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2011/097571 A2 (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 \i\ 11 August 2011 (11.08.2011) 2011/097571 A2 (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 38/22 (2006.01) A61P 11/06 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/573 (2006.01) A61P 11/00 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, A61P 29/00 (2006.01) A61P 37/00 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, PCT/US201 1/023917 KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (22) International Filing Date: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, 7 February 201 1 (07.02.201 1) NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, (25) Filing Language: English TT, TZ, UA, 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, 61/302,325 8 February 2010 (08.02.2010) US GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, 13/021,950 7 February 201 1 (07.02.201 1) US ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (71) Applicant (for all designated States except US): EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, PRAIRIE PHARMACEUTICALS, LLC [US/US]; LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, 1041 1 Motor City Drive, Suite 750, Bethesda, MD 20817 SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (US). GW, ML, MR, NE, SN, TD, TG). (72) Inventor; and Published: (71) Applicant : DU, Tao, Tom [US/US]; 12209 Pissaro — without international search report and to be republished Drive, North Potomac, MD 20878 (US). upon receipt of that report (Rule 48.2(g)) (74) Agent: WEATHERSPOON, John, K.; STEIN MCEWEN, LLP, 1400 Eye Street, NW, Suite 300, Wash ington, DC 20005 (US). < (54) Title: METHODS FOR THE USE OF PROGESTOGEN AS A GLUCOCORTICOID SENSITIZER © (57) Abstract: Provided are methods and kits for administering progestogen as a glucocorticoid sensitizer to restore corticosteroid sensitivity or reverse the glucocorticoid insensitivity or enhance glucocorticoid sensitivity, in order to treat one or more glucocor- ticoid insensitivity related diseases or conditions. For example, these include methods for reversing the glucocorticoid insensitivi- ty in a subject having no history of menstrual cycle-related exacerbation or allergy to self-hormones, particularly progesterone, such as premenstrual or perimenstrual deterioration in the symptoms, e.g., premenstrual worsening of atopic dermatitis or premen- strual exacerbations of asthma, and exhibiting relatively or totally refractory responses to glucocorticoid therapy, e.g., glucocorti- coid resistance. The methods and kits provide for the administration of a sex hormone to the subject who is corticosteroid depen dent or corticoid resistant or unresponsive or intolerant to corticosteroids. METHODS FOR THE USE OF PROGESTOGEN AS A GLUCOCORTICOID SENSITIZER CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application Serial Number 61/302,325 that was filed on February 8, 2010, the entire disclosure of which is hereby incorporated by reference. FIELD OF THE INVENTION Glucocorticoid insensitivity presents a profound management problem in diseases/conditions treated with glucocorticoids because the therapy is not effective. The present invention relates to methods and kits for administering progestogen as a glucocorticoid sensitizer to restore corticosteroid sensitivity or reverse the glucocorticoid insensitivity or enhance glucocorticoid sensitivity, in order to treat one or more glucocorticoid insensitivity related diseases or conditions. For example, the present invention relates to methods for reversing the glucocorticoid insensitivity in a subject having no history of menstrual cycle-related exacerbation or allergy to self-hormones, particularly progesterone, such as premenstrual or perimenstrual deterioration in the symptoms, e.g., premenstrual worsening of atopic dermatitis or premenstrual exacerbations of asthma, and exhibiting relatively or totally refractory responses to glucocorticoid therapy, e.g., glucocorticoid resistance. The methods and kits of the present invention provide for the administration of a sex hormone to the subject who is corticosteroid dependent or corticoid resistant or unresponsive or intolerant to corticosteroids. BACKGROUND OF THE INVENTION Glucocorticoids are the first-line treatment for various immune-inflammatory and allergic diseases. For example, the autoimmune diseases include more than 70 chronic disorders that affect about 5% of the US population, and include those that most occur in women (> 80%) such as Sjogren's syndrome, SLE, autoimmune thyroid disease (Hashimoto's thyroiditis and well as Graves' disease) and scleroderma, or relatively common among women (60-75%) such as rheumatoid arthritis (RA), multiple sclerosis (MS) and myasthenia gravis; or those that occur at a similar female:male ratio such as sarcoid and inflammatory bowel diseases. Glucocorticoid insensitivity presents a profound management problem in those diseases/conditions treated with steroids, and twenty to forty percent of patients may fail to achieve disease control. The glucocorticoid insensitivity may present as relatively or totally refractory to glucocorticoid therapy; unresponsive or intolerant to corticosteroids; unresponsive to an adequate induction dose of corticosteroids; initially responsive to corticosteroids but relapses quickly upon drug withdrawal or dose tapering (corticosteroid dependent); corticoid resistant, e.g., requires a very high dose treatment; or "difficult to treat" or severe condition. For example, 20-30% of patients with severe and steroid-resistant Crohn's Disease will not respond to steroid therapy (Michetti P, Mottet C, Juillerat P, Felley C, Vader J-P, Burnand B, Gonvers J-J, Froehlich F: Severe and Steroid-Resistant Crohn's Disease. Digestion 2005;71:19-25). Diseases/conditions related to glucocorticoid insensitivity may include: refractory inflammatory bowel disease, such as Refractory ulcerative colitis and children with severe Crohn disease, corticosteroid refractory asthma or glucocorticoid resistant asthma or symptomatic corticosteroid dependent asthma, desquamative interstitial pneumonia refractory to corticosteroid, refractory inflammatory myopathies, refractory myasthenia gravis, refractory pemphigus vulgaris, methotrexaterefractory RA patients, refractory nephrotic syndrome in adults, corticosteroid dependent systemic lupus erythematosus (SLE), primary Sjogren's syndrome, systemic vasculitis and polymyositis, chronic graft- versus-host disease, corticosteroid dependent or refractory multiple sclerosis, refractory sprue-like disease, steroid-resistant sarcoidosis, refractory mucosal lesions of pemphigus vulgaris, refractory Schnitzler syndrome, resistant dermatitis of the head and neck, severe refractory atopic dermatitis, refractory Idiopathic thrombocytopenia purpura, refractory orbital myositis, refractory or recurrent lymphomas, critically ill patients with sepsis or acute respiratory distress syndrome (ARDS) or relative adrenal insufficiency, corticosteroid-dependent conditions (e.g., rosacea, polymyalgia rheumatic, giant cell arteritis, polymyositis, dermatomyositis, Kawasaki syndrome, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, Stiff man syndrome etc.,). Glucocorticoid insensitivity has serious health, societal, and economic costs. For example, a small percentage of patients with asthma (5-10%) have severe corticosteroid-refractory condition that often fails to respond but these patients account for >50% of the total asthma health care costs. Glucocorticoids suppress inflammation mainly as a result of both activation of anti inflammatory genes and suppression of pro-inflammatory genes. The activation of anti- inflammatory gene expression starts as glucocorticoid binds cytosolic glucocorticoid receptor (GR), which is activated and translocates to the nucleus. Once in the nucleus, it binds to glucocorticoid response elements (GREs) and transcriptional coactivator molecules, and causes acetylation of core histones, which leads to the expression of anti- inflammatory genes. Inflammatory stimuli switch on multiple inflammatory genes that encode cytokines, chemokines, adhesion molecules, inflammatory enzymes, and receptors via pro-inflammatory transcription factors, such as nuclear factor Β (NFKB) and activator protein 1, and the recruitment of co-repressor molecules. Activated glucocorticoid receptors bind to the coactivators in the nucleus to inhibit histone acetytransferase (HAT) activity directly and recruit histone deacetylase 2 (HDAC2), leading to suppression of the activated inflammatory genes. Several possible molecular mechanisms of glucocorticoid resistance have been recognized, and include genetic susceptibility, lack of or defective binding to GR and translocation, reduced GR expression, lack of co-repressor activity, or enhanced activation of inflammatory pathways. For example, glucocorticoid
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