FXR agonist compositions for combination therapy
The present application relates to a pharmaceutical composition comprising a combination of an FXR agonist and at least one additional therapeutic agent that lowers the glucose level in the blood, stimulates insulin secretion, and/or increases insulin sensitivity. The present application relates to use of the pharmaceutical composition for the treatment or prevention of a FXR mediated disease or condition, such as NAFLD and NASH, a disease or condition related to an elevated level of glucose in the blood, decreased secretion of insulin, and/or decreased insulin sensitivity such as hyperglycemia, diabetes, obesity, and insulin resistance, or for lowering the glucose level in the blood, stimulating insulin secretion, and/or increasing insulin sensitivity.
1. A pharmaceutical composition comprising an FXR agonist, at least one additional therapeutic agent, and optionally one or more pharmaceutically acceptable carriers, wherein the FXR agonist is a compound of formula I:
or a pharmaceutically acceptable salt or amino acid conjugate thereof, wherein:
R 1 is hydrogen or unsubstituted C 1 -C 6 alkyl;
R 2 is hydrogen or α-hydroxyl;
R 4 is hydroxyl or hydrogen; and
R 7 is hydroxyl or hydrogen,
wherein the at least one additional therapeutic agent is a GLP-1 receptor agonist selected from exenatide/exendin-4, liraglutide, taspoglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, BRX-0585 (Pfizer/Biorexis), and CJC-1134-PC (exendin-4 conjugated to human albumin), wherein the pharmaceutical composition is in a form for oral administration.
2. The pharmaceutical composition of claim 1 , wherein the GLP-1 receptor agonist is liraglutide.
3. The pharmaceutical composition of claim 1 , wherein the GLP-1 receptor agonist is selected from exenatide/exendin-4, liraglutide, taspoglutide, lixisenatide, albiglutide, dulaglutide, and semaglutide.
4. The pharmaceutical composition of claim 1 , wherein the FXR agonist is Compound 1:
or a pharmaceutically acceptable salt or amino acid conjugate thereof.
5. A method of treating or preventing non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), comprising administering the pharmaceutical composition of claim 1 to a subject in need thereof.
6. A method of treating or preventing a disease or condition related to an elevated level of glucose in the blood, decreased secretion of insulin, and/or decreased insulin sensitivity, comprising administering the pharmaceutical composition of claim 1 to a subject in need thereof.
7. The method of claim 6 , wherein the disease or condition is selected from NAFLD, NASH, hyperglycemia, diabetes, obesity, and insulin resistance.
8. A method of lowering the glucose level in the blood, stimulating insulin secretion, and/or increasing insulin sensitivity, comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 1 to a subject in need thereof.