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(12) Patent Application Publication (10) Pub. No.: US 2016/0213639 A1 SUZUKI Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0213639 A1 SUZUKI Et Al US 20160213639A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0213639 A1 SUZUKI et al. (43) Pub. Date: Jul. 28, 2016 (54) COMPOSITIONS AND METHODS FOR Related U.S. Application Data TREATING NON-ALCOHOLIC (60) Provisional application No. 61/887,824, filed on Oct. STEATO HEPATITIS 7, 2013. (71) Applicant: MOCHIDA PHARMACEUTICAL Publication Classification CO.,LTD., Tokyo (JP) (51) Int. Cl. (72) Inventors: Ayako SUZUKI, Little Rock, AR (US); A63L/232 (2006.01) Tsuyoshi HARADA, Tokyo (JP); A619/00 (2006.01) Kiyoshi MIZUGUCHI, Tokyo (JP) A613 L/565 (2006.01) (52) U.S. Cl. (21) Appl. No.: 14/914,444 CPC ............. A6 IK3I/232 (2013.01); A61 K3I/565 (2013.01); A61 K9/0053 (2013.01) (22) PCT Filed: Oct. 6, 2014 (57) ABSTRACT (86). PCT No.: PCT/UP2014/077120 Compositions and methods for the treatment of non-alcoholic S371 (c)(1), steatohepatitis and related disorders are provided herein, for (2) Date: Feb. 25, 2016 example in women under 50 or pre-menopausal women. Patent Application Publication Jul. 28, 2016 Sheet 2 of 9 US 2016/0213639 A1 Figure 2 placebo - 79, p=0.039 105, p=0.024 Placebo - EPA27OO 2.2, p=0.23G 0.3, p=0.688 Patent Application Publication Jul. 28, 2016 Sheet 3 of 9 US 2016/0213639 A1 Figure 3 Placebo Men aeso Nao Placebo I - I - EPA2700 0.5, p=0.477 0.8, p=0.837 Men age250 N=31 Placebo EPA1800 3.5, p=0.243 1.4, p=0.759 EPA2700 0.6, p=0.672 O.7, p=0.711 Patent Application Publication Jul. 28, 2016 Sheet 4 of 9 US 2016/0213639 A1 Figure 4 (8R,9S,135,14S)-3-hydroxy-13- (8R,9S,13S,145,17S)-13-methyl-(8R,9S,13S, 14S1.6R, 17R)-3- methyl-6,7,8,9,11,12,13,14,15,16. 6,7,8,9,11,12,14,15,16, methyl decahydrocyclopentata)phenanthr17-decahydrocyclopentata 6,7,8,9,11,12,14,15,16, en- 17- one phenanth rere-3,17-diol 17-decahydrocyclopentata) phenanthrene-3,16,17-triol Patent Application Publication Jul. 28, 2016 Sheet 5 of 9 US 2016/0213639 A1 Figure 5 658 Patients were assessed for eligibility 45 Were excluded 372 Did not meet criteria 21 Declined to participate 22 had other reason 243 Underwent randomization 75 Were assigned to receive 82 Were assigned to receive 86 Were assigned to receive placebo EPA-E 1800 mg/day EPA-E 2700 mg/day 75 Received placebo 82 Received placebo 86 Received placebo Were included in analysis of Were included in analysis of Were included in analysis of primary outcorne primary outcome primary outcome 20 Were ineligible for 27 Were ineligible for 22 Were ineligible for Efficacy Evaluable Sets Efficacy Evaluable Sets Efficacy Evaluable Sets 5. Withdrew consent 5. Withdrew consent 4. Withdrew consent 2 Were lost to follow-up 6 Were lost to follow-up 4 Were lost to follow-up 3 Were low compliance 3 Were low compliance 3 Were low compliance 55 Underwent baseline and 55 Underwent baseline and 64 Underwent baseline and end-of-study biopsy end-of-study biopsy end-of-study biopsy Patent Application Publication Jul. 28, 2016 Sheet 6 of 9 US 2016/0213639 A1 Figure 6 Placebo EPA-E EPA-E P value Nr. 75 (1800 mg/day) (nT2700mg/day) Mean it S.D. Ne 82 Ni 86 Age (yrs) S0.5 + 2.4 478 - 2.5 47.8 Malcs (n) 32 34 29 Caucasian n (%) 68 (90.7 77 (94) 75 (87) African American 3 (4) 3 (3.7) 2 (2.3) Others 4 (5.3) 2 (2.4) 9 (0.5) BMI (kg/m) 33.6 t 5.9 35.8 cit 6.6 34.8 6.3 Hemoglobin (gm/d) i. i. 5 39: 5 WBC (cclls/mm) 6.8 9 6.7 - 23 Platelicts (cells x 1000mm) 233 it 58 229 it 63 Fasting insulin (millini) Fasting ghucose (mg/dl) 5 - 29. 0 - 24 HOMA-IR 9.5 - 21 7.9 - 8.4 Type 2 diabetics (n) 5 24 Total Cholesterol (mg/dl) 192 it 44 90 : 49 DE-chocsterol (mg/dl) 7 39 ()8 sh: 4) 2 : HDL-cholescrol (mg/dl) 45 it 44.5 8 456 d. 14.9 Triglycerides (mg/dl) ISO .. 5 83 - 127 1781. 106 AST (UT) 67 - 49 G3 it 37 ALT" (IU?) 94 - 65 S7 - 5 Alk Phos (UI) 92 it 4 8() - 22 Bilirubin (mg/dl) 0.6 s ().3 0.5 + 0.25 Albumin (gmidi) 45 it (0.4 hsCRP (mg/L) 5.8 it 6. 6.3 it 6.5 CK8 (UL) 886 the S90 78 - 655 Hyaluronic acid (ng/mL) 738 - 84 56.7 8 Type IV collagen (ng/mL) 64.9 : 106 48.9 at 66 Procollagen III polypeptide 8.05 - 5.04 (ng/mL) Adiponectin (ug/ml) . 4.7 - 2.5 CD-40 ligand pg/Ital) 537 d: 229 Patent Application Publication Jul. 28, 2016 Sheet 7 of 9 US 2016/0213639 A1 Figure 7 Paracter Placebo EPA-E EPA-E P value Ns 55 800 mg/day) (2700 mg/day) No. 55 No. 64 Proportion of responders' 32.7 NAS S is 37 9 WS 4 Steatosis 2.) vs 6 2.0 vs 1.6 Lobular inflammation 5 WS 14 7 is 5. Cytologic ballooning l. vs 0.7 2 's .9 Fibrosis 4 vs. 4 4 vs 4 *Proportion of subjects who met primary cfficacy endpoint at one year (end of study) Patent Application Publication Jul. 28, 2016 Sheet 8 of 9 US 2016/0213639 A1 Figure 8 Wariable Change from Baseline to Month 2 Placebo EPA-E 800 EPA-E 2700 (N=55) mg/day mg/day Mican k. S.D. (Nr.55) (N-64) Mean the S.D. Mean : S.D. AST (UIL) - 49 it 45.7 -95 it 32 -3 tie 46 ALT (UFL) -24. at 48.3 -0.6 is 44 -3. SS Alk Phos (UFL) -2 at 17.2 - a 4.9 -2.4 de S4 Bilirubin (mg/dL) -0 at O2 O2 as 0.7 O.O. O. 9 Album in gmidL) 0.06 at 0.30 O.7 at 0.26 OO at 023 HBA (%) ... as 0.43 0.2 s .75 O. Sai OS6 Glucose (mg/dL) -O.9 as 2.0 6.73. O it 3.9 HOMA -O.0 s. 3.52 60 it 7.2 -0.86 as 9S Adiponectin (ig/mL) (.32 at 6S 0.09: O.8) O. : 0.99 CKS (UFL) r - 54 it 3 - St. 64 -6.3 is Hyaluronic acid (ng/mL) -0 at 5-78 -438 (.25 -2. Orie 4S.99 Procollagen III peptide (ng/mL) S. -0.97 at 3.90 -0.99 is 2.96 -O is 36 Collagen EV (ng/mL). -18.2 is 518 - a 4.9 5 is 385 Total cholescrol (mg/dL) at 3S S.O. i. 29.2 LDL cholesterol (mg/dL) 88 at 27, 44 253 HDL cholestco (mg/dL) 42 at 8.5 -Oct 7.09 Triglyceridics (mg/dL) -95 79.8 -39 it 60 Body Weight (kg) -0.35 at 53. BMI (kg/m2) -37 is 3S -0 at S9 hsCRP (mg/L) S -0.3 at 4.S. 0.9 is 3S -2 at 3.83 Ferritin ng/mL) -7 is is -5.8s. 68. -77 - 13.8 CD40 ligand pg/mL) S -SC). 389.S - 1997.8 29C9 is 2547.5 These were analyzed using the c?ficacy evaluable dataset and Wilcoxon two-sample test. * Everything except for ALT (EPA-E 2700 mg/day vs. Placebo) and Triglycerides (EPA-E 2700 mg/day vs. Placebo) were P valuc > 0.05. ALT (EPA-E 2700 mg/day vs. Placebo) is 0.03.04. Triglyceridcs (EPA-E 2700 mg/day vs. Placcbo) P value = 0.0386 : There were analyzed using ?cwer thc number of subjects than the efficacy evaluable dataset becausc of some missing values. The accurate number of subjects is as statcd below. Placebo: EPA-E 800 mg/day: EPA-E 2700 mg/day IOMA N=53 : Nass 2; Nirs9 Adiponectin Natá8 : N=50: N-56 CK 8 N=49 : Na5 : N=59 Hyaluronic acid Na, 47 : N-50 : N-58 Procollage III peptide EN 47 : Nr.51 : N =58 Collagen IV Nars () : Nars 1 : N-58 hsCRP N=5 : N=52; N=59) Ferritin Nss NorS2 : Nais8 CD40 ligand N=48 : Nac47 : N=56 Patent Application Publication Jul. 28, 2016 Sheet 9 of 9 US 2016/0213639 A1 Figure 9 US 2016/0213639 A1 Jul. 28, 2016 COMPOSITIONS AND METHODS FOR 0006. In yet another aspect of the present invention, a TREATING NON-ALCOHOLIC method is provided for treating a fatty liver disease or disorder STEATO HEPATITIS in a subject in need thereof, comprising: selecting a subject having or Suspected of having a fatty liver disease or disorder, BACKGROUND OF THE INVENTION wherein the Subject can receive a hormone replacement therapy; and administering atherapeutically effective amount 0001 Heavy alcohol use is known to lead to liver compli of a pharmaceutical composition comprising at least one cations, including alcoholic hepatitis which is often charac compound selected from the group consisting of ethyl eicosa terized by fatty liver and inflammation. Alcoholic hepatitis pentanoate (EPA-E), eicosapentaenoic acid (EPA) and its can ultimately lead to cirrhosis of the liver (Scarring) and pharmaceutically acceptable amides, salts, esters and phos hardening of the liver tissue. However, individuals that do not pholipids. In some cases EPA-E or EPA present may be at consume excessive amounts of alcohol can also be found to least 40% by weight in total of the fatty acids and their have liver disease complications.
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