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(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 27 August 2009 (27.08.2009) WO 2009/105234 A2 (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/40 (2006.01) A61K 31/57 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/36 (2006.01) A61K 31/12 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, A61K 31/50 (2006.01) A61P 1/16 (2006.01) CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (21) International Application Number: HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, PCT/US2009/001061 KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (22) International Filing Date: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, 19 February 2009 (19.02.2009) NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, (25) Filing Language: English UG, US, UZ, VC, VN, ZA, ZM, ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 61/066,259 19 February 2008 (19.02.2008) US GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, (71) Applicant (for all designated States except US): COM- TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, BINATORX, INCORPORATED [US/US]; 245 First ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Street, Sixteenth Floor, Cambridge, MA 02142 (US). MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, (72) Inventors; and MR, NE, SN, TD, TG). (75) Inventors/Applicants (for US only): LIN, Stephen [US/ US]; 174 Stone Cliff Road, Princeton, NJ 08540 (US). Published: STAUNTON, Jane [US/US]; 12 Knoll Street, Roslin- — without international search report and to be republished dale, MA 0213 1 (US). SUI, Jinliang [US/US]; 180 Rice upon receipt of that report (Rule 48.2(g)) Avenue, Northborough, MA 01532 (US). (74) Agents: BELLIVEAU, Michael, J . et al; Clark & El- bing LLP, 101 Federal Street, Boston, MA 021 10 (US). (54) Title: METHODS AND COMPOSITIONS FOR THE TREATMENT OF DISORDERS ASSOCIATED WITH DEFECTS OF THE CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR GENE OR PROTEIN (57) Abstract: The present invention features compositions, methods, and kits for treating, or ameliorating disorders associated with a de fect in the cystic fibrosis transmembrane con ductance regulator (CFTR) gene or protein (e.g., cystic fibrosis). Figure 1 METHODS AND COMPOSITIONS FOR THE TREATMENT OF DISORDERS ASSOCIATED WITH DEFECTS OF THE CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR GENE OR PROTEIN Background of the Invention Cystic fibrosis (CF) is a lethal, autosomal-recessive genetic disease, affecting approximately 30,000 individuals in the United States. CF is characterized by defective chloride transport, resulting from a mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR gene encodes a linear chloride channel protein in the plasma membrane of certain epithelial cells, where it regulates the flow of chloride ions in response to phosphorylation by a cyclic AMP-dependent kinase. Many mutations of the CFTR protein have been reported, the most common of which is a deletion of a phenylalanine residue (∆F508 CFTR). Although most people without CF have two working copies of the CFTR gene, only one is needed to prevent CF. The principal clinical manifestation of CF is the resulting respiratory disease, characterized by airway obstruction due to the presence of thick mucus that is difficult to clear from airway passages. This airway mucus contributes to recurrent bacterial infections and impaired respiration, eventually resulting in death. Treatment of CF involves the thinning of mucosal obstructions, treating bacterial infections, using anti-inflammatory compositions to treat lung inflammation, and opening airways with bronchodilators. However, even with such treatments, frequent hospitalization is often required as the disease progresses. Accordingly, improvements are needed for the treatment of CF and other disorders associated with defects of the CFTR gene or protein. Summary of the Invention The present invention features compositions, methods, and kits for treating or ameliorating disorders associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein (e.g., cystic fibrosis). The invention features a composition that includes an agent selected from Table 1. Desirably, the agent is present in an amount that, when administered to a patient, is sufficient to treat or ameliorate a disorder associated with a defect in the CFTR gene or protein. In another aspect, the invention features a composition that includes a first agent selected from Table 1 or 2 and a second, different agent selected from Table 1, 2, or 3. Desirably, the agents are present in amounts that, when administered together to a patient, are sufficient to treat or ameliorate a disorder associated with a defect in the CFTR gene or protein. In another aspect, the invention features a composition that includes active ingredients and excipients, wherein the active ingredients are, for example, a first compound from Table 1 or 2 and a second compound from Table 1, 2, or 3. In another aspect, the invention features a composition that includes a first agent selected from Table 1, a second agent selected from Table 2, and a third agent selected from Table 3. Desirably, the agents are present in amounts that, when administered together to a patient, are sufficient to treat or ameliorate a disorder associated with a defect in the CFTR gene or protein. The compositions of the invention may be formulated, for example, for oral administration, systemic administration, or for inhalation. The invention also features a method for treating or ameliorating a disorder associated with a defect in the CFTR gene or protein by administering to a patient an agent selected from Table 1 in an amount sufficient to treat or ameliorate the disorder. In another aspect, the invention features a method for treating or ameliorating a disorder associated with a defect in the CFTR gene or protein that includes administering to a patient a first agent selected from Table 1 and a second, different agent selected from Table 1, 2, or 3, wherein the agents are present in amounts that, when administered together to a patient, are sufficient to treat or ameliorate the disorder. In another aspect, the invention features a method for treating or ameliorating a disorder associated with a defect in the CFTR gene or protein that includes administering to a patient a first agent selected from Table 1, a second agent selected from Table 2, and a third agent selected from Table 3, wherein the agents are present in amounts that, when administered together to a patient, are sufficient to treat or ameliorate the disorder. The agents of the methods may be administered substantially simultaneously in amounts that together are sufficient to treat or ameliorate the disorder. Alternatively, the agents may be administered within 1, 2, 4, 6, 12, or 24 hours of each other, within 7 days of each other, within 14 days of each other, or within 28 days of each other. The agents may be administered by any appropriate route, e.g., by oral administration, systemic administration, or inhalation. The invention also features a kit that includes at least one agent selected from Table 1 and instructions for administering the agent to a patient having a disorder associated with a defect in the CFTR gene or protein (e.g., cystic fibrosis). In another aspect, the invention features a kit that includes a first agent selected from Table 1, a second, different agent selected from Table 1, 2, or 3, and instructions for administering the agents to a patient having a disorder associated with a defect in the CFTR gene or protein (e.g., cystic fibrosis). In another aspect, the invention features a kit that includes a first agent selected from Table 1, a second agent selected from Table 2, a third agent selected from Table 3, and instructions for administering the agents to a patient having a disorder associated with a defect in the CFTR gene or protein (e.g., cystic fibrosis). Combinations of the compounds described herein may be used as therapeutic agents in the compositions, methods, and kits of the present invention. Such combinations include, e.g., Corr-4a and HC toxin; Corr-4a and valproic acid; Corr-4a and suberoylanilide hydroxamic acid; atorvastatin calcium and HC toxin; prednisolone and suberoylanilide hydroxamic acid; quinestrol and suberoylanilide hydroxamic acid; chlormadinone acetate and Corr-4a; 2-APB and histone deacetylase inhibitor III; staurosporine and suberoylanilide hydroxamic acid; BAY 60-7550 and suberoylanilide hydroxamic acid; drotaverine hydrochloride and suberoylanilide hydroxamic acid; BAY 60-7550 and CF-C3; CF-C6 and gliquidone; Corr-4a and LY 294002; Corr-4a and flunixin meglumine; clofarabine and quinestrol; and CF- P5 and suberoylanilide hydroxamic acid. By "an amount sufficient" is meant the amount of a compound, alone or in combination with another compound or therapeutic regimen, required to treat or ameliorate a disorder, such as cystic fibrosis, in a clinically relevant manner. A sufficient amount of an active compound used to practice the present invention for therapeutic treatment of, e.g., cystic fibrosis, varies depending upon the manner of administration, age, and general health of the patient.

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