Compounds and methods for treatment of primary biliary cholangitis

Abstract

The present invention relates to, inter alia, methods of treatment and combinations of (R)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1) useful for the treatment of primary biliary cholangitis (PBC). In some embodiments, the methods further comprise administering Compound 1, or a pharmaceutically salt, solvate, or hydrate thereof, in combination with a compound selected from the group consisting of: an antihistamine (diphenhydramine), cholestyramine (questran, prevalite), rifampin, an opioid antagonist (naloxone), pilocarpine (isopto carpine, salagen), cevimeline (evox-ac), calcium and/or vitamin D supplement, and vitamin A, D, E and/or K supplement. Other embodiments, relate to titration packages for enabling compliance with a regimen of changing dosage of a medication over a period of time for the treatment of primary biliary cholangitis (PBC).

1 . A method of treating primary biliary cholangitis (PBC) in an individual in need thereof comprising administering a therapeutically effective amount of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid (Compound 1), or a pharmaceutically salt, solvate, or hydrate thereof, the method comprising:
 (a) analyzing one or more samples from the individual for a first level of at least one biomarker obtained prior to the treatment with Compound 1;   (b) administering Compound 1 to the individual;   (c) analyzing one or more samples from the individual for a second level of the at least one biomarker obtained after the treatment with Compound 1; and   (d) (i) continuing administration of Compound 1 if the second level of the at least one biomarker in step (c) is less than or about equal to the corresponding first level of the at least one biomarker in step (a); or   (ii) discontinuing administration of Compound 1 if the second level of the at least one biomarker in step (c) is greater than the corresponding first level of the at least one biomarker in step (a); wherein the at least one biomarker is selected from the group consisting of: (i) anti-gp210; (ii) anti-sp100; (iii) serum high sensitivity C-reactive protein (hsCRP), (iv) alanine transaminase (ALT); (v) aspartate transaminase (AST); (vi) gamma-glutamyl transferase (GGT); (vii) antimitochondrial antibodies (AMA); (viii) Golgi protein 73 (GP73); (viii) bile acid; (x) complement factor 4 (C4); (xi) IgG; and (xii) IgM.   
     
     
         2 . (canceled) 
     
     
         3 . The method according to  claim 1 , wherein the individual was previously treated with a therapeutically effective amount of ursodeoxycholic acid (UDCA). 
     
     
         4 . The method according to  claim 1 , wherein the individual is currently treated with a therapeutically effective amount of ursodeoxycholic acid (UDCA). 
     
     
         5 . (canceled) 
     
     
         6 . The method according to  claim 1 , wherein the individual was previously treated with ursodeoxycholic acid (UDCA) and the individual had an inadequate response to UDCA. 
     
     
         7 . The method or use according to  claim 6 , wherein the individual had an inadequate response to UDCA as determined by an alkaline phosphate (ALP)>1.67x upper limit of normal (ULN) for the individual. 
     
     
         8 - 14 . (canceled) 
     
     
         15 . The method according to  claim 1 , wherein the therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is administered orally. 
     
     
         16 . (canceled) 
     
     
         17 . The method according to  claim 1 , wherein the therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is in an amount equivalent to about 1.0 mg to about 5 mg of Compound 1. 
     
     
         18 . The method according to  claim 1 , wherein the therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is in an amount equivalent to about 1 mg to about 2 mg. 
     
     
         19 . The method according to  claim 1  wherein the therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is in an amount equivalent to about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, or about 2 mg of Compound 1. 
     
     
         20 . The method according to  claim 1  , wherein the therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is in an amount equivalent to about 1 mg of Compound 1. 
     
     
         21 . The method according to  claim 1  , wherein the therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is in an amount equivalent to about 2 mg of Compound 1. 
     
     
         22 . The method according to  claim 1  , wherein the therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is administered once daily. 
     
     
         23 . The method according to  claim 1  , wherein the Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is an L-arginine salt of Compound 1. 
     
     
         24 . The method according to  claim 1  , wherein the Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is an anhydrous, non-solvated crystalline form of the L-arginine salt of Compound 1. 
     
     
         25 - 31 . (canceled) 
     
     
         32 . A method of treating an individual in need thereof with (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid (Compound 1) comprising:
 (a) administering Compound 1 to the individual;   (b) analyzing one or more samples from the individual for the level of at least one biomarker obtained after the treatment with Compound 1 ; and   (c) (i) continuing administration of Compound 1 if the at least one biomarker is less than or equal to a predetermined level for the at least one biomarker prior to treatment of Compound 1 ; or   (ii) discontinuing administration of Compound 1 if the at least one biomarker is greater than a predetermined level for the at least one biomarker prior to treatment of Compound 1 ;   wherein the at least one biomarker is selected from the group consisting of: (i) anti-gp210; (ii) anti-splOO; (iii) serum high sensitivity C-reactive protein (hsCRP), (iv) alanine transaminase (ALT); (v) aspartate transaminase (AST); (vi) gamma-glutamyl transferase (GGT); (vii) antimitochondrial antibodies (AMA); (viii) Golgi protein 73 (GP73); (viii) bile acid; (x) complement factor 4 (C4); (xi) IgG; and (xii) IgM.   
     
     
         33 - 40 . (canceled) 
     
     
         41 . The method of  claim 1 , wherein the second level of the at least one biomarker in step (c) is 2% less, 5% less, 10% less, 12% less, 15% less, 17% less, 20% less, 22% less, 25% less, 30% less, 35% less, 40% less, 45% less, 50% less, or > 50% less than the corresponding first level of the at least one biomarker in step (a). 
     
     
         42 . The method of  claim 1 , wherein the at least one biomarker is two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve biomarkers selected from the group consisting of: (i) anti-gp210; (ii) anti-splOO; (iii) serum high sensitivity C-reactive protein (hsCRP); (iv) alanine transaminase (ALT); (v) aspartate transaminase (AST); (vi) gamma-glutamyl transferase (GGT); (vii) antimitochondrial antibodies (AMA); (viii) Golgi protein 73 (GP73); (viii) bile acid; (x) complement factor 4 (C4); (xi) IgG; and (xii) IgM. 
     
     
         43 . The method of  claim 1 , wherein the at least one biomarker in step (c) is two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve biomarkers selected from the group consisting of: (i) anti-gp210; (ii) anti-splOO; (iii) serum high sensitivity C-reactive protein (hsCRP); (iv) alanine transaminase (ALT); (v) aspartate transaminase (AST); (vi) gamma-glutamyl transferase (GGT); (vii) antimitochondrial antibodies (AMA); (viii) Golgi protein 73 (GP73); (viii) bile acid; (x) complement factor 4 (C4); (xi) IgG; and (xii) IgM. 
     
     
         44 . The method of  claim 32 , wherein the individual has primary biliary cholangitis (PBC). 
     
     
         45 . The method of  claim 32 , wherein the individual has fatigue, pruritus, eye dryness, and/or Sjogren’s syndrome (SS). 
     
     
         46 . The method of  claim 32 , wherein the at least one biomarker is two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve biomarkers selected from the group consisting of:
 (i) anti-gp210; (ii) anti-splOO; (iii) serum high sensitivity C-reactive protein (hsCRP); (iv) alanine transaminase (ALT); (v) aspartate transaminase (AST); (vi) gamma-glutamyl transferase (GGT); (vii) antimitochondrial antibodies (AMA); (viii) Golgi protein 73 (GP73); (viii) bile acid; (x) complement factor 4 (C4); (xi) IgG; and (xii) IgM.