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

Patent metadata

Field	Value
Publication number	US-11241481-B2
Application number	US-201916600139-A
Country	US
Kind code	B2
Filing date	Oct 11, 2019
Priority date	Jun 16, 2014
Publication date	Feb 8, 2022
Grant date	Feb 8, 2022

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.

First claim

What is claimed is:

1. 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 apical sodium bile acid transporter (ASBT) inhibitor, an autoimmune agent, azathioprine, cochicine, 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);

thereby reducing bile acid synthesis in the subject without inducing hepatocellular carcinoma (HCC) formation.

2. The method of claim 1 , wherein the cytokine is IL-12.

3. The method of claim 1 , wherein the steroid is a glucocorticoid.

4. The method of claim 1 , wherein the subject has nonalcoholic steatohepatitis (NASH).

5. The method of claim 1 , wherein the subject has primary biliary cirrhosis (PBC).

6. The method of claim 1 , wherein the subject has cholestasis.

7. The method of claim 1 , wherein the subject has primary sclerosing cholangitis (PSC).

8. The method of claim 1 , wherein the subject has bile acid diarrhea (BAD) or bile acid malabsorption.

9. The method of claim 1 , wherein the subject has pregnancy intrahepatic cholestasis (PIC).

10. The method of claim 1 , wherein the subject has liver fibrosis.

11. The method of claim 1 , wherein the subject has nonalcoholic fatty liver disease (NAFLD).

12. The method of claim 1 , wherein the subject has cirrhosis.

13. The method of claim 1 , wherein the polypeptide comprises the amino acid sequence set forth in SEQ ID NO:69.

14. The method of claim 1 , wherein the polypeptide consists of the amino acid sequence set forth in SEQ ID NO:69.

15. The method of claim 1 , wherein the method comprises administration of SEQ ID NO:69 and an ASBT inhibitor.

16. The method of claim 15 , wherein the ASBT inhibitor is selected from the group consisting of LUM001 and SC-435.

Assignees

• Ngm Biopharmaceuticals Inc

Inventors

• Ling Lei
• Tian Hui

Classifications

• A61K31/52

  Purines, e.g. adenine · CPC title

• A61K31/575

  substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol · CPC title

• C07K14/50

  Fibroblast growth factor [FGF] · CPC title

• A61K38/28

  Insulins · CPC title

• C07K2319/00

  Fusion polypeptide · CPC title