Methods and uses for modulating bile acid homeostasis and treatment of bile acid disorders and diseases

Abstract

Provided herein are methods of modulating bile acid homeostasis or treating a bile-acid related or associated disorder, comprising using variants and fusions of fibroblast growth factor 19 (FGF19), variants and fusions of fibroblast growth factor 21 (FGF21), fusions of FGF19 and/or FGF21, and variants or fusions of FGF19 and/or FGF21 proteins and peptide sequences (and peptidomimetics), in combination with agents effective in modulating bile acid homeostasis or treating a bile-acid related or associated disorder.

1 .- 69 . (canceled) 
     
     
         70 . A method of reducing bile acid synthesis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO:141, thereby reducing bile acid synthesis in the subject without inducing hepatocellular carcinoma (HCC) formation. 
     
     
         71 . The method of  claim 70 , wherein the method further comprises administering to the subject at least one additional agent, wherein the additional agent is an anti-CD20 agent, an anti-CD80 agent, an anti-cytokine antibody, an anti-retroviral therapy, an apical sodium bile acid transporter (ASBT) inhibitor, an autoimmune agent, azathioprine, colchicine, a CSCL10 neutralizing antibody, a CXCR3 ligand, cyclosporine, a cytokine anti-inflammatory drug (CSAID), a cytokine, a growth factor, a fibrate, a fish oil, an immune checkpoint inhibitor, a non-steroidal anti-inflammatory drug (NSAID), a farnesoid X receptor (FXR) agonist, a steroid, a chenodeoxycholic acid (CDCA), an obeticholic acid (OCA), or an ursodeoxycholic acid (UDCA). 
     
     
         72 . The method of  claim 71 , wherein the cytokine is IL-12. 
     
     
         73 . The method of  claim 71 , wherein the steroid is a glucocorticoid. 
     
     
         74 . The method of  claim 70 , wherein the subject has nonalcoholic steatohepatitis (NASH). 
     
     
         75 . The method of  claim 70 , wherein the subject has primary biliary cirrhosis (PBC). 
     
     
         76 . The method of  claim 70 , wherein the subject has cholestasis. 
     
     
         77 . The method of  claim 70 , wherein the subject has primary sclerosing cholangitis (PSC). 
     
     
         78 . The method of  claim 70 , wherein the subject has bile acid diarrhea (BAD) or bile acid malabsorption. 
     
     
         79 . The method of  claim 70 , wherein the subject has pregnancy intrahepatic cholestasis (PIC). 
     
     
         80 . The method of  claim 70 , wherein the subject has liver fibrosis. 
     
     
         81 . The method of  claim 70 , wherein the subject has nonalcoholic fatty liver disease (NAFLD). 
     
     
         82 . The method of  claim 70 , wherein the subject has cirrhosis. 
     
     
         83 . The method of  claim 70 , wherein the polypeptide comprises the amino acid sequence set forth in SEQ ID NO:141. 
     
     
         84 . The method of  claim 70 , wherein the polypeptide consists of the amino acid sequence set forth in SEQ ID NO:141. 
     
     
         85 . The method of  claim 71 , wherein the method comprises administration of SEQ ID NO:141 and an ASBT inhibitor. 
     
     
         86 . The method of  claim 85 , wherein the ASBT inhibitor is selected from the group consisting of LUM001 and SC-435. 
     
     
         87 . A method of reducing bile acid synthesis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of
 (i) a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO:69, and   (ii) at least one additional agent,
 wherein the additional agent is an anti-CD20 agent, an anti-CD80 agent, an anti-cytokine antibody, an anti-retroviral therapy, an ASBT inhibitor, an autoimmune agent, azathioprine, colchicine, a CSCL10 neutralizing antibody, a CXCR3 ligand, cyclosporine, a CSAID, a cytokine, a growth factor, a fibrate, a fish oil, an immune checkpoint inhibitor, a NSAID, a FXR agonist, a steroid, a CDCA, an OCA, or an UDCA; 
   thereby reducing bile acid synthesis in the subject without inducing HCC formation.   
     
     
         88 . The method of  claim 87 , wherein the cytokine is IL-12. 
     
     
         89 . The method of  claim 87 , wherein the steroid is a glucocorticoid. 
     
     
         90 . The method of  claim 87 , wherein the subject has NASH, PBC, cholestasis, PSC, BAD or bile acid malabsorption, PIC, liver fibrosis, NAFLD or liver cirrhosis. 
     
     
         91 . The method of  claim 87 , wherein the polypeptide comprises the amino acid sequence set forth in SEQ ID NO:69. 
     
     
         92 . The method of  claim 87 , wherein the polypeptide consists of the amino acid sequence set forth in SEQ ID NO:69. 
     
     
         93 . A method of reducing bile acid synthesis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of
 (i) a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO:52, and   (ii) at least one additional agent,
 wherein the additional agent is an anti-CD20 agent, an anti-CD80 agent, an anti-cytokine antibody, an anti-retroviral therapy, an ASBT inhibitor, an autoimmune agent, azathioprine, colchicine, a CSCL10 neutralizing antibody, a CXCR3 ligand, cyclosporine, a CSAID, a cytokine, a growth factor, a fibrate, a fish oil, an immune checkpoint inhibitor, a NSAID, a FXR agonist, a steroid, a CDCA, an OCA, or an UDCA; 
   thereby reducing bile acid synthesis in the subject without inducing HCC formation.   
     
     
         94 . The method of  claim 93 , wherein the cytokine is IL-12. 
     
     
         95 . The method of  claim 93 , wherein the steroid is a glucocorticoid. 
     
     
         96 . The method of  claim 93 , wherein the subject has NASH, PBC, cholestasis, PSC, BAD or bile acid malabsorption, PIC, liver fibrosis, NAFLD or liver cirrhosis. 
     
     
         97 . The method of  claim 93 , wherein the polypeptide comprises the amino acid sequence set forth in SEQ ID NO:52. 
     
     
         98 . The method of  claim 93 , wherein the polypeptide consists of the amino acid sequence set forth in SEQ ID NO:52.