Treatment of non-alcoholic fatty liver disease or non-alcoholic steatohepatitis with delayed-release 6-mercaptopurine

Abstract

Methods of treating patients suffering from non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), including those also suffering front type II diabetes mellitus (T2DM), with a delayed release pharmaceutical composition comprising 6-mercaptopurine are disclosed.

What is claimed is 
     
         1 . A method of treating a human patient suffering from nonalcoholic fatty liver disease (NAFLD), comprising periodically administering to the human patient a delayed release pharmaceutical composition comprising a pharmaceutically acceptable carrier and an amount of 6-mercaptopurine (6-MP) effective to treat the human patient. 
     
     
         2 . The method of  claim 1 , wherein the NAFLD is simple steatosis or non-alcoholic steatohepatitis (NASH). 
     
     
         3 . (canceled) 
     
     
         4 . A method of treating a human patient suffering from NASH, comprising periodically administering to the human patient a delayed release pharmaceutical composition comprising a pharmaceutically acceptable carrier and an amount of 6-MP effective to treat the human patient. 
     
     
         5 . The method of  claim 1 , wherein the human patient is also suffering from type II diabetes mellitus (T2DM), type I diabetes mellitus (T1DM), pre-diabetes or insulin resistance, or obesity, wherein obesity is defined as the patient having a body mass index of ≧30. 
     
     
         6 - 8 . (canceled) 
     
     
         9 . The method of  claim 1 , wherein the patient has HbA1c levels between 6.5-8.5%, a NAFLD activity score of 0 or more, any degree of steatosis, evidence of liver fibrosis, inflammation or steatosis, no evidence of liver fibrosis, a score of at least 1 in both steatosis and lobular inflammation, a hepatocyte ballooning score of at least 1, a fibrosis score by transient. Elastography with Fibroscan of ≧F1, or a magnetic resonance imaging (MRI) determined liver fat fraction of at least 10%. 
     
     
         10 - 16 . (canceled) 
     
     
         17 . The method of  claim 1 , wherein the patient is male and has an alanine aminotransferase (ALT) level between 31 and 105 IU/L, inclusive, or wherein the patient is female and has an ALT level between 20 and 120 IU/L, inclusive. 
     
     
         18 - 19 . (canceled) 
     
     
         20 . The method of  claim 1 , wherein the patient is also being administered thiazolidinediones (glitazones), a stable dose for 3 months of dipeptidyl peptidase 4 inhibitors (gliptins), or glucagon-like peptide-1 analogs or long acting insulin, metformin and/or sulfonylureas or DDP4 and/or long acting insulin, immune modulatory agents, systemic steroids or daily treatment with non-steroidal anti-inflammatory drugs, aspirin in an amount of >100 mg/day, ibuprofen, naproxen, meloxicam and/or celecoxib, or 5-ASA. 
     
     
         21 - 25 . (canceled) 
     
     
         26 . The method of  claim 1 , wherein the delayed release pharmaceutical composition administered to the patient contains 0.0001 mg to 1000 mg of 6-MP, or is adjusted over time based on the patient's tolerability 
     
     
         27 - 33 . (canceled) 
     
     
         34 . The method of  claim 1 , wherein the delayed release pharmaceutical composition is administered daily, twice per day, less often than once daily. 
     
     
         35 - 36 . (canceled) 
     
     
         37 . The method of  claim 1 , wherein the delayed release pharmaceutical composition is administered to a patient who is contemporaneously receiving, or who has previously received, NAFLD or NASH therapy, who is contemporaneously receiving any type of treatment for NAFLD, NASH, insulin resistance, or diabetes, who is contemporaneously receiving lipid-lowering medications, insulin-sensitizing medications, anti-oxidant medications, anti-apoptotic medications, and anti-cytokine medications, who is contemporaneously receiving T2DM therapy, or who is contemporaneously receiving metformin, sulfonylureas, meglitinides, thiazolidinediones, DDP-4 inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors, and insulin therapy. 
     
     
         38 - 42 . (canceled) 
     
     
         43 . The method of  claim 1 , wherein the delayed release pharmaceutical composition is administered for 24 weeks, and administration of the delayed release pharmaceutical composition results in improvement of a symptom of NAFLD, NASH, or T2DM relative to baseline after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 weeks of administration, results in improvement of a symptom of NAFLD or NASH, selected from the group consisting of weight loss, fatigue, enlarged liver, or skin discoloration, results in improvement of a symptom of NAFLD or NASH, selected from the group consisting of weight loss, fatigue, enlarged liver, or skin discoloration, results in improvement of a symptom of T2DM, selected from the group consisting of polyuria, polydipsia, polyphagia, weight loss, blurred vision, lower extremity paresthesias, or a yeast infection, results in an improvement in insulin resistance, results in improvement of a symptom of pre diabetes results in a reduction of HbA1c relative to baseline after 4, 12, or 24 weeks of administration, results in an improvement in HOMA or HOMA IR score relative to baseline after 24 weeks of administration, results in a reduction in percentage fat content of the liver relative to baseline after 24 weeks of administration, results in an ALT response after 24 weeks of administration, wherein the ALT response is an ALT level lower than 35 IU/L for women or an ALT level lower than 40 IU/L for men results in a reduction in serum ALT relative to baseline, results in a reduction in serum ALT levels relative to baseline after 24 weeks of administration, results in no change or a decrease in body weight relative to baseline after 2, 4, 12, or 24 weeks of administration, results in an improvement in serum lipid profile relative to baseline after 2, 4, 12, or 24 weeks of administration, results in an improvement in C-reactive protein (CRP) level relative to baseline after 4, 12, or 24 week of administration, results in an improvement in an immunological markers relative to baseline after 2, 4, 12, or 24 weeks of administration, results in an improvement in mean serum ALT relative to baseline after 2, 4, 8, 12, 16 20, or 24 weeks of administration, results in an improvement in mean serum aspartate aminotransferase (AST) relative to baseline after 2, 4, 8, 12, 16, 20, or 24 weeks of administration, results in an improvement in GLP-1 level relative to baseline after 2, 4, 12, or 24 weeks of administration, results in an improvement in adiponectin level relative to baseline after 2, 4, 12, or 24 weeks of administration, results in an improvement in fasting glucose or fasting insulin levels relative to baseline after 2, 4, 12, or 24 weeks of administration, or results in a reduction in liver fibrosis relative to baseline after 24 weeks of administration. 
     
     
         44 - 68 . (canceled) 
     
     
         69 . The method of  claim 1 , wherein the administration of the delayed release pharmaceutical composition to the patient is effective to treat, prevent or results in the improvement of a symptom of any liver disease having liver fibrosis or inflammation as an underlying factor in the liver disease or having liver fibrosis or inflammation associated with the pathogenesis of the liver disease, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), autoimmune hepatitis (AIB), or graft versus host disease (GVHD). 
     
     
         70 - 80 . (canceled) 
     
     
         81 . The method of  claim 1 , wherein the administration of the delayed release pharmaceutical composition results in an improvement in a blood inflammation biomarker, results in an improvement in a liver fibrosis of cell death biomarker, results in an improvement in an oxidative stress biomarker, or results in post treatment NAS of 3 points or less. 
     
     
         82 - 87 . (canceled) 
     
     
         88 . The method of  claim 1 , wherein the patient is administered the delayed release pharmaceutical composition for ≦24 weeks, or ≧24 weeks. 
     
     
         89 . (canceled) 
     
     
         90 . The method of  claim 4 , wherein the administration of the delayed release pharmaceutical composition results in resolution of NASH without worsening of fibrosis, results in an improvement on liver histology in NASH subjects with fibrosis, results in an improvement in, histologic features of NASH from baseline to end of treatment liver biopsy, results in an improvement in in NASH activity, wherein NASH activity is defined by change in standardized scoring of liver biopsies at baseline and at end of treatment, or results in improvement in NASH by at least 2 points spread across at least 2 of the NAS components. 
     
     
         91 - 98 . (canceled) 
     
     
         99 . A package comprising
 (a) a delayed release pharmaceutical composition comprising an amount of 6-mercaptopurine (6-NP) and a pharmaceutically acceptable carrier;   (b) instructions for use of the delayed release pharmaceutical composition to treat a human patient suffering from nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH).   
     
     
         100 . (canceled)