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(12) Patent Application Publication (10) Pub. No.: US 2011/0195031 A1 Du (43) Pub US 2011 0195031A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0195031 A1 Du (43) Pub. Date: Aug. 11, 2011 (54) METHODS FOR THE USE OF A6IP3L/00 (2006.01) PROGESTOGENASA GLUCOCORTICOD A6IP 25/00 (2006.01) SENSTIZER A6IP27/02 (2006.01) A6IP 29/00 (2006.01) (75) Inventor: Tao Tom Du, North Potomac, MD A6IP II/00 (2006.01) (US) A6IP3/00 (2006.01) (73) Assignee: PRAIRIE (52) U.S. Cl. ........... 424/43: 514/1 6; 26, . PHARMACEUTICALS, LLC, s Bethesda, MD (US) (57) ABSTRACT (21) Appl. No.: 13/021,950 Provided are methods and kits for administering progestogen as a glucocorticoid sensitizer to restore corticosteroid sensi (22) Filed: Feb. 7, 2011 tivity or reverse the glucocorticoid insensitivity or enhance glucocorticoid sensitivity, in order to treat one or more glu Related U.S. Application Data cocorticoid insensitivity related diseases or conditions. For (60) Provisional8, 2010. application No. 61/302,325, filed on Feb. co1d 1nsensitivityPl thes e include in a su st ject havingfor no historys the of FISA menstrua cycle-related exacerbation or allergy to self-hormones, par O O ticularly progesterone. Such as premenstrual or perimenstrual Publication Classification E.in the SNE 9. NASA worsening (51) Int. Cl. of atopic dermatitis or premenstrual exacerbations of asthma, A 6LX 39/395 (2006.01) and exhibiting relatively or totally refractory responses to A6 IK3I/56 (2006.01) glucocorticoid therapy, e.g., glucocorticoid resistance. The A6 IK 9/12 (2006.01) methods and kits provide for the administration of a sex A 6LX 3/57 (2006.01) hormone to the subject who is corticosteroid dependent or A6 IK 38/13 (2006.01) corticoid resistant or unresponsive or intolerant to corticos A6IP 9/00 (2006.01) teroids. Patent Application Publication Aug. 11, 2011 Sheet 1 of 12 US 2011/O195031 A1 I"OIH § 008 00/ 009 009 0017 008 OOT 0 (u/8d) z Patent Application Publication Aug. 11, 2011 Sheet 2 of 12 US 2011/0195031A1 Z'OIH X3C]- uO40n poud Z-II peon pu-WHd uO uO2Cuu% Patent Application Publication Aug. 11, 2011 Sheet 3 of 12 US 2011/O195031 A1 WOT-OTXBC] +//ZTI %SZ %9 Patent Application Publication Aug. 11, 2011 Sheet 4 of 12 US 2011/O195031 A1 +438 %ST %9 Patent Application Publication Aug. 11, 2011 Sheet 5 of 12 Patent Application Publication Aug. 11, 2011 Sheet 6 of 12 US 2011/0195031 A1 70% 60% E 50% 's us 40% 9 30% E E 20% s E 1.0% d p O% O SS -10% -20% -30% E. p Ref - 17HPC Ref -- 17HPC Ref -- 17HPC 10-5 PHA = (Ref) M --O-- Subj#1 0% -21% - - -O-- Subj#2 O% 25% 53% -A-Subj#3 O% 2% 1.7% 15% -0-Subj#4 O% 23% 13% 25% O% 17% O% -8% O% 13% 20% --Subj#8 O% 40% 1.8% 8% O% 28% 8 - A - Subj#10 0% 6% --B - Subj#11 0% 18% Patent Application Publication Aug. 11, 2011 Sheet 7 of 12 US 2011/O195031 A1 80% .9 t 60% t- g) 9 A. r 40% 9 s O . C 20% A. un O 5 O% aul E S >g3 -20% y - S. N a S M. M. 9, -4.0% g t C P -60% IL2/4 + DEX + IL2/4 + DEX + L2/4 + DEX 10 IL2/4 + DEX 10 PHA PHA-- 17HPC + PHA + 17HPC + PHA + 17HPC 10-10 M -A-Subj#1 O% 1.6% 40% 52% - - -g) - Subj#2 1.6% 43% 63% -3% 47% 38% 34% 27% 39% -0-Subj#5 -19% -20% -35% ---O--- Subj#6 9% O% 7% --Subj#7 3% 6% 1.8% - A - Subj#8 8% 4% 36% --E--Subj#9 -40% -7% 1% -e-Subj#10 15% 42% 45% -e-Subj#11 46% 42% 33% - - - - Mean 7% 20% 27% Patent Application Publication Aug. 11, 2011 Sheet 8 of 12 US 2011/O195031 A1 FIG. 8 60% 50% 40% 30% 20% 1.0% O% s-s-s-s-s-s-s 36 - -10% 3. -20% IL2/4 + Dex 10 1OM + PHA Ref-- P4 10-10 Ref-- P4 10-8 Ref-- P4 10-5 M M M (=Ref) O% 41% - - - - - - Subj#2 O% -1% O - X -- Subj#4 O% O% -- "A" - Subj#5 O% 22% -e-Subj#6 O% -15% O% 27% 39% O% 26% 48% Patent Application Publication Aug. 11, 2011 Sheet 9 of 12 US 2011/0195031 A1 80% 60% - 2 - A - - , , 40% A o P O M 20% i. C ar C O% O -20% ? -40% C 4. -60% o 9 -80% - - - -2. s SS 0. -100% t Ref-- MPA 10- Ref -- MPA 10 Ref+ MPA 10. an 10 M 8 M 5 M PHA (=Ref) Patent Application Publication Aug. 11, 2011 Sheet 10 of 12 US 2011/O195031 A1 FIG. 10 14 1O i 6 E. s: 4. O DeX + 17HPC10- Dex + 17HPC 10 11M 1OM C50 7.5 O9749 12.01514 10.20306 Patent Application Publication Aug. 11, 2011 Sheet 11 of 12 US 2011/O195031 A1 FIG. 11 1.20% 100% 80% 60% DeX 10-6M 40% 20% DEX 10E- DEX +17HPC DEX + 17HPC DEX + 17HPC DEX -- 17HPC 6M 10E-11M 10E-10M 10E-7M 10E-5 M Patent Application Publication Aug. 11, 2011 Sheet 12 of 12 US 2011/O195031 A1 s > Š wo & s s t s O veh O n I N. wo f P eMez-1 peonpu WHd go uoquu% X C S US 2011/O 195031 A1 Aug. 11, 2011 METHODS FOR THE USE OF 0004 Diseases/conditions related to glucocorticoid insen PROGESTOGENASA GLUCOCORTICOD sitivity may include: refractory inflammatory bowel disease, SENSTIZER such as Refractory ulcerative colitis and children with severe Crohn disease, corticosteroid refractory asthma or glucocor CROSS-REFERENCE TO RELATED ticoid resistant asthma or symptomatic corticosteroid depen APPLICATIONS dent asthma, descquamative interstitial pneumonia refractory to corticosteroid, refractory inflammatory myopathies, 0001. This application claims priority to U.S. Provisional refractory myasthenia gravis, refractory pemphigus Vulgaris, Patent Application Ser. No. 61/302.325 that was filed on Feb. methotrexaterefractory RA patients, refractory nephrotic 8, 2010, the entire disclosure of which is hereby incorporated syndrome in adults, corticosteroid dependent systemic lupus by reference. erythematosus (SLE), primary Sjogren's syndrome, systemic vasculitis and polymyositis, chronic graft-Versus-host dis FIELD OF THE INVENTION ease, corticosteroid dependent or refractory multiple Sclero sis, refractory sprue-like disease, Steroid-resistant sarcoido 0002 Glucocorticoid insensitivity presents a profound sis, refractory mucosal lesions of pemphigus Vulgaris, management problem in diseases/conditions treated with glu refractory Schnitzler syndrome, resistant dermatitis of the cocorticoids because the therapy is not effective. The present head and neck, severe refractory atopic dermatitis, refractory invention relates to methods and kits for administering Idiopathic thrombocytopenia purpura, refractory orbital progestogen as a glucocorticoid sensitizer to restore corticos myositis, refractory or recurrent lymphomas, critically ill teroid sensitivity or reverse the glucocorticoid insensitivity or patients with sepsis or acute respiratory distress syndrome enhance glucocorticoid sensitivity, in order to treat one or (ARDS) or relative adrenal insufficiency, corticosteroid-de more glucocorticoid insensitivity related diseases or condi pendent conditions (e.g., rosacea, polymyalgia rheumatic, tions. For example, the present invention relates to methods giant cell arteritis, polymyositis, dermatomyositis, Kawasaki for reversing the glucocorticoid insensitivity in a Subject hav syndrome, Guillain-Barre Syndrome, chronic inflammatory ing no history of menstrual cycle-related exacerbation or demyelinating polyneuropathy, multifocal motor neuropathy, allergy to self-hormones, particularly progesterone, such as Stiff man syndrome etc.). Glucocorticoid insensitivity has premenstrual or perimenstrual deterioration in the symptoms, serious health, Societal, and economic costs. For example, a e.g., premenstrual worsening of atopic dermatitis or premen small percentage of patients with asthma (5-10%) have severe strual exacerbations of asthma, and exhibiting relatively or corticosteroid-refractory condition that often fails to respond totally refractory responses to glucocorticoid therapy, e.g., but these patients account for >50% of the total asthma health glucocorticoid resistance. The methods and kits of the present Care COStS. invention provide for the administration of a sex hormone to 0005 Glucocorticoids suppress inflammation mainly as a the subject who is corticosteroid dependent or corticoid resis result of both activation of anti-inflammatory genes and Sup tant or unresponsive or intolerant to corticosteroids. pression of pro-inflammatory genes. The activation of anti inflammatory gene expression starts as glucocorticoid binds BACKGROUND OF THE INVENTION cytosolic glucocorticoid receptor (GR), which is activated and translocates to the nucleus. Once in the nucleus, it binds 0003 Glucocorticoids are the first-line treatment for vari to glucocorticoid response elements (GREs) and transcrip ous immune-inflammatory and allergic diseases. For tional coactivator molecules, and causes acetylation of core example, the autoimmune diseases include more than 70 histones, which leads to the expression of anti-inflammatory chronic disorders that affect about 5% of the US population, genes. Inflammatory stimuli Switch on multiple inflammatory and include those that most occur in women (>80%) such as genes that encode cytokines, chemokines, adhesion mol Sjogren's syndrome, SLE, autoimmune thyroid disease ecules, inflammatory enzymes, and receptors via pro-inflam (Hashimoto's thyroiditis and well as Graves’ disease) and matory transcription factors, such as nuclear factor KB scleroderma, or relatively common among women (60-75%) (NFKB) and activator protein 1, and the recruitment of co such as rheumatoid arthritis (RA), multiple sclerosis (MS) repressor molecules. Activated glucocorticoid receptors bind and myasthenia gravis; or those that occurata similar female: to the coactivators in the nucleus to inhibit histone acetyl male ratio Such as Sarcoid and inflammatory bowel diseases. transferase (HAT) activity directly and recruit histone Glucocorticoid insensitivity presents a profound manage deacetylase 2 (HDAC2), leading to Suppression of the acti ment problem in those diseases/conditions treated with ste vated inflammatory genes.
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