Compositions comprising EPA and obeticholic acid and methods of use thereof

• US 9,814,733 B2
• Filed: 12/31/2013
• Issued: 11/14/2017
• Est. Priority Date: 12/31/2012
• Status: Active Grant

• Current Assignee: Amarin Pharmaceuticals Ireland Limited (Amarin Corporation plc)
• Original Assignee: A ARIN Pharmaceuticals Ireland Limited
• Inventors: Zakrzewski, Joseph S.
• Primary Examiner(s): Maewall, Snigdha
• Application Number:
  US14/145,212
• Publication Number:
  US 20140186438A1
• Time in Patent Office: 1,414 Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/202 having three or more double bonds, e.g. linolenic eicosanoids, e.g. leukotrienes A61K31/557
• CPC Class Codes: A61K 31/232 having three or more double bonds, e.g. etretinate
• CPC Class Codes: A61K 31/575 substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Abstract

In various embodiments, the present invention provides compositions comprising eicosapentaenoic acid or a derivative thereof and obeticholic acid or a derivative thereof. In other embodiments, the present invention provides methods of treating and/or preventing NASH and/or PBC comprising co-administering to a subject in need thereof eicosapentaenoic acid or a derivative thereof and obeticholic acid or a derivative thereof.

Claims

1. A method of treating or preventing NASH in a subject, the method comprising co-administering orally to the subject a pharmaceutical composition comprising at least about 80%, by weight of all fatty acids present, eicosapentaenoic acid or a derivative thereof, less than about 10%, by weight of all fatty acids present, docosahexaenoic acid or its esters, and obeticholic acid or a pharmaceutically acceptable salt, ester, glycine conjugate, or taurine derivative thereof.

2. The method of claim 1, wherein the method comprises co-administering orally to the subject about 2 g to about 4 g per day of a pharmaceutical composition comprising and about 1 mg to about 500 mg of obeticholic acid or a pharmaceutically acceptable salt, ester, glycine conjugate, taurine derivative thereof.

3. The method of claim 1, wherein the method comprises co-administering orally to the subject about 2 to about 4 capsules per day, each capsule comprising about 500 mg to about 1.1 g of ethyl eicosapentaenoate and not more than about 10% docosahexaenoic acid or its esters, by weight of all fatty acids present, and about 1 mg to about 500 mg of obeticholic acid or a pharmaceutically acceptable salt, ester, glycine conjugate, taurine derivative thereof.

4. The method of claim 1, wherein before administration of the pharmaceutical composition, the subject or mammal has one or more of:

an elevated baseline alanine aminotransferase (“

ALT”

) level, an elevated baseline aspartate aminotransferase (“

AST”

) level, liver fibrosis, an elevated baseline gamma-glutanyl transferase level, an elevated baseline alkaline phosphatase level, an elevated baseline antimitochondrial antibody level, an elevated baseline antinuclear antibody level, an elevated total serum bilirubin level, and an elevated transaminase level.

5. The method of claim 1, wherein after administration of the pharmaceutical composition for a period of time, the subject or mammal has one or more of:

a reduced alanine aminotransferase (“

ALT”

) level, a reduced aspartate aminotransferase (“

AST”

) level, reduced liver fibrosis, a reduced gamma-glutanyl transferase level, a reduced alkaline phosphatase level, a reduced antimitochondrial antibody level, a reduced antinuclear antibody level, a reduced total serum bilirubin level, and a reduced transaminase level compared to baseline, to a second subject who has not received the pharmaceutical composition, or to placebo control.

6. The method of claim 5, wherein a triglyceride level, an IgM level, and/or a C-reactive protein level is reduced in the subject compared to baseline, compared to a second subject who has not received the pharmaceutical composition, or compared to placebo control.

7. The method of claim 1, wherein the subject is administered the pharmaceutical composition daily for a period of at least 2 weeks or at least 12 weeks.

8. The method of claim 1, wherein the pharmaceutical composition comprises at least about 85%, by weight of all fatty acids present, ethyl eicosapentaenoate.

9. The method of claim 8, wherein the pharmaceutical composition comprises at least about 90%, by weight of all fatty acids present, ethyl eicosapentaenoate.

10. The method of claim 1, wherein the pharmaceutical composition comprises less than about 5%, by weight of all fatty acids present, docosahexaenoic acid or its esters.

11. The method of claim 1, wherein the pharmaceutical composition comprises substantially no docosahexaenoic acid or its esters.

12. The method of claim 1, wherein the subject is not administered an additional NASH.

13. The method of claim 1, wherein the subject is administered an additional NASH.

14. The method of claim 13, wherein the additional NASH therapeutic agent is selected from the group consisting of:

L-alanine and pharmaceutically acceptable salts thereof

ursodeoxycholic acid or a pharmaceutically acceptable derivative thereof;

23-N-carbacinnamyloxy-3α

,7α

-dihydroxy-5β

-norcholanylamine or a pharmaceutically acceptable derivative thereof;

15. The method of claim 1, wherein the subject is administered about 4 g per day of the pharmaceutical composition.

16. The method of claim 3, wherein the subject is administered about 4 capsules per day.

17. The method of claim 1, wherein the subject consumes a Western diet.