HK1098359A

HK1098359A - Combination therapy for hcv infection

Info

Publication number: HK1098359A
Application number: HK07104765.8A
Authority: HK
Inventors: E.埃特; J．J．阿拉姆; R．S．考夫曼
Original assignee: 沃泰克斯药物股份有限公司
Priority date: 2003-10-11
Filing date: 2004-10-12
Publication date: 2007-07-20

Description

Combination therapy for HCV infection

Technical Field

The present invention relates to therapeutic combinations comprising VX-497, ribavirin, and interferon. The present invention also relates to methods of treating an HCV infection or alleviating one or more symptoms thereof in a patient using the therapeutic combinations of the present invention. The invention also provides a kit comprising a therapeutic combination of the invention. The invention also provides pharmaceutical regimens for administering the therapeutic combinations of the invention.

Background

HCV is an RNA virus, belonging to the flaviviridae family. Acute infection with HCV causes a generally mild, often asymptomatic, acute hepatitis. However, at least 85% of patients infected with HCV do not completely clear the virus and develop chronic infections of the liver. Once chronic hepatitis c is established, spontaneous clearance of the virus rarely occurs and most patients with chronic hepatitis c develop slowly progressive liver disease. Twenty years after infection, most patients have overt chronic hepatitis and have cirrhosis in at least 20%. The long-term sequelae of chronic hepatitis c include cirrhosis, liver failure, and hepatocellular carcinoma. HCV is estimated to infect 1 hundred million and 7 million people worldwide. Over a decade later, the number of deaths due to hepatitis c is expected to increase dramatically as a greater proportion of currently infected patients enter the third decade of their infection.

Typical symptoms of HCV infection include elevated ALT, positive anti-HCV antibody assay, positive HCV-RNA assay demonstrating the presence of HCV, clinical features of chronic liver disease, or hepatocellular injury.

Prior to 1999, a therapy approved by the European Union (EU) for chronic HCV infection was interferonAlpha (IFN-. alpha.), e.g. Intron^®A，Viraferon^®Or Infergen^®. The response rate was poor, with only 20% of patients achieving a Sustained Virological Response (SVR) after six months of treatment. SVR refers to the number of patients with undetectable HCV RNA six months after termination of treatment. The lack of a persistent antiviral response coupled with the need for injection, and the various side effects of the drug (including flu-like syndrome, nausea, anorexia, insomnia and depression) limit the use of this therapy.

Ribavirin, a broad-spectrum antiviral agent, has been reported to be active against chronic hepatitis c. Ribavirin, when used alone, reduces liver enzyme levels in most patients during treatment. However, liver enzymes return to baseline values when treatment ceases. Additionally, ribavirin treatment only minimally and transiently reduced serum HCV RNA levels. A more favorable effect has been obtained with ribavirin in combination with IFN-alpha. In two large controlled trials of ribavirin 1000-. After 6 months of treatment, the SVR of the combination therapy ranged from 29-32% and 6-17% with IFN- α alone (the latter representing 48 weeks of treatment). Over a longer course of combination therapy for 48 weeks, a slightly higher proportion of untreated patients exhibited SVR (37-42%). This combination therapy was approved by the EMEA regulation in 1999 and marketed by Schering Plough corporation. Limitations of ribavirin therapy include the development of drug-induced hemolytic anemia. Most patients show an average reduction in hemoglobin of 2-3g/dL over the course of treatment. A reduction in hemoglobin concentration to less than 10g/dL was observed in about 8% of patients receiving combination therapy, necessitating a reduction in ribavirin dose. Ribavirin treatment is also associated with non-specific constitutional symptoms such as fatigue, insomnia, depression and vertigo. In recent experimental reports, a small fraction of patients receiving ribavirin in combination with IFN- α require dose reduction or treatment discontinuation to control toxicity, which is often due to hemolytic anemia. In addition, it has been suggested that hemolysis may damage the liver by increasing iron absorption.

To further increase the SVR rate of ribavirin in combination with IFN- α, recent developments have focused on the interferon component of therapy. Polyethylene glycol (PEG) molecules are covalently bound to interferon proteins through a process known as pegylation. Pegylation results in an increase in protein half-life followed by reduced renal clearance and proteolysis. Pegylated interferon alpha (PEG-IFN-alpha) compared to standard IFN-a, serum concentrations showed less variability, resulting in a more consistent antiviral pressure against the virus. Two different PEG-IFN-alpha products have been investigated. PEG-IFN-alpha 2a (Pegasys)^®Roche Laboratories) bound to a 40kDa PEG molecule, resulting in a serum half-life of approximately 80 hours. PEG-IFN-. alpha.2b (PEG-Intron)^TMOr ViraferonPEG^TM(ii) a Schering Plough) bind to 12kDa PEG molecules and have a serum half-life of about 31 hours.

Phase III studies have been completed in which PEG-IFN-. alpha.2a (Pegasys) was evaluated^®) + antiviral activity of ribavirin after a 48 week treatment course given to a treatment-naive hepatitis C patient. 1,149 patients were enrolled in the study and received 180. mu.g PEG-IFN-. alpha.2a + ribavirin, 180. mu.g PEG-IFN-. alpha.2a + placebo or PEG-IFN-. alpha.2b + ribavirin. The SVR for the PEG-IFN-. alpha.2a + ribavirin group (56%) demonstrated a statistically significant increase compared to PEG-IFN-. alpha.2a (30%) and IFN-. alpha.2b + ribavirin (45%). At that time Pegasys^®Combinations with ribavirin have not been approved by FDA or EMEA regulations.

In a phase III study of untreated patients, PEG-IFN-. alpha.2b (PEG-Intron) was evaluated^TM/ViraferonPEG^TM) + antiviral activity of ribavirin combination. A total of 1,530 patients were enrolled in the study and randomized into one of three treatment groups; 1.5 μ g/kg PEG-IFN-. alpha.2b was treated with ribavirin at 800 mg/day once per week for 48 weeks, 1.5 μ g/kg PEG-IFN-. alpha.2b was treated with ribavirin at 1000 mg/day for 4 weeks once per week, followed by 0.5 μ g/kg PEG-IFN-2b was treated with ribavirin at 1000 mg/day for 44 weeks once per week, or IFN-. alpha.2b + ribavirin for 48 weeks. SVR rates were 54%, 47% and 47%. PEG-Intron^TMCombination with ribavirin was approved by the u.s. and e.u. regulatory agencies in 2001.

Methods of treating HCV infection using ribavirin and interferon alpha are disclosed, for example, in U.S. Pat. No. 4, 6,299,872, U.S. Pat. No. 3, 6,387,365, U.S. Pat. No. 3, 6,172,046, and U.S. Pat. No. 6,472,373, the disclosures of which are incorporated herein by reference.

The combination of pegylated interferon and ribavirin, while effective, has drawbacks. SVR rates in the 50-55% range are associated with toxicity of both drugs, suggesting the need for additional effective therapies to increase safety. There is a need for an effective therapy against HCV infection that reduces side effects and enhances efficacy.

Disclosure of Invention

It is an object of the present invention to provide a therapeutic combination comprising VX-497, ribavirin, and interferon.

It is another object of the present invention to provide a method of treating an HCV infection or alleviating one or more symptoms thereof in a patient comprising administering to said patient a composition of the present invention.

It is yet another object of the present invention to provide a pharmaceutical regimen for treating HCV infection in a patient.

Detailed description of the invention

The definitions used herein are as follows:

"Peg-Intron" means PEG-Intron^®Polyethylene glycol interferon alpha-2 b available from Schering Corporation, Kenilworth, NJ;

"Intron" means Intron-A^®Interferon alpha-2 b, available from schering corporation, Kenilworth, NJ;

"ribavirin" means ribavirin (1-beta-D-ribofuranosyl-1H-1, 2, 4-triazole-3-carboxamide), available from ICN PharmaceuticalInc., Costa Mesa, CA; described in the Merck Index, entry 8365, Twolfth Edition; rebetol, from Schering Corporation, Kenilworth, N.J., may also be used^®Or Copegus from Hoffmann-La Roche, Nutley, NJ^®；

"Pagasys" means Pegasys^®Polyethylene glycol interferon alpha-2 a, obtainable from Hoffmann-La Roche, Nutley, NJ;

"Roferon" means Roferon^®The recombinant interferon alpha-2 a can be obtained from Hoffmann-LaRoche, Nutley and NJ;

"Berefor" means Berefor^®Interferon alpha 2, available from boehringer ingelheim Pharmaceutical, inc., ridgfield, CT;

Sumiferon^®a purified blend of natural alpha interferons, such as Sumiferon, available from Sumitomo Japan;

Wellferon^®interferon α n1, available from Glaxo _ Wellcome ltd, GreatBritain;

Alferon^®a mixture of natural alpha interferons prepared by Inteferon Science, available from Purdue Frederick co., CT;

"VX-497" represents a compound having the following structural formula:

or a pharmaceutically acceptable salt thereof.

VX-497 is a potent inhibitor of IMPDH identified by Vertex Pharmaceuticals Inc. and is described in U.S. Pat. No. 5, 6,541,496.

"bid" means twice daily;

"tid" means three times daily;

"qid" means four times daily;

"biw" means twice weekly;

"tiw" means three times per week.

The term "therapeutic combination" as used herein denotes a combination of one or more active drug substances, i.e. a therapeutically active compound. Typically, each compound of the therapeutic combination of the present invention is present in a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier. The compounds of the therapeutic combinations of the present invention may be administered simultaneously as part of a regimen or separately.

According to one embodiment, the present invention provides a therapeutic combination comprising VX-497 and ribavirin.

According to another embodiment, the present invention provides a therapeutic combination comprising an IMPDH inhibitor (e.g., VX-497), ribavirin, and interferon.

The first component of the therapeutic combination, namely VX-497, is comprised in a composition. Such a composition comprises VX-497 ("VX-497 composition") and a pharmaceutically acceptable adjuvant or carrier.

Preferably, the VX-497 composition comprises VX-497 in an amount sufficient for a dosage of at least about 60 mg/day.

According to another embodiment, the VX-497 composition comprises VX-497 in an amount sufficient for a dosage of between about 60 mg/day to about 220 mg/day.

According to another embodiment, the VX-497 composition comprises VX-497 in an amount sufficient for a dosage of between about 60 mg/day to about 150 mg/day.

According to another embodiment, the VX-497 composition comprises VX-497 in an amount sufficient for a dosage of between about 70 mg/day to about 120 mg/day.

According to another embodiment, the VX-497 composition comprises VX-497 in an amount sufficient for a dosage of between about 80 mg/day to about 100 mg/day.

According to another embodiment, the VX-497 composition comprises VX-497 in an amount sufficient for a dosage of between about 85 mg/day to about 90 mg/day.

According to another embodiment, the VX-497 composition comprises VX-497 in an amount sufficient for a dosage of between about 90 mg/day to about 220 mg/day.

According to another embodiment, the VX-497 composition comprises VX-497 in an amount sufficient for a dosage of between about 90 mg/day to about 120 mg/day.

According to another embodiment, the VX-497 composition comprises VX-497 in an amount sufficient for a dosage of between about 100 mg/day to about 110 mg/day.

According to another embodiment, the VX-497 composition comprises VX-497 in an amount sufficient for a dosage of about 100 mg/day.

According to another embodiment, the VX-497 composition comprises VX-497 in an amount sufficient for a dosage of between about 150 mg/day to about 220 mg/day.

According to another embodiment, the VX-497 composition comprises VX-497 in an amount sufficient for a dosage of between about 170 mg/day to about 210 mg/day.

According to another embodiment, the VX-497 composition comprises VX-497 in an amount sufficient for a dosage of between about 180 mg/day to about 210 mg/day.

According to another embodiment, the VX-497 composition comprises VX-497 in an amount sufficient for a dosage of about 200 mg/day.

According to one embodiment, the VX-497 composition comprises VX-497 in a formulation suitable for dosing once daily, bid, tid, qid, five times daily, or six times daily. For example, if the VX-497 composition comprises VX-497 in a dosage of about 100 mg/day and dosing with bid is desired, the VX-497 composition will comprise VX-497 in a formulation, e.g., a tablet, comprising about 50mg VX-497.

According to another embodiment, the VX-497 composition comprises VX-497 in a formulation suitable for dosing bid.

Alternatively, the VX-497 composition comprises VX-497 in a formulation suitable for dosing tid.

According to another embodiment, the VX-497 composition comprises VX-497 in an amount sufficient for a dosage of between about 90 mg/day to about 120 mg/day, wherein said VX-497 is formulated for dosing bid.

According to another embodiment, the VX-497 composition comprises VX-497 in an amount sufficient for a dosage of between about 100 mg/day to about 110 mg/day, wherein said VX-497 is formulated for dosing bid.

According to another embodiment, the VX-497 composition comprises VX-497 in an amount sufficient for a dosage of about 100 mg/day, wherein said VX-497 is formulated for dosing bid.

In the therapeutic combinations of the present invention, VX-497 may be replaced with other IMPDH inhibitors known in the art. Preferably, such other IMPDH inhibitors are used in doses that provide comparable exposure levels in patients (e.g., in serum plasma) as compared to the exposure levels of the corresponding VX-497 dose. Examples of such other IMPDH inhibitors include, for example, Cellcept, VX-944, VX-148, and mizorubin.

The second component of the therapeutic combination, ribavirin, is contained within a composition ("ribavirin composition"). Typically, such a composition comprises ribavirin and a pharmaceutically acceptable adjuvant or carrier.

According to one embodiment, the ribavirin composition comprises ribavirin in an amount sufficient for a dosage of between about 400 mg/day to about 1200 mg/day.

According to another embodiment, the ribavirin composition comprises ribavirin in an amount sufficient for a dosage of between about 800 mg/day to about 1200 mg/day.

According to another embodiment, the ribavirin composition comprises ribavirin in an amount sufficient for a dosage of between about 1000 mg/day to about 1200 mg/day.

According to another embodiment, the ribavirin composition comprises ribavirin in an amount sufficient for a dosage of about 1000 mg/day or about 1200 mg/day.

According to another embodiment, the ribavirin composition comprises ribavirin in an amount sufficient for a dosage of between about 300 mg/day to 800 mg/day, and more preferably between about 300 mg/day to about 700 mg/day. Alternatively, and even more preferably, it is present in an amount sufficient to achieve a dosage of between 500 mg/day to about 700 mg/day. Alternatively, and still more preferably, it is present in an amount sufficient to achieve a dosage of between 400 mg/day to about 600 mg/day.

According to another embodiment, ribavirin is Rebetol^®Or Copegus^®。

According to one embodiment, the ribavirin composition comprises ribavirin in a formulation suitable for once daily, bid, tid, qid, five times daily, or six times daily. For example, if a therapeutic combination comprises ribavirin at a dose of about 1000 mg/day and five administrations per day are desired, the therapeutic combination will comprise ribavirin in a formulation (e.g., a tablet) containing, for example, about 200mg of ribavirin.

Alternatively, the ribavirin compositions comprise ribavirin in a formulation suitable for administration of at least bid. Further preferably, ribavirin is formulated for dosing bid, tid, qid or five times daily. Preferably, ribavirin is formulated for dosing bid or tid. Even more preferably, ribavirin is formulated for dosing bid.

The term "interferon" as used herein refers to members of a family of highly homologous species-specific proteins that inhibit viral replication and cellular proliferation, as well as modulate immune responses, such as interferon alpha, interferon beta or interferon gamma. Merck Index, entry 5015, Twolfth Edition.

According to another embodiment, the therapeutic combination of the invention utilizes natural interferon-alpha 2 a. Alternatively, the therapeutic combinations of the present invention utilize natural interferon-alpha 2 b. Preferably, the therapeutic combination of the invention utilizes recombinant interferon-alpha 2a or 2 b. Further preferably, the interferon is pegylated interferon alfa 2a or 2 b. Interferons suitable for use in the present invention include:

(a)Intron，

(b)Peg-Intron，

(c)Pegasys，

(d)Roferon，

(e)Berofor，

(f)Sumiferon，

(g)Wellferon，

(h) consensus interferon-alpha, available from Amgen, inc., Newbury Park, CA,

(i)Alferon；

(j)Viraferon^®；

(k)Infergen^®。

according to another embodiment, the therapeutic combination comprises VX-497 and an interferon selected from Intron, Peg-Intron, Pegasys, Roferon, Berofor, Sumiferon, Wellferon, consensus interferon alpha, or Alferon.

According to another embodiment, the therapeutic combination comprises VX-497 and one of Intron, Roferon, Peg-Intron, or Pegasys.

According to another embodiment, the therapeutic combination comprises Intron or Roferon at a dose sufficient to achieve about 4000000 IU to about 12000000 IU per week. Preferably, the content of Intron or Roferon is sufficient to achieve a dose of about 6000000 IU to about 10000000 IU. Further preferably, Intron or Roferon is present in an amount sufficient to achieve a dosage of about 8000000 IU to about 9000000 IU. Even more preferably, Intron or Roferon is present in an amount sufficient to achieve a dosage of about 9000000 IU.

The amount of Peg-Intron or Pegasys in the therapeutic combination of the invention depends on the body weight of the patient to be treated.

According to one embodiment, the therapeutic combination comprises Peg-Intron or Pegasys in an amount sufficient to achieve a dosage of about 0.5 μ g/kg/week to about 2 μ g/kg/week. According to another embodiment, Peg-Intron or Pegasys is present in an amount sufficient for a dosage of about 1 μ g/kg/week to about 2 μ g/kg/week. Alternatively, Peg-Intron or Pegasys is present in an amount sufficient to achieve a dosage of about 1.5 μ g/kg/week.

Pharmaceutical carriers and adjuvants useful in formulating each of VX-497 and ribavirin are known in the art. Formulations containing VX-497 are disclosed in U.S. Pat. No. 5, 6,541,496, the disclosure of which is incorporated herein by reference. Formulations comprising ribavirin are disclosed in US4,211,771.

According to another embodiment, the present invention provides a kit for treating an HCV infection in a patient. The kits of the invention comprise any one of the therapeutic combinations of the invention. The kit further comprises instructions for using the therapeutic combination. The kit may be tailored to the needs of different classes or types of patients or other clinically relevant factors, such as age, weight, concomitant diseases/conditions, severity and stage of HCV infection, responsiveness or non-responsiveness to prior treatment, propensity for side effects, and the like. For example, the therapeutic combination in the kit may be designed in a dosage suitable for a patient weighing, for example, 75 kg. Alternatively, the therapeutic combination in the kit may be designed in a dosage suitable for a patient weighing, for example, less than or equal to 75 kg. Alternatively, the therapeutic combination in the kit may be designed for pediatric use, where the pediatric dosage varies depending on factors such as age, weight, disease severity, and the like.

According to another embodiment, the present invention provides a kit comprising:

(i) a plurality of VX-497 compositions;

(ii) a plurality of ribavirin compositions;

(iii) a plurality of interferon compositions; and

(iv) the description of the above composition applies.

According to another embodiment, the kit comprises VX-497 compositions, wherein each composition comprises VX-497 in a dosage according to any one of the above embodiments. In one embodiment, each of the compositions contains at least, and preferably, about 50mg of VX-497. In one embodiment, each of the compositions contains at least, and preferably, about 1000mg of VX-497.

According to another embodiment, the kit comprises ribavirin compositions, wherein each composition contains a preferred dosage of ribavirin as described above. According to another embodiment, each of said compositions contains about 200mg of ribavirin. Preferably, each of the compositions contains about 200mg of ribavirin in a capsule.

According to another embodiment, the kit comprises interferon alpha compositions, wherein each composition contains a dose of interferon as described above. Preferably, the interferon in the kit is Intron, Peg-Intron, Roferon, or Pegasys. Further preferably, the interferon is Peg-Intron or Pegasys.

According to another embodiment, the kit comprises the interferon alpha formulation in a single dose vial or in a multiple dose vial. Preferably, interferon alpha is in a formulation suitable for injection.

According to another embodiment, the present invention provides a method of treating an HCV infection or alleviating one or more symptoms thereof in a patient comprising the step of administering to the patient a therapeutic combination according to the present invention. According to one embodiment, the patient has an HCV genotype 1 infection.

According to another embodiment, the methods of the present invention may be used to treat an HCV infection or alleviate one or more symptoms of an HCV infection in a treatment-naive patient, i.e., a patient that has not received any prior treatment for an HCV infection.

According to another embodiment, the methods of the invention can be used to treat HCV infection or alleviate one or more symptoms thereof in a patient who is non-responsive to interferon monotherapy.

According to another embodiment, the methods of the present invention may be used to treat HCV infection or alleviate one or more symptoms thereof in a patient who is non-responsive to combination therapy with ribavirin and interferon.

According to an alternative embodiment, the present invention provides a method of reducing HCV-RNA levels in a patient in need thereof, comprising the step of administering to said patient a therapeutic combination according to the present invention. Preferably, the methods of the invention can reduce the patient's HCV-RNA levels below detectable levels.

As used herein, a detectable level of HCV RNA means that there are at least 100 copies of HCV RNA per ml of patient serum as measured by the quantitative multicycle reverse transcriptase PCT method. Such methods are well known in the art.

According to another embodiment, the present invention provides a pharmaceutical regimen comprising administering to a patient in need thereof a therapeutic combination according to the present invention for at least 12 weeks. In one embodiment, the pharmaceutical regimen comprises administering the therapeutic combination to a patient in need thereof for between about 12 weeks and about 24 weeks. Alternatively, the therapeutic combination is administered for at least 24 weeks. According to an alternative embodiment, the therapeutic combination is administered until the patient's HCV RNA level is below a detectable level.

According to another embodiment, the pharmaceutical regimen comprises administering to a patient in need thereof for at least about 12 weeks:

(i) a therapeutically effective amount of VX-497 bid;

(ii) a therapeutically effective amount of ribavirin bid;

(iii) a therapeutically effective amount of interferon alpha is administered once weekly.

According to one embodiment, VX-497 is dosed at least 40mg bid. Alternatively, VX-497 is dosed at between about 40mg bid to about 120mg bid. In another embodiment, VX-497 is dosed at about 50mg bid. In another embodiment, VX-497 is dosed at about 100mg bid.

According to another embodiment, the dose of ribavirin is selected from 400 mg/day, 600 mg/day, 800 mg/day, 1000 mg/day, or 1200 mg/day, wherein each daily dose is divided into multiple administrations throughout the day. The dose of each of the above multiple daily administrations is preferably 200mg, 300mg, 400mg, 500mg, or 600 mg.

According to another embodiment, interferon alpha is administered once a week. Preferably, Intron or Roferon is administered once a week. Alternatively, pegylated interferon is administered once a week. Preferably, the pegylated interferon comprises Peg-Intron or Pegasys. Preferred dosages of interferon alpha in a pharmaceutical regimen have been mentioned above.

Examples

A24-week, double-blind, randomized, placebo-controlled study was performed on 31 patients who did not respond to ribavirin/Peg-Intron therapy. The patients were divided into three groups. All three groups received ribavirin/Peg-Intron therapy. One group was given placebo, while the second group was given VX-49725 mg bid. And a third group administered VX-497 in a dosage according to the present invention.

More than 80% of patients in the third group receiving ribavirin, Peg-Intron, and VX-497 in doses according to the present invention reached undetectable levels of HCVRNA at the end of 24 weeks.

Claims

1. A therapeutic combination comprising VX-497 and ribavirin.

2. A therapeutic combination comprising VX-497, ribavirin, and interferon.

3. The therapeutic combination according to claim 2, wherein said interferon is interferon alpha 2 a.

4. The therapeutic combination according to any one of claims 1-3, comprising VX-497 in an amount sufficient for a dosage of at least about 60 mg/day.

5. The therapeutic combination according to claim 4, comprising VX-497 in an amount sufficient for a dosage of between about 60 mg/day to about 220 mg/day.

6. The therapeutic combination according to claim 5, comprising VX-497 in an amount sufficient for a dosage of between about 60 mg/day to about 150 mg/day.

7. The therapeutic combination according to claim 6, comprising VX-497 in an amount sufficient for a dosage of between about 70 mg/day to about 120 mg/day.

8. The therapeutic combination according to claim 7, comprising VX-497 in an amount sufficient for a dosage of between about 80 mg/day to about 100 mg/day.

9. The therapeutic combination according to claim 8, comprising VX-497 in an amount sufficient for a dosage of between about 85 mg/day to about 90 mg/day.

10. The therapeutic combination according to claim 4, comprising VX-497 in an amount sufficient for a dosage of between about 90 mg/day to about 220 mg/day.

11. The therapeutic combination according to claim 10, comprising VX-497 in an amount sufficient for a dosage of between about 90 mg/day to about 120 mg/day.

12. The therapeutic combination according to claim 11, comprising VX-497 in an amount sufficient for a dosage of between about 100 mg/day to about 110 mg/day.

13. The therapeutic combination according to claim 12, comprising VX-497 in an amount sufficient for a dosage of about 100 mg/day.

14. The therapeutic combination according to claim 4, comprising VX-497 in an amount sufficient for a dosage of between about 150 mg/day to about 220 mg/day.

15. The therapeutic combination according to claim 14, comprising VX-497 in an amount sufficient for a dosage of between about 180 mg/day to about 210 mg/day.

16. The therapeutic combination according to claim 15, comprising VX-497 in an amount sufficient for a dosage of about 200 mg/day.

17. The therapeutic combination according to any one of claims 1-16, comprising VX-497 in a formulation suitable for dosing once daily, twice daily, three times daily, four times daily, five times daily, six times daily.

18. The therapeutic combination according to claim 17, comprising VX-497 in a formulation suitable for dosing bid.

19. The therapeutic combination according to claim 17, comprising VX-497 in a formulation suitable for dosing thrice daily.

20. The therapeutic combination according to claim 17, comprising VX-497 in an amount sufficient for a dosage of between about 90 mg/day to about 120 mg/day, wherein said VX-497 is formulated for dosing bid.

21. The therapeutic combination according to claim 20, comprising VX-497 in an amount sufficient for a dosage of between 100 mg/day to about 110 mg/day, wherein said VX-497 is formulated for dosing bid.

22. The therapeutic combination according to claim 21, comprising VX-497 in an amount sufficient for a dosage of about 100 mg/day, wherein said VX-497 is formulated for dosing bid.

23. The therapeutic combination according to any one of claims 1-4, comprising ribavirin in an amount sufficient for a dosage of between 400 mg/day to about 1200 mg/day.

24. The therapeutic combination according to claim 23, comprising ribavirin in an amount sufficient for a dosage of between about 800 mg/day to about 1200 mg/day.

25. The therapeutic combination according to claim 24, comprising ribavirin in an amount sufficient for a dosage of between about 1000 mg/day to about 1200 mg/day.

26. The therapeutic combination according to claim 25, comprising ribavirin in an amount sufficient for a dosage of about 1000 mg/day or about 1200 mg/day.

27. The therapeutic combination according to claim 26, comprising ribavirin in an amount sufficient for a dosage of between about 300 mg/day to about 800 mg/day, more preferably between about 300 mg/day to about 700 mg/day.

28. The therapeutic combination according to claim 27, comprising ribavirin in an amount sufficient for a dosage of between about 500 mg/day to about 700 mg/day.

29. The therapeutic combination according to claim 28, comprising ribavirin in an amount sufficient for a dosage of between about 400 mg/day to about 600 mg/day.

30. The therapeutic combination according to any one of claims 1-29, wherein said ribavirin is rebeol^®Or Copegus^®。

31. The therapeutic combination according to any one of claims 1-4, comprising ribavirin in a formulation suitable for administration once daily, twice daily, three times daily, four times daily, five times daily, or six times daily.

32. The therapeutic combination according to claim 31, comprising ribavirin in a formulation suitable for at least twice daily administration.

33. The therapeutic combination according to any one of claims 1-32, comprising interferon alpha 2 a.

34. The therapeutic combination according to claim 33, wherein said interferon is selected from the group consisting of:

(a)Intron，

(b)Peg-Intron，

(c)Pegasys，

(d)Roferon，

(e)Berofor，

(f)Sumiferon，

(g)Wellferon，

(h) the alpha-interferon is shared by the two genes,

(i)Alferon；

(j)Viraferon^®(ii) a Or

(k)Infergen^®。

35. The therapeutic combination according to claim 34, wherein said interferon is selected from Intron, Peg-Intron, Pegasys, Roferon, Berofor, Sumiferon, Wellferon, consensus interferon, or Alferon.

36. The therapeutic combination according to claim 34, wherein said interferon is Intron, Roferon, Peg-Intron, or Pegasys.

37. The therapeutic combination according to claim 36, wherein Intron or Roferon is present in an amount sufficient for a dosage of about 4000000 IU/week to about 12000000 IU/week.

38. The therapeutic combination according to claim 37, wherein Intron or Roferon is present in an amount sufficient to achieve a dosage of about 6000000 IU/week to 10000000 IU/week.

39. The therapeutic combination according to claim 38, wherein Intron or Roferon is present in an amount sufficient to achieve a dosage of about 8000000 IU/week to about 9000000 IU/week.

40. The therapeutic combination according to claim 39, wherein Intron or Roferon is present in an amount sufficient to achieve a dosage of about 9000000 IU/week.

41. The therapeutic combination according to claim 36, wherein Peg-Intron or Pegasys is present in an amount sufficient for a dosage of between about 0.5 μ g/kg/week to about 2 μ g/kg/week.

42. The therapeutic combination according to claim 41, wherein Peg-Intron or Pegasys is present in an amount sufficient for a dosage of between about 1 μ g/kg/week to about 2 μ g/kg/week.

43. The therapeutic combination according to claim 42, wherein Peg-Intron or Pegasys is present in an amount sufficient for a dosage of about 1.5 μ g/kg/week.

44. A kit, comprising:

(i) the therapeutic combination according to any one of claims 1-43; and

(ii) instructions for using the combinations.

45. The kit of claim 44, comprising:

(i) a plurality of VX-497 formulations;

(ii) a plurality of ribavirin formulations;

(iii) a plurality of interferon preparations; and

(iv) instructions for using the formulation.

46. A method of treating HCV infection or alleviating one or more symptoms thereof in a patient comprising the step of administering to the patient a therapeutic combination according to any one of claims 1 to 43.

47. The method of claim 46, wherein the HCV infection is genotypic.

48. The method of claim 46 or 47, wherein the patient is a treatment-naive patient.

49. The method of claim 46 or 47, wherein said patient is non-responsive to interferon monotherapy.

50. The method of claims 46-47, wherein said patient is non-responsive to combination therapy with ribavirin and interferon.

51. A method of reducing HCV-RNA levels in a patient in need thereof, comprising the step of administering to said patient the therapeutic combination of any one of claims 1 to 43.

52. The method of claim 51, wherein the patient's HCV-RNA levels are reduced below detectable levels.

53. A pharmaceutical regimen comprising administering to a patient in need thereof the therapeutic combination according to any one of claims 1-43 until the patient's HCV RNA level is below a detectable level.

54. The pharmaceutical regimen according to claim 53, wherein said therapeutic combination is administered for at least 12 weeks.

55. The pharmaceutical regimen according to claim 53, wherein said therapeutic combination is administered for at least 24 weeks.

56. The pharmaceutical regimen according to claim 53, comprising administering to a patient in need thereof for at least about 12 weeks.

57. The pharmaceutical regimen according to claim 53, comprising administering VX-497 twice daily to a patient in need thereof; ribavirin is administered twice daily; and interferon alpha once a week.

58. The pharmaceutical regimen according to claim 57, wherein VX-497 is dosed at least 40mg b.i.d.

59. The pharmaceutical regimen according to claim 58, wherein VX-497 is dosed at between about 40mg b.i.d. to about 120mg b.i.d.

60. The pharmaceutical regimen according to claim 59, wherein the dose of ribavirin is selected from the group consisting of 400 mg/day, 600 mg/day, 800 mg/day, 1000 mg/day, or 1200 mg/day, wherein each daily dose is divided into multiple administrations throughout the day.

61. The pharmaceutical regimen according to claim 57, wherein said interferon α is administered once weekly.

62. The pharmaceutical regimen according to claim 61, wherein said interferon α is Intron or Roferon.

63. The pharmaceutical regimen according to claim 61, wherein said interferon α is pegylated interferon.

64. The pharmaceutical regimen according to claim 63, wherein said pegylated interferon is Peg-Intron or Pegasys.