodiments, the non-tuberculous mycobacterial infection involves M. avium, M. avium subsp. hominissuis (MAH), M. abscessus, M. chelonae. M. bolletii, M. kansasii, M. ulcerans,M. avium complex (MAC) (M avium and M. ini race Hula re). M. chimaera, M. conspicuum, M. peregrinum, M. immunogenum, M. xenopi, M. marinum,M. malmoense,M. mucogenicum, M. nonchromogenicum, M. scrofulaceum, M. simiae, M. smegmatis,M. szulgai,M. terrae,M. terrae complex, M. haemophilum, M. genavense, M. gordonae, M. fortuitum, M. fortuitum complex (M fortuitum andAf chelonae), or a combination thereof.

[0029] In some embodiments, the CMS is inhaled in nebulized form. In some embodiments, the nebulized form is produced by a mesh nebulizer. In some embodiments, the nebulized form is produced by a jet nebulizer. In some embodiments, the nebulized form is produced by an ultrasonic nebulizer. In some embodiments, the nebulized form is an aqueous solution containing CMS. In some embodiments, the aqueous solution is a saline solution.

[0030] In some embodiments, the period of time over which the frequency of pulmonary exacerbation is reduced is at least 28 days. In some embodiments, the period of time over which the frequency of pulmonary exacerbation is reduced is at least 60 days. In some embodiments, the period of time over which the frequency of pulmonary exacerbation is reduced is at least 90 days. In some embodiments, the period of time over which the frequency of pulmonary exacerbation is reduced is at least 120 days. In some embodiments, the period of time over which the frequency of pulmonary exacerbation is reduced is at least 150 days. In some embodiments, the period of time over which the frequency of pulmonary exacerbation is reduced is at least 180 days.

[0031] In some embodiments, the CMS is administered once a day for a period of at least 60 days. In some embodiments, the CMS is administered once a day for a period of at least 90 days. In some embodiments, the CMS is administered once a day for a period of at least 120 days. In some embodiments, the CMS is administered once a day for a period of at least 150 days. In some embodiments, the CMS is administered once a day for a period of at least 180 days.

[0032] In some embodiments, the amount of CMS administered once daily is in the range of 2.5 MIU to 6 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3 MIU to 6 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3.5 MIU to 6 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3.6 MIU to 6 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 4 MIU to 6 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 4.5 MIU to 6 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 5 MIU to 6 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 5.5 MIU to 6 MIU. In some embodiments, the amount of CMS administered once daily is 6 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 2.5 MIU to 5.5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3 MIU to 5.5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3.5 MIU to 5.5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3.6 MIU to 5.5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 4 MIU to 5.5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 4.5 MIU to 5.5 MIU. In some embodiments, the amount of CMS administered once daily is 5.5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 2.5 MIU to 5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3 MIU to 5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3.5 MIU to 5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3.6 MIU to 5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 4 MIU to 5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 4.5 MIU to 5 MIU. In some embodiments, the amount of CMS administered once daily is 5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 2.5 MIU to 4.5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3 MIU to 4.5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3.5 MIU to 4.5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3.6 MIU to 4.5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 4 MIU to 4.5 MIU. In some embodiments, the amount of CMS administered once daily is 4.5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 2.5 MIU to 4 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3 MIU to 4 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3.5 MIU to 4 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3.6 MIU to 4 MIU. In some embodiments, the amount of CMS administered once daily is 4 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 2.5 MIU to 3.6 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3 MIU to 3.6 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3.5 MIU to 3.6 MIU. In some embodiments, the amount of CMS administered once daily is 3.6 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 2.5 MIU to 3.5 MIU. In some embodiments, in the range of 3 MIU to 3.5 MIU. In some embodiments, the amount of CMS administered once daily is 3.5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 2.5 MIU to 3 MIU. In some embodiments, the amount of CMS administered once daily is 3 MIU. In some embodiments, the amount of CMS administered once daily is 2.5 MIU.

[0033] In some embodiments, the once-daily administration is completed within 60 minutes of the beginning of administration. In some embodiments, the once-daily administration is completed within 45 minutes of the beginning of administration. In some embodiments, the once-daily administration is completed within 30 minutes of the beginning of administration. In some embodiments, the once-daily administration is completed within 20 minutes of the beginning of administration. In some embodiments, the once-daily administration is completed within 15 minutes of the beginning of administration.

[0034] There is also provided, in accordance with an embodiment of the invention, colistimethate sodium (CMS) for use in improving the condition of a patient suffering from Non-Cystic Fibrosis Bronchiectasis (NCFB), wherein CMS is administered to the patient once per day by inhalation in an amount of from 2.5 million international units (MIU) to 6 MIU of CMS for a period of at least 28 days, wherein improving the condition comprises reducing the frequency of pulmonary exacerbation relative to the frequency of pulmonary exacerbation prior to treatment, wherein pulmonary exacerbation is defined as

[0035] (a) either

[0036] (i) being diagnosed as requiring systemic (oral, intravenous or intramuscular) antibiotic treatment, or

[0037] (ii) exhibiting concurrently at least 3 of the following 8 symptoms or signs for at least 24 hours: increased cough, increased sputum volume and / or consistency, increased sputum purulence, new or increased haemoptysis, increased wheezing, increased dysphonea, increased fatigue or malaise, and episodes of fever (temperature >38°C), and

[0038] (b) being treated with a systemic antibiotic.

[0039] There is also provided, in accordance with an embodiment of the invention, colistimethate sodium (CMS) for use in improving the condition of a patient suffering from Non-Cystic Fibrosis Bronchiectasis (NCFB), wherein CMS is administered to the patient once per day by inhalation in an amount of from 2.5 million international units (MIU) to 6 MIU of CMS for a period of at least 28 days, wherein improving the condition comprises reducing the frequency of pulmonary exacerbation relative to the frequency of pulmonary exacerbation prior to treatment, wherein pulmonary exacerbation is defined as

[0040] (a) being diagnosed as requiring systemic (oral, intravenous or intramuscular) antibiotic treatment and (b) being treated with a systemic antibiotic.

[0041] There is also provided, in accordance with an embodiment of the invention, colistimethate sodium (CMS) for use in improving the condition of a patient suffering from Non-Cystic Fibrosis Bronchiectasis (NCFB), wherein CMS is administered to the patient one per day by inhalation in an amount of from 2.5 million international units (MIU) to 6 MIU of CMS for a period of at least 28 days, wherein improving the condition comprises reducing the frequency of pulmonary exacerbation relative to the frequency of pulmonary exacerbation prior to treatment, wherein pulmonary exacerbation is defined as

[0042] (a) both

[0043] (i) being diagnosed as requiring systemic (oral, intravenous or intramuscular) antibiotic treatment and

[0044] (ii) exhibiting concurrently at least 3 of the following 8 symptoms or signs for at least 24 hours: increased cough, increased sputum volume and / or consistency, increased sputum purulence, new or increased haemoptysis, increased wheezing, increased dysphonea, increased fatigue or malaise, and episodes of fever (temperature >38°C), and

[0045] (b) being treated with a systemic antibiotic.

[0046] In some embodiments, a short-acting bronchodilator is administered by inhalation 15 to 30 minutes before commencement of the administration of CMS.

[0047] In some embodiments, the patient also has a pulmonary Pseudomonas aeruginosa infection.

[0048] In some embodiments, the patient also has a nontuberculous mycobacterium (NTM) infection.

[0049] In some embodiments, the non-tuberculous mycobacterial infection involves M. avium, M. avium subsp. hominissuis (MAH), M. abscessus, M. chelonae,M. bolletii,M. kansasii, M. ulcerans, M. avium complex (MAC) (M avium and / V / . iniracellulare). M. chimaera, M. conspicuum,M. peregrinum, M. immunogenum, M. xenopi, M. marinum,M. malmoense,M. mucogenicum, M. nonchromogenicum, M. scrofulaceum, M. simiae, M. smegmatis,M. szulgai,M. terrae,M. terrae complex, M. haemophilum, M. genavense, M. gordonae, M. fortuitum, M. fortuitum complex (M fortuitum and / V / . chelonae), or a combination thereof.

[0050] In some embodiments, the CMS is inhaled in nebulized form. In some embodiments, the nebulized form is produced by a mesh nebulizer. In some embodiments, the nebulized form is produced by a jet nebulizer. In some embodiments, the nebulized form is produced by an ultrasonic nebulizer. In some embodiments, the nebulized form is an aqueous solution containing CMS. In some embodiments, the aqueous solution is a saline solution. In some embodiments, the period of time over which the frequency of pulmonary exacerbation is reduced is at least 28 days. In some embodiments, the period of time over which the frequency of pulmonary exacerbation is reduced is at least 60 days. In some embodiments, the period of time over which the frequency of pulmonary exacerbation is reduced is at least 90 days. In some embodiments, the period of time over which the frequency of pulmonary exacerbation is reduced is at least 120 days In some embodiments, the period of time over which the frequency of pulmonary exacerbation is reduced is at least 150 days. In some embodiments, the period of time over which the frequency of pulmonary exacerbation is reduced is at least 180 days.

[0051] In some embodiments, the CMS is administered once a day for a period of at least 60 days. In some embodiments, the CMS is administered once a day for a period of at least 90 days. In some embodiments, the CMS is administered once a day for a period of at least 120 days. In some embodiments, the CMS is administered once a day for a period of at least 150 days. In some embodiments, the CMS is administered once a day for a period of at least 180 days.

[0052] In some embodiments, the amount of CMS administered once daily is at least 2.5 MIU. In some embodiments, the amount of CMS administered once daily is at least 3 MIU. In some embodiments, the amount of CMS administered once daily is at least 3.5 MIU. In some embodiments, the amount of CMS administered once daily is at least 3.6 MIU. In some embodiments, the amount of CMS administered once daily is at least 4 MIU. In some embodiments, the amount of CMS administered once daily is at least 4.5 MIU. In some embodiments, the amount of CMS administered once daily is at least 5 MIU. In some embodiments, the amount of CMS administered once daily is at least 5.5 MIU. In some embodiments, the amount of CMS administered once daily is not more than 6 MIU. In some embodiments, the amount of CMS administered once daily is 6 MIU. In some embodiments, the amount of CMS administered once daily is 2.5 MIU. In some embodiments, the amount of CMS administered once daily is 3 MIU. In some embodiments, the amount of CMS administered once daily is 3.5 MIU. In some embodiments, the amount of CMS administered once daily is 3.6 MIU. In some embodiments, the amount of CMS administered once daily is 4 MIU. In some embodiments, the amount of CMS administered once daily is 4.5 MIU. In some embodiments, the amount of CMS administered once daily is 5 MIU. In some embodiments, the amount of CMS administered once daily is 5.5 MIU.

[0053] In some embodiments, the amount of CMS administered once daily is in the range of 2.5 MIU to 6 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3 MIU to 6 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3.5 MIU to 6 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3.6 MIU to 6 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 4 MIU to 6 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 4.5 MIU to 6 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 5 MIU to 6 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 5.5 MIU to 6 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 2.5 MIU to

[0054] 5.5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3 MIU to

[0055] 5.5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3.5 MIU to 5.5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3.6 MIU to 5.5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 4 MIU to 5.5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of

[0056] 4.5 MIU to 5.5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 2.5 MIU to 5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3 MIU to 5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of

[0057] 3.5 MIU to 5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of

[0058] 3.6 MIU to 5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 4 MIU to 5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of

[0059] 4.5 MIU to 5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of

[0060] 2.5 MIU to 4.5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3 MIU to 4.5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3.5 MIU to 4.5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3.6 MIU to 4.5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 4 MIU to 4.5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 2.5 MIU to 4 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3 MIU to 4 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3.5 MIU to 4 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3.6 MIU to 4 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 2.5 MIU to 3.6 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3 MIU to 3.6 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3.5 MIU to 3.6 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 2.5 MIU to 3.5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 3 MIU to 3.5 MIU. In some embodiments, the amount of CMS administered once daily is in the range of 2.5 MIU to 3 MIU.

[0061] In some embodiments, the once-daily administration is completed within 60 minutes of the beginning of administration. In some embodiments, the once-daily administration is completed within 45 minutes of the beginning of administration. In some embodiments, the once-daily administration is completed within 30 minutes of the beginning of administration. In some embodiments, the once-daily administration is completed within 20 minutes of the beginning of administration. In some embodiments, the once-daily administration is completed within 15 minutes of the beginning of administration.

[0062] There is also provided, in accordance with an embodiment of the invention, a sealed container comprising from 2 million international units (MIU) to 6 MIU of colistimethate sodium (CMS). In some embodiments, the container is vial.

[0063] There is also provided, in accordance with an embodiment of the invention, a pharmaceutical dosage form comprising from 2 million international units (MIU) to 6 MIU of colistimethate sodium (CMS).

[0064] In some embodiments, the container or pharmaceutical dosage form is a capsule. In some embodiments, the CMS in the sealed container or pharmaceutical dosage form is in powder form. In some embodiments, the CMS in the sealed container or pharmaceutical dosage form is in solution.

[0065] In some embodiments, the sealed container or pharmaceutical dosage form contains at least 2.5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains at least 3 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains at least 3.5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains at least 3.6 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains at least 4 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains at least 4.5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains at least 5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains at least 5.5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains not more than 6 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains 6 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains 2.5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains 3 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains 3.5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains 3.6 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains 4 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains 4.5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains 5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains 5.5 MIU CMS.

[0066] In some embodiments, the sealed container or pharmaceutical dosage form contains from 2.5 MIU to 6 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 3 MIU to 6 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 3.5 MIU to 6 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 3.6 MIU to 6 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 4 MIU to 6 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 4.5 MIU to 6 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 5 MIU to 6 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 5.5 MIU to 6 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains 6 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 2.5 MIU to 5.5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 3 MIU to 5.5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 3.5 MIU to 5.5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 3.6 MIU to 5.5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 4 MIU to 5.5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 4.5 MIU to 5.5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 5 MIU to 5.5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains 5.5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 2.5 MIU to 5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 3 MIU to 5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 3.5 MIU to 5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 3.6 MIU to 5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 4 MIU to 5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 4.5 MIU to 5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains 5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 2.5 MIU to 4.5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 3 MIU to 4.5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 3.5 MIU to 4.5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 3.6 MIU to 4.5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 4 MIU to 4.5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains 4.5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 2.5 MIU to 4 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 3 MIU to 4 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 3.5 MIU to 4 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 3.6 MIU to 4 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains 4 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 2.5 MIU to 3.6 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 3 MIU to 3.6 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 3.5 MIU to 3.6 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains 3.6 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 2.5 MIU to 3.5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains from 3 MIU to 3.5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains 3.5 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage contains from 2.5 MIU to 3 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form contains 3 MIU CMS. In some embodiments, the sealed container or pharmaceutical dosage form 2.5 MIU CMS.

[0067] Detailed Description

[0068] To deliver medication by inhalation, a nebulizer is often used. Nebulizers are devices that turn liquid into a mist (aerosol) that can easily be inhaled. There are presently three main types of nebulizers available: jet nebulizers, ultrasonic nebulizers, and mesh nebulizers. Jet nebulizers used compressed gas to make an aerosol. Ultrasonic nebulizers make an aerosol through high-frequency vibrations; the aerosol particles are larger than with a jet nebulizer. In a mesh nebulizer, liquid passes through a very fine mesh to form the aerosol. Mesh nebulizers produce the smallest particles of the three types.

[0069] Examples of some suitable nebulizers, which are also may be referred to herein as “inhalation devices”, are the Respironics 1-neb® AAD with a 0.3 ml or 0.5 ml medication chamber, and the Pari eFlow® Rapid and Pari EC Sprint with Pari Boy® SX compressor. In this context, “AAD” means “Adaptive Aerosol Delivery” system, which is designed to continuously adapt to changes in the patient's breathing pattern, and to pulse aerosol only during the inspiratory part of the breathing cycle. This eliminates waste of aerosol during exhalation, and allows precise aerosol (dose) delivery.

[0070] Colistimethate Sodium (CMS) is the sodium salt of colistimethate, a broad-spectrum polymyxin antibiotic against most aerobic Gram-negative bacteria except Proteus bacteria. Colistimethate sodium contains the pentasodium salt of the penta(methanesulfonic acid) derivative of colistin A as the major component, and a small proportion of the petasodium salt of the pentamethanesulfonate derivative of colistin B. As sulfomethylated forms of colistin, they require hydrolyzation of the sulfomethyl groups to become the active form of the drug, viz. colistin. CMS is thus a prodrug of colistin. The active ingredient of "colistin" is represented chemically by a mix of polymyxin El and polymyxin E2; Chemical Abstracts have assigned the number 1066-17-7 to colistin. According to the European Pharmacopoeia, colistin should contain more than 77% of polymyxin El, polymyxin E2, polymyxin E3, polymyxin Eli and polymyxin E1-7MOA, but less than 10% of each of the minor components polymyxin E3, polymyxin El- i and polymyxin El -MO A.

[0071] Per the European Medicines Agency (EMA), doses of CMS should always be expressed in International Units (IU) of colistimethate sodium. The following conversion table (Table 1) from the EMA may be used as a reference (ref. “European Medicines Agency completes 5 review of polymyxinbased medicines”, December 16, 2014):

[0072] ’Nominal potency of the drug substance = 12,500 lU / mg

[0073] CMS is authorized for parenteral (intravenous, intramuscular, inhalation, aerosolized and intrathecal / intraventricular) use, in the management of adult and paediatric chronic pulmonary infections due to Pseudomonas.

[0074] CMS can be found, inter alia, under the following commercial names:

[0075] • Colobreathe® dry powder for inhalation. Each capsule contains 1.6625 million international units, equivalent to 125 mg of colistimethate sodium. This preparation is licensed only for chronic pulmonary infections in people aged 6 years and older.

[0076] • Colomycin® injection powder for solution for inhalation using a nebuliser. Each vial contains 1 or 2 million international units of colistimethate sodium (dose equivalent not specified).

[0077] • Promixin® / Tadim®: powder (1 million international units).

[0078] In general, it is desirable to decrease the number of daily doses of a drug, as this is expected to lead to better patient compliance with the dosing regimen. This is especially so in the case of inhaled drugs, as the inhalation apparatus must to be assembled before each use; the solution or suspension to be used in the nebulizer needs to be prepared; the actual inhalation of the drug by the patient requires several minutes each time; and after each use, the apparatus must be disassembled and cleaned. However, it is noted that all three of these aforementioned commercial CMS medications are administered twice- to thrice-daily. See, e.g., the following web pages: Colobreathe®: www.ema.europa.eu / en / medicines / human / EPAR / colobreathe (twice daily dosing: “The recommended dose is one capsule twice daily, taken as close as possible to 12 hours apart.”)

[0079] Colomycin®: www.medicines . org .uk / emc / product / 1094 / smpc (2-3 times daily dosing: “The usual dose for adults, adolescents and children aged 2 years or older is 1-2 million units two to three times per day (maximum 6 million units per day).”

[0080] Promixin®: www.medicines. org.uk / emc / product / 4 / smpc (2-3 times daily dosing for persons over 2 years old, twice daily for children 2 years old and under)

[0081] This reflects the fact that until now, it has been thought that higher doses of CMS than those approved for existing forms of CMS - which would be necessary for once-a-day administration - would not be well- tolerated by patients, e.g. it has been thought that such higher doses would irritate the lungs to an unacceptable extent. For example, the patient package insert for Colomycin® statesm “If you think that you have given yourself too much Colomycin, you should contact your doctor or nurse immediately for advice or, if they are not available, contact or go to your nearest hospital accident and emergency department. If too much Colomycin is accidentally given, the side effects can be serious and can include kidney problems, muscle weakness and difficulty (or even stopping) breathing.”

[0082] In practicing the presently claimed invention, it is expected that patients will be inhale CMS once a day for at least 28 days, although longer periods of administration may be utilized.

[0083] It may be desirable to administer to the patient via inhalation a short-acting bronchodilator, 15-30 minutes prior to administration of the CMS.

[0084] As an example of how the CMS is administered, Colfmair (a brand of CMS sold as packages each containing 2 MIU (160 g) of CMS as a white powder) may be reconstituted with 4 mb of 0.9% saline solution per package. This will then be put in the medication reservoir of a nebulizer such as the eFlowra z ® nebulizer system (PARI Pharma GmbH) and immediately inhaled by the patient in accordance with the manufacturer’s instructions for use of the nebulizer. If it is necessary to use more than one package of CMS, for example because of a limitation in the volume of the medication reservoir of the nebulizer, then when the inhaler stops after completing administration of the first package, the remaining small volume in the nebulizer should be discarded, and immediately thereafter the contents of the second package should be reconstituted with another 4 mb of 0.9% saline solution, the reconstituted CMS transferred into the medication reservoir, inhalation using the nebulizer resumed until completion of administration of the second package. Both doses should be administered in quick succession during a single treatment session. If a third package is required, the procedure described for the second package should be repeated. It will be appreciated that the packages of CMS are often in the form vials. For purposes of assessing the frequency of pulmonary exacerbations, the start of a pulmonary exacerbation (pex) is defined as the initiation date of systemic antibacterials, and the end date of a pex is defined based on the treating physician’s judgment of resolution of symptoms or the conclusion of treatment with systemic antibacterials, whichever occurs later, regardless of the number of different consecutive antibacterial treatments required.

[0085] If another course of antibacterials is initiated 14 or more days after stopping the previous course of antibacterials, the initiation of the second course of antibacterials marks the onset of a new pex, as long as the symptoms of the previous pulmonary exacerbation have resolved. If a second course of antibacterials is initiated less than 14 days after stopping the previous course of antibacterials, the initiation of the second course of antibacterials does not mark the onset of a new pex, regardless of whether symptoms have resolved.

[0086] In a study in which four subjects were dosed once daily with 4 million IU of colistimethate sodium by inhalation for 28 days, a minor adverse event that was possibly related to CMS administration (mild dysphonia) was observed in one subject following the initial dose, but the subject recovered from this and the event this did not recur over the remainder of the study. In the other three subjects, no adverse events were observed over the course of the study.

Claims

Claims1. A method for improving the condition of a patient suffering from Non-Cystic Fibrosis Bronchiectasis (NCFB), comprising administering to the patient by inhalation from 2.5 million international units (MIU) to 6 MIU of colistimethate sodium (CMS) once a day for a period of at least 28 days, wherein improving the condition comprises reducing the frequency of pulmonary exacerbation relative to the frequency of pulmonary exacerbation prior to treatment, wherein pulmonary exacerbation is defined as(a) either(i) being diagnosed as requiring systemic (oral, intravenous or intramuscular) antibiotic treatment, or(ii) exhibiting concurrently at least 3 of the following 8 symptoms or signs for at least 24 hours: increased cough, increased sputum volume and / or consistency, increased sputum purulence, new or increased haemoptysis, increased wheezing, increased dysphonea, increased fatigue or malaise, and episodes of fever (temperature >38°C), and(b) being treated with a systemic antibiotic.

2. A method for improving the condition of a patient suffering from Non-Cystic Fibrosis Bronchiectasis (NCFB), comprising administering to the patient by inhalation from 2.5 million international units (MIU) to 6 MIU of colistimethate sodium (CMS) once a day for a period of at least 28 days, wherein improving the condition comprises reducing the frequency of pulmonary exacerbation relative to the frequency of pulmonary exacerbation prior to treatment, wherein pulmonary exacerbation is defined as(a) being diagnosed as requiring systemic (oral, intravenous or intramuscular) antibiotic treatment and(b) being treated with a systemic antibiotic.

3. A method for improving the condition of a patient suffering from Non-Cystic Fibrosis Bronchiectasis (NCFB), comprising administering to the patient by inhalation from 2.5 million international units (MIU) to 6 MIU of colistimethate sodium (CMS) once a day for a period of at least 28 days, wherein improving the condition comprises reducing the frequency of pulmonary exacerbation relative to the frequency of pulmonary exacerbation prior to treatment, wherein pulmonary exacerbation is defined as(a) both(i) being diagnosed as requiring systemic (oral, intravenous or intramuscular) antibiotic treatment and(ii) exhibiting concurrently at least 3 of the following 8 symptoms or signs for at least 24 hours: increased cough, increased sputum volume and / or consistency, increased sputum purulence, new or increased haemoptysis, increased wheezing, increased dysphonea, increased fatigue or malaise, and episodes of fever (temperature >38°C), and(b) being treated with a systemic antibiotic.

4. The method of any one of claims 1 to 3, wherein a short-acting bronchodilator is administered by inhalation 15 to 30 minutes before commencement of the administration of CMS.

5. The method of any one of claims 1 to 4, wherein the patient also has a pulmonary Pseudomonas aeruginosa infection.

6. The method of any one of claims 1 to 5, wherein the patient also has a nontuberculous mycobacterium (NTM) infection.

7. The method of claim 6, wherein the non-tuberculous mycobacterial infection involves M. avium, M. avium subsp. hominissuis (MAH), M. abscessus. M. chelonae, M. bollelii. M. kansasii, M. ulcerans, M. avium complex (MAC) (M avium and M. iniracellulare). M. chimaera, M. conspicuum, M. peregrinum, M. immunogenum, M. xenopi, M. marinum, M. malmoense,M. mucogenicum, M. nonchromogenicum,M. scrofulaceum, M. simiae, M. smegmatis,M. szulgai, M. terrae, M. terrae complex, M. haemophilum, M. genavense, M. gordonae,M. fortuitum, M. fortuitum complex (M fortuitum and M. chelonae), or a combination thereof.

8. The method of any one of claims 1 to 7 wherein the CMS is inhaled in nebulized form.

9. The method of claim 8, wherein the nebulized form is produced by a mesh nebulizer.

10. The method of claim 8, wherein the nebulized form is produced by a jet nebulizer.

11. The method of claim 8, wherein the nebulized form is produced by an ultrasonic nebulizer.

12. The method of any one of claims 8 to 11, wherein the nebulized form is an aqueous solution containing CMS.

13. The method of claim 12, wherein the aqueous solution is a saline solution.

14. The method of any one of claims 1 to 13, where the period of time over which the frequency of pulmonary exacerbation is reduced is at least 28 days.

15. The method of claim 14, where the period of time over which the frequency of pulmonary exacerbation is reduced is at least 60 days.

16. The method of claim 14, where the period of time over which the frequency of pulmonary exacerbation is reduced is at least 90 days.

17. The method of claim 14, where the period of time over which the frequency of pulmonary exacerbation is reduced is at least 120 days.

18. The method of claim 14, where the period of time over which the frequency of pulmonary exacerbation is reduced is at least 150 days.

19. The method of claim 14, where the period of time over which the frequency of pulmonary exacerbation is reduced is at least 180 days.

20. The method of any one of claims 1 to 19, wherein the CMS is administered once a day for a period of at least 60 days.

21. The method of claim 20, wherein the CMS is administered once a day for a period of at least 90 days.

22. The method of claim 20, wherein the CMS is administered once a day for a period of at least 120 days.

23. The method of claim 20, wherein the CMS is administered once a day for a period of at least 150 days.

24. The method of claim 20, wherein the CMS is administered once a day for a period of at least 180 days.

25. The method of any one of claims 1 to 24, wherein the amount of CMS administered once daily is at least 2.5 MIU.

26. The method of claim 25, wherein the amount of CMS administered once daily is at least 3 MIU.

27. The method of claim 26, wherein the amount of CMS administered once daily is at least 3.5 MIU.

28. The method of claim 27, wherein the amount of CMS administered once daily is at least 3.6 MIU.

29. The method of claim 28, wherein the amount of CMS administered once daily is at least 4 MIU.

30. The method of claim 29, wherein the amount of CMS administered once daily is at least 4.5MIU.

31. The method of claim 30, wherein the amount of CMS administered once daily is at least 5 MIU.

32. The method of claim 31, wherein the amount of CMS administered once daily is at least 5.5MIU.

33. The method of any one of claims 25-32, wherein the amount of CMS administered once daily is not more than 6 MIU.

34. The method of claim 33, wherein the amount of CMS administered once daily is 6 MIU.

35. The method of any one of claims 1 to 24, wherein the amount of CMS administered once daily is in the range of 2.5 MIU to 6 MIU.

36. The method of claim 35, wherein the amount of CMS administered once daily is in the range of 3 MIU to 6 MIU.

37. The method of claim 36, wherein the amount of CMS administered once daily is in the range of 3.5 MIU to 6 MIU.

38. The method of claim 37, wherein the amount of CMS administered once daily is in the range of 3.6 MIU to 6 MIU.

39. The method of claim 38, wherein the amount of CMS administered once daily is in the range of 4 MIU to 6 MIU.

40. The method of claim 38, wherein the amount of CMS administered once daily is in the range of 4.5 MIU to 6 MIU.

41. The method of claim 40, wherein the amount of CMS administered once daily is in the range of 5 MIU to 6 MIU.

42. The method of claim 41, wherein the amount of CMS administered once daily is in the range of 5.5 MIU to 6 MIU.

43. The method of any one of claims 1 to 24, wherein the amount of CMS administered once daily is in the range of 2.5 MIU to 5.5 MIU.

44. The method of claim 43, wherein the amount of CMS administered once daily is in the range of 3 MIU to 5.5 MIU.

45. The method of claim 44, wherein the amount of CMS administered once daily is in the range of 3.5 MIU to 5.5 MIU.

46. The method of claim 45, wherein the amount of CMS administered once daily is in the range of 3.6 MIU to 5.5 MIU.

47. The method of claim 46, wherein the amount of CMS administered once daily is in the range of 4 MIU to 5.5 MIU.

48. The method claim 47, wherein the amount of CMS administered once daily is in the range of 4.5 MIU to 5.5 MIU.

49. The method of claim 48, wherein the amount of CMS administered once daily is 5.5 MIU.

50. The method of any one of claims 1 to 24, wherein the amount of CMS administered once daily is in the range of 2.5 MIU to 5 MIU.

51. The method of claim 50, wherein the amount of CMS administered once daily is in the range of 3 MIU to 5 MIU.

52. The method of claim 51, wherein the amount of CMS administered once daily is in the range of 3.5 MIU to 5 MIU.

53. The method of claim 52, wherein the amount of CMS administered once daily is in the range of 3.6 MIU to 5 MIU.

54. The method of claim 53, wherein the amount of CMS administered once daily is in the range of 4 MIU to 5 MIU.

55. The method of claim 54, wherein the amount of CMS administered once daily is in the range of 4.5 MIU to 5 MIU.

56. The method of claim 55, wherein the amount of CMS administered once daily is 5 MIU.

57. The method of any one of claims 1 to 24, wherein the amount of CMS administered once daily is in the range of 2.5 MIU to 4.5 MIU.

58. The method of claim 57, wherein the amount of CMS administered once daily is in the range of 3 MIU to 4.5 MIU.

59. The method of claim 58, wherein the amount of CMS administered once daily is in the range of 3.5 MIU to 4.5 MIU.

60. The method of claim 59, wherein the amount of CMS administered once daily is in the range of 3.6 MIU to 4.5 MIU.

61. The method of claim 60, wherein the amount of CMS administered once daily is in the range of 4 MIU to 4.5 MIU.

62. The method of claim 61, wherein the amount of CMS administered once daily is 4.5 MIU.

63. The method of any one of claims 1 to 24, wherein the amount of CMS administered once daily is in the range of 2.5 MIU to 4 MIU.

64. The method of claim 63, wherein the amount of CMS administered once daily is in the range of 3 MIU to 4 MIU.

65. The method of claim 64, wherein the amount of CMS administered once daily is in the range of 3.5 MIU to 4 MIU.

66. The method of claim 65, wherein the amount of CMS administered once daily is in the range of 3.6 MIU to 4 MIU.

67. The method of claim 66, wherein the amount of CMS administered once daily is 4 MIU.

68. The method of any one of claims 1 to 24, wherein the amount of CMS administered once daily is in the range of 2.5 MIU to 3.6 MIU.

69. The method of claim 68, wherein the amount of CMS administered once daily is in the range of 3 MIU to 3.6 MIU.

70. The method of claim 69, wherein the amount of CMS administered once daily is in the range of 3.5 MIU to 3.6 MIU.

71. The method of claim 70, wherein the amount of CMS administered once daily is 3.6 MIU.

72. The method of any one of claims 1 to 24, wherein the amount of CMS administered once daily is in the range of 2.5 MIU to 3.5 MIU.

73. The method of claim 72, wherein the amount of CMS administered once daily is in the range of 3 MIU to 3.5 MIU.

74. The method of claim 73, wherein the amount of CMS administered once daily is 3.5 MIU.

75. The method of any one of claims 1 to 24, wherein the amount of CMS administered once daily is in the range of 2.5 MIU to 3 MIU.

76. The method of claim 75, wherein the amount of CMS administered once daily is 3 MIU.

77. The method of claim 75, wherein the amount of CMS administered once daily is 2.5.

78. The method of any one of claims 1 to 77 wherein the once-daily administration is completed within 60 minutes of the beginning of administration.

79. The method of claim 78 wherein the once-daily administration is completed within 45 minutes of the beginning of administration.

80. The method of claim 79, wherein the once-daily administration is completed within 30 minutes of the beginning of administration.

81. The method of claim 80, wherein the once-daily administration is completed within 20 minutes of the beginning of administration.

82. The method of claim 81, wherein the once-daily administration is completed within 15 minutes of the beginning of administration.

83. Colistimethate sodium (CMS) for use in improving the condition of a patient suffering from Non- Cystic Fibrosis Bronchiectasis (NCFB), wherein CMS is administered to the patient once per day by inhalation in an amount of from 2.5 million international units (MIU) to 6 MIU of CMS for a period of atleast 28 days, wherein improving the condition comprises reducing the frequency of pulmonary exacerbation relative to the frequency of pulmonary exacerbation prior to treatment, wherein pulmonary exacerbation is defined as(a) either(i) being diagnosed as requiring systemic (oral, intravenous or intramuscular) antibiotic treatment, or(ii) exhibiting concurrently at least 3 of the following 8 symptoms or signs for at least 24 hours: increased cough, increased sputum volume and / or consistency, increased sputum purulence, new or increased haemoptysis, increased wheezing, increased dysphonea, increased fatigue or malaise, and episodes of fever (temperature >38°C), and(b) being treated with a systemic antibiotic.

84. Colistimethate sodium (CMS) for use in improving the condition of a patient suffering from Non- Cystic Fibrosis Bronchiectasis (NCFB), wherein CMS is administered to the patient once per day by inhalation in an amount of from 2.5 million international units (MIU) to 6 MIU of CMS for a period of at least 28 days, wherein improving the condition comprises reducing the frequency of pulmonary exacerbation relative to the frequency of pulmonary exacerbation prior to treatment, wherein pulmonary exacerbation is defined as(a) being diagnosed as requiring systemic (oral, intravenous or intramuscular) antibiotic treatment and(b) being treated with a systemic antibiotic.

85. Colistimethate sodium (CMS) for use in improving the condition of a patient suffering from Non- Cystic Fibrosis Bronchiectasis (NCFB), wherein CMS is administered to the patient one per day by inhalation in an amount of from 2.5 million international units (MIU) to 6 MIU of CMS for a period of at least 28 days, wherein improving the condition comprises reducing the frequency of pulmonary exacerbation relative to the frequency of pulmonary exacerbation prior to treatment, wherein pulmonary exacerbation is defined as(a) both(i) being diagnosed as requiring systemic (oral, intravenous or intramuscular) antibiotic treatment and(ii) exhibiting concurrently at least 3 of the following 8 symptoms or signs for at least 24 hours: increased cough, increased sputum volume and / or consistency, increased sputum purulence, newor increased haemoptysis, increased wheezing, increased dysphonea, increased fatigue or malaise, and episodes of fever (temperature >38°C), and(b) being treated with a systemic antibiotic.

86. CMS for use according to of any one of claims 83 to 85, wherein a short-acting bronchodilator is administered by inhalation 15 to 30 minutes before commencement of the administration of CMS.

87. CMS for use according to any one of claims 83 to 86, wherein the patient also has a pulmonary Pseudomonas aeruginosa infection.

88. CMS for use according to any one of claims 83 to 87, wherein the patient also has a nontuberculous mycobacterium (NTM) infection.

89. CMS for use according to claim 88, wherein the non-tuberculous mycobacterial infection involves M. avium, M. avium subsp. hominissuis (MAH), M. abscessus, M. chelonae, M. bolletii, M. kansasii, M. ulcerans, M. avium complex (MAC) (M avium and A7. intracellulare), M. chimaera, M. conspicuum, M. peregrinum, M. immunogenum, M. xenopi, M. marinum, M. malmoense,M. mucogenicum, M. nonchromogenicum,M. scrofulaceum, M. simiae, M. smegmatis,M. szulgai, M. terrae, M. terrae complex, M. haemophilum, M. genavense, M. gordonae,M. fortuitum, M. fortuitum complex (M fortuitum and M. chelonae), or a combination thereof.

90. CMS for use according to any one of claims 83 to 89 wherein the CMS is inhaled in nebulized form.

91. CMS for use according to claim 90, wherein the nebulized form is produced by a mesh nebulizer.

92. CMS for use according to claim 90, wherein the nebulized form is produced by a jet nebulizer.

93. CMS for use according to claim 90, wherein the nebulized form is produced by an ultrasonic nebulizer.

94. CMS for use according to any one of claims 90 to 93, wherein the nebulized form is an aqueous solution containing CMS.

95. CMS for use according to claim 94, wherein the aqueous solution is a saline solution.

96. CMS for use according to any one of claims 83 to 95, where the period of time over which the frequency of pulmonary exacerbation is reduced is at least 28 days.

97. CMS for use according to claim 96, where the period of time over which the frequency of pulmonary exacerbation is reduced is at least 60 days.

98. CMS for use according to claim 96, where the period of time over which the frequency of pulmonary exacerbation is reduced is at least 90 days.

99. CMS for use according to claim 96, where the period of time over which the frequency of pulmonary exacerbation is reduced is at least 120 days.

100. CMS for use according to claim 96, where the period of time over which the frequency of pulmonary exacerbation is reduced is at least 150 days.

101. CMS for use according to claim 96, where the period of time over which the frequency of pulmonary exacerbation is reduced is at least 180 days.

102. CMS for use according to any one of claims 83 to 101, wherein the CMS is administered once a day for a period of at least 60 days.

103. CMS for use according to claim 102, wherein the CMS is administered once a day for a period of at least 90 days.

104. CMS for use according to claim 102, wherein the CMS is administered once a day for a period of at least 120 days.

105. CMS for use according to claim 102, wherein the CMS is administered once a day for a period of at least 150 days.

106. CMS for use according to claim 102, wherein the CMS is administered once a day for a period of at least 180 days.

107. CMS for use according to any one of claims 83 to 106, wherein the amount of CMS administered once daily is at least 2.5 MIU.

108. CMS for use according to claim 107, wherein the amount of CMS administered once daily is at least 3 MIU.

109. CMS for use according to claim 108, wherein the amount of CMS administered once daily is at least3.5 MIU.

110. CMS for use according to claim 109, wherein the amount of CMS administered once daily is at least3.6 MIU.

111. CMS for use according to claim 110, wherein the amount of CMS administered once daily is at least4 MIU.

112. CMS for use according to claim 111, wherein the amount of CMS administered once daily is at least4.5 MIU.

113. CMS for use according to claim 112, wherein the amount of CMS administered once daily is at least5 MIU.

114. CMS for use according to claim 113, wherein the amount of CMS administered once daily is at least5.5 MIU.

115. CMS for use according to any one of claims 107-114, wherein the amount of CMS administered once daily is not more than 6 MIU.

116. CMS for use according to claim 115, wherein the amount of CMS administered once daily is 6 MIU.

117. CMS for use according to any one of claims 83 to 106, wherein the amount of CMS administered once daily is in the range of 2.5 MIU to 6 MIU.

118. CMS for use according to claim 117, wherein the amount of CMS administered once daily is in the range of 3 MIU to 6 MIU.

119. CMS for use according to claim 118, wherein the amount of CMS administered once daily is in the range of 3.5 MIU to 6 MIU.

120. CMS for use according to claim 119, wherein the amount of CMS administered once daily is in the range of 3.6 MIU to 6 MIU.

121. CMS for use according to claim 120, wherein the amount of CMS administered once daily is in the range of 4 MIU to 6 MIU.

122. CMS for use according to claim 121, wherein the amount of CMS administered once daily is in the range of 4.5 MIU to 6 MIU.

123. CMS for use according to claim 122, wherein the amount of CMS administered once daily is in the range of 5 MIU to 6 MIU.

124. CMS for use according to claim 118, wherein the amount of CMS administered once daily is in the range of 5.5 MIU to 6 MIU.

125. CMS for use according to any one of claims 83 to 106, wherein the amount of CMS administered once daily is in the range of 2.5 MIU to 5.5 MIU.

126. CMS for use according to claim 125, wherein the amount of CMS administered once daily is in the range of 3 MIU to 5.5 MIU.

127. CMS for use according to claim 126, wherein the amount of CMS administered once daily is in the range of 3.5 MIU to 5.5 MIU.

128. CMS for use according to claim 127, wherein the amount of CMS administered once daily is in the range of 3.6 MIU to 5.5 MIU.

129. CMS for use according to claim 128, wherein the amount of CMS administered once daily is in the range of 4 MIU to 5.5 MIU.

130. CMS for use according to claim 129, wherein the amount of CMS administered once daily is in the range of 4.5 MIU to 5.5 MIU.

131. CMS for use according to claim 130, wherein the amount of CMS administered once daily is 5.5 MIU.

132. CMS for use according to any one of claims 83 to 106, wherein the amount of CMS administered once daily is in the range of 2.5 MIU to 5 MIU.

133. CMS for use according to claim 132, wherein the amount of CMS administered once daily is in the range of 3 MIU to 5 MIU.

134. CMS for use according to claim 133, wherein the amount of CMS administered once daily is in the range of 3.5 MIU to 5 MIU.

135. CMS for use according to claim 134, wherein the amount of CMS administered once daily is in the range of 3.6 MIU to 5 MIU.

136. CMS for use according to claim 135, wherein the amount of CMS administered once daily is in the range of 4 MIU to 5 MIU.

137. CMS for use according to claim 136, wherein the amount of CMS administered once daily is in the range of 4.5 MIU to 5 MIU.

138. CMS for use according to claim 137, wherein the amount of CMS administered once daily is 5 MIU.

139. CMS for use according to any one of claims 83 to 106, wherein the amount of CMS administered once daily is in the range of 2.5 MIU to 4.5 MIU.

140. CMS for use according to claim 139, wherein the amount of CMS administered once daily is in the range of 3 MIU to 4.5 MIU.

141. CMS for use according to claim 140, wherein the amount of CMS administered once daily is in the range of 3.5 MIU to 4.5 MIU.

142. CMS for use according to claim 141, wherein the amount of CMS administered once daily is in the range of 3.6 MIU to 4.5 MIU.

143. CMS for use according to claim 142, wherein the amount of CMS administered once daily is in the range of 4 MIU to 4.5 MIU.

144. CMS for use according to claim 143, wherein the amount of CMS administered once daily is 4.5 MIU.

145. CMS for use according to any one of claims 83 to 106, wherein the amount of CMS administered once daily is in the range of 2.5 MIU to 4 MIU.

146. CMS for use according to claim 145, wherein the amount of CMS administered once daily is in the range of 3 MIU to 4 MIU.

147. CMS for use according to claim 146, wherein the amount of CMS administered once daily is in the range of 3.5 MIU to 4 MIU.

148. CMS for use according to claim 147, wherein the amount of CMS administered once daily is in the range of 3.6 MIU to 4 MIU.

149. CMS for use according to claim 148, wherein the amount of CMS administered once daily is 4 MIU.

150. CMS for use according to any one of claims 83 to 106, wherein the amount of CMS administered once daily is in the range of 2.5 MIU to 3.6 MIU.

151. CMS for use according to claim 150, wherein the amount of CMS administered once daily is in the range of 3 MIU to 3.6 MIU.

152. CMS for use according to claim 151, wherein the amount of CMS administered once daily is in the range of 3.5 MIU to 3.6 MIU.

153. CMS for use according to claim 152, wherein the amount of CMS administered once daily is 3.6 MIU.

154. CMS for use according to any one of claims 83 to 106, wherein the amount of CMS administered once daily is in the range of 2.5 MIU to 3.5 MIU.

155. CMS for use according to claim 154, wherein the amount of CMS administered once daily is in the range of 3 MIU to 3.5 MIU.

156. CMS for use according to claim 155, wherein the amount of CMS administered once daily is 3.5 MIU.

157. CMS for use according to any one of claims 83 to 106, wherein the amount of CMS administered once daily is in the range of 2.5 MIU to 3 MIU.

158. CMS for use according to claim 157, wherein the amount of CMS administered once daily is 3 MIU.

159. CMS for use according to claim 157, wherein the amount of CMS administered once daily is 2.5 MIU.

160. CMS for use according to any one of claims 83 to 159, wherein the once-daily administration is completed within 60 minutes of the beginning of administration.

161. CMS for use according to claim 160 wherein the once-daily administration is completed within 45 minutes of the beginning of administration.

162. CMS for use according to claim 161, wherein the once-daily administration is completed within 30 minutes of the beginning of administration.

163. CMS for use according to claim 162, wherein the once-daily administration is completed within 20 minutes of the beginning of administration.

164. CMS for use according to claim 163, wherein the once-daily administration is completed within 15 minutes of the beginning of administration.

165. A sealed container comprising from 2 million international units (MIU) to 6 MIU of colistimethate sodium (CMS).

166. The sealed container of claim 165 wherein the container is a vial.

167. A pharmaceutical dosage form comprising from 2 million international units (MIU) to 6 MIU of colistimethate sodium (CMS).

168. The sealed container of claim 165 or the pharmaceutical dosage form of claim 167 wherein the container or pharmaceutical dosage form is a capsule.

169. The sealed container or pharmaceutical dosage form of any one of claims 165 to 168 wherein the CMS is in powder form.

170. The sealed container or pharmaceutical dosage form of any one of claims 165 to 168 wherein the CMS is in solution.

171. The sealed container or pharmaceutical dosage form of any one of claims 165 to 170 which contains from 2.5 MIU to 6 MIU CMS.

172. The sealed container or pharmaceutical dosage form of claim 171 which contains from 3 MIU to 6 MIU CMS.

173. The sealed container or pharmaceutical dosage form of claim 172 which contains from 3.5 MIU to 6 MIU CMS.

174. The sealed container or pharmaceutical dosage form of claim 173 which contains from 3.6 MIU to 6 MIU CMS.

175. The sealed container or pharmaceutical dosage form of claim 174 which contains from 4 MIU to 6 MIU CMS.

176. The sealed container or pharmaceutical dosage form of claim 175 which contains from 4.5 MIU to 6MIU CMS.

177. The sealed container or pharmaceutical dosage form of claim 176 which contains from 5 MIU to 6 MIU CMS.

178. The sealed container or pharmaceutical dosage form of claim 177 which contains from 5.5 MIU to 6 MIU CMS.

179. The sealed container or pharmaceutical dosage form of claim 178 which contains 6 MIU CMS.

180. The sealed container or pharmaceutical dosage form of any one of claims 165 to 170 which contains from 2.5 MIU to 5.5 MIU CMS.

181. The sealed container or pharmaceutical dosage form of claim 180 which contains from 3 MIU to 5.5 MIU CMS.

182. The sealed container or pharmaceutical dosage form of claim 181 which contains from 3.5 MIU to5.5 MIU CMS.

183. The sealed container or pharmaceutical dosage form of claim 182 which contains from 3.6 MIU to5.5 MIU CMS.

184. The sealed container or pharmaceutical dosage form of claim 183 which contains from 4 MIU to 5.5 MIU CMS.

185. The sealed container or pharmaceutical dosage form of claim 184 which contains from 4.5 MIU to5.5 MIU CMS.

186. The sealed container or pharmaceutical dosage form of claim 185 which contains from 5 MIU to 5.5 MIU CMS.

187. The sealed container or pharmaceutical dosage form of claim 186 which contains 5.5 MIU CMS.

188. The sealed container or pharmaceutical dosage form of any one of claims 165 to 170 which contains from 2.5 MIU to 5 MIU CMS.

189. The sealed container or pharmaceutical dosage form of claim 188 which contains from 3 MIU to 5MIU CMS.

190. The sealed container or pharmaceutical dosage form of claim 189 which contains from 3.5 MIU to 5 MIU CMS.

191. The sealed container or pharmaceutical dosage form of claim 190 which contains from 3.6 MIU to 5 MIU CMS.

192. The sealed container or pharmaceutical dosage form of claim 191 which contains from 4 MIU to 5 MIU CMS.

193. The sealed container or pharmaceutical dosage form of claim 192 which contains from 4.5 MIU to 5 MIU CMS.

194. The sealed container or pharmaceutical dosage form of claim 193 which contains 5 MIU CMS.

195. The sealed container or pharmaceutical dosage form of any one of claims 165 to 170 which contains from 2.5 MIU to 4.5 MIU CMS.

196. The sealed container or pharmaceutical dosage form of claim 195 which contains from 3 MIU to 4.5 MIU CMS.

197. The sealed container or pharmaceutical dosage form of claim 196 which contains from 3.5 MIU to 4.5 MIU CMS.

198. The sealed container or pharmaceutical dosage form of claim 197 which contains from 3.6 MIU to 4.5 MIU CMS.

199. The sealed container or pharmaceutical dosage form of claim 198 which contains from 4 MIU to 4.5 MIU CMS.

200. The sealed container or pharmaceutical dosage form of claim 199 which contains 4.5 MIU CMS.

201. The sealed container or pharmaceutical dosage form of any one of claims 165 to 170 which contains from 2.5 MIU to 4 MIU CMS.

202. The sealed container or pharmaceutical dosage form of claim 201 which contains from 3 MIU to 4 MIU CMS.

203. The sealed container or pharmaceutical dosage form of claim 202 which contains from 3.5 MIU to 4 MIU CMS.

204. The sealed container or pharmaceutical dosage form of claim 203 which contains from 3.6 MIU to 4MIU CMS.

205. The sealed container or pharmaceutical dosage form of claim 204 which contains 4 MIU CMS.

206. The sealed container or pharmaceutical dosage form of any one of claims 165 to 170 which contains from 2.5 MIU to 3.6 MIU CMS.

207. The sealed container or pharmaceutical dosage form of claim 206 which contains from 3 MIU to 3.6 MIU CMS.

208. The sealed container or pharmaceutical dosage form of claim 207 which contains from 3.5 MIU to 3.6 MIU CMS.

209. The sealed container or pharmaceutical dosage form of claim 208 which contains 3.6 MIU CMS.

210. The sealed container or pharmaceutical dosage form of any one of claims 165 to 170 which contains from 2.5 MIU to 3.5 MIU CMS.

211. The sealed container or pharmaceutical dosage form of claim 210 which contains from 3 MIU to 3.5 MIU CMS.

212. The sealed container or pharmaceutical dosage form of claim 211 which contains 3.5 MIU CMS.

213. The sealed container or pharmaceutical dosage form of any one of claims 165 to 170 which contains from 2.5 MIU to 3 MIU CMS.

214. The sealed container or pharmaceutical dosage form of claim 213 which contains 3 MIU CMS.

215. The sealed container or pharmaceutical dosage form of claim 213 which contains 2.5 MIU CMS.

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