(19) *EP002533799B1* (11) EP 2 533 799 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 38/22 (2006.01) A61K 31/573 (2006.01) (2006.01) (2006.01) 20.11.2019 Bulletin 2019/47 A61P 29/00 A61P 11/06 A61P 11/00 (2006.01) A61P 37/00 (2006.01) (21) Application number: 11740491.3 (86) International application number: (22) Date of filing: 07.02.2011 PCT/US2011/023917 (87) International publication number: WO 2011/097571 (11.08.2011 Gazette 2011/32) (54) METHODS FOR THE USE OF PROGESTOGEN AS A GLUCOCORTICOID SENSITIZER VERFAHREN ZUR VERWENDUNG VON PROGESTOGEN ALS GLUCOCORTICOID-SENSIBILISIERER PROCÉDÉ POUR L’UTILISATION DE PROGESTOGÈNE COMME SENSIBILISATEUR AUX GLUCOCORTICOÏDES (84) Designated Contracting States: (56) References cited: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB EP-A1- 0 934 745 WO-A2-01/70208 GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO WO-A2-2004/096151 US-A- 4 559 332 PL PT RO RS SE SI SK SM TR US-A- 4 720 489 US-A1- 2002 173 669 US-A1- 2006 182 691 US-A1- 2006 216 231 (30) Priority: 07.02.2011 US 201113021950 US-A1- 2006 275 360 US-A1- 2007 042 038 08.02.2010 US 302325 P US-A1- 2009 035 375 (43) Date of publication of application: • Bhattacharya: "Pharmacology", 2009, Elsevier 19.12.2012 Bulletin 2012/51 page 378, • Derwin: "Medicinal Natural Products", 2004, (73) Proprietors: Elsevier pages 273-275, • Du, Tao Tom • SCHINDLER A E ET AL: "Classification and North Potomac, MD 20878 (US) pharmacology of progestins", MATURITAS, • Prairie Pharmaceuticals, LLC ELSEVIER SCIENCE PUBLISHERS IRELAND Bethesda, MD 20817 (US) LTD, IR, vol. 46, no. Suppl. 1, 10 December 2003 (2003-12-10), pages S7-S16, XP002404629, ISSN: (72) Inventor: DU, Tao, Tom 0378-5122, DOI: North Potomac, MD 20878 (US) 10.1016/J.MATURITAS.2003.09.014 (74) Representative: Schiweck Weinzierl Koch Patentanwälte Partnerschaft mbB Ganghoferstraße 68 B 80339 München (DE) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 533 799 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 533 799 B1 Description FIELD OF THE INVENTION 5 [0001] Glucocorticoid insensitivity presents a profound management problem in diseases/conditions treated with glu- cocorticoids because the therapy is not effective. The present invention relates to methods and kits for use in 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 con- ditions. For example, the present invention relates to the use of compositions and kits in methods for reversing the 10 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., pre- menstrual worsening of atopic dermatitis or premenstrual exacerbations of asthma, and exhibiting relatively or totally refractory responses to glucocorticoid therapy, e.g., glucocorticoid resistance. The compositions and kits of the present invention provide for the administration of a sex hormone to the subject who is corticosteroid dependent or corticoid 15 resistant or unresponsive or intolerant to corticosteroids. BACKGROUND OF THE INVENTION [0002] Glucocorticoids are the first-line treatment for various immune-inflammatory and allergic diseases. For example, 20 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 rheu- matoid 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 25 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; unre- sponsive or intolerant to corticosteroids; unresponsive to an adequate induction doseof corticosteroids; initially responsive to corticosteroids but relapses quickly upon drug withdrawal or dose tapering (corticosteroid dependent); corticoid re- sistant, e.g., requires a very high dose treatment; or "difficult to treat" or severe condition. For example, 20-30% of 30 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). [0003] 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 gluco- 35 corticoid resistant asthma or symptomatic corticosteroid dependent asthma, desquamative interstitial pneumonia, re- fractory to corticosteroid, refractory inflammatory myopathies, refractory myasthenia gravis, refractory pemphigus vul- garis, 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 40 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 45 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. [0004] Glucocorticoids suppress inflammation mainly as a result of both activation of anti-inflammatory genes and 50 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 inflam- matory genes that encode cytokines, chemokines, adhesion molecules, inflammatory enzymes, and receptors via pro- 55 inflammatory transcription factors, such as nuclear factor κB (NFκB) and activator protein 1, and the recruitment of co- repressor molecules. Activated glucocorticoid receptors bind to the coactivators in the nucleus to inhibit histone acetyl- transferase (HAT) activity directly and recruit histone deacetylase 2 (HDAC2), leading to suppression of the activated inflammatory genes. 2 EP 2 533 799 B1 [0005] 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 receptors might be phosphorylated by several kinases (e.g., p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and extracellular signal-regulated 5 kinase) that results in the defective binding, alterations in their stability, translocation to the nucleus, binding to DNA, and interaction with other proteins. Excessive activation of the transcription factor activator protein 1 can prevent GRs binding to glucocorticoid response elements (GREs) or inhibiting nuclear factor κB; Nitric oxide (NO) can nitrate tyrosine residues on GRs; GRs can also be ubiquitinated (Ub), which results in degradation of GR by the proteasome; reduced histone deacetylase-2 (HDAC2) expression, raised macrophage migration inhibitory factor, and increased P-glycopro- 10 tein-mediated drug efflux (Peter J Barnes, Ian M Adcock. Glucocorticoid resistance in inflammatory diseases. Lancet 2009; 373: 1905- 17). [0006] The clinical and biological mechanisms of steroid-dependency are not well understood compared with those determining steroid-resistance.