Treatment of hepatitis c virus with telaprevir (vx-950) in patients non-responsive to treatment with pegylated interferon-alpha 2a/2b and ribavirin

Abstract

The present invention relates to antiviral therapies and compositions for treating or preventing Hepatitis C infections in patients and relates to other methods disclosed herein. The invention also relates to kits and pharmaceutical packs comprising compositions and dosage forms. The invention also relates to processes for preparing these compositions, dosages, kits, and packs.

What is claimed is: 
     
         1 . A therapeutic regimen comprising administering to a P/R non-responsive patient VX-950, or a pharmaceutically acceptable salt thereof,
 in an amount of about 100 mg to about 1500 mg;   in an amount of about 300 mg to about 1500 mg;   in an amount of about 300 mg to about 1250 mg;   in an amount of about 450 mg;   in an amount of about 750 mg;   in an amount of about 1125 mg; or   in an amount of about 1250 mg; wherein this amount of VX-950 or its salt is administered once, twice, or three times per day.   
     
     
         2 . The therapeutic regimen according to  claim 1 , wherein VX-950, or a pharmaceutically acceptable salt thereof, is
 in an amount of about 300 mg to about 1500 mg;   in an amount of about 300 mg to about 1250 mg;   in an amount of about 450 mg;   in an amount of about 750 mg;   in an amount of about 1125 mg; or   in an amount of about 1250 mg; wherein this amount of VX-950 or its salt is administered once, twice, or three times per day.   
     
     
         3 . A method for treating or preventing a Hepatitis C virus infection in a P/R non-responsive patient comprising administering to the patient VX-950, or a pharmaceutically acceptable salt thereof, in an amount of about 100 mg to about 1500 mg. 
     
     
         4 . The method according to  claim 3 , wherein VX-950, or a pharmaceutically acceptable salt thereof, is in an amount of about 300 mg to about 1500 mg. 
     
     
         5 . The method according to  claim 4 , wherein VX-950, or a pharmaceutically acceptable salt thereof, is in an amount of about 300 mg to about 1250 mg. 
     
     
         6 . The method according to  claim 5 , wherein VX-950, or a pharmaceutically acceptable salt thereof, is in an amount of about 450 mg. 
     
     
         7 . The method according to  claim 5 , wherein VX-950, or a pharmaceutically acceptable salt thereof, is in an amount of about 750 mg. 
     
     
         8 . The method according to  claim 5 , wherein VX-950, or a pharmaceutically acceptable salt thereof, is in an amount of about 1250 mg. 
     
     
         9 . The method according to any one of  claims 3 - 8 , wherein said amount of VX-950 is administered once a day. 
     
     
         10 . The method according to any of  claims 3 - 8 , wherein said amount of VX-950 is administered twice a day. 
     
     
         11 . The method according to any of  claims 3 - 8 , wherein said amount of VX-950 is administered three times a day. 
     
     
         12 . The method according to any of  claims 3 - 11 , further comprising administering an immunomodulatory agent, an antiviral agent, another inhibitor of HCV NS3/4A protease, an inhibitor of a target in the HCV life cycle other than NS3/4A protease, an inhibitor of internal ribosome entry, a broad-spectrum viral inhibitor, another cytochrome P-450 inhibitor, an inhibitor of viral cellular entry, or a combination thereof. 
     
     
         13 . The method according to  claim 12 , wherein said immunomodulatory agent is α-, β-, or γ-interferon or thymosin; the antiviral agent is ribavirin, amantadine, or telbivudine; and the inhibitor of another target in the HCV life cycle is an inhibitor of HCV helicase, polymerase, or metalloprotease. 
     
     
         14 . A method for treating a P/R non-responsive patient infected with Hepatitis C virus comprising administering to the patient VX-950 in an amount of about 750 mg, 3 times per day, every 8 hours. 
     
     
         15 . A method for treating a P/R non-responsive patient infected with Hepatitis C virus comprising administering to the patient VX-950 in an amount effective to achieve at least about a 2 log 10  decrease of Hepatitis C virus RNA in the plasma. 
     
     
         16 . A method for treating a P/R non-responsive patient infected with Hepatitis C virus comprising administering to the patient VX-950 in an amount effective to achieve at least about a 4 log 10  decrease in Hepatitis C virus RNA in the plasma. 
     
     
         17 . A method for treating a P/R non-responsive patient infected with Hepatitis C virus comprising administering to the patient VX-950 in an amount effective to reduce the Hepatitis C virus RNA to undetectable levels in the plasma. 
     
     
         18 . A method for treating a P/R non-responsive patient infected with Hepatitis C virus comprising administering to the patient VX-950 in an amount effective to achieve a sustained viral response. 
     
     
         19 . The method according to any one of  claims 3 - 18 , wherein the patient is infected with genotype 1 Hepatitis C virus. 
     
     
         20 . A method for treating liver damage, liver inflammation, steatosis, fatty liver, NAFLD, NASH, alcoholic steatosis, or Reye's syndrome in a P/R non-responsive patient comprising administering to the patient VX-950 in an amount of about 1350 mg daily, about 2250 mg daily, or about 2500 mg daily. 
     
     
         21 . A method for hepatoprotection in a P/R non-responsive patient comprising administering to the patient VX-950 in an amount of about 1350 mg daily, about 2250 mg daily, or about 2500 mg daily. 
     
     
         22 . A method for decreasing ALT levels in a P/R non-responsive patient comprising administering to the patient VX-950. 
     
     
         23 . A method for normalizing ALT levels in a P/R non-responsive patient with elevated ALT levels comprising administering to the patient a pharmaceutically effective amount of VX-950. 
     
     
         24 . The method of  claim 22  or  claim 23  wherein VX-950 is administered to the patient in an amount of about 1350 mg daily, about 2250 mg daily, or about 2500 mg daily. 
     
     
         25 . The method of any of  claims 20 - 24  wherein the patient is infected with HCV. 
     
     
         26 . The method of any one of  claims 20 - 24  wherein the patient is not infected with HCV. 
     
     
         27 . A method for providing VX-950 to a P/R non-responsive human in need thereof, comprising administering to the human a dosage form comprising VX-950, wherein the dosage form provides to the human an average plasma concentration (C avg ) of VX-950 of at least about 750 ng/mL after the administration. 
     
     
         28 . The method of  claim 27 , wherein the average plasma concentration (C avg ) of VX-950 is about 750 ng/mL to about 1250 ng/mL after the administration. 
     
     
         29 . The method of  claim 28 , wherein the average plasma concentration (C avg ) of VX-950 is about 1000 ng/mL after the administration. 
     
     
         30 . The method of any of  claims 27 - 29 , wherein the C avg  is obtained or attained within 3 hours after the administration. 
     
     
         31 . The method of  claim 30 , wherein the C avg  is obtained or attained within 2 hours after the administration. 
     
     
         32 . The method according to  claim 31 , wherein the C avg  is obtained or attained within 1 hour after the administration. 
     
     
         33 . The method of any of  claims 27 - 32 , further comprising maintaining a minimum trough plasma VX-950 level of about 750 ng/mL to about 1500 ng/mL over the 24 hour period. 
     
     
         34 . A method of treating a P/R non-responsive human having a HCV infection, comprising administering to the human at least one dosage form comprising VX-950 over a 24-hour period, wherein the dosage form is administered to maintain a minimum trough plasma VX-950 level of about 750 ng/mL to about 1500 ng/mL over the 24-hour period. 
     
     
         35 . The method of  claim 33  or  claim 34 , wherein the dosage form is administered to maintain a trough plasma VX-950 level minimum of about 750 ng/mL over the 24-hour period. 
     
     
         36 . The method of  claim 33  or  claim 34 , wherein the dosage form is administered to maintain a trough plasma VX-950 level minimum of about 1000 ng/mL over the 24-hour period. 
     
     
         37 . The method of any of  claims 27 - 36 , wherein VX-950 is present in the dosage form in an amount of about 750 mg. 
     
     
         38 . The method of  claim 37 , wherein the dosage form is administered three times per day. 
     
     
         39 . The method of any of  claims 27 - 38 , wherein the one or both of the C avg  and the trough level is maintained over about 12 weeks. 
     
     
         40 . The method of any of  claims 3 - 39 , further comprising the step of administering an interferon. 
     
     
         41 . The method of  claim 40 , wherein the interferon is pegylated interferon. 
     
     
         42 . The method of  claim 40  or  claim 41 , wherein the interferon is administered in an amount of about 180 μg/ml. 
     
     
         43 . The method of any of  claims 40 - 42 , further comprising the step of administering ribavirin. 
     
     
         44 . The method of any of  claims 1 - 43 , wherein the VX-950 is formulated as disclosed in Example 6 herein. 
     
     
         45 . A therapeutic regimen comprising administering to a P/R non-responsive patient VX-950, or a pharmaceutically acceptable salt thereof, over an initial phase, wherein the initial phase extends for a period of about 12 weeks. 
     
     
         46 . The therapeutic regimen of  claim 45 , further comprising administering Peg-IFN over a secondary phase, wherein the secondary phase occurs after the initial phase and extends for a period of less than 36 weeks. 
     
     
         47 . The therapeutic regimen of  claim 45  or  46  further comprising administering Peg-IFN with VX-950 in the initial phase. 
     
     
         48 . The therapeutic regimen of any of  claims 45 - 47  further comprising administering RBV with Peg-IFN in the secondary phase. 
     
     
         49 . The therapeutic regimen of any of  claims 45 - 48 , further comprising administering RBV with VX-950 and Peg-IFN in the initial phase. 
     
     
         50 . A therapeutic regimen comprising administering to a P/R non-responsive patient Peg-IFN and RBV with VX-950 in an initial phase and administering Peg-IFN with RBV over a secondary phase, wherein the secondary phase occurs after the initial phase and extends for a period of less than 48 weeks. 
     
     
         51 . The therapeutic regimen of  claim 50 , wherein the secondary phase extends for a period of less than 24 weeks. 
     
     
         52 . The therapeutic regimen of  claim 51 , wherein the secondary phase extends for a period of about 12 weeks. 
     
     
         53 . The therapeutic regimen of  claim 50 , wherein the initial phase extends for a period of less than 24 weeks. 
     
     
         54 . The therapeutic regimen of  claim 51 , wherein the initial phase extends for a period of about 12 weeks. 
     
     
         55 . The therapeutic regimen of  claim 1 , wherein the P/R non-responsive patient is a week 4 null responder. 
     
     
         56 . The therapeutic regimen of  claim 1 , wherein the P/R non-responsive patient is a week 12 null responder. 
     
     
         57 . The therapeutic regimen of  claim 1 , wherein the P/R non-responsive patient is a partial responder. 
     
     
         58 . The therapeutic regimen of  claim 1 , wherein the P/R non-responsive patient is a breakthrough responder. 
     
     
         59 . The therapeutic regimen of  claim 1 , wherein the P/R non-responsive patient is a relapser responder. 
     
     
         60 . The therapeutic regimen of  claim 50 , wherein the VX-950, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 300 mg to about 1250 mg. 
     
     
         61 . The therapeutic regimen of  claim 60 , wherein the VX-950, or a pharmaceutically acceptable salt thereof, is administer in an amount of about 450 mg. 
     
     
         62 . The therapeutic regimen of  claim 60 , wherein the VX-950, or a pharmaceutically acceptable salt thereof, is administer in an amount of about 750 mg. 
     
     
         63 . The therapeutic regimen of  claim 60 , wherein the VX-950, or a pharmaceutically acceptable salt thereof, is administer in an amount of about 1250 mg. 
     
     
         64 . The therapeutic regimen of  claim 60 , wherein the amount is administered once per day. 
     
     
         65 . The therapeutic regimen of  claim 60 , wherein the amount is administered twice per day. 
     
     
         66 . The therapeutic regimen of  claim 60 , wherein the amount is administered three times per day. 
     
     
         67 . The therapeutic regimen of  claim 60 , wherein the amount is administered every 24 hours. 
     
     
         68 . The therapeutic regimen of  claim 60 , wherein the amount is administered every 12 hours. 
     
     
         69 . The therapeutic regimen of  claim 60 , wherein the amount is administered every 8 hours.