PHARMACEUTICAL COMPOSITIONS COMPRISING A FXR AGONIST AND A FIBRATE FOR USE IN THE TREATMENT OF CHOLESTATIC LIVER DISEASE
The present invention relates to a pharmaceutical composition comprising a combination of an FXR agonist and a fibrate. Also disclosed is use of the combination for the treatment, amelioration or prevention of an FXR mediated disease or condition, such as primary biliary cholangitis (PBC).
1 . A method for preventing, ameliorating or treating a cholestatic liver disease, comprising administering to a patient in need thereof a pharmaceutical composition comprising a combination of an FXR agonist and a fibrate, and optionally one or more pharmaceutically acceptable carriers.
2 . The method of claim 1 , wherein the FXR agonist is of formula A:
or a pharmaceutically acceptable salt, solvate, amino acid, sulfate or glucuronide conjugate, or prodrug thereof, wherein:
R 1 is OH, alkoxy, or oxo;
R 2 and R 3 are each independently H, OH, OSO 3 H, OCOCH 3 , OPO 3 H 2 , halogen, or alkyl optionally substituted with one or more halogen or OH, or R 2 and R 3 taken together with the carbon atom to which they are attached form a carbonyl;
R 4 is H, halogen, alkyl optionally substituted with one or more halogen or OH, alkenyl, or alkynyl;
R 5 and R 6 are each independently H, OH, OSO 3 H, OCOCH 3 , OPO 3 H 2 , halogen, or alkyl optionally substituted with one or more halogen or OH, or R 5 and R 6 taken together with the carbon atom to which they are attached form a carbonyl;
R 7 is OH, OSO 3 H, SO 3 H, OSO 2 NH 2 , SO 2 NH 2 , OPO 3 H 2 , PO 3 H 2 , CO 2 H, C(O)NHOH, NH(CH 2 ) 2 SO 3 H, NHCH 2 CO 2 H, tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, oxazolidine-dionyl, thiazolidine-dionyl, 3-hydroxyisoxazolyl, 3 -hydroxyisothiazolyl, pyrimidine, 3,5-difluoro-4-hydroxyphenyl or 2,4-difluoro-3 -hydroxyphenyl;
R 8 , R 9 , and R 10 are each independently H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH, or R 8 and R 9 taken together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic or heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S, or R 9 and R 10 taken together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic or heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O, and S;
R 11 and R 12 are each independently H or OH;
m is 0, 1, or 2;
n is 0 or 1; and
p is 0 or 1.
3 . The method of claim 1 or 2 , wherein the FXR agonist of formula A is of formula 1:
or a pharmaceutically acceptable salt or amino acid conjugate thereof.
4 . The method of claim 1 or 2 , wherein the FXR agonist of formula A is of formula 2:
or a pharmaceutically acceptable salt or amino acid conjugate thereof.
5 . The method of claim 1 or 2 , wherein the FXR agonist of formula A is of formula 3:
or a pharmaceutically acceptable salt thereof.
6 . The method of any one of claims 1 , 2 , and 5 , wherein the FXR agonist of formula A is Compound 3a or Compound 3b:
7 . The method of any one of claims 1 - 3 , wherein the FXR agonist of formula A is obeticholic acid (OCA) or a pharmaceutically acceptable salt or amino acid conjugate thereof.
8 . The method of any one of claims 1 - 7 , wherein the fibrate is bezafibrate.
9 . The method of any one of claims 1 - 8 , wherein the cholestatic liver disease is primary biliary cholangitis.
10 . A method for treating a cholestatic liver disease in a patient in need thereof, comprising administering to the patient a composition comprising obeticholic acid (OCA) or a pharmaceutically acceptable salt or amino acid conjugate thereof in the amount of 5-50 mg and bezafibrate in the amount of 200-400 mg, wherein the composition is administered once daily (QD).
11 . A method for treating PBC in a patient in need thereof, comprising administering to the patient obeticholic acid (OCA) or a pharmaceutically acceptable salt or amino acid conjugate thereof in the amount of 5-50 mg once daily (QD) and bezafibrate in the amount of 200-400 mg QD.
12 . The method of any one of claims 7 - 11 , wherein OCA or a pharmaceutically acceptable salt or amino acid conjugate thereof is administered in the amount of 5-50 mg.
13 . The method of any one of claims 7 - 12 , wherein OCA or a pharmaceutically acceptable salt or amino acid conjugate thereof is administered in the amount of 5 mg.
14 . The method of any one of claims 7 - 12 , wherein OCA or a pharmaceutically acceptable salt or amino acid conjugate thereof is administered in the amount of 10 mg.
15 . The method of any one of claims 7 - 14 , wherein bezafibrate is administered in the amount of 200 mg.
16 . The method of any one of claims 7 - 14 , wherein bezafibrate is administered in the amount of 400 mg.
17 . The method of any one of claims 1 - 16 , further comprising a step of assessing, monitoring, measuring, or detecting liver function.
18 . The method of claim 17 , wherein the step of assessing, monitoring, measuring, or detecting liver function comprises performing a non-invasive assay.
19 . The method of claim 18 , wherein the non-invasive assay is a HepQuant SHUNT assay.
20 . The method of any one of claims 1 - 19 , wherein the patient has an inadequate response to, or is intolerant to, ursodeoxycholic acid treatment.
21 . A composition comprising obeticholic acid (OCA) or a pharmaceutically acceptable salt or amino acid conjugate thereof in the amount of 5-50 mg and bezafibrate in the amount of 200-400 mg for use in the treatment of PBC, wherein the composition is for administration once daily.
22 . Use of a composition comprising obeticholic acid (OCA) or a pharmaceutically acceptable salt or amino acid conjugate thereof in the amount of 5-50 mg and bezafibrate in the amount of 200-400 mg in the manufacture of a medicament for the treatment of PBC, wherein the composition is for administration once daily.
23 . Obeticholic acid (OCA) or a pharmaceutically acceptable salt or amino acid conjugate thereof for use in combination with bezafibrate in the treatment of PBC, wherein the OCA or a pharmaceutically acceptable salt or amino acid conjugate thereof is for administration in the amount of 5-50 mg once daily (QD) and bezafibrate is for administration in the amount of 200-400 mg QD.
24 . Use of obeticholic acid (OCA) or a pharmaceutically acceptable salt or amino acid conjugate thereof in combination with bezafibrate in the manufacture of a medicament for use in the treatment of PBC, wherein the OCA or a pharmaceutically acceptable salt or amino acid conjugate thereof is for administration in the amount of 5-50 mg once daily (QD) and bezafibrate is for administration in the amount of 200-400 mg QD.
25 . A combinational therapy for the treatment of PBC, comprising administration of obeticholic acid (OCA) or a pharmaceutically acceptable salt or amino acid conjugate thereof in the amount of 5-50 mg once daily (QD) and bezafibrate in the amount of 200-400 mg QD.