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WO 2010/139985 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 9 December 2010 (09.12.2010) WO 2010/139985 Al (51) International Patent Classification: (74) Agent: PERRY, Robert, Edward; Gill Jennings & Every A61K 31/137 (2006.01) A61P 9/00 (2006.01) LLP, Broadgate House, 7 Eldon Street, London, Greater A61K 31/436 (2006.01) A61P 11/00 (2006.01) London EC2M 7LH (GB). A61K 45/06 (2006.01) A61P 11/06 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/GB20 10/050905 AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (22) International Filing Date: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 28 May 2010 (28.05.2010) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (25) Filing Language: English KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (26) Publication Language: English NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (30) Priority Data: SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, 0909352.7 1 June 2009 (01 .06.2009) GB TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 0918727.9 26 October 2009 (26.10.2009) GB (84) Designated States (unless otherwise indicated, for every 0918728.7 26 October 2009 (26.10.2009) GB kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): BIOCO- GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, PEA LIMITED [GB/GB]; 100 Fetter Lane, London ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, EC4A IBN (GB). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (72) Inventors; and LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, (75) Inventors/Applicants (for US only): BANNISTER, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Robin, Mark [GB/GB]; Biocopea Limited, 100 Fetter GW, ML, MR, NE, SN, TD, TG). Lane, London, Greater London EC4A IBN (GB). BREW, John [GB/GB]; Biocopea Limited, 100 Fetter Published: Lane, London, Greater London EC4A IBN (GB). — with international search report (Art. 21(3)) (54) Title: THE USE OF AMLEXANOX IN THE THERAPY OF NEUTROPHIL-DRIVEN DISEASES Effect of oral BC1025 on LPS lung neutrophilia 1 (57) Abstract: An agent, which is amlexanox, is useful in the therapy of a disease associated with neutrophilia. THE USE O F AMLEXANOX IN THE THERAPY O F NEUTROPHIL-DRIVEN DISEASES Field of the Invention This invention relates to the use of amlexanox in therapy of diseases associated with neutrophilia Background of the Invention Chronic respiratory diseases, including sarcoidosis, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), acute respiratory distress syndrome (ARDS) and asthma, constitute a major health problem, but they are poorly treated by current therapies. Such therapies include inhaled corticosteroids, but their use is not always efficacious and may give rise to undesirable side-effects, including systemic side-effects. Many respiratory conditions involve a lung injury component and there are no single agent therapies that are able to treat such diseases. Often, such diseases require two or three co-administered medicines. Amlexanox is a compound that has been approved for the treatment of mouth ulcers and, as a nasal spray, as an anti-allergy agent. It is disclosed in US41 43042; the suggested therapies are of allergic asthma, allergic dermatitis, hay fever and other allergic diseases, and the proposed routes of administration are oral and by injectable solutions, inhalation and ointments. Respiratory inflammation characterised by eosinophil infiltration, namely asthma, is characterised by reversible loss of lung function with no tissue damage. Asthma is often characterised by increased collagen lay down in lung connective tissue, and does not involve neutrophil infiltration. Irreversible obstructive lung diseases such as COPD, bronchiectasis and ARDS are strongly associated with destructive lung inflammation. They are characterised by environmental inflammatory triggers such as smoking and infection, resulting in leukocyte infiltration and the release of cytokines, chemokines and a multitude of inflammatory mediators. These mediators cause leukocytes, primarily neutrophils, to release destructive agents such as superoxide anions, matrix metalloproteases and cathepsin E . These neutrophil- derived molecules cause destruction of the lung's gaseous exchange cellular layers and its supporting connective tissue, resulting in progressive and irreversible lung damage and irreversible loss of lung function. Unlike irreversible obstructive lung diseases, reversible obstructive lung diseases, such as asthma, are mainly characterised by respiratory inflammation characterised by primarily eosinophilic infiltration and reversible loss of lung function with no tissue destruction. Asthma is characterised by bronchial hypersensitivity to triggers (such as cold, exercise and allergens) that causes obstructive bronchospasm. Such diseases are entirely reversible once the trigger is removed or the patient is treated with bronchodilators. Reversible and irreversible obstructive lung diseases are pathologically very different. They involve different parts of the immune system. Reversible obstructive lung disease is driven by activation of the Th2 immune system, while irreversible obstructive lung disease characterised by the activation of the innate immune system. Therefore, irreversible and reversible obstructive lung diseases are thought to require very different therapeutic approaches. For example, inhaled corticosteroids are known to be very effective treatments for the majority of reversible obstructive lung disease patients, while they have little therapeutic effect in irreversible obstructive lung disease. WO2009/007673 discloses a combination of mast cell inhibitor and a PPARy agonist, for treating inflammatory disorders. COPD is listed as one of a number of inflammatory disorders and amlexanox is listed as one of a number of mast cell inhibitors. Mast cell inhibitors do not generally inhibit neutrophilia. Oral administration is listed as one of a number of possible routes of administration. Taniguchi et al, 1990, and Kimishoto et a/, 2006, for example, report that amlexanox has effects on neutrophils, which are opposite to the effects that would be beneficial in the treatment of COPD. This is based primarily around its effects on leukotriene B4 and S100A12. Specifically, amlexanox has been shown to increase LTB4 production, which would be detrimental to COPD. Neutrophils are normally found in the blood stream. However, during the acute phase of inflammation, particularly as a result of bacterial infection and some cancers, neutrophils migrate toward the site of inflammation, firstly through the blood vessels, then through interstitial tissue, following chemical signals (such as lnterleukin-8 (IL-8), Interferon-gamma (IFN-gamma), and C5a) in a process called chemotaxis. Taniguchi et al 1990 reports that amlexanox has effects on neutrophil biology. However, the concentrations of amlexanox used in the vitro experiments are higher than anything that is achievable in vivo. Summary of the Invention Given the reports in the literature, it was therefore surprising to find that amlexanox, when administered orally, is effective in the therapy of LPS-induced pulmonary neutrophilia. Amlexanox has a history of use in atopic disease such as allergic rhinitis and asthma (Th2 disease). Consequently, it is highly unexpected for such a molecule to inhibit neutrophilia (Th1/innate type inflammation). That is the principle on which the invention is based. The invention may be of particular value for administration to patients having a chronic respiratory disease, e.g. associated with evidence of infection or inflammation. An advantage of the invention may lie in reduced systemic side-effects associated with the active agent. It has been found that amlexanox has little or no effect as a bronchodilator; therefore, it would not be useful to treat allergic asthma. Given the prior art, it is surprising that inhaled amlexanox has utility in the therapy of conditions involving destructive lung inflammation, e.g. COPD and ARDS. Both are characterised by inflammatory triggers that result in leukocyte infiltration, the release of cytokines, chemokines and a multitude of inflammatory mediators. These mediators cause leuokocytes, primarily neutrophils, to release destructive agents such as superoxide anions, matrix metalloproteases and cathepsin E. These neutrophil-derived molecules cause destruction of the lung's gaseous exchange cellular layers and its supporting connective tissue, resulting in progressive and irreversible lung damage and irreversible loss of lung function. Unlike asthma, COPD is characterised by activation of the innate immune system. According to a first aspect, the present invention is therefore amlexanox as an active agent to be delivered orally, for the treatment of a condition associated with neutrophilia. Amlexanox may also be useful for the treatment of asthma. However, as amlexanox is not a bronchodilator, the subject to be treated should also be receiving treatment with a bronchodilator. According to a second aspect, the present invention is therefore amlexanox as an active agent to be
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