Compositions and Methods for Treating Non-Alcoholic Steatohepatitis

Abstract

The disclosure provides for a method for treating a fatty liver disorder in a subject in need thereof, comprising selecting a subject having or suspected of having a fatty liver disease or disorder, wherein the subject is non diabetic, pre-diabetic, mildly diabetic, or has normal or substantially normal biliary tract function; and administering a therapeutically effective amount of a pharmaceutical composition comprising ethyl eicosapentanoate (EPA-E). In some cases EPA-E present may be at least 40% by weight in total of the fatty acids and their derivatives.

What is claimed is: 
     
         1 . A method for treating a fatty liver disorder in a human subject in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition that comprises eicosapentaenoic acid (EPA), ethyl eicosapentanoate (EPA-E), or a pharmaceutically acceptable salt thereof to the subject,
 wherein the subject has a serum gamma glutamyl transferase (GGT) activity level higher than 33 IU/L before the administering, and   wherein the administering results in a reduction of 1% to about 90% of alkaline phosphatase (ALP) concentration in the subject.   
     
     
         2 . The method of  claim 1 , wherein the subject's serum HbA1c level is equal to or less than 6.4% or the subject's fasting serum glucose level is equal to or less than 125 mg/dl, before the administering. 
     
     
         3 . The method of  claim 1 , wherein the administering further results in an improvement of serum eicosapentaenoic acid/arachidonic acid (EPA/AA) ratio, as compared to a baseline EPA/AA ratio, of equal to or greater than 0.4 in the subject. 
     
     
         4 . The method of  claim 1 , wherein the subject is not treated with an anti-diabetic agent. 
     
     
         5 . The method of  claim 1 , wherein the administering is in combination with administering one or more anti-diabetic agents. 
     
     
         6 . The method of  claim 1 , wherein the subject has a:
 i) non-alcoholic fatty liver disease activity score (NAS) greater than or equal to 3; or   ii) steatosis score equal to or greater than 1; or   iii) lobular inflammation score equal to or greater than 1; or   iv) ballooning score equal to or greater than 1; or   v) fibrosis score equal to or greater than 1.   
     
     
         7 . The method of  claim 6 , further comprising improving a steatosis and lobular inflammation condition of the subject; wherein the subject exhibits, as compared to a baseline pretreatment level, at least 1% reduction for: alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), TG/High-density lipoprotein (HDL) ratio, Free fatty acid, arachidonic acid (AA), monounsaturated fatty acid (MUFA), Palmitoleic acid, Oleic acid, Oleic acid/Stearic acid ratio, Palmitoleic acid/Palmitic acid ratio, Stearic acid/Palmitic acid ratio, γ-linoleic acid/Linoleic acid ratio, Adrenic acid/AA ratio, Ferritin, Thioredoxin, Tumor necrosis factor (TNF a), Soluble Tumor Necrosis Factor Receptor 1 (sTNF-R1), Soluble Tumor Necrosis Factor Receptor 2 (sTNF-R2), High Sensitivity C-reactive protein (Hs-CRP), Connective Tissue Growth Factor (CTGF), Soluble Cluster of Differentiation 40 (sCD40), Leptin, complement factor D, cytokeratin 18 (CK18) fragment, serum High Mobility Group Box 1 (HMGB1), Fas, procollagen III peptide or PAI-1; at least 5% increase for EPA or EPA/AA ratio; at least 1% increase for Docosapentaenoic acid (DPA), or AA/Homo-γ-linoleic acid ratio; or no worsening of ALP, bilirubin, High Density Lipoprotein Cholesterol (HDL-C), Low Density Lipoprotein Cholesterol (LDL-C), Total Cholesterol (TC), non-HDL-C, Homeostatic Model Assessment Insulin Resistance (HOMA-IR), Glucose, Fasting plasma glucose, postprandial plasma glucose, Oral Glucose Tolerance Test (OGTT), platelet count or Body Mass Index (BMI). 
     
     
         8 . The method of  claim 5 , wherein the anti-diabetic agent is selected from the following group:
 peroxisome proliferator-activated receptor gamma (PPARγ) agonists, biguanides, protein tyrosine phosphatase-1B (PTP-1B) inhibitors, meglitinides, a glucoside hydrolase inhibitors, insulin secreatagogues, A2 antagonists, insulin and related compounds, non-thiazolidinediones, glycogen synthase kinase 3β (GSK 3β)/glycogen synthase kinase 3 (GSK 3) inhibitors, dipeptidyl peptidase IV (DPP-IV) inhibitors, peptides, sulfonylureas, and nonsulfonylurea secretagogues.   
     
     
         9 . The method of  claim 1 , wherein the fatty liver disorder is selected from the group consisting of Non-Alcoholic Fatty Liver Disease (NAFLD), and Non-Alcoholic Steatohepatitis (NASH). 
     
     
         10 . The method of  claim 1 , comprising administering the EPA-E to the subject in an amount between about 1800 and about 2700 mg per day. 
     
     
         11 . The method of  claim 1 , comprising administering to the subject at least 1800 mg of the EPA-E per day. 
     
     
         12 . The method of  claim 1 , comprising administering to the subject at least 2700 mg of the EPA-E per day. 
     
     
         13 . The method of  claim 1 , wherein the subject is further characterized by having at least one condition selected from the group consisting of high triglycerides, low HDL-C, impaired glucose tolerance, and impaired metabolic syndrome. 
     
     
         14 . The method of  claim 7 , wherein the subject exhibits, as compared to a baseline pretreatment level, at least 5% reduction in ALT and/or AST. 
     
     
         15 . The method of  claim 1 , further comprising determining in the subject prior to treatment a baseline level in serum of at least one member selected from the group consisting of ALT in a range of 10 to 300 IU/L, AST in a range of 10 to 250 IU/L, HDL-C in a range of 25 to 55 mg/dl, LDL-C in a range of 100 to 200 mg/dl, triglycerides in a range of 100 to 1000 mg/dl, TC in a range of 170 to 300 mg/dl, High TG, low HDL-C, TG/HDL-C ratio in a range of 3.75 to 10, non-HDL-C in a range of 100 to 250 mg/dl, Free fatty acid in a range of 400 to 1000 μEq/L, HOMA-IR in a range of 1.5 to 5, HbA1c in a range of 5.7 to 10%, and Fasting plasma glucose in a range of 100 to 200 mg/dl. 
     
     
         16 . The method of  claim 1 , wherein the pharmaceutical composition is administered to the subject 1 to 4 times per day. 
     
     
         17 . The method of  claim 1 , wherein the pharmaceutical composition is a self-emulsifying composition that comprises 50 to 95% by weight of the EPA-E. 
     
     
         18 . The method of  claim 1 , wherein the pharmaceutical composition comprises 5 to 50% by weight of an emulsifier having a hydrophilic lipophilic balance of at least 10. 
     
     
         19 . The method of  claim 1 , wherein the pharmaceutical composition comprises ethanol, the content of which is up to 4% by weight in relation to the total content of the self-emulsifying composition. 
     
     
         20 . The method of  claim 1 , wherein the pharmaceutical composition comprises an emulsifier that is at least one member selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, polyethylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, and lecithin. 
     
     
         21 . The method of  claim 1 , wherein the pharmaceutical composition comprises a lecithin. 
     
     
         22 . The method of  claim 1 , wherein the pharmaceutical composition comprises a polyhydric alcohol. 
     
     
         23 . The method of  claim 1 , wherein the pharmaceutical composition further contains at least one member selected from the group consisting of docosahexaenoic acid, a pharmaceutically acceptable salt, and a pharmaceutically acceptable ester thereof. 
     
     
         24 . The method of  claim 1 , wherein the pharmaceutical composition comprises the EPA. 
     
     
         25 . The method of  claim 1 , wherein the pharmaceutical composition further comprises ethyl docosahexaenoate. 
     
     
         26 . The method of  claim 1 , wherein the pharmaceutical composition comprises an emulsifier, and wherein the total content of the emulsifier is 10 to 100 parts by weight in relation to 100 parts by weight of at least one compound selected from the group consisting of ω3 polyunsaturated fatty acids and their pharmaceutically acceptable salts and esters in the pharmaceutical composition. 
     
     
         27 . The method of  claim 1 , wherein EPA-E present in the pharmaceutical composition is at least 40% by weight in total of fatty acids and derivatives thereof. 
     
     
         28 . The method of  claim 1 , wherein the pharmaceutical composition-comprises the EPA-E. 
     
     
         29 . The method of  claim 1 , wherein the subject is non diabetic, pre-diabetic, or mildly diabetic.