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(12) Patent Application Publication (10) Pub. No.: US 2013/0243873 A1 Aversa Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2013/0243873 A1 Aversa Et Al US 20130243873A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0243873 A1 AVersa et al. (43) Pub. Date: Sep. 19, 2013 (54) MMUNOMODULATORY COMPOSITIONS Publication Classification (75) Inventors: Vincenzo Aversa, Ridgewood Swords (51) Int. C. (IE); Ivan Coulter, Mount Merrion (IE): A638/3 (2006.01) Mónica Torres Rosa, Dublin (IE): A619/16 (2006.01) Bernard Francis McDonald, A613 L/502 (2006.01) Castleblayney (IE) (52) U.S. C. CPC ............... A61K 38/13 (2013.01); A61 K3I/502 (73) Assignee: Sigmoid Pharma Limited, Dublin (IE) (2013.01); A61 K9/16 (2013.01); A61K 9/167 (2013.01) (21) Appl. No.: 13/989,372 USPC ......... 424/495; 424/278.1; 424/499: 424/490 (22) PCT Fled: Nov. 25, 2011 (86) PCT NO.: PCT/EP2011/071088 (57) ABSTRACT S371 (c)(1), (2), (4) Date: May 23, 2013 Immunomodulator formulations for use in the treatment of disease of the GI tract. The formulations comprise a hydroxy (30) Foreign Application Priority Data lase inhibitor and/or an immunosuppressant. Exemplary for mulations comprise hydralazine as a hydroxylase inhibitor Nov. 25, 2010 (GB) ................................... 102OO32.7 and/or cyclosporin A as an immunosuppressant. Patent Application Publication Sep. 19, 2013 Sheet 1 of 23 US 2013/0243873 A1 105 - 100 95 - 90 - -- No DSS -- DSS 2.5% ... DSS - A 85 - DSS - B -- DSS - C 80 O 1 2 3 4 5 6 Figure 1 10 9 -(e-NO DSS 8 on to DSS 2.5% 7 Yori:WWWW DSS -- A DSS - B 6 -ie- DSS - C 5 4 3 2 1 O Figure 2 Patent Application Publication Sep. 19, 2013 Sheet 2 of 23 US 2013/0243873 A1 NODSS DSS 2.5% DSS 2.5% - A DSS 2.5% + B DSS 2.5% - C Figure 3 Patent Application Publication Sep. 19, 2013 Sheet 3 of 23 US 2013/0243873 A1 110 - 105 100 -4- No DSS 2 wo. DSS 25% 95 DSS 25% - A w 3xxx DSS 25% + B s orm DSS 25% - C s 90 mism DSS 25% - D is | T |"ow DSS 25% + E 85 -a-DSS 25% - F 8O 75 O 1 2 3. 4. 5 6 Days Figure 4 -- No DSS ---. DSS 2.5% DSS 25% + A DSS 2.5% + B ? -- DSS 2.5% + C -- DSS 2.5% + D wa. DSS 2.5% + E -a-DSS 2.5% + F Figure 5 Patent Application Publication Sep. 19, 2013 Sheet 4 of 23 US 2013/0243873 A1 NO DSS DSS only DSS - A DSS + B DSS - C DSS - D DSS + E DSS + F Figure 6 Patent Application Publication Sep. 19, 2013 Sheet 5 of 23 US 2013/0243873 A1 110 - 100 -. ---- - - - 90 - N 80 - I -- No DSS 70 - soles. DSS 2.5% DSS + Hydarlazine Oral 50mg/kg 60 - i.e. DSS + Hydalazine (I.P 25mg/kg 50 1 2 3 4 5 6 7 Figure 7 12 - -0- No DSS 10 rises. DSS 2.5% DSS + Hydralazine Oral 50mg/kg 8 - so. DSS + Hydralazine I.P. 25mg/kg 6 4 - 2 O (Y (Y O 1 2 3 4 5 7 -2 - Figure 8 Patent Application Publication Sep. 19, 2013 Sheet 6 of 23 US 2013/0243873 A1 -- No DSS contro now site DSS 4% Hydariazine 60u M + DSS 4% Hydaralazine 30uM+ DSS 4% -- Hydarazine 15uM + DSS 4% 200 300 Figure 9 Hydralazine dose O 5 10 25 50 um HF-1 C 3- Actin Figure 10 Patent Application Publication Sep. 19, 2013 Sheet 7 of 23 US 2013/0243873 A1 i his is 5% is s' s: is ..., still shiele Figure 11 O 15 -O-SmPill (CyA) O metro CyA (ip) 05 -v- CyA (oral) 100-f mom Untreated -0. SmPill (Vehicle) 95 3. 4. Weeks of Treatment Figure 12 Patent Application Publication Sep. 19, 2013 Sheet 8 of 23 US 2013/0243873 A1 15 O P<0.001 105 P<0.001 OO 95 90 Jntreated Cy A (ip) Cy A (oral) SmPill (CyA) SmPill (Vehicle) Figure 13 Untreated CyA (ip) Cy A (oral) SmPill (CyA) SmPill (Vehicle) Figure 14 Patent Application Publication Sep. 19, 2013 Sheet 9 of 23 US 2013/0243873 A1 P<0.01 P<0.001 H - Untreated Cy A (ip) Cy A (oral) SmPill (CyA) SnPill (Vehicle) Figure 15 Untreated Cy A (ip) CyA (oral) SmPill (CyA) SmPill (Vehicle) Figure 16 Patent Application Publication Sep. 19, 2013 Sheet 10 of 23 US 2013/0243873 A1 P<0.05 P<0.05 Untreated Cy A (ip) CyA (oral) SmPill (CyA) SmPill (Vehicle) Figure 17 P<0.05 P<0.05 2OOO H Untreated Cy A (ip) CyA (oral) SmPill (CyA) SmPill (Vehicle) Figure 18A Patent Application Publication Sep. 19, 2013 Sheet 11 of 23 US 2013/0243873 A1 TNFO P<0.05 Untreated Cy A (ip) Cy A (oral) SmPill (CyA) SmPill (Vehicle) Figure 18B IL-17 Untreated Cy A (ip) Cy A (oral) SmPill (CyA) SmPill (Vehicle) Figure 18C Patent Application Publication Sep. 19, 2013 Sheet 12 of 23 US 2013/0243873 A1 P<0.01 P<0.01 gs v O.O Untreated CyA (ip) CyA (oral) SmPill (CyA) SmPill (Vehicle) Figure 19 IL-1B 6OO 5OO AOO E s, 300 2OO OO O Untreated Cy A (ip) Cy A (oral) SmPill (CyA) SmPill (Vehicle) Figure 20A Patent Application Publication Sep. 19, 2013 Sheet 13 of 23 US 2013/0243873 A1 TNF-C. 2OO 900 E S. 600 3OO O Cy A (ip) CyA (oral) SmPil? (CyA) SmPill Figure 20B IL-17 P<0.05< P-O.O.5. OOO H - 750 5. 500 2SO O Untreated Cy A (ip) Cy A (oral) SmPill (CyA) SmPill (Vehicle) Figure 20O Patent Application Publication Sep. 19, 2013 Sheet 14 of 23 US 2013/0243873 A1 3 - --- sixwow w 9. s s 9 - s s E 95 - ss N 5. * , 93 - NNY - is - ^N S --Healthy Control SS stopped co-ESS regg'very 83 - ...ESS 2.3% cowry - I - SS 2.3a row-He --SS 25% recovery - Cya 87 - it. ESS 2.5% repower Cat-Hys 85 I I I I I g 3. 4. 5. 8. 8 9. 2 3 4 5. S. 7 9 days Figure 21 - - Healthy Control soose ESS Orciso.:ry - ooco 3S 3.3% ei'i, --ESS 25% stavery. Hya on ESS 25% is govery - Cya 7 - ww.ova. ESS 25% savery - Cyat-Hya 5 - s 3 - - ......corks...as4.s: 1 3. 4. 5 7 8 9 11 2 3 14 5. 17 8 9 Days Figure 22 Patent Application Publication Sep. 19, 2013 Sheet 15 of 23 US 2013/0243873 A1 fueluoodrufflew uoloo Patent Application Publication Sep. 19, 2013 Sheet 16 of 23 US 2013/0243873 A1 105 - 1 OO is assi 9 5 9 O -- DSS Aeries. DSS - -- DSS + Hyaf Cya (low lewel) 85 - re-or DSS + Hya Cya (High Lewel) 8O O 1 2 3 4. 5 6 Days Figure 24 --ODSS woo. SS25 Figure 25 Patent Application Publication Sep. 19, 2013 Sheet 17 of 23 US 2013/0243873 A1 8 O 4.6 OO E 2 O O 8 Figure 26 Patent Application Publication Sep. 19, 2013 Sheet 18 of 23 US 2013/0243873 A1 O 18 16 1. 12 1 O s O 25 uMDrug A PBS Figure 27 al LPS 35OO + LPS 3O. SO OOO O rice & r ET 5 25 SO X S. O 5 SO EtO uMCyA RBS th. Drug A Figure 28 Patent Application Publication Sep. 19, 2013 Sheet 19 of 23 US 2013/0243873 A1 5000 3 –g– nT8]onT-EAJN 5 8 Figure 29 4000 55 !Lae InTxilonT-BAHN Figure 30 Patent Application Publication Sep. 19, 2013 Sheet 20 of 23 US 2013/0243873 A1 4000 3OOO [nT8]onT-BAJN OOO 1OOO RSSSSSSSSSSSSSSSS Figure 31 Healthy Control DSS 2.5% No recovery 14 day recovery with Cyclosporine 14 day recovery 14 day recovery with Cyclosporine + Hydralazine 14 day recovery with Hydralazine Figure 32 Patent Application Publication Sep. 19, 2013 Sheet 21 of 23 US 2013/0243873 A1 Figure 33 Figure 34 Patent Application Publication Sep. 19, 2013 Sheet 22 of 23 US 2013/0243873 A1 Figure 35 Figure 36 Patent Application Publication Sep. 19, 2013 Sheet 23 of 23 US 2013/0243873 A1 Figure 37 Figure 38 Figure 39 US 2013/0243873 A1 Sep. 19, 2013 IMMUNOMODULATORY COMPOSITIONS microbiota, gut permeability, and mucosal immunity. Dia betes 57 (10): 2555-62; Liu Z, Li N, Neu J (April 2005). 0001. This invention relates to immunomodulatory com "Tight junctions, leaky intestines, and pediatric diseases'. positions and to therapeutic methods using immunomodula Acta Paediatr. 94 (4): 386-93; Maes M. Inflammatory and tory compositions. The invention also relates to methods of oxidative and nitrosative stress pathways underpinning making the compositions, methods of using them, and other chronic fatigue, somatization and psychosomatic symptoms. Subject matter. Curr Opin Psychiatry. 2009 January; 22(1): 75-83; de Magis tris L. Familiari V. Pascotto A, Sapone A, Frolli A, lardino P. BACKGROUND Carteni M. De Rosa M, Francavilla R. Riegler G. Militerni R. 0002 Disorders of the intestine, disorders of the colon, Bravaccio C. Alterations of the intestinal barrier in patients and disorders associated with or Suspected of being associ with autism spectrum disorders and in their first-degree rela ated with a dysfunctional intestine and/or dysfunctional tives. J Pediatr Gastroenterol Nutr. 2010 October; 51(4):418 colon, are an unmet medical need. The present invention 24; Sandek A, Rauchhaus M, Anker SD, von Haehling S comprises products, methods and uses which are useful in (September 2008). “The emerging role of the gut in chronic relation to treating Such disorders. heart failure'. Curr Opin Clin Nutr Metab Care 11 (5): 632-9: 0003 More particularly, inflammatory Bowel Disease Terjung B, Spengler U (February 2009).
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