Diagnostics and methods for treatment of non-alcoholic hepatic steatosis and hepatic steatohepatitis, and prevention of complications thereof

Abstract

The present invention is directed to a System characterization of NASH that combines Modeling and Biomarkers, enabling pharmaceutical compositions and methods of treatment that relate to the inhibition, resolution and/or prevention of Non Alcoholic Fatty Liver Disease (NAFLD) and Non Alcoholic Steatohepatitis (NASH). Said conditions are Liver related complications among the array of manifestations of metabolic syndromes, including Type 2 diabetes, hyperlipidemia, weight gain, abdominal obesity, insulin resistance, hypertension, atherosclerosis, fatty liver diseases and certain chronic inflammatory states that lead to these manifestations, among others. In additional aspects, the present invention relates to compositions and methods which may be used to treat, inhibit or reduce the likelihood of NASH and NAFLD complications in patients with hepatitis viral infections, including Hepatitis B and Hepatitis C viral infections, as well as the secondary disease states and/or conditions which are often associated with such viral infections, including hepatic steatosis (steatohepatitis), cirrhosis, fatty liver and hepatocellular cancer, metabolic syndrome complications including cardiovascular diseases, neurodegenerative diseases and premature ageing, among other disease states or conditions.

1 . A method for the diagnosis and treatment of non-alcohol fatty liver disease (NAFLD) and/or non-alcoholic steatohepatitis (NASH) in a patient suspected of or having NAFLD and/or NASH, the method comprising obtaining a biological sample from the patient, measuring biomarkers in the biological sample which are indicative of inflammation, steatosis and/or fibrosis of the liver and other potentially affected organs of the patient and incorporating measurements of the biomarkers into a mathematical model, wherein the mathematical model computes the health of the liver and other affected organs to determine whether or not the patient requires therapy for NAFLD and/or NASH; and
 the patient undergoes therapy for the treatment of NAFLD and/or NASH based upon the results of the mathematical model, wherein the treatment comprises administering an effective amount of a traditional pharmacologically active agent, a composition comprising an ileal brake hormone releasing substance effective to increase the release of ileal brake hormones in said patient or a composition comprising an ileal brake hormone releasing substance effective to increase the release of ileal brake hormones in combination with a pharmacologically active agent.   
     
     
         2 . The method according to  claim 1  wherein the measurements obtained from the biological sample of the patient indicate insulin resistance in said patient, the current biopsy score of the patient, the risk of progressive changes in the biopsy score, the risk of the progression of steatosis, the risk of progression of fibrosis, the risk of developing hepatocellular carcinoma, the degree of metabolic syndrome associated disease components, the indices of cardiovascular and metabolic risk and wherein said method is used to predict the responsiveness of said patient to said therapy. 
     
     
         3 . The method according to  claim 1  wherein said method comprises:
 A. determining a calculated biopsy score as wCombBiopsy Predict; 
 B. determining a wCombLiver signal; 
 C. determining an FS index; and 
 D. determining a Cardiovascular risk index. 
 
     
     
         4 . The method of  claim 3 , wherein the wCombLiver Signal is calculated using a weighted function comprised of biomarkers from said patient or subject which includes Alkaline Phosphatase, ALT, AST, Total Bilirubin, Insulin Concentration, hsCRP, platelet count, Total Protein, Prothrombin time, INR, Lymphocyte count, Waist circumference, Direct Bilirubin, lymphocytes, GGT, Weight, BMI, LDH, HbA1c, Statin dose, Use of Pioglitazone, Use of Fibric acid drugs and Use of Statins. 
     
     
         5 . The method of  claim 3 , wherein said patient is found to have a wCombLiver signal greater than two standard deviations above normal which indicates that the patient is in need of said treatment to lower the risk of Progressive Liver Damage characterized by hepatic steatosis, fibrosis, cirrhosis, liver failure or combinations thereof, whether or not the complications are directly caused by Metabolic Syndrome in said patient or modified further by said additional risk factors placing said patient at risk for at least one Liver disease, Liver disease progression or complication, wherein said treatment comprises administering to said patient a composition comprising an ileal brake hormone releasing substance alone or in combination with a drug used to treat or resolve additional aspects of said Liver Damage condition or risk of disease progression to cirrhosis or hepatocellular carcinoma. 
     
     
         6 . The method of any of  claim 3 [− 5 ], wherein said FS index is calculated as: Where S/D ratio (SD) is a ratio of Glucose Supply Index (S) to Insulin Demand Index (D); and
 wherein (S) is calculated as follows:
   1+[aggregate of carbohydrate exposure (CE)+hepatic glucose uptake (HGU)+hepatic gluconeogenesis (GNG) and+insulin resistance (IR)], and (D) is calculated as follows: 
   1+[aggregate of peripheral glucose uptake (PGU)+peripheral insulin exposure (PIE)]. 
 
 
     
     
         7 . The method of  claim 6 , wherein said patient with NAFLD or NASH is found to have an FS Index value above 60, which indicates that the patient is in need of said treatment to lower the risk of Metabolic Syndrome progression to include Insulin Resistance, Hyperglycemia, Type 2 Diabetes, Hyperlipidemia, Hypertension and/or Abdominal Obesity, whether or not said complications are directly caused by Metabolic Syndrome or modified by said NAFLD or NASH, placing said patient at risk for at least one FS index linked progression or complication, the method further comprising administering to said individual an ileal brake hormone releasing composition optionally in combination with a traditional pharmacologically active drug used to treat or resolve said metabolic syndrome complication or risk. 
     
     
         8 - 9 . (canceled) 
     
     
         10 . A method for treating NASH and/or NAFLD which includes biomarker testing, computation of said disease progression, diagnosis of extent and/or severity of disease, risk stratification, and personalized treatment, whereby beneficial outcome from treatment with an ileal brake hormone releasing substance improves the biopsy score thus indicating improvement in the severity of the disease and whereby said treatment lowers the risk for complications of the disease including fibrosis, cirrhosis, and hepatocellular carcinoma. 
     
     
         11 . The method of any of  claim 10 , wherein said patient's risk of progression of NAFLD or NASH has been determined, and treatment of said patient with an effective amount of a traditional pharmacologically active agent results in a higher second wCombLiver signal, wCombBiopsy Predict signal, FS index and CV index value relative to a first value, indicates that the patient or subject is in need of a change in dosing of the first drug and/or the addition of an ileal brake hormone releasing substance and said patient is treated with a higher dose and/or said substance. 
     
     
         12 - 14 . (canceled) 
     
     
         15 . The method according to any of  claim 3 , wherein said patient is clinically diagnosed as being at risk for or having NASH and/or NAFLD and said patient is treated with said pharmacologically active agent and/or said composition comprising an ileal brake hormone releasing substance, wherein said patient responds to said treatment as evidenced by changes in wComb Biopsy Predict signal and calculated FS index or CV index after said patient undergoes treatment for at least six months, preferably at least 12 months. 
     
     
         16 - 17 . (canceled) 
     
     
         18 . The method according to any of  claim 3 , wherein said patient has a viral infection and is treated with an anti-viral agent in combination with said pharmacologically active agent and/or said composition comprising an ileal brake hormone releasing substance, said treatment resolving NASH and/or NAFLD, reducing the likelihood of fibrosis and/or cirrhosis and controlling the accelerated aging from chronic viral infection by controlling the onset and progression of aging associated MetS. 
     
     
         19 - 20 . (canceled) 
     
     
         21 . The method according to any of  claim 1 , wherein said traditional pharmaceutically active agent is selected from the group consisting of anti-diabetes drugs, SGLT-2 inhibitors, statin drugs, hormones, GLP-1 drugs, a biguanide (e.g. Metformin), a DPP-IV inhibitor (e.g. Sitagliptin), and mixtures thereof. 
     
     
         22 . The method according to  claim 21  wherein said traditional pharmaceutically active agent is administered to said patient in combination with a composition comprising an ileal brake hormone releasing substance. 
     
     
         23 . The method according to  claim 22  wherein said ileal brake hormone releasing substance is selected from the group consisting of starches, sugars, lipids, proteins, amino-acids and mixtures thereof. 
     
     
         24 - 25 . (canceled) 
     
     
         26 . The method according to  claim 22 , wherein said ileal brake hormone releasing agent in said composition is overcoated with a low dose of statin wherein said composition lowers LDL to approximately the same level or lower than the levels obtained by administering a two-fold higher dose of said statin alone (in the absence of said ileal brake hormone releasing agent). 
     
     
         27 - 28 . (canceled) 
     
     
         29 . The method according to  claim 26  wherein said statin overcoating dissolves in the duodenum to release said statin in said patient's duodenum, and the majority of said ileal brake hormone releasing substance is released in said patient's ileum. 
     
     
         30 . The method according to  claim 21 , wherein said composition comprises said ileal brake hormone releasing substance with a low dose of metformin and wherein said composition provides a magnitude of HbA1c lowering which is greater than or equivalent to by comparison a two-fold higher dose of metformin alone. 
     
     
         31 - 37 . (canceled) 
     
     
         38 . The method according to any of  claim 1  wherein said composition comprises an effective dose of an ileal brake hormone releasing substance, wherein said ileal brake hormone releasing substance on is administered in a dosage from 5 grams to 20 grams of dextrose combined with a dosage of from 0.25 grams to 4 grams of a lipid wherein at least 50% of said ileal brake hormone releasing composition is released in the ileum of said individual. 
     
     
         39 - 40 . (canceled) 
     
     
         41 . The method according to  claim 1 , wherein the patient is being treated for NAFLD or NASH with a combination of said ileal brake hormone releasing substance in combination with at least additional one agent selected from the group consisting of obeticholic acid, elafibranor, aramchol, simtuzumab, cenicriviroc, emricasan, IMM124E, BMS-986036, NGM282, GS9674, MSDC-0602, VK2809, MN-001, GS4998, GR-MD-02, NDI-010976, RG-125, DUR-928, CER-209, Solithromycin and PXS-4728A. 
     
     
         42 - 56 . (canceled) 
     
     
         57 . The method of  claim 1 , wherein the ileal brake composition activates or re-activates L-cells of the ileum, thereby producing the chemical and physiological characteristics of an activated ileal brake in a manner similar to RYGB surgery, whereby the use of said composition in an effective dosage in said patient with NASH or NAFLD, said composition synergistically lowers the post treatment biomarker amount or measured score of one or more of insulin resistance, liver enzymes including ALT and AST, ALT/AST ratio, Fib4, HDL, LDL, triglycerides, Alpha fetoprotein, lymphocytes, platelets, wComb liver signal, wComb predicted biopsy score and one or more of calculated or measured scores of steatosis or fibrosis, whereby said change in biomarker is further defined by comparison of measurements taken before versus after said treatment with said composition. 
     
     
         58 - 70 . (canceled)