WO2005037214A2 - Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of hcv replication - Google Patents
Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of hcv replication Download PDFInfo
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- WO2005037214A2 WO2005037214A2 PCT/US2004/033970 US2004033970W WO2005037214A2 WO 2005037214 A2 WO2005037214 A2 WO 2005037214A2 US 2004033970 W US2004033970 W US 2004033970W WO 2005037214 A2 WO2005037214 A2 WO 2005037214A2
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- WIPO (PCT)
- Prior art keywords
- alkyl
- ifn
- optionally substituted
- hydroxy
- alkoxy
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
Definitions
- the present invention relates to compounds, processes for their synthesis, compositions and methods for the treatment of hepatitis C virus (HCN) infection.
- HCN hepatitis C virus
- the present invention provides novel peptides analogs, pharmaceutical compositions containing such analogs and methods for using these analogs in the treatment of HCN infection.
- HCN infection is the most common chronic blood borne infection in the United States. Although the numbers of new infections have declined, the burden of chronic infection is substantial, with Centers for Disease Control estimates of 3.9 million (1.8%) infected persons in the United States.
- Chronic liver disease is the tenth leading cause of death among adults in the United States, and accounts for approximately 25,000 deaths annually, or approximately 1% of all deaths. Studies indicate that 40% of chronic liver disease is HCN-related, resulting in an estimated 8,000-10,000 deaths each year. HCN-associated end- stage liver disease is the most frequent indication for liver transplantation among adults.
- HCN is an enveloped positive strand R ⁇ A virus in the Flaviviridae family.
- the single strand HCN R ⁇ A genome is approximately 9500 nucleotides in lingth and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids.
- ORF open reading frame
- this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural ( ⁇ S) proteins of the virus.
- ⁇ S structural and non-structural
- the generation of mature nonstructural proteins ⁇ S2, NS3, NS4, NS4A, NS4B, NS5A, and NS5B
- ⁇ S2 mature nonstructural proteins
- the first viral protease cleaves at the NS2-NS3 junction of the polyprotein.
- the second viral protease is serine protease contained within the N-terminal region of NS3 (herein referred to as "NS3 protease").
- NS3 protease mediates all of the subsequent cleavage events at sites downstream relative to the position of NS3 in the polyprotein (i.e., sites located between the C-terminus of NS3 and the C-terminus of the polyprotein).
- NS3 protease exhibits activity both in cis, at the NS3-NS4 cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, and NS5A-NS5B sites.
- the NS4A protein is believed to serve multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components.
- the formation of the complex between NS3 and NS4A is necessary for NS3- mediated processing events and enhances proteolytic efficiency at all sites recognized by NS3.
- the NS3 protease also exhibits nucleoside triphosphatase and RNA helicase activities.
- NS5B is an RNA-dependent RNA polymerase involved in the replication of HCN R ⁇ A.
- R 1 is each independently H, halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3- cycloalkyl, C -10 alkylcycloalkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro, C 6 or ⁇ o aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, SO 2 NR 5 R 6 , NHC(O)R 5 , NHC(O)NR 5 R 6 , NHC(S)NR 5 R 6 , NR S R 6 , C(O)R 5 , C(O)OR 5 , C(O)NR 5 R 6 , SO m R 5 , NHSO 2 R 5 ;
- R 2 is H, C ⁇ -6 alkyl, C 3-7 cycloalkyl, C 4- ⁇ 0 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C ⁇ -6 alkyl, C 3-7 cycloalkyl, C 4- ⁇ o alkylcycloalkyl, C 2-6 alkenyl, C ⁇ -6 alkoxy, hydroxy-C ⁇ -6 alkyl, C ⁇ -6 alkyl optionally substituted with up to 5 fluoro, C ⁇ -6 alkoxy optionally substituted with up to 5 fluoro;
- R 3 is H, C ⁇ -6 alkyl, -C(O)R 5 , C(O)OR 5 , C(O)NR 5 R 6 , C(S)NR 5 R 6 , S(O) 2 R 5 ;
- R 5 and R 6 are each independently H, C ⁇ -6 alkyl, C 3 .
- Y is a sulfonimide of the formula -C(O)NHS(O) 2 R 4 , where R 4 is C 1-6 alkyl, C 3 . 7 cycloalkyl, C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, C 1-6 alkoxy, amido or phenyl, or R 4 is C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3- cycloalkyl, C 4-10 alkylcycloalkyl, C 2- 6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro; or Y is a carboxylic acid or pharmaceutically acceptable salt or ester thereof;
- a pharmaceutical composition comprising an NS3 inhibitor that is a compound of formula I (e.g., formulas I-NII), or a therapeutically acceptable salt or ester thereof, in admixture with pharmaceutically acceptable carrier.
- an NS3 inhibitor that is a compound of formula I (e.g., formulas I-NII), or a therapeutically acceptable salt or ester thereof, in admixture with pharmaceutically acceptable carrier.
- any pharmaceutically acceptable prodrug derivative of a compound of formula I e.g., formulas I-NII
- the prodrug is capable of providing increased gastrointestinal or liver absorption.
- a method of treating a patient having a hepatitis C viral infection comprising administering to the patient an amount of a compound of formula I, or a therapeutically acceptable salt or ester thereof, or a pharmaceutical composition comprising the compound of formula I, in combination with an amount of one or more additional antiviral agent(s), effective to achieve a sustained viral response in the patient.
- hepatic fibrosis used interchangeably herein with “liver fibrosis,” refers to the growth of scar tissue in the liver that can occur in the context of a chronic hepatitis infection.
- the terms "individual,” “host,” “subject,” and “patient” are used interchangeably herein, and refer to a mammal, including, but not limited to, primates, including simians and humans.
- liver function refers to a normal function of the liver, including, but not limited to, a synthetic function, including, but not limited to, synthesis of proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'-nucleosidase, ⁇ - glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics; and the like.
- serum proteins e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine trans
- sustained viral response refers to the response of an individual to a treatment regimen for HCN infection, in terms of serum HCN titer.
- a sustained viral response refers to no detectable HCV R ⁇ A (e.g., less than about 500, less than about 200, or less than about 100 genome copies per milliliter serum) found in the patient's serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of treatment.
- Treatment failure patients generally refers to HCN-infected patients who failed to respond to previous therapy for HCN (referred to as “non-responders") or who initially responded to previous therapy, but in whom the therapeutic response was not maintained (referred to as “relapsers").
- the previous therapy generally can include treatment with IF ⁇ - ⁇ monotherapy or IF ⁇ - ⁇ combination therapy, where the combination therapy may include administration of IF ⁇ - ⁇ and an antiviral agent such as ribavirin.
- treatment refers to obtaining a desired pharmacologic and/or physiologic effect.
- the effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse affect attributable to the disease.
- Treatment covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease.
- the terms "individual,” “host,” “subject,” and “patient” are used interchangeably herein, and refer to a mammal, including, but not limited to, murines, simians, humans, mammalian farm animals, mammalian sport animals, and mammalian pets.
- a "specific pirfenidone analog,” and all grammatical variants thereof, refers to, and is limited to, each and every pirfenidone analog shown in Table 1.
- Type I interferon receptor agonist refers to any naturally occurring or non-naturally occurring ligand of human Type I interferon receptor, which binds to and causes signal transduction via the receptor.
- Type I interferon receptor agonists include interferons, including naturally-occurring interferons, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising an interferon and a heterologous protein, shuffled interferons; antibody specific for an interferon receptor; non-peptide chemical agonists; and the like.
- Type II interferon receptor agonist refers to any naturally occurring or non-naturally occurring ligand of human Type II interferon receptor that binds to and causes signal transduction via the receptor.
- Type II interferon receptor agonists include native human interferon- ⁇ , recombinant IFN- ⁇ species, glycosylated IFN- ⁇ species, pegylated IFN- ⁇ species, modified or variant IFN- ⁇ species, IFN- ⁇ fusion proteins, antibody agonists specific for the receptor, non-peptide agonists, and the like.
- a Type III interferon receptor agonist refers to any naturally occurring or non-naturally occurring ligand of humanIL-28 receptor ⁇ ("IL-28R”), the amino acid sequence of which is described by Sheppard, et al, infra., that binds to and causes signal transduction via the receptor.
- IL-28R humanIL-28 receptor ⁇
- interferon receptor agonist refers to any Type I interferon receptor agonist, Type II interferon receptor agonist, or Type III interferon receptor agonist.
- dosing event refers to administration of an antiviral agent to a patient in need thereof, which event may encompass one or more releases of an antiviral agent from a drug dispensing device.
- the term "dosing event,” as used herein includes, but is not limited to, installation of a continuous delivery device (e.g., a pump or other controlled release injectible system); and a single subcutaneous injection followed by installation of a continuous delivery system.
- Continuous delivery as used herein (e.g., in the context of “continuous delivery of a substance to a tissue”) is meant to refer to movement of drug to a delivery site, e.g., into a tissue in a fashion that provides for delivery of a desired amount of substance into the tissue over a selected period of time, where about the same quantity of drug is received by the patient each minute during the selected period of time.
- Controlled release as used herein (e.g., in the context of “controlled drug release”) is meant to encompass release of substance (e.g., a Type I or Type III interferon receptor agonist, e.g., IFN- ⁇ ) at a selected or otherwise controllable rate, interval, and/or amount, which is not substantially influenced by the environment of use.
- substance e.g., a Type I or Type III interferon receptor agonist, e.g., IFN- ⁇
- Controlled release thus encompasses, but is not necessarily limited to, substantially continuous delivery, and patterned delivery (e.g., intermittent delivery over a period of time that is interrupted by regular or irregular time intervals).
- “Patterned” or “temporal” as used in the context of drug delivery is meant delivery of drug in a pattern, generally a substantially regular pattern, over a pre-selected period of time (e.g., other than a period associated with, for example a bolus injection).
- “Patterned” or “temporal” drug delivery is meant to encompass delivery of drug at an increasing, decreasing, substantially constant, or pulsatile, rate or range of rates (e.g., amount of drug per unit time, or volume of drug formulation for a unit time), and further encompasses delivery that is continuous or substantially continuous, or chronic.
- controlled drug delivery device is meant to encompass any device wherein the release (e.g., rate, timing of release) of a drug or other desired substance contained therein is controlled by or determined by the device itself and not substantially influenced by the environment of use, or releasing at a rate that is reproducible within the environment of use.
- substantially continuous as used in, for example, the context of “substantially continuous infusion” or “substantially continuous delivery” is meant to refer to delivery of drug in a manner that is substantially uninterrupted for a pre-selected period of drug delivery, where the quantity of drug received by the patient during any 8 hour interval in the pre-selected period never falls to zero.
- substantially continuous drug delivery can also encompass delivery of drug at a substantially constant, pre-selected rate or range of rates (e.g., amount of drug per unit time, or volume of drug formulation for a unit time) that is substantially uninterrupted for a pre-selected period of drug delivery.
- substantially steady state as used in the context of a biological parameter that may vary as a function of time, it is meant that the biological parameter exhibits a substantially constant value over a time course, such that the area under the curve defined by the value of the biological parameter as a function of time for any 8 hour period during the time course (AUC8hr) is no more than about 20% above or about 20% below, and preferably no more than about 15% above or about 15% below, and more preferably no more than about 10% above or about 10% below, the average area under the curve of the biological parameter over an 8 hour period during the time course (AUC8hr average).
- the serum concentration of the drug is maintained at a substantially steady state during a time course when the area under the curve of serum concentration of the drug over time for any 8 hour period during the time course (AUCShr) is no more than about 20% above or about 20% below the average area under the curve of serum concentration of the drug over an 8 hour period in the time course (AUC ⁇ hr average), i.e., the AUC8hr is no more than 20% above or 20% below the AUCShr average for the serum concentration of the drug over the time course.
- AUCShr area under the curve of serum concentration of the drug over time for any 8 hour period during the time course
- AUC ⁇ hr average the average area under the curve of serum concentration of the drug over an 8 hour period in the time course
- the present invention provides compounds of formula I, as well as pharmaceutical compositions and formulations comprising any compound of formula I.
- a subject compound is useful for treating HCN infection and other disorders, as discussed below.
- COMPOSITIONS [0036] The present invention provides compounds having the general formula I:
- R 1 and R 2 are each independently H, halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3- cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro, C 6 or lo aryl, pyridal, pyrimidal, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, S(O) 2 NR 6 R 7 , NHC(O)NR 6 R 7 , NHC(S)NR 6 R 7 , C(O)NR 6 R 7 , NR 6 R 7 , C(O)R 8 , C(O)OR 8 , NHC(O)R 8 , NHC(O)OR 8 , SO
- R 4 is H, C ⁇ -6 alkyl, C 3-7 cycloalkyl, C 4- ⁇ 0 alkylcycloalkyl phenyl or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C ⁇ -6 alkyl, C 3- cycloalkyl, C - ⁇ 0 alkylcycloalkyl, C 2-6 alkenyl, C ⁇ -6 alkoxy, hydroxy-C ⁇ -6 alkyl, C ⁇ -6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro;
- R 5 is C ⁇ - 6 alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , C(O)OR 8 , S(O) 2 R 8 , or
- R 6 and R 7 are each independently H, C 1-6 alkyl, C 3 _ cycloalkyl, C -10 alkylcycloalkyl or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3- cycloalkyl, C - ⁇ o alkylcycloalkyl, C 2-6 alkenyl, hydroxy-C ⁇ -6 alkyl, C ⁇ -6 alkyl optionally substituted with up to 5 fluoro, C ⁇ -6 alkoxy optionally substituted with up to 5 fluoro; or R 6 and R 7 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
- R 8 is C ⁇ -6 alkyl, C 3- cycloalkyl, C 4- ⁇ o alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C ⁇ -6 alkoxy, or phenyl; or R 8 is C 6 or ⁇ o aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C ⁇ _ 6 alkyl, C 3- cycloalkyl, C 4 _ ⁇ o alkylcycloalkyl, C 2- 6 alkenyl, C ⁇ _ 6 alkoxy, hydroxy-C ⁇ -6 alkyl, C ⁇ -6 alkyl optionally substituted with up to 5 fluoro, C ⁇ -6 alkoxy optionally substituted with up to 5 fluoro; or R 8 is C ⁇ -6 alkyl optionally substituted with up to 5 fluoro groups; or R 8 is a tetrahydrofuran ring linked throught
- Y is a sulfonimide of the formula -C(O)NHS(O) 2 R 9 , where R 9 is C 1-6 alkyl, C 3 . 7 cycloalkyl, C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6 alkoxy, or phenyl, or R 9 is C 6 or ⁇ o aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3- cycloalkyl, C4.
- R 9 is a C ⁇ -6 alkyl optionally substituted with up to 5 fluoro groups, NR 6 R 7 , or (CO)OH, or R 9 is a heteroaromatic ring optionally substituted up to two times with halo, cyano, nitro, hydroxyl, or C ⁇ -6 alkoxy; or Y is a carboxylic acid or pharmaceutically acceptable salt, solvate, or prodrug thereof;
- R 10 and R 11 are each independently H, C ⁇ -6 alkyl, C 3-7 cycloalkyl, C -10 alkylcycloalkyl, C 6 or 10 aryl, hydroxy-C 1-6 alkyl, Ci- 6 alkyl optionally substituted with up to 5 fluoro, (CH 2 ) n NR 6 R 7 , (CH 2 ) n C(O)OR 14 where R 14 is H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6 alkoxy, or phenyl; or R 14 is C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3- cycloalkyl, C -10 alkylcycloalkyl, C 2-6 alkenyl, C 1-6
- cycloalkyl C 4-10 alkylcycloalkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro; or R 10 and R 11 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or R 10 and R 11 are combined as O;
- R 12 and R 13 are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 6 or 10 aryl, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, (CH 2 ) n NR 6 R 7 , (CH 2 )nC(O)OR 14 where R 14 is H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4 - 10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C ⁇ -6 alkoxy, or phenyl; or R 14 is C 60 r 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C ⁇ -6 alkyl, C 3- cycloalkyl, C 4 .
- R 12 and R 13 are optionally substituted by up to three halo, cyano, nitro, hydroxy, C ⁇ -6 alkyl, C 3-7 cycloalkyl, C -1 o alkylcycloalkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro; or R and R are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohex
- R 20 is H, C 1-6 alkyl, C 3- cycloalkyl, C 4-10 alkylcycloalkyl, C 6 or 10 aryl, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, (CH 2 ) felicitNR 6 R 7 , (CH 2 ) n C(O)OR 14 where R 14 is H, C 1-6 alkyl, C 3- cycloalkyl, C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6 alkoxy, or phenyl; or R 14 is C 6 or l o aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3- cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-
- (m)V is selected from O, S, or NH;
- W when V is O or S, W is selected from O, NR 15 , or CR 15 ; when N is ⁇ H, W is selected from ⁇ R 15 or CR 15 , where R 15 is H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl or C 1-6 alkyl optionally substituted with up to 5 fluoro;
- R 21 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6 alkoxy, C 1-6 alkyl optionally
- R is C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3- cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro; or or R 21 is pyridal, pyrimidal, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy; and (q) R 22 is Ci- 6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, wliich are all optionally substituted from one to three times with halo,
- R 1 and R 2 are each independently H, halo, cyano, hydroxy, C 1-3 alkyl, C 1-3 alkoxy
- R 5 is, C(O)NR 6 R 7 , C(O)R 8 , C(O)OR 8 ;
- R 6 and R 7 are each independently H, C ⁇ -6 alkyl, C 3-7 cycloalkyl, C 4- ⁇ 0 alkylcycloalkyl or phenyl;
- R 8 is C 1-6 alkyl, C 3- cycloalkyl, C -10 alkylcycloalkyl or 3-tetrahydofuryl.
- Y is a sulfonimide of the formula -C(O)NHS(O) 2 R 9 , where R 9 is C 1-3 alkyl, C 3-7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C 1-3 alkyl, C 3- cycloalkyl, C 1-3 alkoxy, or Y is a carboxylic acid or pharmaceutically acceptable salt, solvate, or prodrug thereof;
- R 10 and R 11 are each independently H, C 1-3 alkyl, or R 10 and R 11 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
- (g) W is selected from O or NH;
- R and R are each independently H, halo, cyano, hydroxy, C 1-3 alkyl, C 1-3 alkoxy
- R 5 is, C(O)NR 6 R 7 , C(O)R 8 , C(O)OR 8 ;
- R 8 is C 1-6 alkyl, C 3 . 7 cycloalkyl, C 4-10 alkylcycloalkyl or 3-tetrahydofuryl.
- Y is a sulfonimide of the formula -C(O)NHS(O) 2 R 9 , where R 9 is C 1-3 alkyl, C 3-7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C 1-3 alkyl, C - cycloalkyl, C 1-3 alkoxy, or Y is a carboxylic acid or pharmaceutically acceptable salt, solvate, or prodrug thereof;
- W is selected from O or NH
- R 1 and R 2 are each independently H, halo, cyano, hydroxy, C 1-3 alkyl, C 1-3 alkoxy;
- R 5 is C(O)OR 8 or C(O)NHR 8 ;
- R 8 is C 1-6 alkyl, C 5-6 cycloalkyl, or 3-tetrahydofuryl;
- R 9 is C 1- alkyl, C 3-4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C 1-3 alkyl, C 1-3 alkoxy;
- R 10 and R 11 are each independently H, C 1-3 alkyl, or R 10 and R 11 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
- W is selected from O or NH
- R and R are each independently H, halo, cyano, hydroxy, C 1-3 alkyl, C 1-3 alkoxy
- R 5 is C(O)OR 8 or C(O)NHR 8
- R 8 is Ci- 6 alkyl, C 5-6 cycloalkyl, or 3-tetrahydofuryl.
- R 9 is C 1-3 alkyl, C 3-5 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C 1-3 alkyl, C ⁇ -3 alkoxy
- R 10 and R 11 are each independently H, C ⁇ -3 alkyl, or C 4-5 cycloalkyl.
- (f) is selected from O or NH
- R 1 and R 2 are each independently H, chloro, fluoro, cyano, hydroxy, C ⁇ -3 alkyl, C 1-3 alkoxy
- R 5 is C(O)OR 8 or C(O) ⁇ HR 8
- R 8 is C 1-6 alkyl, C 5-6 cycloalkyl
- R 9 is C 1-3 alkyl, C 3-4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C 1-3 alkyl, C 1-3 alkoxy
- R 10 and R n are each independently H, C 1-3 alkyl, or R 10 and R 11 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl.
- R 1 and R 2 are each independently H, chloro, fluoro, cyano, hydroxy, C 1-3 alkyl, C 1-3 alkoxy
- R 5 is C(O)OR 8 or C(O)NHR 8
- R 8 is C 1-6 alkyl, C 5-6 cycloalkyl
- R 9 is C 1-3 alkyl, C 3- cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C 1-3 alkyl, C ⁇ _ 3 alkoxy
- R 1 and R 2 are each independently H, halo, cyano, hydroxy, C ⁇ -3 alkyl, C ⁇ -3 alkoxy;
- R 4 is H
- R 5 is, C(O) ⁇ R 6 R 7 , C(O)R 8 , C(O)OR 8 ;
- R 8 is Ci- 6 alkyl, C 3- cycloalkyl, C 4- ⁇ o alkylcycloalkyl or 3-tetrahydofuryl;
- Y is a sulfonimide of the formula -C(O)NHS(O) 2 R 9 , where R 9 is C 1-3 alkyl, C 3-7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C 1-3 alkyl, C 3- cycloalkyl, C ⁇ - alkoxy, or Y is a carboxylic acid or pharmaceutically acceptable salt, solvate, or prodrug thereof;
- R 10 and R 11 are each independently H, C ⁇ -3 alkyl, or R 10 and R 11 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
- R 20 is H, C ⁇ -6 alkyl, C 3-7 cycloalkyl, C 4- ⁇ 0 alkylcycloalkyl, C 6 or 10 aryl, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, (CH 2 ) n NR R 7 , (CH 2 ) n C(O)OR 14 where R 14 is H, C 1-6 alkyl, C 3- cycloalkyl, C -10 alkylcycloalkyl, which are all optionally substituted from one to tliree times with halo, cyano, nitro, hydroxy, C 1-6 alkoxy, or phenyl; or R 14 is C 6 o r 10 aryl wliich is optionally substituted by up to tliree halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl
- W is selected from O or NH
- the present invention provides compounds having the general formula IX:
- R 1 and R 2 are each independently H, halo, cyano, hydroxy, C 1-3 alkyl, C 1-3 alkoxy;
- R 4 is H
- R 5 is, C(O)NR R 7 , C(O)R 8 , C(O)OR 8 ;
- R 8 is C 1-6 alkyl, C 3- cycloalkyl, C -10 alkylcycloalkyl or 3-tetrahydofuryl;
- Y is a sulfonimide of the formula -C(O)NHS(O) 2 R 9 , where R 9 is C 1-3 alkyl, C 3-7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C 1-3 alkyl, C 3-7 cycloalkyl, C 1-3 alkoxy, or Y is a carboxylic acid or pharmaceutically acceptable salt, solvate, or prodrug thereof;
- R 10 and R 11 are each independently H, C 1-3 alkyl, or R 10 and R 11 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
- R 20 is H, C 1-6 alkyl, C 3- cycloalkyl, C 4-10 alkylcycloalkyl, C 6 or 10 aryl, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, (CH 2 ) n NR 6 R 7 , (CH 2 ) n C(O)OR 14 where R 14 is H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6 alkoxy, or phenyl; or R 14 is C 6 or 10 aryl which is optionally substituted by up to tliree halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-1 o alkylcycloalkyl, C 2-6 alkenyl, C 1-6
- W is selected from O or NH
- compositions including pharmaceutical compositions, comprising compounds of the general formulas I-NII, and salts, esters, or other derivatives thereof.
- a subject pharmaceutical composition comprises a subject compound; and a pharmaceutically acceptable excipient.
- pharmaceutically acceptable excipients are known in the art and need not be discussed in detail herein. Pharmaceutically acceptable excipients have been amply described in a variety of publications, including, for example, A.
- the pharmaceutically acceptable excipients such as vehicles, adjuvants, carriers or diluents, are readily available to the public.
- pharmaceutically acceptable auxiliary substances such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.
- a subject compound inhibits the enzymatic activity of a hepatitis virus C (HCN) protease ⁇ S3. Whether a subject compound inhibits HCN ⁇ S3 can be readily determined using any known method. Typical methods involve a determination of whether an HCV polyprotein or other polypeptide comprising an NS3 recognition site is cleaved by NS3 in the presence of the agent.
- HCV hepatitis virus C
- a subject compound inhibits NS3 enzymatic activity by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, or more, compared to the enzymatic activity of NS3 in the absence of the compound.
- a subject compound inhibits enzymatic activity of an HCN ⁇ S3 protease with an IC 50 of less than about 50 ⁇ M, e.g., a subject compound inhibits an HCN ⁇ S3 protease with an IC 50 of less than about 40 ⁇ M, less than about 25 ⁇ M, less than about 10 ⁇ M, less than about 1 ⁇ M, less than about 100 nM, less than about 80 nM, less than about 60 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM, or less.
- a subject compound inhibits HCN viral replication.
- a subject compound inhibits HCN viral replication by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, or more, compared to HCV viral replication in the absence of the compound.
- Whether a subject compound inhibits HCN viral replication can be determined using methods Icnown in the art, including an in vitro viral replication assay. TREATING A HEPATITIS VIRUS INFECTION
- Whether a subject method is effective in treating an HCN infection can be determined by a reduction in viral load, a reduction in time to seroconversion (virus undetectable in patient serum), an increase in the rate of sustained viral response to therapy, a reduction of morbidity or mortality in clinical outcomes, or other indicator of disease response.
- an effective amount of a compound of formula I, and optionally one or more additional antiviral agents is an amount that is effective to reduce viral load or achieve a sustained viral response to therapy.
- Whether a subject method is effective in treating an HCN infection can be determined by measuring viral load, or by measuring a parameter associated with HCN infection, including, but not limited to, liver fibrosis, elevations in serum transaminase levels, and necroinflammatory activity in the liver. Indicators of liver fibrosis are discussed in detail below.
- the method involves administering an effective amount of a compound of formula I, optionally in combination with an effective amount of one or more additional antiviral agents.
- an effective amount of a compound of formula I, and optionally one or more additional antiviral agents is an amount that is effective to reduce viral titers to undetectable levels, e.g., to about 1000 to about 5000, to about 500 to about 1000, or to about 100 to about 500 genome copies/mL serum.
- an effective amount of a compound of formula I, and optionally one or more additional antiviral agents is an amount that is effective to reduce viral load to lower than 100 genome copies/mL serum.
- an effective amount of a compound of formula I, and optionally one or more additional antiviral agents is an amount that is effective to achieve a 1.5-log, a 2- log, a 2.5-log, a 3-log, a 3.5-log, a 4-log, a 4.5-log, or a 5-log reduction in viral titer in the serum of the individual.
- an effective amount of a compound of formula I, and optionally one or more additional antiviral agents is an amount that is effective to achieve a sustained viral response, e.g., no detectable HCN R ⁇ A (e.g., less than about 500, less than about 400, less than about 200, or less than about 100 genome copies per milliliter serum) is found in the patient's serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of therapy.
- a sustained viral response e.g., no detectable HCN R ⁇ A (e.g., less than about 500, less than about 400, less than about 200, or less than about 100 genome copies per milliliter serum) is found in the patient's serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of therapy.
- a subject method is effective in treating an HCN infection can be determined by measuring a parameter associated with HCN infection, such as liver fibrosis. Methods of determining the extent of liver fibrosis are discussed in detail below.
- the level of a serum marker of liver fibrosis indicates the degree of liver fibrosis.
- levels of serum alanine aminotransferase (ALT) are measured, using standard assays. In general, an ALT level of less than about 45 international units is considered normal.
- an effective amount of a compound of formula I, and optionally one or more additional antiviral agents is an amount effective to reduce ALT levels to less than about 45 IU/ml serum.
- a therapeutically effective amount of a compound of formula I, and optionally one or more additional antiviral agents is an amount that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or to a placebo-treated individual.
- Methods of measuring serum markers include immunological-based methods, e.g., enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.
- an effective amount of a compound of formula I and an additional antiviral agent is synergistic amount.
- a "synergistic combination" or a “synergistic amount” of a compound of formula I and an additional antiviral agent is a combined dosage that is more effective in the therapeutic or prophylactic treatment of an HCN infection than the incremental improvement in treatment outcome that could be predicted or expected from a merely additive combination of (i) the therapeutic or prophylactic benefit of the compound of formula I when administered at that same dosage as a monotherapy and (ii) the therapeutic or prophylactic benefit of the additional antiviral agent when administered at the same dosage as a monotherapy.
- a selected amount of a compound of formula I and a selected amount of an additional antiviral agent are effective when used in combination therapy for a disease, but the selected amount of the compound of formula I and/or the selected amount of the additional antiviral agent is ineffective when used in monotherapy for the disease.
- the invention encompasses (1) regimens in which a selected amount of the additional antiviral agent enhances the therapeutic benefit of a selected amount of the compound of formula I when used in combination therapy for a disease, where the selected amount of the additional antiviral agent provides no therapeutic benefit when used in monotherapy for the disease (2) regimens in which a selected amount of the compound of formula I enhances the therapeutic benefit of a selected amount of the additional antiviral agent when used in combination therapy for a disease, where the selected amount of the compound of formula I provides no therapeutic benefit when used in monotherapy for the disease and (3) regimens in which a selected amount of the compound of formula I and a selected amount of the additional antiviral agent provide a therapeutic benefit when used in combination therapy for a disease, where each of the selected amounts of the compound of formula I and the additional antiviral agent, respectively, provides no therapeutic benefit when used in monotherapy for the disease.
- a "synergistically effective amount" of a compound of formula I and an additional antiviral agent, and its grammatical equivalents, shall be understood to include any regimen encompassed by any of (l)-(3) above. Fibrosis
- the instant invention provides methods for treating liver fibrosis (including forms of liver fibrosis resulting from, or associated with, HCN infection), generally involving administering a therapeutic amount of a compound of formula I, and optionally one or more additional antiviral agents. Effective amounts of compounds of formula I, with and without one or more additional antiviral agents, as well as dosing regimens, are as discussed below.
- liver fibrosis reduction is determined by any of a number of well-established techniques for measuring liver fibrosis and liver function.
- Liver fibrosis reduction is determined by analyzing a liver biopsy sample.
- An analysis of a liver biopsy comprises assessments of two major components: necroinflammation assessed by "grade” as a measure of the severity and ongoing disease activity, and the lesions of fibrosis and parenchymal or vascular remodeling as assessed by "stage” as being reflective of long- term disease progression. See, e.g., Brunt (2000) Hepatol. 31:241-246; and METANIR (1994) Hepatology 20: 15-20.
- a score is assigned.
- a number of standardized scoring systems exist which provide a quantitative assessment of the degree and severity of fibrosis. These include the METANIR, Knodell, Scheuer, Ludwig, and Ishak scoring systems.
- the METANIR scoring system is based on an analysis of various features of a liver biopsy, including fibrosis (portal fibrosis, centrilobular fibrosis, and cirrhosis); necrosis (piecemeal and lobular necrosis, acidophilic retraction, and ballooning degeneration); inflammation (portal tract inflammation, portal lymphoid aggregates, and distribution of portal inflammation); bile duct changes; and the Knodell index (scores of periportal necrosis, lobular necrosis, portal inflammation, fibrosis, and overall disease activity).
- each stage in the METANIR system is as follows: score: 0, no fibrosis; score: 1, stellate enlargement of portal tract but without septa formation; score: 2, enlargement of portal tract with rare septa formation; score: 3, numerous septa without cirrhosis; and score: 4, cirrhosis.
- Knodell's scoring system also called the Hepatitis Activity Index, classifies specimens based on scores in four categories of histologic features: I. Periportal and/or bridging necrosis; II. Intralobular degeneration and focal necrosis; III. Portal inflammation; and IN. Fibrosis.
- scores are as follows: score: 0, no fibrosis; score: 1, mild fibrosis (fibrous portal expansion); score: 2, moderate fibrosis; score: 3, severe fibrosis (bridging fibrosis); and score: 4, cirrhosis. The higher the score, the more severe the liver tissue damage.
- Stage 1 Fibrous expansion of some portal areas, with or without short fibrous septa
- stage 2 Fibrous expansion of most portal areas, with or without short fibrous septa
- stage 3 Fibrous expansion of most portal areas with occasional portal to portal (P-P) bridging
- stage 4 Fibrous expansion of portal areas with marked bridging (P-P) as well as portal-central (P-C)
- stage 5 Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); stage 6, Cirrhosis, probable or definite.
- Child-Pugh scoring system which comprises a multicomponent point system based upon abnormalities in serum bilirubin level, serum albumin level, prothrombin time, the presence and severity of ascites, and the presence and severity of encephalopathy. Based upon the presence and severity of abnormality of these parameters, patients may be placed in one of three categories of increasing severity of clinical disease: A, B, or C.
- a therapeutically effective amount of a compound of formula I, and optionally one or more additional antiviral agents is an amount that effects a change of one unit or more in the fibrosis stage based on pre- and post-therapy liver biopsies.
- a therapeutically effective amount of a compound of formula I, and optionally one or more additional antiviral agents reduces liver fibrosis by at least one unit in the METANIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.
- Secondary, or indirect, indices of liver function can also be used to evaluate the efficacy of treatment with a compound of formula I. Morphometric computerized semi- automated assessment of the quantitative degree of liver fibrosis based upon specific staining of collagen and/or serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Secondary indices of liver function include, but are not limited to, serum transaminase levels, prothrombin time, bilirubin, platelet count, portal pressure, albumin level, and assessment of the Child-Pugh score.
- An effective amount of a compound of formula I, and optionally one or more additional antiviral agents is an amount that is effective to increase an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or to a placebo-treated individual.
- Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.
- Serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method.
- Serum markers of liver fibrosis include, but are not limited to, hyaluronate, N-terminal procollagen III peptide, 7S domain of type IV collagen, C-terminal procollagen I peptide, and laminin.
- Additional biochemical markers of liver fibrosis include ⁇ - 2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein A, and gamma glutamyl transpeptidase.
- a therapeutically effective amount of a compound of formula I, and optionally one or more additional antiviral agents is an amount that is effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about ' 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or to a placebo-treated individual.
- ELISA enzyme-linked immunosorbent assays
- radioimmunoassays radioimmunoassays
- Quantitative tests of functional liver reserve can also be used to assess the efficacy of treatment with an interferon receptor agonist and pirfenidone (or a pirfenidone analog). These include: indocyanine green clearance (ICG), galactose elimination capacity (GEC), aminopyrine breath test (ABT), antipyrine clearance, monoethylglycine-xylidide (MEG-X) clearance, and caffeine clearance.
- a "complication associated with cirrhosis of the liver” refers to a disorder that is a sequellae of decompensated liver disease, i.e., or occurs subsequently to and as a result of development of liver fibrosis, and includes, but it not limited to, development of ascites, variceal bleeding, portal hypertension, jaundice, progressive liver insufficiency, encephalopathy, hepatocellular carcinoma, liver failure requiring liver transplantation, and liver-related mortality.
- a therapeutically effective amount of a compound of formula I, and optionally one or more additional antiviral agents is an amount that is effective in reducing the incidence (e.g., the likelihood that an individual will develop) of a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or to a placebo-treated individual.
- liver function increases liver function.
- Liver functions include, but are not limited to, synthesis of proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'-nucleosidase, ⁇ -glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics; and the like.
- proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate trans
- liver function is increased is readily ascertainable by those skilled in the art, using well-established tests of liver function.
- markers of liver function such as albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, bilirubin, and the like, can be assessed by measuring the level of these markers in the serum, using standard immunological and enzymatic assays.
- Splanchnic circulation and portal hemodynamics can be measured by portal wedge pressure and/or resistance using standard methods.
- Metabolic functions can be measured by measuring the level of ammonia in the serum.
- serum proteins normally secreted by the liver are in the normal range can be determined by measuring the levels of such proteins, using standard immunological and enzymatic assays. Those skilled in the art know the normal ranges for such serum proteins. The following are non-limiting examples.
- the normal level of alanine transaminase is about 45 IU per milliliter of serum.
- the normal range of aspartate transaminase is from about 5 to about 40 units per liter of serum.
- Bilirubin is measured using standard assays. Normal bilirubin levels are usually less than about 1.2 mg/dL.
- Serum albumin levels are measured using standard assays. Normal levels of serum albumin are in the range of from about 35 to about 55 g/L.
- Prolongation of prothrombin time is measured using standard assays. Normal prothrombin time is less than about 4 seconds longer than control.
- a therapeutically effective amount of a compound of formula I, and optionally one or more additional antiviral agents is one that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more.
- a therapeutically effective amount of a compound of formula I, and optionally one or more additional antiviral agents is an amount effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range.
- a therapeutically effective amount of a compound of formula I, and optionally one or more additional antiviral agents is also an amount effective to increase a reduced level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range.
- Type I interferon receptor agonists include an IFN- ⁇ ; an IFN- ⁇ ; an IFN-tau; an IFN- ⁇ ; antibody agonists specific for a Type I interferon receptor; and any other agonist of Type I interferon receptor, including non-polypeptide agonists.
- Interferon-Alpha Interferon-Alpha
- IFN- ⁇ any known IFN- ⁇ can be used in the instant invention.
- interferon-alpha refers to a family of related polypeptides that inhibit viral replication and cellular proliferation and modulate immune response.
- IFN- ⁇ includes naturally occurring IFN- ⁇ ; synthetic IFN- ⁇ ; derivatized IFN- ⁇ (e.g., PEGylated IFN- ⁇ , glycosylated IFN- ⁇ , and the like); and analogs of naturally occurring or synthetic IFN- ⁇ ; essentially any IFN- ⁇ that has antiviral properties, as described for naturally occurring IFN- ⁇ .
- Suitable alpha interferons include, but are not limited to, naturally-occurring IFN- ⁇
- IFN- ⁇ 2a including, but not limited to, naturally occurring IFN- ⁇ 2a, IFN- ⁇ 2b
- recombinant interferon alpha-2b such as Intron-A interferon available from Schering Corporation, Kenilworth, N.J.
- recombinant interferon alpha-2a such as Roferon interferon available from Hoffmann-La Roche, Nutley, N.
- interferon alpha-2C such as Berofor alpha 2 interferon available from Boehringer Ingelheim Pharmaceutical, Inc., Ridgef ⁇ eld, Conn.
- interferon alpha- nl a purified blend of natural alpha interferons such as Sumiferon available from Sumitomo, Japan or as Wellferon interferon alpha-nl (INS) available from the Glaxo- Wellcome Ltd., London, Great Britain
- interferon alpha-n3 a mixture of natural alpha interferons made by Interferon Sciences and available from the Purdue Frederick Co., Norwalk, Conn., under the Alferon Tradename.
- IFN- ⁇ also encompasses consensus IFN- ⁇ .
- Consensus IFN- ⁇ (also referred to as “CIFN” and “IFN-con” and “consensus interferon”) encompasses but is not limited to the amino acid sequences designated IFN-conl, IFN-con2 and IFN-con3 which are disclosed in U.S. Pat. Nos. 4,695,623 and 4,897,471; and consensus interferon as defined by determination of a consensus sequence of naturally occurring interferon alphas (e.g., Infergen®, InterMune, Inc., Brisbane, Calif.).
- IFN-conl is the consensus interferon agent in the Infergen® alfacon-1 product.
- IFN-con The Infergen® consensus interferon product is referred to herein by its brand name (Infergen®) or by its generic name (interferon alfacon-1). DNA sequences encoding IFN-con may be synthesized as described in the aforementioned patents or other standard methods. Use of CIFN is of particular interest.
- fusion polypeptides comprising an
- IFN- ⁇ and a heterologous polypeptide Suitable IFN- ⁇ fusion polypeptides include, but are not limited to, Albuferon-alphaTM (a fusion product of human albumin and IFN- ⁇ ; Human Genome Sciences; see, e.g., Osborn et al. (2002) J. Pharmacol. Exp. Therap. 303:540-548). Also suitable for use in the present invention are gene-shuffled forms of IFN- ⁇ . See., e.g., Masci et al. (2003) Curr. Oncol. Rep. 5:108-113. PEGylated Interferon-AIpha
- IFN- ⁇ also encompasses derivatives of IFN- ⁇ that are derivatized (e.g., are chemically modified) to alter certain properties such as serum half-life.
- IFN- ⁇ includes glycosylated IFN- ⁇ ; IFN- ⁇ derivatized with polyetliylene glycol ("PEGylated IFN- ⁇ "); and the like. PEGylated IFN- ⁇ , and methods for making same, is discussed in, e.g., U.S. Patent Nos. 5,382,657; 5,981,709; and 5,951,974.
- PEGylated IFN- ⁇ encompasses conjugates of PEG and any of the above-described IFN- ⁇ molecules, including, but not limited to, PEG conjugated to interferon alpha-2a (Roferon, Hoffman La-Roche, Nutley, N. J.), interferon alpha 2b (Intron, Schering-Plough, Madison, N. J.), interferon alpha-2c (Berofor Alpha, Boehringer Ingelheim, Ingelheim, Germany); and consensus interferon as defined by determination of a consensus sequence of naturally occurring interferon alphas (Infergen®, InterMune, Inc., Brisbane, Calif).
- any of the above-mentioned IFN- ⁇ polypeptides can be modified with one or more polyethylene glycol moieties, i.e., PEGylated.
- the PEG molecule of a PEGylated IFN- ⁇ polypeptide is conjugated to one or more amino acid side chains of the IFN- ⁇ polypeptide.
- the PEGylated IFN- ⁇ contains a PEG moiety on only one amino acid.
- the PEGylated IFN- ⁇ contains a PEG moiety on two or more amino acids, e.g., the IFN- ⁇ contains a PEG moiety attached to two, three, four, five, six, seven, eight, nine, or ten different amino acid residues.
- IFN- ⁇ may be coupled directly to PEG (i.e., without a linking group) through an amino group, a sulfhydryl group, a hydroxyl group, or a carboxyl group.
- the PEGylated IFN- ⁇ is PEGylated at or near the amino terminus (N-terminus) of the IFN- ⁇ polypeptide, e.g., the PEG moiety is conjugated to the IFN- ⁇ polypeptide at one or more amino acid residues from amino acid 1 through amino acid 4, or from amino acid 5 through about 10.
- the PEGylated IFN- ⁇ is PEGylated at one or more amino acid residues from about 10 to about 28.
- the PEGylated IFN- ⁇ is PEGylated at or near the carboxyl terminus (C-terminus) of the IFN- ⁇ polypeptide, e.g., at one or more residues from amino acids 156-166, or from amino acids 150 to 155.
- the PEGylated IFN- ⁇ is PEGylated at one or more amino acid residues at one or more residues from amino acids 100-114.
- amino acids at which PEGylation is to be avoided include amino acid residues from amino acid 30 to amino acid 40; and amino acid residues from amino acid 113 to amino acid 149.
- PEG is attached to IFN- ⁇ via a linking group.
- the linking group is any biocompatible linking group, where "biocompatible" indicates that the compound or group is non-toxic and may be utilized in vitro or in vivo without causing injury, sickness, disease, or death.
- PEG can be bonded to the linking group, for example, via an ether bond, an ester bond, a thiol bond or an amide bond.
- Suitable biocompatible linking groups include, but are not limited to, an ester group, an amide group, an imide group, a carbamate group, a carboxyl group, a hydroxyl group, a carbohydrate, a succinimide group (including, for example, succinimidyl succinate (SS), succinimidyl propionate (SPA), succinimidyl butanoate (SBA), succinimidyl carboxymethylate (SCM), succinimidyl succinamide (SSA) or N-hydroxy succinimide (NHS)), an epoxide group, an oxycarbonylimidazole group (including, for example, carbonyldimidazole (CDI)), a nitro phenyl group (including, for example, nitrophenyl carbonate (NPC) or trichlorophenyl carbon
- succinimidyl propionate (SPA) and succinimidyl butanoate (SBA) ester-activated PEGs are described in U.S. Pat. No. 5,672,662 (Harris, et al.) and WO 97/03106.
- Pegylated IFN- ⁇ is discussed in, e.g., U.S. Patent Nos.
- Pegylated IFN- ⁇ encompasses conjugates of PEG and any of the above-described IFN- ⁇ molecules, including, but not limited to, PEG conjugated to interferon alpha-2a (Roferon, Hoffman LaRoche, Nutley, N.
- PEGylated Roferon is known as Pegasys (Hoffman LaRoche); interferon alpha 2b (Intron, Schering-Plough, Madison, NJ.), where PEGylated Intron is known as PEG-Intron (Schering- Plough); interferon alpha-2c (Berofor Alpha, Boehringer Ingelheim, Ingelheim, Germany); and consensus interferon (CIFN) as defined by determination of a consensus sequence of naturally occurring interferon alphas (Infergen®, InterMune, Inc., Brisbane, Calif), where PEGylated Infergen is referred to as PEG-Infergen.
- the PEG is a monomethoxyPEG molecule that reacts with primary amine groups on the IFN- ⁇ polypeptide.
- Methods of modifying polypeptides with monomethoxy PEG via reductive alkylation are known in the art. See, e.g., Chamow et al. (1994) Bioconj. Chem. 5:133-140.
- PEG is linked to IFN- ⁇ via an SPA linking group.
- SPA esters of PEG, and methods for making same, are described in U.S. Patent No. 5,672,662.
- SPA linkages provide for linkage to free amine groups on the IFN- ⁇ polypeptide.
- a PEG molecule is covalently attached via a linkage that comprises an amide bond between a propionyl group of the PEG moiety and the epsilon amino group of a surface-exposed lysine residue in the IFN- ⁇ polypeptide.
- a linkage that comprises an amide bond between a propionyl group of the PEG moiety and the epsilon amino group of a surface-exposed lysine residue in the IFN- ⁇ polypeptide.
- Such a bond can be formed, e.g., by condensation of an ⁇ -methoxy, omega propanoic acid activated ester of PEG (mPEGspa).
- one monopegylated CIFN conjugate preferred for use herein has a linear PEG moiety of about 30 kD attached via a covalent linkage to the CIFN polypeptide, where the covalent linkage is an amide bond between a propionyl group of the PEG moiety and the epsilon amino group of a surface-exposed lysine residue in the CIFN polypeptide, where the surface-exposed lysine residue is chosen from lys 31 , lys 50 , lys 71 , lys 84 , lys , lys , lys , lys , and lys , and the amide bond is formed by condensation of an ⁇ - methoxy, omega propanoic acid activated ester of PEG.
- Polyethylene glycol Polyethylene glycol
- Polyethylene glycol suitable for conjugation to an IFN- ⁇ polypeptide is soluble in water at room temperature, and has the general formula R(O-CH 2 -CH 2 ) n O-R, where R is hydrogen or a protective group such as an alkyl or an alkanol group, and where n is an integer from 1 to 1000. Where R is a protective group, it generally has from 1 to 8 carbons.
- PEG has at least one hydroxyl group, e.g., a terminal hydroxyl group, which hydroxyl group is modified to generate a functional group that is reactive with an amino group, e.g., an epsilon amino group of a lysine residue, a free amino group at the N- terminus of a polypeptide, or any other amino group such as an amino group of asparagine, glutamine, arginine, or histidine.
- an amino group e.g., an epsilon amino group of a lysine residue, a free amino group at the N- terminus of a polypeptide, or any other amino group such as an amino group of asparagine, glutamine, arginine, or histidine.
- PEG is derivatized so that it is reactive with free carboxyl groups in the IFN- ⁇ polypeptide, e.g., the free carboxyl group at the carboxyl terminus of the IFN- ⁇ polypeptide.
- Suitable derivatives of PEG that are reactive with the free carboxyl group at the carboxyl-terminus of IFN- ⁇ include, but are not limited to PEG-amine, and hydrazine derivatives of PEG (e.g., PEG-NH-NH 2 ).
- PEG is derivatized such that it comprises a terminal thiocarboxylic acid group, -COSH, which selectively reacts with amino groups to generate amide derivatives.
- -SH a terminal thiocarboxylic acid group
- selectivity of certain amino groups over others is achieved.
- -SH exhibits sufficient leaving group ability in reaction with N-terminal amino group at appropriate pH conditions such that the ⁇ -amino groups in lysine residues are protonated and remain non-nucleophilic.
- reactions under suitable pH conditions may make some of the accessible lysine residues to react with selectivity.
- the PEG comprises a reactive ester such as an N-hydroxy succinimidate at the end of the PEG chain.
- a reactive ester such as an N-hydroxy succinimidate at the end of the PEG chain.
- Such an N-hydroxysuccinimidate-containing PEG molecule reacts with select amino groups at particular pH conditions such as neutral 6.5-7.5.
- the N-terminal amino groups may be selectively modified under neutral pH conditions.
- accessible-NH 2 groups of lysine may also react.
- the PEG can be conjugated directly to the IFN- ⁇ polypeptide, or through a linker.
- a linker is added to the IFN- ⁇ polypeptide, forming a linker-modified IFN- ⁇ polypeptide.
- Such linkers provide various functionalities, e.g., reactive groups such sulfhydryl, amino, or carboxyl groups to couple a PEG reagent to the linker-modified IFN- ⁇ polypeptide.
- the PEG conjugated to the IFN- ⁇ polypeptide is linear. In other embodiments, the PEG conjugated to the IFN- ⁇ polypeptide is branched. Branched PEG derivatives such as those described in U.S. Pat. No. 5,643,575, "star-PEG's” and multi-armed PEG's such as those described in Shearwater Polymers, Inc. catalog "Polyethylene Glycol Derivatives 1997-1998.” Star PEGs are described in the art including, e.g., in U.S. Patent No. 6,046,305.
- PEG having a molecular weight in a range of from about 2 kDa to about 100 kDa is generally used, where the term "about,” in the context of PEG, indicates that in preparations of polyethylene glycol, some molecules will weigh more, some less, than the stated molecular weight.
- PEG suitable for conjugation to IFN- ⁇ has a molecular weight of from about 2 IcDa to about 5 kDa, from about 5 kDa to about 10 kDa, from about 10 kDa to about 15 kDa, from about 15 kDa to about 20 kDa, from about 20 kDa to about 25 IcDa, from about 25 IcDa to about 30 IcDa, from about 30 IcDa to about 40 kDa, from about 40 kDa to about 50 IcDa, from about 50 IcDa to about 60 IcDa, from about 60 IcDa to about 70 IcDa, from about 70 IcDa to about 80 IcDa, from about 80 IcDa to about 90 kDa, or from about 90 kDa to about 100 IcDa.
- the PEG moiety can be attached, directly or via a linker, to an amino acid residue at or near the N-terminus, internally, or at or near the C-terminus of the IFN- ⁇ polypeptide. Conjugation can be carried out in solution or in the solid phase. N-terminal linkage
- known methods for selectively obtaining an N-terminally chemically modified IFN- ⁇ are used.
- a method of protein modification by reductive alkylation which exploits differential reactivity of different types of primary amino groups (lysine versus the N-terminus) available for derivatization in a particular protein can be used.
- substantially selective derivatization of the protein at the N-terminus with a carbonyl group containing polymer is achieved.
- the reaction is performed at pH which allows one to take advantage of the pK a differences between the ⁇ - amino groups of the lysine residues and that of the ⁇ -amino group of the N-terminal residue of the protein.
- 5,985,265 provide predominantly monoPEGylated products.
- the purification procedures aimed at removing the excess reagents and minor multiply PEGylated products remove the N-terminal blocked polypeptides.
- such processes lead to significant increases in manufacturing costs.
- examination of the structure of the well-characterized Infergen® Alfacon-1 CIFN polypeptide amino acid sequence reveals that the clipping is approximate 5% at the carboxyl terminus and thus there is only one major C- terminal sequence.
- N-terminally PEGylated IFN- ⁇ is not used; instead, the IFN- ⁇ polypeptide is C-terminally PEGylated.
- a PEG reagent that is selective for the C-terminal can be prepared with or without spacers.
- polyethylene glycol modified as methyl ether at one end and having an amino function at the other end may be used as the starting material.
- Preparing or obtaining a water-soluble carbodiimide as the condensing agent can be carried out.
- Coupling IFN- ⁇ (e.g., Infergen® Alfacon-1 CIFN or consensus interferon) with a water-soluble carbodiimide as the condensing reagent is generally carried out in aqueous medium with a suitable buffer system at an optimal pH to effect the amide linkage.
- a high molecular weight PEG can be added to the protein covalently to increase the molecular weight.
- ED AC ED AC
- l-ethyl-3- (3-dimethylaminopropyl) carbodiimide a suitable reagent.
- the water solubility of ED AC allows for direct addition to a reaction without the need for prior organic solvent dissolution.
- Excess reagent and the isourea formed as the by-product of the cross-linking reaction are both water-soluble and may easily be removed by dialysis or gel filtration.
- a concentrated solution of ED AC in water is prepared to facilitate the addition of a small molar amount to the reaction. The stock solution is prepared and used immediately in view of the water labile nature of the reagent.
- the optimal reaction medium to be in pH range between 4.7 and 6.0. However the condensation reactions do proceed without significant losses in yields up to pH 7.5. Water may be used as solvent.
- the medium will be 2-(N-morpholino)ethane sulfonic acid buffer pre-titrated to pH between 4.7 and 6.0.
- 0.1M phosphate in the pH 7-7.5 may also be used in view of the fact that the product is in the same buffer.
- the ratios of PEG amine to the IFN- ⁇ molecule is optimized such that the C- terminal carboxyl residue(s) are selectively PEGylated to yield monoPEGylated derivative(s).
- PEG amine has been mentioned above by name or structure, such derivatives are meant to be exemplary only, and other groups such as hydrazine derivatives as in PEG-NH-NH 2 which will also condense with the carboxyl group of the IFN- ⁇ protein, can also be used.
- the reactions can also be conducted on solid phase.
- Polyethylene glycol can be selected from list of compounds of molecular weight ranging from 300-40000. The choice of the various polyethylene glycols will also be dictated by the coupling efficiency and the biological performance of the purified derivative in vitro and in vivo i.e., circulation times, anti viral activities etc.
- suitable spacers can be added to the C-terminal of the protein.
- the spacers may have reactive groups such as SH, NH 2 or COOH to couple with appropriate PEG reagent to provide the high molecular weight IFN- ⁇ derivatives.
- a combined solid/solution phase methodology can be devised for the preparation of C-terminal pegylated interferons. For example, the C-terminus of IFN- ⁇ is extended on a solid phase using a Gly-Gly-Cys-NH 2 spacer and then monopegylated in solution using activated dithiopyridyl-PEG reagent of appropriate molecular weights.
- C-terminal PEGylation Another method of achieving C-terminal PEGylation is as follows. Selectivity of C- terminal PEGylation is achieved with a sterically hindered reagent which excludes reactions at carboxyl residues either buried in the helices or internally in IFN- ⁇ .
- a sterically hindered reagent which excludes reactions at carboxyl residues either buried in the helices or internally in IFN- ⁇ .
- one such reagent could be a branched chain PEG ⁇ 40kd in molecular weight and this agent could be synthesized as follows:
- COOH is condensed with a suitable agent e.g., dicyclohexyl carbodiimide or water-soluble EDC to provide the branched chain PEG agent OH 3 C-(CH 2 CH 2 O) n - CH2CH 2 NHCOCH(NH2)CH2OCH 3 -(CH2CH 2 O) n -CH2CH 2 NHCOCH2.
- a suitable agent e.g., dicyclohexyl carbodiimide or water-soluble EDC
- This reagent can be used in excess to couple the amino group with the free and flexible carboxyl group of IFN- ⁇ to form the peptide bond.
- PEGylated IFN- ⁇ is separated from unPEGylated IFN- ⁇ using any known method, including, but not limited to, ion exchange chromatography, size exclusion chromatography, and combinations thereof.
- the products are first separated by ion exchange chromatography to obtain material having a charge characteristic of monoPEGylated material (other multi- PEGylated material having the same apparent charge may be present), and then the monoPEGylated materials are separated using size exclusion chromatography.
- IFN- ⁇ IFN- ⁇
- interferon-beta includes IFN- ⁇ polypeptides that are naturally occurring; non-naturally-occurring IFN- ⁇ polypeptides; and analogs of naturally occurring or non-naturally occurring IFN- ⁇ that retain antiviral activity of a parent naturally-occurring or non-naturally occurring IFN- ⁇ .
- beta interferons can be delivered by the continuous delivery method of the present invention.
- Suitable beta interferons include, but are not limited to, naturally- occurring IFN- ⁇ ; IFN- ⁇ la, e.g., Avonex® (Biogen, Inc.), and Rebif® (Serono, SA); IFN- ⁇ lb (Betaseron®; Berlex); and the like.
- the IFN- ⁇ formulation may comprise an N-blocked species, wherein the N-terminal amino acid is acylated with an acyl group, such as a formyl group, an acetyl group, a malonyl group, and the like. Also suitable for use is a consensus IFN- ⁇ .
- IFN- ⁇ polypeptides can be produced by any known method. DNA sequences encoding
- IFN- ⁇ may be synthesized using standard methods.
- IFN- ⁇ polypeptides are the products of expression of manufactured DNA sequences transformed or transfected into bacterial hosts, e.g., E. coli, or in eukaryotic host cells (e.g., yeast; mammalian cells, such as CHO cells; and the like).
- the IFN- ⁇ is "recombinant IFN- ⁇ .”
- the host cell is a bacterial host cell
- the IFN- ⁇ is modified to comprise an N- terminal methionine.
- IFN- ⁇ as described herein may comprise one or more modified amino acid residues, e.g., glycosylations, chemical modifications, and the like.
- IFN-tau may comprise one or more modified amino acid residues, e.g., glycosylations, chemical modifications, and the like.
- interferon-tau includes IFN-tau polypeptides that are naturally occurring; non- naturally-occurring IFN-tau polypeptides; and analogs of naturally occurring or non-naturally occurring IFN-tau that retain antiviral activity of a parent naturally-occurring or non-naturally occurring IFN-tau.
- Suitable tau interferons include, but are not limited to, naturally-occurring IFN-tau;
- IFN-tau may comprise an amino acid sequence as set forth in any one of GenBank
- IFN-tau polypeptide may be altered in various ways known in the art to generate targeted changes in sequence.
- a variant polypeptide will usually be substantially similar to the sequences provided herein, i.e. will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids.
- the sequence changes may be substitutions, insertions or deletions.
- Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).
- Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e.g., acetylation, or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like. Also included are modifications of glycosylation, e.g. those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e.g. by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes. Also embraced are sequences that have phosphorylated amino acid residues, e.g. phosphotyrosine, phosphoserine, or phosphothreonine.
- modifications of glycosylation e.g. those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps;
- the IFN-tau formulation may comprise an N-blocked species, wherein the N-terminal amino acid is acylated with an acyl group, such as a formyl group, an acetyl group, a malonyl group, and the like. Also suitable for use is a consensus IFN-tau.
- IFN-tau polypeptides can be produced by any known method. DNA sequences encoding IFN-tau may be synthesized using standard methods. In many embodiments, IFN-tau polypeptides are the products of expression of manufactured DNA sequences transformed or transfected into bacterial hosts, e.g., E. coli, or in eukaryotic host cells (e.g., yeast; mammalian cells, such as CHO cells; and the like). In these embodiments, the IFN-tau is "recombinant IFN-tau.” Where the host cell is a bacterial host cell, the IFN-tau is modified to comprise an N-terminal methionine.
- IFN-tau as described herein may comprise one or more modified amino acid residues, e.g., glycosylations, chemical modifications, and the like.
- IFN- ⁇ may comprise one or more modified amino acid residues, e.g., glycosylations, chemical modifications, and the like.
- interferon-omega includes IFN- ⁇ polypeptides that are naturally occurring; non-naturally-occurring IFN- ⁇ polypeptides; and analogs of naturally occurring or non-naturally occurring IFN- ⁇ that retain antiviral activity of a parent naturally-occurring or non-naturally occurring IFN- ⁇ .
- Suitable omega interferon can be delivered by the continuous delivery method of the present invention.
- Suitable IFN- ⁇ include, but are not limited to, naturally-occurring IFN- ⁇ ; recombinant IFN- ⁇ , e.g., Biomed 510 (BioMedicines); and the like.
- IFN- ⁇ may comprise an amino acid sequence as set forth in GenBank Accession No.
- any known IFN- ⁇ polypeptide may be altered in various ways known in the art to generate targeted changes in sequence.
- a variant polypeptide will usually be substantially similar to the sequences provided herein, i.e. will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids.
- the sequence changes may be substitutions, insertions or deletions.
- Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).
- Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e.g., acetylation, or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like. Also included are modifications of glycosylation, e.g. those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e.g. by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes. Also embraced are sequences that have phosphorylated amino acid residues, e.g. phosphotyrosine, phosphoserine, or phosphothreonine.
- modifications of glycosylation e.g. those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps;
- the IFN- ⁇ formulation may comprise an N-blocked species, wherein the N-terminal amino acid is acylated with an acyl group, such as a formyl group, an acetyl group, a malonyl group, and the like. Also suitable for use is a consensus IFN- ⁇ .
- IFN- ⁇ polypeptides can be produced by any Icnown method. DNA sequences encoding
- IFN- ⁇ may be synthesized using standard methods.
- IFN- ⁇ polypeptides are the products of expression of manufactured DNA sequences transformed or transfected into bacterial hosts, e.g., E. coli, or in eukaryotic host cells (e.g., yeast; mammalian cells, such as CHO cells; and the like).
- the IFN- ⁇ is "recombinant IFN- ⁇ .”
- the host cell is a bacterial host cell
- the IFN- ⁇ is modified to comprise an N- terminal methionine.
- IFN- ⁇ as described herein may comprise one or more modified amino acid residues, e.g., glycosylations, chemical modifications, and the like.
- modified amino acid residues e.g., glycosylations, chemical modifications, and the like.
- the interferon receptor agonist is in some embodiments an agonist of a Type III interferon receptor (e.g., "a Type III interferon agonist").
- Type III interferon agonists include an IL-28b polypeptide; and IL-28a polypeptide; and IL-29 polypeptide; antibody specific for a Type III interferon receptor; and any other agonist of Type III interferon receptor, including non-polypeptide agonists.
- IL-28A, IL-28B, and IL-29 (referred to herein collectively as "Type III interferons" or
- Type III IFNs are described in Sheppard et al. (2003) Nature 4:63-68. Each polypeptide binds a heterodimeric receptor consisting of IL-10 receptor ⁇ chain and an IL-28 receptor ⁇ . Sheppard et al. (2003), supra. The amino acid sequences of IL-28A, IL-28B, and IL-29 are found under GenBank Accession Nos. NP_742150, NP 742151 , and NP_742152, respectively.
- the amino acid sequence of a Type III IFN polypeptide may be altered in various ways known in the art to generate targeted changes in sequence.
- a variant polypeptide will usually be substantially similar to the sequences provided herein, i.e. will. differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids.
- the sequence changes may be substitutions, insertions or deletions. Scanning mutations that systematically introduce alanine, or other residues, may be used to determine key amino acids. Specific amino acid substitutions of interest include conservative and non-conservative changes.
- Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).
- Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e.g., acetylation, or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like. Also included are modifications of glycosylation, e.g. those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e.g. by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes.
- sequences that have phosphorylated amino acid residues e.g. phosphotyrosine, phosphoserine, or phosphothreonine.
- polypeptides that have been modified using ordinary chemical techniques so as to improve their resistance to proteolytic degradation, to optimize solubility properties, or to render them more suitable as a therapeutic agent.
- the backbone of the peptide may be cyclized to enhance stability (see Friedler et al. (2000) J. Biol. Chem. 275:23783-23789).
- Analogs may be used that include residues other than naturally occurring L-amino acids, e.g. D-amino acids or non-naturally occurring synthetic amino acids.
- the protein may be pegylated to enhance stability.
- the polypeptides may be fused to albumin.
- polypeptides may be prepared by in vitro synthesis, using conventional methods as known in the art, by recombinant methods, or may be isolated from cells induced or naturally producing the protein. The particular sequence and the manner of preparation will be determined by convenience, economics, purity required, and the like. If desired, various groups may be introduced into the polypeptide during synthesis or during expression, which allow for linking to other molecules or to a surface. Thus cysteines can be used to make thioethers, histidines for linking to a metal ion complex, carboxyl groups for forming amides or esters, amino groups for forming amides, and the like. Type II Interferon receptor agonists
- Type II interferon receptor agonists include any naturally-occurring or non-naturally- occurring ligand of a human Type II interferon receptor which binds to and causes signal transduction via the receptor.
- Type II interferon receptor agonists include interferons, including naturally-occurring interferons, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising an interferon and a heterologous protein, shuffled interferons; antibody specific for an interferon receptor; non-peptide chemical agonists; and the like.
- a specific example of a Type II interferon receptor agonist is IFN- ⁇ and variants thereof. Wlwar the present invention exemplifies use of an IFN- ⁇ polypeptide, it will be readily apparent that any Type II interferon receptor agonist can be used in a subject method. Interferon-Gamma
- the nucleic acid sequences encoding IFN- ⁇ polypeptides may be accessed from public databases, e.g., Genbank, journal publications, etc. While various mammalian IFN- ⁇ polypeptides are of interest, for the treatment of human disease, generally the human protein will be used. Human IFN- ⁇ coding sequence may be found in Genbank, accession numbers XI 3274; N00543; and ⁇ M_000619. The corresponding genomic sequence may be found in Genbank, accession numbers J00219; M37265; and N00536. See, for example. Gray et al. (1982) Nature 295:501 (Genbank X13274); and Rinderlcnecht etal. (1984) J.B.C. 259:6790.
- IF ⁇ - ⁇ lb (Actimmune®; human interferon) is a single-chain polypeptide of 140 amino acids. It is made recombinantly in E.coli and is unglycosylated. Rinderlcnecht et al. (1984) J. Biol Chem. 259:6790-6797. Recombinant IF ⁇ - ⁇ as discussed in U.S. Patent No. 6,497,871 is also suitable for use herein.
- the IFN- ⁇ to be used in the methods of the present invention may be any of natural
- Human IFN- ⁇ exhibits the antiviral and anti-proliferative properties characteristic of the interferons, as well as a number of other immunomodulatory activities, as is known in the art.
- IFN- ⁇ is based on the sequences as provided above, the production of the protein and proteolytic processing can result in processing variants thereof.
- the unprocessed sequence provided by Gray et al., supra, consists of 166 amino acids (aa).
- coli was originally believed to be 146 amino acids, (commencing at amino acid 20) it was subsequently found that native human IFN- ⁇ is cleaved after residue 23, to produce a 143 aa protein, or 144 aa if the terminal methionine is present, as required for expression in bacteria.
- the mature protein can additionally be cleaved at the C terminus after reside 162 (referring to the Gray et al. sequence), resulting in a protein of 139 amino acids, or 140 amino acids if the initial methionine is present, e.g. if required for bacterial expression.
- the N-terminal methionine is an artifact encoded by the mRNA translational "start" signal AUG that, in the particular case of E. coli expression is not processed away. In other microbial systems or eukaryotic expression systems, methionine may be removed.
- IFN- ⁇ peptides for use in the subject methods, any of the native IFN- ⁇ peptides, modifications and variants thereof, or a combination of one or more peptides may be used.
- IFN- ⁇ peptides of interest include fragments, and can be variously truncated at the carboxyl terminus relative to the full sequence. Such fragments continue to exhibit the characteristic properties of human gamma interferon, so long as amino acids 24 to about 149 (numbering from the residues of the unprocessed polypeptide) are present. Extraneous sequences can be substituted for the amino acid sequence following amino acid 155 without loss of activity. See, for example, U.S. Patent No. 5,690,925.
- Native IFN- ⁇ moieties include molecules variously extending from amino acid residues 24-150; 24-151, 24-152; 24- 153, 24-155; and 24-157. Any of these variants, and other variants known in the art and having IFN- ⁇ activity, may be used in the present methods.
- the sequence of the IFN- ⁇ polypeptide may be altered in various ways known in the art to generate targeted changes in sequence.
- a variant polypeptide will usually be substantially similar to the sequences provided herein, i.e., will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids.
- the sequence changes may be substitutions, insertions or deletions.
- Scanning mutations that systematically introduce alanine, or other residues, may be used to determine key amino acids.
- Specific amino acid substitutions of interest include conservative and non-conservative changes.
- Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).
- Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e.g., acetylation, or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like.
- the invention contemplates the use of IFN- ⁇ variants with one or more non-naturally occurring glycosylation and/or pegylation sites that are engineered to provide glycosyl- and/or PEG- derivatized polypeptides with reduced serum clearance, such as the IFN- ⁇ polypeptide variants described in International Patent Publication No. WO 01/36001.
- glycosylation e.g., those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e.g., by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes.
- sequences that have phosphorylated amino acid residues e.g., phosphotyrosine, phosphoserine, or phosphothreonine.
- polypeptides that have been modified using ordinary chemical techniques so as to improve their resistance to proteolytic degradation, to optimize solubility properties, or to render them more suitable as a therapeutic agent.
- the backbone of the peptide may be cyclized to enhance stability (see Friedler et al. (2000) J Biol. Chem. 275:23783-23789).
- Analogs may be used that include residues other than naturally occurring L-amino acids, e.g., D-amino acids or non-naturally occurring synthetic amino acids.
- the protein may be pegylated to enhance stability.
- polypeptides may be prepared by in vitro synthesis, using conventional methods as known in the art, by recombinant methods, or may be isolated from cells induced or naturally producing the protein. The particular sequence and the manner of preparation will be determined by convenience, economics, purity required, and the like. If desired, various groups may be introduced into the polypeptide during synthesis or during expression, which allow for linking to other molecules or to a surface. Thus cysteines can be used to make thioethers, histidines for linking to a metal ion complex, carboxyl groups for forming amides or esters, amino groups for forming amides, and the like.
- the polypeptides may also be isolated and purified in accordance with conventional methods of recombinant synthesis.
- a lysate may be prepared of the expression host and the lysate purified using HPLC, exclusion chromatography, gel electrophoresis, affinity chromatography, or other purification technique.
- the compositions which are used will comprise at least 20% by weight of the desired product, more usually at least about 75% by weight, preferably at least about 95% by weight, and for therapeutic purposes, usually at least about 99.5% by weight, in relation to contaminants related to the method of preparation of the product and its purification. Usually, the percentages will be based upon total protein. Pirfenidone and Analogs Thereof
- Pirfenidone (5-methyl-l-phenyl-2-(lH)-pyridone) and specific pirfenidone analogs are disclosed for the treatment of fibrotic conditions.
- a "fibrotic condition” is one that is amenable to treatment by administration of a compound having anti-fibrotic activity.
- Ri carbocyclic (saturated and unsaturated), heterocyclic (saturated or unsaturated), alkyls (saturated and unsaturated). Examples include phenyl, benzyl, pyrimidyl, naphthyl, indolyl, pyrrolyl, furyl, thienyl, imidazolyl, cyclohexyl, piperidyl, pyrrolidyl, morpholinyl, cyclohexenyl, butadienyl, and the like. ⁇ >
- Ri can further include substitutions on the carbocyclic or heterocyclic moieties with substituents such as halogen, nitro, amino, hydroxyl, alkoxy, carboxyl, cyano, thio, alkyl, aryl, heteroalkyl, heteroaryl and combinations thereof, for example, 4-nitrophenyl, 3-chlorophenyl, 2,5-dinitrophenyl, 4-methoxyphenyl, 5-methyl-pyrrolyl, 2, 5-dichlorocyclohexyl, guanidinyl- cyclohexenyl and the like.
- substituents such as halogen, nitro, amino, hydroxyl, alkoxy, carboxyl, cyano, thio, alkyl, aryl, heteroalkyl, heteroaryl and combinations thereof, for example, 4-nitrophenyl, 3-chlorophenyl, 2,5-dinitrophenyl, 4-methoxyphenyl, 5-methyl-pyrrolyl, 2, 5-dichloro
- R 2 alkyl, carbocylic, aryl, heterocyclic. Examples include: methyl, ethyl, propyl, isopropyl, phenyl, 4-nitrophenyl, thienyl and the like.
- X may be any number (from 1 to 3) of substituents on the carbocyclic or heterocyclic ring.
- the substituents can be the same or different.
- Substituents can include hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, halo, nitro, carboxyl, hydroxyl, cyano, amino, thio, alkylamino, haloaryl and the like.
- the substituents may be optionally further substituted with 1-3 substituents from the group consisting of alkyl, aryl, nitro, alkoxy, hydroxyl and halo groups. Examples include: methyl, 2,3-dimethyl, phenyl, p-tolyl, 4-chlorophenyl, 4-nitrophenyl, 2,5-dichlorophenyl, furyl, thienyl and the like.
- Thymosin- ⁇ (ZadaxinTM; available from SciClone Pharmaceuticals, Inc., San Mateo,
- CA is a synthetic form of thymosin alpha 1, a hormone found naturally in the circulation and produced by the thymus gland. Thymosin- ⁇ increases activity of T cells and NK cells.
- ZadaxinTM formulated for subcutaneous injection is a purified sterile lyophilized preparation of chemically synthesized thymosin alpha 1 identical to human thymosin alpha 1.
- Thymosin alpha 1 is an acetylated polypeptide with the following sequence: Ac - Ser - Asp - Ala - Ala - Nal - Asp - Thr - Ser - Ser - Glu - lie - Thr - Thr - Lys - Asp - Leu - Lys - Glu - Lys - Lys - Glu - Nal - Nal - Glu - Glu - Ala - Glu - Asn - OH, and having a molecular weight of 3,108 daltons.
- the lyophilized preparation contains 1.6 mg synthetic thymosin- ⁇ , 50 mg mannitol, and sodium phosphate buffer to adjust the pH to 6.8.
- Ribavirin, l- ⁇ -D-ribofuranosyl-lH-l,2,4-triazole-3 -carboxamide is a nucleoside analog available from IC ⁇ Pharmaceuticals, Inc., Costa Mesa, Calif, and is described in the
- Ribavirin is generally administered in an amount ranging from about 400 mg to about
- ribavirin is administered throughout the entire course of NS3 inhibitor therapy.
- Levovirin is the L-enantiomer of ribavirin, and exhibits the property of enhancing a
- Levovirin is manufactured by ICN
- Levovirin has the following structure:
- Niramidine is a 3-carboxamidine derivative of ribavirin, and acts as aprodrug of ribavirin. It is efficiently converted to ribavirin by adenosine deaminases. [00176] Niramidine has the following structure:
- Nucleoside analogs that are suitable for use in a subject combination therapy include, but are not limited to, ribavirin, levovirin, viramidine, isatoribine, an L-ribofuranosyl nucleoside as disclosed in U.S. Patent No. 5,559,101 and encompassed by Formula I of U.S. Patent No.
- 5,559,101 e.g., 1- ⁇ -L-ribofuranosyluracil, l- ⁇ -L-ribofuranosyl-5-fluorouracil, 1- ⁇ - L-ribofuranosylcytosine, 9- ⁇ -L-ribofuranosyladenine, 9- ⁇ -L-ribofuranosylhypoxanthine, 9- ⁇ - L-ribofuranosylguanine, 9- ⁇ -L-ribofuranosyl-6-thioguanine, 2-amino- ⁇ -L- ribofuranl[ ,2':4,5]oxazoline, O ,O -anhydro-1- ⁇ -L-ribofuranosyluracil, 1- ⁇ -L- ribofuranosyluracil, l-(2,3,5-tri-O-benzoyl- ⁇ — ribofuranosyl)-4-thiouracil, 1- ⁇ -L- ribofuranosylcytosine, l-
- a subject method comprises administering an effective amount of aNS3 inhibitor and an effective amount of a tumor necrosis factor- ⁇ (TNF- ⁇ ) antagonist.
- TNF- ⁇ antagonists for use herein include agents that decrease the level of TNF- ⁇ synthesis, agents that block or inhibit the binding of TNF- ⁇ to a TNF- ⁇ receptor (TNFR), and agents that block or inhibit TNFR-mediated signal transduction.
- TNFR TNF- ⁇ receptor
- every reference to a "TNF- ⁇ antagonist" or “TNF antagonist” herein will be understood to mean a TNF- ⁇ antagonist other than pirfenidone or a pirfenidone analog.
- TNF receptor polypeptide and "TNFR polypeptide” refer to polypeptides derived from TNFR (from any species) which are capable of binding TNF.
- TNFR Two distinct cell-surface TNFRs have described: Type II TNFR (or p75 TNFR or TNFRII) and Type I TNFR (or p55 TNFR or TNFRI).
- Type II TNFR or p75 TNFR or TNFRII
- Type I TNFR or p55 TNFR or TNFRI
- the mature full-length human p75 TNFR is a glycoprotein having a molecular weight of about 75-80 kilodaltons (kD).
- the mature full- length human p55 TNFR is a glycoprotein having a molecular weight of about 55-60 kD.
- Exemplary TNFR polypeptides are derived from TNFR Type I and/or TNFR type II.
- Soluble TNFR includes p75 TNFR polypeptide; fusions of p75 TNFR with heterologous fusion partners, e.g., the Fc portion of an immunoglobulin.
- TNFR polypeptide may be an intact TNFR or a suitable fragment of TNFR.
- TNFR polypeptides including soluble TNFR polypeptides, appropriate for use in the present invention.
- the TNFR polypeptide comprises an extracellular domain of TNFR.
- the TNFR polypeptide is a fusion polypeptide comprising an extracellular domain of TNFR linked to a constant domain of an immunoglobulin molecule.
- the TNFR polypeptide is a fusion polypeptide comprising an extracellular domain of the p75 TNFR linked to a constant domain of an IgGl molecule.
- an Ig used for fusion proteins is human, e.g., human IgGl .
- TNFR polypeptides may be used in the present invention.
- Multivalent forms of TNFR polypeptides possess more than one TNF binding site.
- the TNFR is a bivalent, or dimeric, form of TNFR.
- a chimeric antibody polypeptide with TNFR extracellular domains substituted for the variable domains of either or both of the immunoglobulin heavy or light chains would provide a TNFR polypeptide for the present invention.
- TNFR antibody polypeptide
- TNFR:Fc chimeric TNFR: antibody polypeptide
- a subject method involves administration of an effective amount of the soluble TNFR ENBREL®.
- ENBREL® is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) TNFR linked to the Fc portion of human IgGl.
- the Fc component of ENBREL® contains the CH2 domain, the CH3 domain and hinge region, but not the CHI domain of IgGl.
- ENBREL® is produced in a Chinese hamster ovary (CHO) mammalian cell expression system. It consists of 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons. Smith et al.
- Monoclonal antibodies that bind TNF- ⁇ .
- Monoclonal antibodies include "humanized" mouse monoclonal antibodies; chimeric antibodies; monoclonal antibodies that are at least about 80%, at least about 90%, at least about 95%, or 100% human in amino acid sequence; and the like. See, e.g., WO 90/10077; WO 90/04036; and WO 92/02190.
- Suitable monoclonal antibodies include antibody fragments, such as Fv, F(ab') 2 and Fab; synthetic antibodies; artificial antibodies; phage display antibodies; and the like.
- Suitable monoclonal antibodies include Infliximab (REMICADE®,
- REMICADE® is a chimeric monoclonal anti-TNF- ⁇ antibody that includes about 25% mouse amino acid sequence and about 75% human amino acid sequence.
- REMICADE® comprises a variable region of a mouse monoclonal anti-TNF- ⁇ antibody fused to the constant region of a human IgGl .
- HUMIRATM is a human, full-length IgGl monoclonal antibody that was identified using phage display technology. Piascik (2003) J Am. Pharm. Assoc. 43:327-328.
- SAPK inhibitors are Icnown in the art, and include, but are not limited to 2-alkyl imidazoles disclosed in U.S. Patent No. 6,548,520; 1,4, 5 -substituted imidazole compounds disclosed in U.S. Patent No. 6,489,325; 1,4,5-substituted imidazole compounds disclosed in U.S. Patent No. 6,569,871; heteroaryl aminophenyl ketone compounds disclosed in Published U.S. Patent Application No. 2003/0073832; pyridyl imidazole compounds disclosed in U.S.
- a stress-activated protein kinase is a member of a family of mitogen- activated protein kinases which are activated in response to stress stimuli.
- SAPK include, but are not limited to, p38 (Lee et al. (1994) Nature 372:739) and c-jun N-terminal kinase (INK).
- TNF antagonist activity may be assessed with a cell-based competitive binding assay.
- radiolabeled TNF is mixed with serially diluted TNF antagonist and cells expressing cell membrane bound TNFR. Portions of the suspension are centrifuged to separate free and bound TNF and the amount of radioactivity in the free and bound fractions determined. TNF antagonist activity is assessed by inhibition of TNF binding to the cells in the presence of the TNF antagonist.
- TNF antagonists may be analyzed for the ability to neutralize TNF activity in vitro in a bioassay using cells susceptible to the cytotoxic activity of TNF as target cells.
- target cells cultured with TNF, are treated with varying amounts of TNF antagonist and subsequently are examined for cytolysis.
- TNF antagonist activity is assessed by a decrease in TNF-induced target cell cytolysis in the presence of the TNF antagonist.
- the invention provides a method comprising administering an effective amount of a subject NS3 inhibitor and an effective amount of an HCV non-structural protein-5 (NS5; RNA-dependent RNA polymerase) inhibitor to an HCN patient in need thereof.
- NS5B inhibitors include, but are not limited to, a compound as disclosed in U.S. Patent No. 6,479,508 (Boehringer-Ingelheim); a compound as disclosed in any of International Patent Application Nos. PCT/CA02/01127, PCT/CA02/01128, and PCT/CA02/01129, all filed on July 18, 2002 by Boehringer Ingelheim; a compound as disclosed in U.S. Patent No.
- anNS5B inhibitor as disclosed in WO 02/100846 Al or WO 02/100851 A2 both Shire
- anNS5B inhibitor as disclosed in WO 01/85172 Al or WO 02/098424 Al both Glaxo SmithKline
- an NS5B inhibitor as disclosed in WO 00/06529 or WO 02/06246 Al both Merck
- an NS5B inhibitor as disclosed in WO 03/000254 Japan Tobacco
- an NS5B inhibitor as disclosed in EP 1 256,628 A2 (Agouron); JTK-002 (Japan Tobacco); JTK-109 (Japan Tobacco); and the like.
- NS5 inhibitors that are specific NS5 inliibitors, e.g., NS5 inliibitors that inhibit NS5 RNA-dependent RNA polymerase and that lack significant inliibitory effects toward other RNA dependent RNA polymerases and toward DNA dependent RNA polymerases. Additional antiviral agents
- Additional antiviral therapeutic agents that can be administered in combination with a subject NS3 inhibitor compound include, but are not limited to, inhibitors of inosine monophosphate dehydrogenase (IMPDH); ribozymes that are complementary to viral nucleotide sequences; antisense RNA inhibitors; and the like.
- IMPDH inosine monophosphate dehydrogenase
- ribozymes that are complementary to viral nucleotide sequences
- antisense RNA inhibitors and the like.
- IMPDH inhibitors that are suitable for use in a subject combination therapy include, but are not limited to, NX-497 ((S)-N-3-[3-(3-methoxy-4-oxazol-5-yl-phenyl)-ureido]-benzyl- carbamic acid tetrahydrofuran-3-yl-ester); Vertex Pharmaceuticals; see, e.g., Markland et al. (2000) Antimicrob. Agents Chemother.
- Ribozyme and antisense antiviral agents that are suitable for use in a subject combination therapy include, but are not limited to, ISIS 14803 (ISIS Pharmaceuticals/Elan Corporation; see, e.g., Witherell (2001) Curr Opin Investig Drugs. 2(11):1523-9); HeptazymeTM; and the like.
- an additional antiviral agent is administered during the entire course of NS3 inhibitor compound treatment.
- an additional antiviral agent is administered for a period of time that is overlapping with that of the NS3 inhibitor compound treatment, e.g., the additional antiviral agent treatment can begin before the NS3 inhibitor compound treatment begins and end before the NS3 inhibitor compound treatment ends; the additional antiviral agent treatment can begin after the NS3 inhibitor compound treatment begins and end after the NS3 inhibitor compound treatment ends; the additional antiviral agent treatment can begin after the NS3 inhibitor compound treatment begins and end before the NS3 inhibitor compound treatment ends; or the additional antiviral agent treatment can begin before the NS3 inhibitor compound treatment begins and end after the NS3 inhibitor compound treatment ends.
- the active agent(s) may be administered to the host using any convenient means capable of resulting in the desired therapeutic effect.
- the agent can be inco ⁇ orated into a variety of formulations for therapeutic administration.
- the agents of the present invention can be formulated into pharmaceutical compositions by combination with appropriate, pharmaceutically acceptable carriers or diluents, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols.
- compositions are provided in formulation with a pharmaceutically acceptable excipient(s).
- pharmaceutically acceptable excipients are known in the art and need not be discussed in detail herein.
- Pharmaceutically acceptable excipients have been amply described in a variety of publications, including, for example, A. Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20th edition, Lippincott, Williams, & Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C.
- compositions such as vehicles, adjuvants, carriers or diluents
- pharmaceutically acceptable auxiliary substances such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.
- an agent is formulated in an aqueous buffer.
- Suitable aqueous buffers include, but are not limited to, acetate, succinate, citrate, and phosphate buffers varying in strengths from 5mM to lOOmM.
- the aqueous buffer includes reagents that provide for an isotonic solution. Such reagents include, but are not limited to, sodium chloride; and sugars e.g., mannitol, dextrose, sucrose, and the like.
- the aqueous buffer further includes a non-ionic surfactant such as polysorbate 20 or 80.
- the formulations may further include a preservative.
- Suitable preservatives include, but are not limited to, a benzyl alcohol, phenol, chlorobutanol, benzalkonium chloride, and the like. In many cases, the formulation is stored at about 4°C. Formulations may also be lyophilized, in which case they generally include cryoprotectants such as sucrose, trehalose, lactose, maltose, mannitol, and the like. Lyophilized formulations can be stored over extended periods of time, even at ambient temperatures.
- administration of the agents can be achieved in various ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, subcutaneous, intramuscular, transdermal, intratracheal,etc, administration.
- administration is by bolus injection, e.g., subcutaneous bolus injection, intramuscular bolus injection, and the like.
- compositions of the invention can be administered orally, parenterally or via an implanted reservoir. Oral administration or administration by injection are preferred.
- Subcutaneous administration of a pharmaceutical composition of the invention is accomplished using standard methods and devices, e.g., needle and syringe, a subcutaneous injection port delivery system, and the like. See, e.g., U.S. Patent Nos. 3,547,119; 4,755,173; 4,531,937; 4,311,137; and 6,017,328.
- a combination of a subcutaneous injection port and a device for administration of a pharmaceutical composition of the invention to a patient through the port is referred to herein as "a subcutaneous injection port delivery system.”
- subcutaneous administration is achieved by bolus delivery by needle and syringe.
- the agents may be administered in the form of their pharmaceutically acceptable salts, or they may also be used alone or in appropriate association, as well as in combination, with other pharmaceutically active compounds.
- the following methods and excipients are merely exemplary and are in no way limiting.
- the agents can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives and flavoring agents.
- conventional additives such as lactose, mannitol, corn starch or potato starch
- binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins
- disintegrators such as corn starch, potato starch or sodium carboxymethylcellulose
- lubricants such as talc or magnesium stearate
- the agents can be formulated into preparations for injection by dissolving, suspending or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
- an aqueous or nonaqueous solvent such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol
- solubilizers isotonic agents
- suspending agents emulsifying agents
- stabilizers and preservatives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
- the agents can be made into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases.
- bases such as emulsifying bases or water-soluble bases.
- the compounds of the present invention can be administered rectally via a suppository.
- the suppository can include vehicles such as cocoa butter, carbowaxes and polyethylene glycols, which melt at body temperature, yet are solidified at room temperature.
- Unit dosage forms for oral or rectal administration such as syrups, elixirs, and suspensions may be provided wherein each dosage unit, for example, teaspoonful, tablespoonful, tablet or suppository, contains a predetermined amount of the composition containing one or more inhibitors.
- unit dosage forms for injection or intravenous administration may comprise the inhibitor(s) in a composition as a solution in sterile water, normal saline or another pharmaceutically acceptable carrier.
- unit dosage form refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of compounds of the present invention calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier or vehicle.
- the specifications for the novel unit dosage forms of the present invention depend on the particular compound employed and the effect to be achieved, and the pharmacodynamics associated with each compound in the host.
- the pharmaceutically acceptable excipients such as vehicles, adjuvants, carriers or diluents, are readily available to the public.
- pharmaceutically acceptable auxiliary substances such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.
- Other antiviral agents are readily available to the public.
- a subject method will in some embodiments be carried out by administering an NS3 inhibitor that is a compound of formula I, and optionally one or more additional antiviral agent(s).
- the method further includes administration of one or more interferon receptor agonist(s).
- Interferon receptor agonists are described above.
- the method further includes administration of pirfenidone or a pirfenidone analog. Pirfenidone and pirfenidone analogs are described above.
- Additional antiviral agents that are suitable for use in combination therapy include, but are not limited to, nucleotide and nucleoside analogs.
- Non-limiting examples include azidothymidine (AZT) (zidovudine), and analogs and derivatives thereof; 2',3'-dideoxyinosine (DDI) (didanosine), and analogs and derivatives thereof; 2',3'-dideoxycytidine (DDC) (dideoxycytidine), and analogs and derivatives thereof; 2'3,'-didehydro-2',3'- dideoxythymidine (D4T) (stavudine), and analogs and derivatives thereof; combivir; abacavir; adefovir dipoxil; cidofovir; ribavirin; ribavirin analogs; and the like.
- the method further includes administration of ribavirin.
- Ribavirin l- ⁇ -D-ribofuranosyl-lH-l,2,4-triazole-3 -carboxamide, available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif, is described in the Merck Index, compound No. 8199, Eleventh Edition. Its manufacture and formulation is described in U.S. Pat. No. 4,211,771.
- the invention also contemplates use of derivatives of ribavirin (see, e.g., U.S. Pat. No. 6,277,830).
- the ribavirin may be administered orally in capsule or tablet form, or in the same or different administration form and in the same or different route as the interferon receptor agonist.
- an additional antiviral agent is administered during the entire course of NS3 inhibitor compound treatment.
- an additional antiviral agent is administered for a period of time that is overlapping with that of the NS3 inhibitor compound treatment, e.g., the additional antiviral agent treatment can begin before the NS3 inhibitor compound treatment begins and end before the NS3 inhibitor compound treatment ends; the additional antiviral agent treatment can begin after the NS3 inhibitor compound treatment begins and end after the NS3 inhibitor compound treatment ends; the additional antiviral agent treatment can begin after the NS3 inhibitor compound treatment begins and end before the NS3 inhibitor compound treatment ends; or the additional antiviral agent treatment can begin before the NS3 inhibitor compound treatment begins and end after the NS3 inhibitor compound treatment ends.
- the NS3 inhibitor compound of the invention can be used in acute or chronic therapy for HCN disease.
- the ⁇ S3 inhibitor compound is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time.
- the NS3 inhibitor compound can be administered 5 times per day, 4 times per day, tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly. In other embodiments, the NS3 inhibitor compound is administered as a continuous infusion.
- an NS3 inhibitor compound of the invention is administered orally.
- an ⁇ S3 inhibitor compound of the invention can be administered to the patient at a dosage from about 0.01 mg to about 100 mg/kg patient bodyweight per day, in 1 to 5 divided doses per day.
- the NS3 inhibitor compound is administered at a dosage of about 0.5 mg to about 75 mg/kg patient bodyweight per day, in 1 to 5 divided doses per day.
- the amount of active ingredient that may be combined with carrier materials to produce a dosage form can vary depending on the host to be treated and the particular mode of administration.
- a typical pharmaceutical preparation can contain from about 5% to about 95% active ingredient (w/w). In other embodiments, the pharmaceutical preparation can contain from about 20% to about 80% active ingredient.
- dose levels can vary as a function of the specific NS3 inhibitor compound, the severity of the symptoms and the susceptibility of the subject to side effects.
- Preferred dosages for a given NS3 inhibitor compound are readily determinable by those of skill in the art by a variety of means.
- a preferred means is to measure the physiological potency of a given interferon receptor agonist.
- multiple doses of NS3 inhibitor compound are administered.
- an NS3 inhibitor compound is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (qid), or three times a day (tid), over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.
- the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of ribavirin.
- Ribavirin can be administered in dosages of about 400 mg, about 800 mg, about 1000 mg, or about 1200 mg per day.
- the invention provides any of the above-described methods modified to include co-administering to the patient a therapeutically effective amount of ribavirin for the duration of the desired course of NS3 inhibitor compound treatment.
- the invention provides any of the -above-described methods modified to include co-administering to the patient about 800 mg to about 1200 mg ribavirin orally per day for the duration of the desired course of NS3 inhibitor compound treatment.
- the invention provides any of the above-described methods modified to include co-administering to the patient (a) 1000 mg ribavirin orally per day if the patient has a body weight less than 75 kg or (b) 1200 mg ribavirin orally per day if the patient has a body weight greater than or equal to 75 kg, where the daily dosage of ribavirin is optionally divided into to 2 doses for the duration of the desired course of NS3 inhibitor compound treatment.
- the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of levovirin.
- Levovirin is generally administered in an amount ranging from about 30 mg to about 60 mg, from about 60 mg to about 125 mg, from about 125-mg to about 200 mg, from about 200 mg to about 300 gm, from about 300 mg to about 400 mg, from about 400 mg to about 1200 mg, from about 600 mg to about 1000 mg, or from about 700 to about 900 mg per day, or about 10 mg/kg body weight per day.
- levovirin is administered orally in dosages of about 400, about 800, about 1000, or about 1200 mg per day for the desired course of NS3 inhibitor compound treatment.
- the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of viramidine.
- Niramidine is generally administered in an amount ranging from about 30 mg to about 60 mg, from about 60 mg to about 125 mg, from about 125 mg to about 200 mg, from about 200 mg to about 300 gm, from about 300 mg to about 400 mg, from about 400 mg to about 1200 mg, from about 600 mg to about 1000 mg, or from about 700 to about 900 mg per day, or about 10 mg/kg body weight per day.
- viramidine is administered orally in dosages of about 800, or about 1600 mg per day for the desired course of ⁇ S3 inhibitor compound treatment.
- the methods provide for combination therapy comprising administering anNS3 inhibitor compound as described above, and an effective amount of thymosin- ⁇ .
- Thymosin- ⁇ (ZadaxinTM) is generally administered by subcutaneous injection.
- Thymosin- ⁇ can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously for the desired course of NS3 inhibitor compound treatment.
- thymosin- ⁇ is administered twice per week for the desired course of NS3 iiihibitor compound treatment.
- Effective dosages of thymosin- ⁇ range from about 0.5 mg to about 5 mg, e.g., from about 0.5 mg to about 1.0 mg, from about 1.0 mg to about 1.5 mg, from about 1.5 mg to about 2.0 mg, from about 2.0 mg to about 2.5 mg, from about 2.5 mg to about 3.0 mg, from about 3.0 mg to about 3.5 mg, from about 3.5 mg to about 4.0 mg, from about 4.0 mg to about 4.5 mg, or from about 4.5 mg to about 5.0 mg.
- thymosin- ⁇ is administered in dosages containing an amount of 1.0 mg or 1.6 mg.
- Thymosin- ⁇ can be administered over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.
- thymosin- ⁇ is administered for the desired course of NS3 inhibitor compound treatment.
- the methods provide for combination therapy comprising administering an NS3 inhibitor compound as described above, and an effective amount of an interferon receptor agonist.
- a compound of formula I and a Type I or III interferon receptor agonist are co-administered in the treatment methods of the invention.
- Type I interferon receptor agonists suitable for use herein include any interferon- ⁇ (IFN- ⁇ ).
- the interferon- ⁇ is a PEGylated interferon- ⁇ .
- the interferon- ⁇ is a consensus interferon, such as INFERGEN® interferon alfacon-1.
- the interferon- ⁇ is a monoPEG (30 kD, linear)-ylated consensus interferon.
- Effective dosages of an IFN- ⁇ range from about 3 ⁇ g to about 27 ⁇ g, from about 3 MU to about 10 MU, from about 90 ⁇ g to about 180 ⁇ g, or from about 18 ⁇ g to about 90 ⁇ g.
- Effective dosages of Infergen® consensus IFN- ⁇ include about 3 ' ⁇ g, about 6 ⁇ g, about 9 ⁇ g, about 12 ⁇ g, about 15 ⁇ g, about 18 ⁇ g, about 21 ⁇ g, about 24 ⁇ g, about 27 ⁇ g, or about 30 ⁇ g, of drug per dose.
- Effective dosages of IFN- ⁇ 2a and IFN- ⁇ 2b range from 3 million Units (MU) to 10 MU per dose.
- Effective dosages of PEGASYS®PEGylated IFN- ⁇ 2a contain an amount of about 90 ⁇ g to 270 ⁇ g, or about 180 ⁇ g, of drug per dose.
- Effective dosages of PEG- INTRON®PEGylated IFN- ⁇ 2b contain an amount of about 0.5 ⁇ g to 3.0 ⁇ g of drug per kg of body weight per dose.
- Effective dosages of PEGylated consensus interferon (PEG-CIFN) contain an amount of about 18 ⁇ g to about 90 ⁇ g, or from about 27 ⁇ g to about 60 ⁇ g, or about 45 ⁇ g, of CIFN amino acid weight per dose of PEG-CIFN.
- Effective dosages of monoPEG (30 kD, linear)-ylated CIFN contain an amount of about 45 ⁇ g to about 270 ⁇ g, or about 60 ⁇ g to about 180 ⁇ g, or about 90 ⁇ g to about 120 ⁇ g, of drug per dose.
- IFN- ⁇ can be administered daily, every other day, once a week, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.
- Type II interferon receptor agonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time.
- Dosage regimens can include tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or monthly administrations.
- the invention provides any of the above- described methods in which the desired dosage of IFN- ⁇ is administered subcutaneously to the patient by bolus delivery qd, qod, tiw, biw, qw, qow, three times per month, or monthly, or is administered subcutaneously to the patient per day by substantially continuous or continuous delivery, for the desired treatment duration.
- the invention provides any of the above-described methods in which the desired dosage of PEGylated IFN- ⁇ (PEG-IFN- ⁇ ) is administered subcutaneously to the patient by bolus delivery qw, qow, three times per month, or monthly for the desired treatment duration.
- an NS3 inhibitor compound and a Type II interferon receptor agonist are co-administered in the treatment methods of the invention.
- Type II interferon receptor agonists suitable for use herein include any interferon- ⁇ (IFN- ⁇ ).
- Effective dosages of IFN- ⁇ can range from about 0.5 ⁇ g/m 2 to about 500 ⁇ g/m 2 , usually from about 1.5 ⁇ g/m 2 to 200 ⁇ g/m 2 , depending on the size of the patient. This activity is based on 10 6 international units (U) per 50 ⁇ g of protein. IFN- ⁇ can be administered daily, every other day, tliree times a week, or substantially continuously or continuously.
- IFN- ⁇ is administered to an individual in a unit dosage form of from about 25 ⁇ g to about 500 ⁇ g, from about 50 ⁇ g to about 400 ⁇ g, or from about 100 ⁇ g to about 300 ⁇ g. In particular embodiments of interest, the dose is about 200 ⁇ g IFN- ⁇ . In many embodiments of interest, IFN- ⁇ lb is administered.
- the dosage is 200 ⁇ g IFN- ⁇ per dose
- the amount of IFN- ⁇ per body weight is 200 ⁇ g IFN- ⁇ per dose
- the body surface area of subject individuals generally ranges from about 1.33 m 2 to about 2.50 m 2 .
- an IFN- ⁇ dosage ranges from about 150 ⁇ g/m 2 to about 20 ⁇ g/m 2 .
- an IFN- ⁇ dosage ranges from about 20 ⁇ g/m 2 to about 30 ⁇ g/m 2 , from about 30 ⁇ g/m 2 to about 40 ⁇ g/m 2 , from about 40 ⁇ g/m 2 to about 50 ⁇ g/m 2 , from about 50 ⁇ g/m to about 60 ⁇ g/m , from about 60 ⁇ g/m to about 70 ⁇ g/m , from about 70 ⁇ g/m to about 80 ⁇ g/m 2 , from about 80 ⁇ g/m 2 to about 90 ⁇ g/m 2 , from about 90 ⁇ g/m 2 to about 100
- the dosage groups range from about 25 ⁇ g/m 2 to about 100 ⁇ g/m 2 . In other embodiments, the dosage groups range from about 25 ⁇ g/m 2 to about 50 ⁇ g/m 2 .
- a Type I or a Type III interferon receptor agonist is administered in a first dosing regimen, followed by a second dosing regimen.
- the first dosing regimen of Type I or a Type III interferon receptor agonist generally involves administration of a higher dosage of the Type I or Type III interferon receptor agonist.
- the first dosing regimen comprises administering CIFN at about 9 ⁇ g, about 15 ⁇ g, about 18 ⁇ g, or about 27 ⁇ g.
- the first dosing regimen can encompass a single dosing event, or at least two or more dosing events.
- the first dosing regimen of the Type I or Type III interferon receptor agonist can be administered daily, every other day, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.
- the first dosing regimen of the Type I or Type III interferon receptor agonist is administered for a first period of time, wliich time period can be at least about 4 weeks, at least about 8 weeks, or at least about 12 weeks.
- the second dosing regimen of the Type I or Type III interferon receptor agonist (also referred to as "the maintenance dose”) generally involves administration of a lower amount of the Type I or Type III interferon receptor agonist.
- the second dosing regimen comprises administering CIFN at a dose of at least about 3 ⁇ g, at least about 9 ⁇ g, at least about 15 ⁇ g, or at least about 18 ⁇ g.
- the second dosing regimen can encompass a single dosing event, or at least two or more dosing events.
- the second dosing regimen of the Type I or Type III interferon receptor agonist can be administered daily, every other day, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously..
- a "priming" dose of a Type II interferon receptor agonist e.g., IFN- ⁇
- IFN- ⁇ is administered for a period of time from about 1 day to about 14 days, from about 2 days to about 10 days, or from about 3 days to about 7 days, before the beginning of treatment with the Type I or Type III interferon receptor agonist. This period of time is referred to as the "priming" phase.
- the Type II interferon receptor agonist treatment is continued throughout the entire period of treatment with the Type I or Type III interferon receptor agonist.
- the Type II interferon receptor agonist treatment is discontinued before the end of treatment with the Type I or Type III interferon receptor agonist.
- the total time of treatment with Type II interferon receptor agonist (including the "priming" phase) is from about 2 days to about 30 days, from about 4 days to about 25 days, from about 8 days to about 20 days, from about 10 days to about 18 days, or from about 12 days to about 16 days.
- the Type II interferon receptor agonist treatment is discontinued once Type I or a Type III interferon receptor agonist treatment begins.
- the Type I or Type III interferon receptor agonist is administered in single dosing regimen.
- the dose of CIFN is generally in a range of from about 3 ⁇ g to about 15 ⁇ g, or from about 9 ⁇ g to about 15 ⁇ g.
- the dose of Type I or a Type III interferon receptor agonist is generally administered daily, every other day, three times a week, every other week, three times per month, once monthly, or substantially continuously.
- the dose of the Type I or Type III interferon receptor agonist is administered for a period of time, which period can be, for example, from at least about 24 weeks to at least about 48 weeks, or longer.
- a "priming" dose of a Type II interferon receptor agonist (e.g., IFN- ⁇ ) is included.
- IFN- ⁇ is administered for a period of time from about 1 day to about 14 days, from about 2 days to about 10 days, or from about 3 days to about 7 days, before the beginning of treatment with the Type I or Type III interferon receptor agonist. This period of time is referred to as the "priming" phase.
- the Type II interferon receptor agonist treatment is continued throughout the entire period of treatment with the Type I or Type III interferon receptor agonist.
- the Type II interferon receptor agonist treatment is discontinued before the end of treatment with the Type I or Type III interferon receptor agonist.
- the total time of treatment with the Type II interferon receptor agonist (including the "priming" phase) is from about 2 days to about 30 days, from about 4 days to about 25 days, from about 8 days to about 20 days, from about 10 days to about 18 days, or from about 12 days to about 16 days.
- Type II interferon receptor agonist treatment is discontinued once Type I or a Type III interferon receptor agonist treatment begins.
- an NS3 inhibitor compound, a Type I or III interferon receptor agonist, and a Type II interferon receptor agonist are co-administered for the desired duration of treatment in the methods of the invention.
- an NS3 inhibitor compound, an interferon- ⁇ , and an interferon- ⁇ are co-administered for the desired duration of treatment in the methods of the invention.
- the invention provides methods using an amount of a Type I or
- Type III interferon receptor agonist, a Type II interferon receptor agonist, and an NS3 inhibitor compound, effective for the treatment of HCV infection in a patient provides methods using an effective amount of an IFN- ⁇ , IFN- ⁇ , and an NS3 inhibitor compound in the treatment of HCV infection in a patient.
- the invention provides a method using an effective amount of a consensus IFN- ⁇ , IFN- ⁇ and an NS3 inliibitor compound in the treatment of HCV infection in a patient.
- an effective amount of a consensus interferon (CIFN) and IFN- ⁇ suitable for use in the methods of the invention is provided by a dosage ratio of 1 ⁇ g CIFN: 10 ⁇ g IFN- ⁇ , where both CIFN and IFN- ⁇ are unPEGylated and unglycosylated species.
- the invention provides any of the above-described methods modified to use an effective amount of INFERGEN®consensus IFN- ⁇ and IFN- ⁇ in the treatment of HCV infection in a patient comprising administering to the patient a dosage of INFERGEN® containing an amount of about 1 ⁇ g to about 30 ⁇ g, of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN- ⁇ containing an amount of about 10 ⁇ g to about 300 ⁇ g of drug per dose of IFN- ⁇ , subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inliibitor compound.
- the invention provides any of the above-described methods modified to use an effective amount of INFERGEN®consensus IFN- ⁇ and IFN- ⁇ in the treatment of virus infection in a patient comprising administering to the patient a dosage of INFERGEN® containing an amount of about 1 ⁇ g to about 9 ⁇ g, of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, tliree times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN- ⁇ containing an amount of about 10 ⁇ g to about 100 ⁇ g of drug per dose of IFN- ⁇ , subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inliibitor compound.
- the invention provides any of the above-described methods modified to use an effective amount of INFERGEN®consensus IFN- ⁇ and IFN- ⁇ in the treatment of virus infection in a patient comprising administering to the patient a dosage of INFERGEN® containing an amount of about 1 ⁇ g of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN- ⁇ containing an amount of about 10 ⁇ g to about 50 ⁇ g of drug per dose of IFN- ⁇ , subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inliibitor compound.
- the invention provides any of the above-described methods modified to use an effective amount of INFERGEN®consensus IFN- ⁇ and IFN- ⁇ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of INFERGEN® containing an amount of about 9 ⁇ g of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN- ⁇ containing an amount of about 90 ⁇ g to about 100 ⁇ g of drug per dose of IFN- ⁇ , subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
- the invention provides any of the above-described methods modified to use an effective amount of INFERGEN®consensus IFN- ⁇ and IFN- ⁇ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of INFERGEN® containing an amount of about 30 ⁇ g of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of IFN- ⁇ containing an amount of about 200 ⁇ g to about 300 ⁇ g of drug per dose of IFN- ⁇ , subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
- the invention provides any of the above-described methods modified to use an effective amount of PEGylated consensus IFN- ⁇ and IFN- ⁇ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGylated consensus IFN- ⁇ (PEG-CIFN) containing an amount of about 4 ⁇ g to about 60 ⁇ g of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN- ⁇ containing an amount of about 30 ⁇ g to about 1,000 ⁇ g of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or administered substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
- PEG-CIFN PEGylated consensus IFN- ⁇
- the invention provides any of the above-described methods modified to use an effective amount of PEGylated consensus IFN- ⁇ and IFN- ⁇ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGylated consensus IFN- ⁇ (PEG-CIFN) containing an amount of about 18 ⁇ g to about 24 ⁇ g of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN- ⁇ containing an amount of about 100 ⁇ g to about 300 ⁇ g of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
- PEG-CIFN PEGylated consensus IFN- ⁇
- an effective amount of IFN- ⁇ 2a or 2b or 2c and IFN- ⁇ suitable for use in the methods of the invention is provided by a dosage ratio of 1 million Units (MU) IFN- ⁇ 2a or 2b or 2c : 30 ⁇ g IFN- ⁇ , where both IFN- ⁇ 2a or 2b or 2c and IFN- ⁇ are unPEGylated and unglycosylated species.
- MU 1 million Units
- the invention provides any of the above-described methods modified to use an effective amount of IFN- ⁇ 2a or 2b or 2c and IFN- ⁇ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of IFN- ⁇ 2a, 2b or 2c containing an amount of about 1 MU to about 20 MU of drug per dose of IFN- ⁇ 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of IFN- ⁇ containing an amount of about 30 ⁇ g to about 600 ⁇ g of drug per dose of IFN- ⁇ , subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inliibitor compound.
- the invention provides any of the above-described methods modified to use an effective amount of IFN- ⁇ 2a or 2b or 2c and IFN- ⁇ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of IFN- ⁇ 2a, 2b or 2c containing an amount of about 3 MU of drug per dose of IFN- ⁇ 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of IFN- ⁇ containing an amount of about 100 ⁇ g of drug per dose of IFN- ⁇ , subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
- the invention provides any of the above-described methods modified to use an effective amount of IFN- ⁇ 2a or 2b or 2c and IFN- ⁇ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of IFN- ⁇ 2a, 2b or 2c containing an amount of about 10 MU of drug per dose of IFN- ⁇ 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of IFN- ⁇ containing an amount of about 300 ⁇ g of drug per dose of IFN- ⁇ , subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
- the invention provides any of the above-described methods modified to use an effective amount of PEGASYS®PEGylated IFN- ⁇ 2a and IFN- ⁇ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGASYS® containing an amount of about 90 ⁇ g to about 360 ⁇ g, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN- ⁇ containing an amount of about 30 ⁇ g to about 1,000 ⁇ g, of drug per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
- the invention provides any of the above-described methods modified to use an effective amount of PEGASYS®PEGylated IFN- ⁇ 2a and IFN- ⁇ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGASYS® containing an amount of about 180 ⁇ g of drug per dose of PEGASYS®, subcutaneously qw, qow, tliree times per month, or monthly, in combination with a total weekly dosage of IFN- ⁇ containing an amount of about 100 ⁇ g to about 300 ⁇ g, of drug per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
- the invention provides any of the above-described methods modified to use an effective amount of PEG-INTRON®PEGylated IFN- ⁇ 2b and IFN- ⁇ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEG-INTRON® containing an amount of about 0.75 ⁇ g to about 3.0 ⁇ g of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN- ⁇ containing an amount of about 30 ⁇ g to about 1,000 ⁇ g of drug per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
- the invention provides any of the above-described methods modified to use an effective amount of PEG-INTRON®PEGylated IFN- ⁇ 2b and IFN- ⁇ in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEG-INTRON® containing an amount of about 1.5 ⁇ g of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN- ⁇ containing an amount of about 100 ⁇ g to about 300 ⁇ g of drug per week administered in divided doses subcutaneously qd, qod, tiw, or biw, or administered substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
- the present invention provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 ⁇ g INFERGEN® consensus IFN- ⁇ administered subcutaneously qd or tiw, and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
- ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
- the present invention provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inliibitor; and a regimen of 9 ⁇ g INFERGEN® consensus IFN- ⁇ administered subcutaneously qd or tiw; 50 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
- ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
- the present invention provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 ⁇ g INFERGEN® consensus IFN- ⁇ administered subcutaneously qd or tiw; 100 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
- ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
- the present invention provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 ⁇ g INFERGEN® consensus IFN- ⁇ administered subcutaneously qd or tiw; and 50 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
- the present invention provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 9 ⁇ g INFERGEN® consensus IFN- ⁇ administered subcutaneously qd or tiw; and 100 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
- the present invention provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of anNS3 inliibitor; and a regimen of 9 ⁇ g INFERGEN® consensus IFN- ⁇ administered subcutaneously qd or tiw; 25 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
- ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
- the present invention provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of anNS3 inhibitor; and a regimen of 9 ⁇ g INFERGEN® consensus IFN- ⁇ administered subcutaneously qd or tiw; 200 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
- ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
- the present invention provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of anNS3 inhibitor; and a regimen of 9 ⁇ g INFERGEN® consensus IFN- ⁇ administered subcutaneously qd or tiw; and 25 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
- the present invention provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of anNS3 inhibitor; and a regimen of 9 ⁇ g INFERGEN® consensus IFN- ⁇ administered subcutaneously qd or tiw; and 200 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
- the present invention provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 100 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw, and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
- ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
- the present invention provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 100 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw; 50 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
- ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
- the present invention provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 100 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw; 100 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
- ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
- the present invention provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 100 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw; and 50 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
- the present invention provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 100 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw; and 100 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
- the present invention provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 150 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw, and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
- ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
- the present invention provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 150 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw; 50 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
- ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
- the present invention provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 150 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw; 100 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
- ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
- the present invention provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of anNS3 inhibitor; and a regimen of 150 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw; and 50 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
- the present invention provides any of the above-described-methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 150 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw; and 100 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
- the present invention provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of anNS3 inhibitor; and a regimen of 200 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw, and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
- ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
- the present invention provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 200 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw; 50 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
- ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
- the present invention provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 200 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw; 100 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
- ribavirin is administered in an amount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
- the present invention provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 200 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw; and 50 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
- the present invention provides any of the above-described methods modified to comprise administering to an individual having an HCV infection an effective amount of an NS3 inhibitor; and a regimen of 200 ⁇ g monoPEG(30 kD, linear)-ylated consensus IFN- ⁇ administered subcutaneously every 10 days or qw; and 100 ⁇ g Actimmune® human IFN- ⁇ lb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
- I interferon receptor agonist e.g., an IFN- ⁇
- Type II interferon receptor agonist e.g., an IFN- ⁇
- a TNF- ⁇ antagonist e.g., a TNF- ⁇ antagonist other than pirfenidone or a pirfenidone analog
- exemplary, non- limiting TNF- ⁇ antagonists that are suitable for use in such combination therapies include ENBREL®, REMICADE®, and HUMIRATM.
- the invention provides a method using an effective amount of
- ENBREL® an effective amount of IFN- ⁇ ; an effective amount of IFN- ⁇ ; and an effective amount of an NS3 inliibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage ENBREL® containing an amount of from about 0.1 ⁇ g to about 23 mg per dose, from about 0.1 ⁇ g to about 1 ⁇ g, from about 1 ⁇ g to about 10 ⁇ g, from about 10 ⁇ g to about 100 ⁇ g, from about 100 ⁇ g to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, or from about 20 mg to about 23 mg of ENBREL®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or once every other month, or per day substantially continuously or continuously, for the desired duration of treatment.
- the invention provides a method using an effective amount of
- REMICADE® an effective amount of IFN- ⁇ ; an effective amount of IFN- ⁇ ; and an effective amount of an NS3 inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage of REMICADE® containing an amount of from about 0.1 mg/kg to about 4.5 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.0 mg/kg, from about 1.0 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to about 2.0 mg/kg, from about 2.0 mg/kg to about 2.5 mg/kg, from about 2.5 mg/kg to about 3.0 mg/kg, from about 3.0 mg/kg to about 3.5 mg/kg, from about 3.5 mg/kg to about 4.0 mg/kg, or from about 4.0 mg/kg to about 4.5 mg/kg per dose of REMICADE®, intravenously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or
- the invention provides a method using an effective amount of
- HUMIRATM an effective amount of IFN- ⁇ ; an effective amount of IFN- ⁇ ; and an effective amount of an NS3 inhibitor in the treatment of an HCV infection in a patient, comprising administering to the patient a dosage of HUMIRATM containing an amount of from about 0.1 ⁇ g to about 35 mg, from about 0.1 ⁇ g to about 1 ⁇ g, from about 1 ⁇ g to about 10 ⁇ g, from about 10 ⁇ g to about 100 ⁇ g, from about 100 ⁇ g to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, or from about 30 mg to about 35 mg per dose of a HUMIRATM, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or once every other month, or per day substantially continuously or continuously, for the desired
- the methods provide for combination therapy comprising administering an NS3 inliibitor compound as described above, and an effective amount of pirfenidone or a pirfenidone analog.
- an NS3 inhibitor compound, one or more interferon receptor agonist(s), and pirfenidone or pirfenidone analog are co- administered in the treatment methods of the invention.
- an NS3 inhibitor compound, a Type I interferon receptor agonist, and pirfenidone (or a pirfenidone analog) are co-administered.
- anNS3 inhibitor compound, a Type I interferon receptor agonist, a Type II interferon receptor agonist, and pirfenidone (or a pirfenidone analog) are co-administered.
- Type I interferon receptor agonists suitable for use herein include any IFN- ⁇ , such as interferon alfa-2a, interferon alfa-2b, interferon alfacon-1, and PEGylated IFN- ⁇ ' s, such as peginterferon alfa-2a, peginterferon alfa-2b, and PEGylated consensus interferons, such as monoPEG (30 kD, linear)-ylated consensus interferon.
- Type II interferon receptor agonists suitable for use herein include any interferon- ⁇ .
- Pirfenidone or a pirfenidone analog can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.
- Effective dosages of pirfenidone or a specific pirfenidone analog include a weight- based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally in one to five divided doses per day.
- Other doses and formulations of pirfenidone and specific pirfenidone analogs suitable for use in the treatment of fibrotic diseases are described in U.S. Pat. Nos., 5,310,562; 5,518,729; 5,716,632; and 6,090,822.
- the invention provides any of the above-described methods modified to include co-administering to the patient a therapeutically effective amount of pirfenidone or a pirfenidone analog for the duration of the desired course of NS3 inhibitor compound treatment.
- Combination therapies with TNF- ⁇ antagonists include co-administering to the patient a therapeutically effective amount of pirfenidone or a pirfenidone analog for the duration of the desired course of NS3 inhibitor compound treatment.
- the methods provide for combination therapy comprising administering an effective amount of anNS3 inhibitor compound as described above, and an effective amount of TNF- ⁇ antagonist, in combination therapy for treatment of an HCV infection.
- Effective dosages of a TNF- ⁇ antagonist range from 0.1 ⁇ g to 40 mg per dose, e.g., from about 0.1 ⁇ g to about 0.5 ⁇ g per dose, from about 0.5 ⁇ g to about 1.0 ⁇ g per dose, from about 1.0 ⁇ g per dose to about 5.0 ⁇ g per dose, from about 5.0 ⁇ g to about 10 ⁇ g per dose, from about 10 ⁇ g to about 20 ⁇ g per dose, from about 20 ⁇ g per dose to about 30 ⁇ g per dose, from about 30 ⁇ g per dose to about 40 ⁇ g per dose, from about 40 ⁇ g per dose to about 50 ⁇ g per dose, from about 50 ⁇ g per dose to about 60 ⁇ g per dose, from about 60 ⁇ g per dose to about 70 ⁇
- effective dosages of a TNF- ⁇ antagonist are expressed as mg/kg body weight.
- effective dosages of a TNF- ⁇ antagonist are from about 0.1 mg/kg body weight to about 10 mg/kg body weight, e.g., from about 0.1 mg/kg body weight to about 0.5 mg/kg body weight, from about 0.5 mg/kg body weight to about 1.0 mg/kg body weight, from about 1.0 mg/kg body weight to about 2.5 mg/kg body weight, from about 2.5 mg/kg body weight to about 5.0 mg/kg body weight, from about 5.0 mg/kg body weight to about 7.5 mg/kg body weight, or from about 7.5 mg/kg body weight to about 10 mg/kg body weight.
- a TNF- ⁇ antagonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time.
- the TNF- ⁇ antagonist can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously.
- a TNF- ⁇ antagonist is administered once per month, twice per month, three times per montn, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.
- a TNF- ⁇ antagonist and an NS3 inhibitor are generally administered in separate formulations.
- a TNF- ⁇ antagonist and an NS3 inhibitor may be administered substantially simultaneously, or within about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 8 hours, about 16 hours, about 24 hours, about 36 hours, about 72 hours, about 4 days, about 7 days, or about 2 weeks of one another.
- the invention provides a method using an effective amount of a
- TNF- ⁇ antagonist and an effective amount of an NS3 inhibitor in the treatment of an HCV infection in a patient comprising administering to the patient a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
- the invention provides a method using an effective amount of
- ENBREL® and an effective amount of an NS3 inhibitor in the treatment of an HCV infection in a patient comprising administering to the patient a dosage ENBREL® containing an amount of from about 0.1 ⁇ g to about 23 mg per dose, from about 0.1 ⁇ g to about 1 ⁇ g, from about 1 ⁇ g to about 10 ⁇ g, from about 10 ⁇ g to about 100 ⁇ g, from about 100 ⁇ g to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, or from about 20 mg to about 23 mg of ENBREL®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or once every other month, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
- the invention provides a method using an effective amount of
- REMICADE® and an effective amount of an NS3 inhibitor in the treatment of an HCV infection in a patient comprising administering to the patient a dosage of REMICADE® containing an amount of from about 0.1 mg/kg to about 4.5 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.0 mg/kg, from about 1.0 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to about 2.0 mg/kg, from about 2.0 mg/kg to about 2.5 mg/kg, from about 2.5 mg/kg to about 3.0 mg/kg, from about 3.0 mg/kg to about 3.5 mg/kg, from about 3.5 mg/kg to about 4.0 mg/kg, or from about 4.0 mg/kg to about 4.5 mg/kg per dose of REMICADE®, intravenously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or once every other month, or per day substantially continuously or continuously, for the desired duration of treatment
- the invention provides a method using an effective amount of
- HUMIRATM and an effective amount of an NS3 inhibitor in the treatment of an HCV infection in a patient comprising administering to the patient a dosage of HUMIRATM containing an amount of from about 0.1 ⁇ g to about 35 mg, from about 0.1 ⁇ g to about 1 ⁇ g, from about 1 ⁇ g to about 10 ⁇ g, from about 10 ⁇ g to about 100 ⁇ g, from about 100 ⁇ g to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, or from about 30 mg to about 35 mg per dose of a HUMIRATM, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or once every other month, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
- the methods provide for combination therapy comprising administering an effective amount of anNS3 inhibitor compound as described above, and an effective amount of thymosin- ⁇ , in combination therapy for treatment of an HCV infection.
- Effective dosages of thymosin- ⁇ range from about 0.5 mg to about 5 mg, e.g., from about 0.5 mg to about 1.0 mg, from about 1.0 mg to about 1.5 mg, from about 1.5 mg to about 2.0 mg, from about 2.0 mg to about 2.5 mg, from about 2.5 mg to about 3.0 mg, from about 3.0 mg to about 3.5 mg, from about 3.5 mg to about 4.0 mg, from about 4.0 mg to about 4.5 mg, or from about 4.5 mg to about 5.0 mg.
- thymosin- ⁇ is administered in dosages containing an amount of 1.0 mg or 1.6 mg.
- the invention provides a method using an effective amount of
- ZADAXINTM thymosin- ⁇ and an effective amount of an NS3 inhibitor in the treatment of an HCV infection in a patient comprising administering to the patient a dosage of ZADAXINTM containing an amount of from about 1.0 mg to about 1.6 mg per dose, subcutaneously twice per week for the desired duration of treatment with the NS3 inhibitor compound.
- Combination therapies with a TNF- ⁇ antagonist and an interferon comprising administering to the patient a dosage of ZADAXINTM containing an amount of from about 1.0 mg to about 1.6 mg per dose, subcutaneously twice per week for the desired duration of treatment with the NS3 inhibitor compound.
- the present invention provides a method of treating an HCV infection in an individual having an HCV infection, the method comprising administering an effective amount of an NS3 inhibitor, and effective amount of a TNF- ⁇ antagonist, and an effective amount of one or more interferons.
- the invention provides any of the above-described methods modified to use an effective amount of IFN- ⁇ and an effective amount of a TNF- ⁇ antagonist in the treatment of HCV infection in a patient comprising administering to the patient a dosage of IFN- ⁇ containing an amount of about 10 ⁇ g to about 300 ⁇ g of drug per dose of IFN- ⁇ , subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
- the invention provides any of the above-described methods modified to use an effective amount of IFN- ⁇ and an effective amount of a TNF- ⁇ antagonist in the treatment of HCV infection in a patient comprising administering to the patient a dosage of IFN- ⁇ containing an amount of about 10 ⁇ g to about 100 ⁇ g of drug per dose of IFN- ⁇ , subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS 3 inhibitor compound.
- the invention provides any of the above-described methods modified to use an effective amount of IFN- ⁇ and an effective amount of a TNF- ⁇ antagonist in the treatment of a virus infection in a patient comprising administering to the patient a total weekly dosage of IFN- ⁇ containing an amount of about 30 ⁇ g to about 1,000 ⁇ g of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or administered substantially continuously or continuously, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
- the invention provides any of the above-described methods modified to use an effective amount of IFN- ⁇ and an effective amount of a TNF- ⁇ antagonist in the treatment of a virus infection in a patient comprising administering to the patient a total weekly dosage of IFN- ⁇ containing an amount of about 100 ⁇ g to about 300 ⁇ g of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or administered substantially continuously or continuously, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inliibitor compound.
- the invention provides any of the above-described methods modified to use an effective amount of INFERGEN® consensus IFN- ⁇ and a TNF- ⁇ antagonist in the treatment of HCV infection in a patient comprising administering to the patient a dosage of INFERGEN® containing an amount of about 1 ⁇ g to about 30 ⁇ g, of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
- the invention provides any of the above-described methods modified to use an effective amount of INFERGEN® consensus IFN- ⁇ and a TNF- ⁇ antagonist in the treatment of HCV infection in a patient comprising administering to the patient a dosage of INFERGEN® containing an amount of about 1 ⁇ g to about 9 ⁇ g, of drug per dose of INFERGEN®, subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day substantially continuously or continuously, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
- the invention provides any of the above-described methods modified to use an effective amount of PEGylated consensus IFN- ⁇ and an effective amount of a TNF- ⁇ antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGylated consensus IFN- ⁇ (PEG-CIFN) containing an amount of about 4 ⁇ g to about 60 ⁇ g of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
- PEG-CIFN PEGylated consensus IFN- ⁇
- the invention provides any of the above-described methods modified to use an effective amount of PEGylated consensus IFN- ⁇ and an effective amount of a TNF- ⁇ antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGylated consensus IFN- ⁇ (PEG-CIFN) containing an amount of about 18 ⁇ g to about 24 ⁇ g of CIFN amino acid weight per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
- PEG-CIFN PEGylated consensus IFN- ⁇
- the invention provides any of the above-described methods modified to use an effective amount of IFN- ⁇ 2a or 2b or 2c and an effective amount of a TNF- ⁇ antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of IFN- ⁇ 2a, 2b or 2c containing an amount of about 1 MU to about 20 MU of drug per dose of IFN- ⁇ 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
- the invention provides any of the above-described methods modified to use an effective amount of IFN- ⁇ 2a or 2b or 2c and an effective amount of a TNF- ⁇ antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of IFN- ⁇ 2a, 2b or 2c containing an amount of about 3 MU of drug per dose of IFN- ⁇ 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
- the invention provides any of the above-described methods modified to use an effective amount of IFN- ⁇ 2a or 2b or 2c and an effective amount of a TNF- ⁇ antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of IFN- ⁇ 2a, 2b or 2c containing an amount of about 10 MU of drug per dose of IFN- ⁇ 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for -the desired duration of treatment with an NS3 inhibitor compound.
- the invention provides any of the above-described methods modified to use an effective amount of PEGASYS®PEGylated IFN- ⁇ 2a and an effective amount of a TNF- ⁇ antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGASYS® containing an amount of about 90 ⁇ g to about 360 ⁇ g, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
- the invention provides any of the above-described methods modified to use an effective amount of PEGASYS®PEGylated IFN- ⁇ 2a and an effective amount of a TNF- ⁇ antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEGASYS® containing an amount of about 180 ⁇ g, of drug per dose of PEGASYS®, subcutaneously qw, qow, three times per month, or monthly, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inliibitor compound.
- the invention provides any of the above-described methods modified to use an effective amount of PEG-INTRON® PEGylated IFN- ⁇ 2b and an effective amount of a TNF- ⁇ antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEG-INTRON® containing an amount of about 0.75 ⁇ g to about 3.0 ⁇ g of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously qw, qow, three times per month, or monthly, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
- the invention provides any of the above-described methods modified to use an effective amount of PEG-INTRON®PEGylated IFN- ⁇ 2b and an effective amount of a TNF- ⁇ antagonist in the treatment of a virus infection in a patient comprising administering to the patient a dosage of PEG-INTRON® containing an amount of about 1.5 ⁇ g of drug per kilogram of body weight per dose of PEG-INTRON®, subcutaneously qw, qow, three times per month, or monthly, in combination with a dosage of a TNF- ⁇ antagonist containing an amount of from about 0.1 ⁇ g to about 40 mg per dose of a TNF- ⁇ antagonist, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously, for the desired duration of treatment with an NS3 inhibitor compound.
- Combination therapies with other antiviral agents with other antiviral agents
- HCV NS3 helicase Other agents such as inhibitors of HCV NS3 helicase are also attractive drugs for combinational therapy, and are contemplated for use in combination therapies described herein.
- Ribozymes such as HeptazymeTM and phosphorothioate oligonucleotides which are complementary to HCV protein sequences and which inhibit the expression of viral core proteins are also suitable for use in combination therapies described herein.
- the additional antiviral agent(s) is administered during the entire course of treatment with the NS3 inhibitor compound of the invention, and the beginning and end of the treatment periods coincide. In other embodiments, the additional antiviral agent(s) is administered for a period of time that is overlapping with that of the NS3 inhibitor compound treatment, e.g., treatment with the additional antiviral agent(s) begins before the NS3 inhibitor compound treatment begins and ends before the NS3 inliibitor compound treatment ends; treatment with the additional antiviral agent(s) begins after the NS3 inhibitor compound treatment begins and ends after the NS3 inhibitor compound treatment ends; treatment with the additional antiviral agent(s) begins after the NS3 inhibitor compound treatment begins and ends before the NS3 inhibitor compound treatment ends; or treatment with the additional antiviral agent(s) begins before the NS3 inliibitor compound treatment begins and ends after the NS3 inhibitor compound treatment ends.
- the NS3 inhibitor compound can be administered together with (i.e., simultaneously in separate formulations; simultaneously in the same formulation; administered in separate formulations and within about 48 hours, within about 36 hours, within about 24 hours, within about 16 hours, within about 12 hours, within about 8 hours, within about 4 hours, within about 2 hours, within about 1 hour, within about 30 minutes, or within about 15 minutes or less) one or more additional antiviral agents.
- any of the above-described methods featuring an IFN- ⁇ regimen can be modified to replace the subject IFN- ⁇ regimen with a regimen of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ comprising administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days for the desired treatment duration with an NS3 inhibitor compound.
- any of the above-described methods featuring an IFN- ⁇ regimen can be modified to replace the subject IFN- ⁇ regimen with a regimen of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ comprising administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ containing an amount of 150 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days for the desired treatment duration with an NS3 inhibitor compound.
- any of the above-described methods featuring an IFN- ⁇ regimen can be modified to replace the subject IFN- ⁇ regimen with a regimen of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ comprising administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ containing an amount of 200 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days for the desired treatment duration with an NS3 inhibitor compound.
- any of the above-described methods featuring an IFN- ⁇ regimen can be modified to replace the subject IFN- ⁇ regimen with a regimen of INFERGEN® interferon alfacon-1 comprising administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously once daily or tliree times per week for the desired treatment duration with an NS3 inhibitor compound.
- any of the above-described methods featuring an IFN- ⁇ regimen can be modified to replace the subject IFN- ⁇ regimen with a regimen of INFERGEN® interferon alfacon-1 comprising administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously once daily or three times per week for the desired treatment duration with an NS3 inhibitor compound.
- any of the above-described methods featuring an IFN- ⁇ regimen can be modified to replace the subject IFN- ⁇ regimen with a regimen of IFN- ⁇ comprising administering a dosage of IFN- ⁇ containing an amount of 25 ⁇ g of drug per dose, subcutaneously tliree times per week for the desired treatment duration with an NS3 inhibitor compound.
- any of the above-described methods featuring an IFN- ⁇ regimen can be modified to replace the subject IFN- ⁇ regimen with a regimen of IFN- ⁇ comprising administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week for the desired treatment duration with an NS3 inliibitor compound.
- any of the above-described methods featuring an IFN- ⁇ regimen can be modified to replace the subject IFN- ⁇ regimen with a regimen of IFN- ⁇ comprising administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week for the desired treatment duration with an NS3 inhibitor compound.
- IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously once weeldy, once every 8 days, or once every 10 days; and (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
- any of the above-described methods featuring a TNF antagonist regimen can be modified to replace the subject TNF antagonist regimen with a TNF antagonist regimen comprising administering a dosage of a TNF antagonist selected from the group of: (a) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (b) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter, or (c) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; for the desired treatment duration with an NS3 inhibitor compound.
- a TNF antagonist selected from the group of: (a) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (b) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter, or (c) adalimumab in
- IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inliibitor compound.
- IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ containing an amount of 150 ⁇ g of drug per dose, subcutaneously once weeldy, once every 8 days, or once every 10 days; and (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
- IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ containing an amount of 150 ⁇ g of drug per dose, subcutaneously once weeldy, once every 8 days, or once every 10 days; and (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
- IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ containing an amount of 200 ⁇ g of drug per dose, subcutaneously once weeldy, ' once every 8 days, or once every 10 days; and (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
- IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ containing an amount of 200 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
- IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN- ⁇ containing an amount of 25 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
- IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
- IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
- IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN- ⁇ containing an amount of 25 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inliibitor compound.
- IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
- IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
- IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN- ⁇ containing an amount of 25 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
- IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
- IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously tliree times per week; and (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
- IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN- ⁇ containing an amount of 25 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inhibitor compound.
- IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; for the desired treatment duration with an NS3 inliibitor compound.
- IFN- ⁇ combination regimen can be modified to replace the subject IFN- ⁇ and IFN- ⁇ combination regimen with an IFN- ⁇ and IFN- ⁇ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously tliree times per week; for the desired treatment duration with an NS3 inhibitor compound.
- IFN- ⁇ and TNF antagonist combination regimen can be modified. to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)- ylated consensus IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week
- IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)- ylated consensus IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weeldy or once every other
- IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)- ylated consensus IFN- ⁇ containing an amount of 150 ⁇ g of drug per dose, subcutaneously once weeldy, once every 8 days, or once every 10 days; (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously tliree times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once we
- IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)- ylated consensus IFN- ⁇ containing an amount of 150 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week;
- IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)- ylated consensus IFN- ⁇ containing an amount of 200 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weeldy or once every other
- IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)- ylated consensus IFN- ⁇ containing an amount of 200 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week;
- IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN- ⁇ containing an amount of 25 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
- IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
- IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously tliree times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
- IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN- ⁇ containing an amount of 25 ⁇ g of drug per dose, subcutaneously tliree times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
- IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
- IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
- IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN- ⁇ containing an amount of 25 ⁇ g of drug per dose, subcutaneously tliree times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
- IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously tliree times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weeldy or once every other week; for the desired treatment duration with an NS3 inhibitor
- IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
- IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN- ⁇ containing an amount of 25 ⁇ g of drug per dose, subcutaneously tliree times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
- IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weeldy or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
- IFN- ⁇ and TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ , IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
- TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weeldy or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
- TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ containing an amount of 150 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
- a dosage of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ containing an amount of 150 ⁇ g of drug per dose
- TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ containing an amount of 200 ⁇ g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
- a dosage of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ containing an amount of 200 ⁇ g of drug per dose
- TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously once daily or tliree times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weeldy or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
- a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 ⁇ g of drug per dose, subcutaneously once daily or tliree times per
- TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously once daily or three times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weeldy or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
- a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 ⁇ g of drug per dose, subcutaneously once daily or three times per week
- TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of IFN- ⁇ containing an amount of 25 ⁇ g of drug per dose, subcutaneously three times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
- TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of IFN- ⁇ containing an amount of 50 ⁇ g of drug per dose, subcutaneously three times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
- TNF antagonist combination regimen can be modified to replace the subject IFN- ⁇ and TNF antagonist combination regimen with an IFN- ⁇ and TNF antagonist combination regimen comprising: (a) administering a dosage of IFN- ⁇ containing an amount of 100 ⁇ g of drug per dose, subcutaneously three times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration with an NS3 inhibitor compound.
- any of the above-described methods that includes a regimen of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ can be modified to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ with a regimen of peginterferon alfa-2a comprising administering a dosage of peginterferon alfa-2a containing an amount of 180 ⁇ g of drug per dose, subcutaneously once weekly for the desired treatment duration with an NS3 inhibitor compound.
- any of the above-described methods that includes a regimen of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ can be modified to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN- ⁇ with a regimen of peginterferon alfa-2b comprising administering a dosage of peginterferon alfa-2b containing an amount of 1.0 ⁇ g to 1.5 ⁇ g of drug per kilogram of body weight per dose, subcutaneously once or twice weekly for the desired treatment duration with an NS3 inliibitor compound.
- any of the above-described methods can be modified to include administering a dosage of ribavirin containing an amount of 400 mg, 800 mg, 1000 mg or 1200 mg of drug orally per day, optionally in two or more divided doses per day, for the desired treatment duration with an NS3 inhibitor compound.
- any of the above-described methods can be modified to include administering a dosage of ribavirin containing (i) an amount of 1000 mg of drug orally per day for patients having a body weight of less than 75 kg or (ii) an amount of 1200 mg of drug orally per day for patients having a body weight of greater than or equal to 75 kg, optionally in two or more divided doses per day, for the desired treatment duration with an NS3 inhibitor compound.
- any of the above-described methods can be modified to replace the subject NS3 inhibitor regimen with an NS3 inliibitor regimen comprising administering a dosage of 0.01 mg to 0.1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired freatment duration with the NS3 inhibitor compound.
- any of the above-described methods can be modified to replace the subject NS3 inhibitor regimen with an NS3 inhibitor regimen comprising administering a dosage of 0.1 mg to 1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with the NS3 inhibitor compound.
- any of the above-described methods can be modified to replace the subject NS3 inhibitor regimen with an NS3 inhibitor regimen comprising administering a dosage of 1 mg to 10 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with the NS3 inliibitor compound.
- any of the above-described methods can be modified to replace the subject NS3 inhibitor regimen with an NS3 inhibitor regimen comprising administering a dosage of 10 mg to 100 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with the NS3 inliibitor compound.
- any of the above-described methods featuring an NS5B inhibitor regimen can be modified to replace the subject NS5B inhibitor regimen with an NS5B inhibitor regimen comprising administering a dosage of 0.01 mg to 0.1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with an NS3 inhibitor compound.
- any of the above-described methods featuring an NS5B inhibitor regimen can be modified to replace the subject NS5B inhibitor regimen with an NS5B inliibitor regimen comprising administering a dosage of 0.1 mg to 1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with an NS3 inhibitor compound.
- any of the above-described methods featuring an NS5B inliibitor regimen can be modified to replace the subject NS5B inhibitor regimen with an NS5B inhibitor regimen comprising administering a dosage of 1 mg to 10 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with an NS3 inliibitor compound.
- any of the above-described methods featuring an NS5B inhibitor regimen can be modified to replace the subject NS5B inhibitor regimen with an NS5B inhibitor regimen comprising administering a dosage of 10 mg to 100 mg of drag per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration with an NS3 inhibitor compound.
- HCV patient is selected according to certain disease parameters exhibited by the patient, such as the initial viral load, genotype of the HCV infection in the patient, liver histology and/or stage of liver fibrosis in the patient.
- the present invention provides any of the above-described methods for the treatment of HCV infection in which the subject method is modified to treat a treatment failure patient for a duration of 48 weeks.
- the invention provides any of the above-described methods for
- HCV in which the subject method is modified to treat a non-responder patient, where the patient receives a 48 week course of therapy.
- the invention provides any of the above-described methods for the treatment of HCV infection in which the subject method is modified to treat a relapser patient, where the patient receives a 48 week course of therapy.
- the invention provides any of the above-described methods for the treatment of HCV infection in which the subject method is modified to treat a na ⁇ ve patient infected with HCV genotype 1, where the patient receives a 48 week course of therapy.
- the invention provides any of the above-described methods for the treatment of HCV infection in which the subject method is modified to treat a na ⁇ ve patient infected with HCV genotype 4, where the patient receives a 48 week course of therapy.
- the invention provides any of the above-described methods for the treatment of HCV infection in which the subject method is modified to treat a na ⁇ ve patient infected with HCV genotype 1, where the patient has a high viral load (HVL), where "HVL” refers to an HCV viral load of greater than 2 x 10 6 HCV genome copies per mL serum, and where the patient receives a 48 week course of therapy.
- HVL high viral load
- the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having advanced or severe stage liver fibrosis as measured by a Knodell score of 3 or 4 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks.
- the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having advanced or severe stage liver fibrosis as measured by a Knodell score of 3 or 4 and then (2) administering to the patient the drag therapy of the subject method for a time period of about 40 weeks to about 50 weeks, or about 48 weeks.
- the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of greater than 2 million viral genome copies per ml of patient serum and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks.
- the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of greater than 2 million viral genome copies per ml of patient serum and then (2) administering to the patient the drug therapy of the subject method for a time period of about 40 weeks to about 50 weeks, or about 48 weeks.
- the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of greater than 2 million viral genome copies per ml of patient serum and no or early stage liver fibrosis as measured by a Knodell score of 0, 1, or 2 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks.
- the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of greater than 2 million viral genome copies per ml of patient serum and no or early stage liver fibrosis as measured by a Knodell score of 0, 1, or 2 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 40 weeks to about 50 weeks, or about 48 weeks.
- the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of less than or equal to 2 million viral genome copies per ml of patient serum and then (2) administering to the patient the drug therapy of the subject method for a time period of about 20 weeks to about 50 weeks, or about 24 weeks to about 48 weeks, or about 30 weeks to about 40 weeks, or up to about 20 weeks, or up to about 24 weeks, or up to about 30 weeks, or up to about 36 weeks, or up to about 48 weeks.
- the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of less than or equal to 2 million viral genome copies per ml of patient serum and then (2) administering to the patient the drug therapy of the subject method for a time period of about 20 weeks to about 24 weeks.
- the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of less than or equal to 2 million viral genome copies per ml of patient serum and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 48 weeks.
- the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then (2) administering to the patient the drag therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks.
- the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then (2) administering to the patient the drag therapy of the subject method for a time period of about 20 weeks to about 50 weeks, or about 24 weeks to about 48 weeks, or about 30 weeks to about 40 weeks, or up to about 20 weeks, or up to about 24 weeks, or up to about 30 weeks, or up to about 36 weeks, or up to about 48 weeks.
- the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then (2) administering to the patient the drag therapy of the subject method for a time period of about 20 weeks to about 24 weeks.
- the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then (2) administering to the patient the drug therapy of the subject method for a time period of at least about 24 weeks.
- the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 or 4 infection and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks.
- the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV infection characterized by any of HCV genotypes 5, 6, 7, 8 and 9 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 20 weeks to about 50 weeks.
- the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV infection characterized by any of HCV genotypes 5, 6, 7, 8 and 9 and then (2) administering to the patient the drag therapy of the subject method for a time period of at least about 24 weeks and up to about 48 weeks.
- Any of the above treatment regimens can be administered to individuals who have been diagnosed with an HCV infection. Any of the above treatment regimens can be administered to individuals who have failed previous treatment for HCV infection ("treatment failure patients," including non-responders and relapsers).
- Individuals who have been clinically diagnosed as infected with HCV are of particular interest in many embodiments.
- Individuals who are infected with HCV are identified as having HCV RNA in their blood, and/or having anti-HCV antibody in their serum.
- Such individuals include anti-HCV ELISA-positive individuals, and individuals with a positive recombinant immunoblot assay (RIBA).
- RIBA positive recombinant immunoblot assay
- Individuals who are clinically diagnosed as infected with HCV include na ⁇ ve individuals (e.g., individuals not previously treated for HCV, particularly those who have not previously received IFN- ⁇ -based and/or ribavirin-based therapy) and individuals who have failed prior treatment for HCV ("treatment failure" patients).
- na ⁇ ve individuals e.g., individuals not previously treated for HCV, particularly those who have not previously received IFN- ⁇ -based and/or ribavirin-based therapy
- individuals who have failed prior treatment for HCV (“treatment failure" patients).
- Treatment failure patients include non-responders (i.e., individuals in whom the HCV titer was not significantly or sufficiently reduced by a previous treatment for HCV, e.g., a previous IFN- ⁇ monotherapy, a previous IFN- ⁇ and ribavirin combination therapy, or a previous pegylated IFN- ⁇ and ribavirin combination therapy); and relapsers (i.e., individuals who were previously treated for HCV, e.g., who received a previous IFN- ⁇ monotherapy, a previous IFN- ⁇ and ribavirin combination therapy, or a previous pegylated IFN- ⁇ and ribavirin combination therapy, whose HCV titer decreased, and subsequently increased).
- non-responders i.e., individuals in whom the HCV titer was not significantly or sufficiently reduced by a previous treatment for HCV, e.g., a previous IFN- ⁇ monotherapy, a previous IFN- ⁇ and ribavirin combination therapy,
- individuals have an HCV titer of at least about
- the patient may be infected with any HCV genotype (genotype 1, including la and lb, 2, 3, 4, 6, etc. and subtypes (e.g., 2a, 2b, 3a, etc.)), particularly a difficult to treat genotype such as HCV genotype 1 and particular HCV subtypes and quasispecies.
- HCV genotype genotype 1, including la and lb, 2, 3, 4, 6, etc. and subtypes (e.g., 2a, 2b, 3a, etc.)
- genotype genotype
- subtypes e.g., 2a, 2b, 3a, etc.
- HCV-positive individuals are HCV-positive individuals (as described above) who exhibit severe fibrosis or early cirrhosis (non-decompensated, Child' s-Pugh class A or less), or more advanced cirrhosis (decompensated, Child' s-Pugh class B or C) due to chronic HCV infection and who are viremic despite prior anti-viral treatment with IFN- ⁇ -based therapies or who cannot tolerate IFN- ⁇ -based therapies, or who have a contraindication to such therapies.
- HCV-positive individuals with stage 3 or 4 liver fibrosis according to the METAVIR scoring system are suitable for treatment with the methods of the present invention.
- individuals suitable for treatment with the methods of the instant invention are patients with decompensated cirrhosis with clinical manifestations, including patients with far-advanced liver cirrhosis, including those awaiting liver transplantation.
- individuals suitable for treatment with the methods of the instant invention include patients with milder degrees of fibrosis including those with early fibrosis (stages 1 and 2 in the METAVIR, Ludwig, and Scheuer scoring systems; or stages 1, 2, or 3 in the Ishak scoring system.).
- Example 1-1 Synthesis of Com ⁇ ound# 101 (Compound AR00220042) by Method A:
- Step 1 Synthesis of 2S-(l ⁇ Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4R-hydroxy- pyrrolidine-1-carboxylic acid tert-butyl ester (3)
- Step 2 Syntheses of 3,4-Dihydro-lH-isoquinoline-2-carboxylic acid 1-tert- butoxycarbonyl-5-(lR-ethoxycarbonyl-2S-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3R-yl ester (5), and 3,4-Dihydro-lH-isoquinoIine-2-carboxylic acid l-tert-butoxycarbonyl-5-
- the dipeptide 3 (300 mg, 0.81 mmol) was dissolved in DCM (8 mL), followed by addition of CDI (163 mg, 1.2 equiv) in one portion. The reaction was stirred at rt overnight. After 15 h, the reaction was complete as monitored by TLC (DCM/MeOH 9:1). 1,2,3,4- tetraliydroisoquinoline (0.32 mL, 3 equiv) was added to the reaction portion- wise, and the reaction was stirred at rt for overnight.
- Step 3 Synthesis of 3,4-Dihydro-ljH-isoquinoline-2-carboxylic acid l-(2S-tert- butoxycarbonylamino-non-8-enoyl) ⁇ 5-(lR ⁇ ethoxycarbonyl-2S-vinyI ⁇ cyclopropylcarbamoyl)-pyrrolidin-3R-yl ester (7)
- the top isomer 5 (118 mg, 0.22 mmol) was dissolved in 4N HCl (dioxane, 8 mL) and left at rt for 90 min to remove the BOC protective group. It was then concentrated down, taken up in acetonitrile and concentrated down again twice. To this light brownish residue was added 4 (66.8 mg, 1.1 equiv) and HATU (93.5 mg, 1.1 equiv), followed by 2 mL DMF under nitrogen. The reaction was cooled on ice-water bath for 15 min, after which a 0.5 mL DMF solution of DIEA (0.13 mL, 4 equiv) was added to the reaction drop-wise wlrier stirring. The ice bath was left to slowly rise to rt and the reaction stirred for overnight.
- 4N HCl dioxane, 8 mL
- Step 4 Synthesis of (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(3,4- dihydro-l J H-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0
- Step 5 Synthesis of (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(3,4- dihydro-lH-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 ' ]nonadec-7-ene-4-carboxylic acid (Compound# 101)
- the macrocyclic ester 8 (60 mg, 0.092 mmol) was dissolved in 0.9 mL of a mixed solvent (THF/MeOH/H2O 2:1:1), followed by addition of LiOH-H 2 O (23 mg, 6 equiv). The mixture was stirred at rt for overnight. After 18h, TLC (DCM/MeOH 9:1) showed a clean new spot with a lower Rf. The reaction was concentrated down to almost dryness and partitioned between IN aq. HCl (15 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (2 x 10 mL).
- Compound AR00220122 [00431] (IS, 4S, 6R, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(3,4-dihydro-lH- isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 4 ' ]nonadec-7-ene-4- carboxylic acid (Compound AR00220122) was prepared similarly according to procedures described in Example 1-1, substituting compound 5 with 6 in Step 3. MS m/e 625 (M + +l).
- Example 1-2 Synthesis of Compound# 101 (Compound AR00220042) by Method B: Method B:
- Step 1 Synthesis of 2S-(l-Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4R-hydroxy- pyrrolidine-1-carboxylic acid tert-butyl ester (3)
- Step 2 Synthesis of lR- ⁇ [l-(2S-tert-Butoxycarbonylamino-non-8-enoyl)-4R-hydroxy- pyrrolidine-2S-carbonyl]-amino ⁇ -2S-vinyl-cyclopropanecarboxylic acid ethyl ester (9)
- Step 3 Synthesis of (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-hydroxy- 2,15-dioxo-3,16-diaza-tricycIo [14.3.0.0 4 ' ]nonadec-7-ene-4-carboxylic acid ethyl ester (10)
- the macrocyclic intermediate 10 (110 mg, 0.22 mmol) was dissolved in DCM (2.2 mL), followed by addition of CDI (45 mg, 0.27 mmol) in one portion. The reaction was stirred at rt overnight. After 15 h, the reaction was complete as monitored by TLC (DCM/MeOH 9:1). 1,2,3,4-tetrahydroisoquinoline (0.14 mL, 1.1 mmol) was added to the reaction drop-wise, and the reaction was stirred at rt for overnight. After 22h, TLC showed reaction complete. The reaction was diluted with DCM (6 mL) and washed with IN aq. HCl (2 2 mL), sat.
- Step 5 Compound 11 was hydrolyzed in the same fashion as described in the Step 5 of Example 1-1 to give compound# 101.
- Compound AR00294383 [00445] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-2,15-dioxo-18-(6- trifluoromethyl-3,4-dihydro-lH-isoquinoline-2-carbonyloxy)-3,16-diaza-tricyclo[14.3.0.0 4 ,6 ]nonadec-7-ene-4-carboxylic acid (compound AR00294383) was synthesized according to Method B, except 6-Trifluoromethyl-l,2,3,4-tetrahydro-isoquinoline was used in Step 4 instead.
- Compound AR00294384 [00446] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(5-fluoro-3,4-dihydro-lH- isoquinoline-2-carbonyIoxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 4 ' 6 ]nonadec-7-ene-4- carboxylic acid (compound AR00294384) was synthesized according to Method B, except 5- fluoromethyl-l,2,3,4-tetrahydro-isoquinoline was used in Step 4 instead.
- Compound AR00304065 [00452] (IS, 4R, 6S, 14S, 18R)-14-tert-Butoxycarbonylamino-18-(4,4-spirocyclobutyl-3,4- dihydro-lH-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza- tricyclo[14.3.0.0 4 ' ]nonadec-7-ene-4-carboxylic acid (compound AR00304065) was synthesized according to Method B, except 4,4-siprocyclobutyl- 1,2,3, 4-tetrahydro-isoquinoline was used in Step 4 instead.
- Compound AR00314578 [00466] (IS, AR, 6S, 14S, 18i )-18-(6-Amino-3,4-dihydro-lH-isoquinoline-2-carbonyloxy)-14- tert-butoxycarbonylamino-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 4 ' 6 ]nonadec-7-ene-4- carboxylic acid (Compound AR00314578) was synthesized according to Method B, except l,2,3,4-Tetrahydro-isoquinolin-6-ylamine was used in Step 4 instead. MS (POS ESI) m/z
- Compound AR00315998 [00472] (IS, 4R, 6S, 14S, 18i-)-14-tert-Butoxycarbonylamino-18-(5-chloro-l,3-dihydro- isoindole-2-carbonyloxy)-2, 15-dioxo-3 , 16-diaza-tricyclo[l 4.3.0.0 4 ' 6 ]nonadec-7-ene-4- carboxylic acid (Compound AR00315998) was synthesized according to Method B, except 5- Chloro-2,3-dihydro-lH-isoindole was used in Step 4 instead.
- Compound AR00315999 [00473] (IS, 4R, 6S, US, 18i-)-14-tert-Butoxycarbonylamino-18-(5,6-dichloro-l,3-dihydro- isoindole-2-carbonyloxy)-2, 15-dioxo-3, 16-diaza-tricyclo[14.3.0.0 4 ' 6 ]nonadec-7-ene-4- carboxylic acid (Compound AR00315999) was synthesized according to Method B, except 5,6-Dichloro-2,3-dihydro-lH-isoindole was used in Step 4 instead.
- Compound AR00320122 [00474] (IS, 4R, 6S, US, 18i?)-14-tert-Butoxycarbonylamino-18-(4i--methyl-3,4-dihydro-lH- isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 4 ' 6 ]nonadec-7-ene-4- carboxylic acid (Compound AR00320122) was synthesized according to Method B, except 4R- Methyl- 1,2,3, 4-tetrahydro-isoquinoline was used in Step 4 instead.
- Compound AR00320123 [00475] (IS, 4R, 6S, 14S, 18i?)-14-tert-Butoxycarbonylamino-18-(4S-methyl-3,4-dihydro-lH- isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 4 ' 6 ]nonadec-7-ene-4- carboxylic acid (Compound AR00320123) was synthesized according to Method B, except 4S- Methyl-l,2,3,4-tetrahydro-isoquinoline was used in Step 4 instead.
- Compound AR00365369 [00491] (15, AR, 65, 145, 18i?)-14-tert-Butoxycarbonylamino-18-(4-fluoro-l,3-dihydro- isoindole-2-carbonyloxy)-2, 15 -dioxo-3 , 16-diaza-tricyclo [ 14.3.0.0 4>6 ]nonadec-7-ene-4- carboxylic acid (Compound AR00365369) was synthesized according to the procedures described in Example 1-2, except that 4-fluoro-2,3-dihydro-lH-isoindole (synthesized according to Example 3-55a) was used to replace 1,2,3, 4-tetrahydro-isoquinoline in Step 4 instead.
- Compound AR00371946 [00492] (15, AR, 65, 145, 18i-)-14-tert-Butoxycarbonylamino-18-[5-(2-morpholin-4-yl-ethoxy)- l,3-dihydro-isoindole-2-carbonyloxy]-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 4 ' 6 ]nonadec-7- ene-4-carboxylic acid (Compound AR00371946) was synthesized according to the procedures described in Example 1-2, except that 5-(2-Morpholin-4-yl-ethoxy)-2,3-dihydro-lH-isoindole (prepared according to the procedures described in J.
- Compound AR00371947 (15, AR, 65, 145, 18i?)-14-tert-Butoxycarbonylamino-18-[5-(2-dimethylamino-ethoxy)- l,3-dihydro-isoindole-2-carbonyloxy]-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 4 ' 6 ]nonadec-7- ene-4-carboxylic acid (Compound AR00371947) was synthesized according to the procedures described in Example 1-2, except that [2-(2,3-Dihydro-lH-isoindol-5-yloxy)-ethyl]-dimethyl- amine (prepared according to the procedures described in J.
- Compound AR00371948 [00494] (15, AR, 6S, US, 18i?)-14-tert-Butoxycarbonylamino-18-[5-(2-isopropylamino-ethoxy)- l,3-dihydro-isoindole-2-carbonyloxy]-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 4 ' 6 ]nonadec-7- ene-4-carboxylic acid (Compound AR00371948) was synthesized according to the procedures described in Example 1-2, except that [2-(2,3-Dihydro-lH-isoindol-5-yloxy)-ethyl]-isopropyl- amine (prepared according to the procedures described in J.
- Step 1 Preparation of (IS, 4R, 6S, 14S, 18R)-14-Amino-18-(3,4-dihydro-lH-isoquinoIine- 2-carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 4 ' 6 ]nonadec-7-ene-4-carboxylic acid ethyl ester.
- Step 2 Preparation of (IS, 4R, 6S, 14S, 18R)-14-Cyclopentyloxycarbonylamino-18-(3,4- dihydro-lH-isoquinoline-2-carbonyIoxy)-2,15-dioxo-3,16-diaza- tricyclo[14.3.0.0 4 ' 6 ]nonadec-7-ene-4-carboxylic acid ethyl ester.
- Step 3 Preparation of (IS, 4R, 6S, 14S, 18R)-14-Cyclopentyloxycarbonylamino-18-(3,4- dihydro-lH-isoquinoline-2-carbonyloxy)-2,15-dioxo-3,16-diaza- tricyclo[14.3.0.0 4 ' 6 ]nonadec-7-ene-4-carboxylic acid (Compound AR00247310).
- Example 2-2 The following compounds were also prepared following the same procedures as aforementioned in Example 2-1, with either the cyclopentyl chloroformate being substituted by other electrophiles, and/or the P2-tetrahydroisoquinoline being substituted by other amine inputs as illustrated in Step 4 of Method B in Example 1-2.
- Example 2-2 The following compounds were also prepared following the same procedures as aforementioned in Example 2-1, with either the cyclopentyl chloroformate being substituted by other electrophiles, and/or the P2-tetrahydroisoquinoline being substituted by other amine inputs as illustrated in Step 4 of Method B in Example 1-2.
- Example 2-2 Example 2-2:
- Compound AR00304125 [00503] (15, AR, 65, 145, 18i?)-18-(3,4-Dihydro-lH-isoquinoline-2-carbonyloxy)-14-(2-fluoro- ethoxycarbonylamino)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 4 ' 6 ]nonadec-7-ene-4-carboxylic acid (Compound AR00304125) was synthesized according to the -procedures described in Example 2-1, except that 2-fluoroethanol was used to form the chloroformate reagent in Step 2 instead of cyclopentanol. MS m/e 615.1 (M + +l).
- Example 2-7 Example 2-7:
- Compound AR00320445 [00511] (15, AR, 65, 145, 18i?)-18-(5,6-Dichloro-l,3-dihydro-isoindole-2-carbonyloxy)-2,15- dioxo- 14-(tetrahydro-furan-3i?-yloxycarbonylamino)-3 , 16-diaza-tricyclo [14.3.0.0 4 ' 6 ]nonadec- 7-ene-4-carboxylic acid (Compound AR00320445) was synthesized according to the procedures described in Examples 1-2 and 2-1, except that 5,6-dichloro-2,3-dihydro-lH- isoindole was used instead in Step 4 of Example 1-2, and that tetrahydro-furan-3i?-ol was used to form the chloroformate reagent in Step 2 of Example 2-1 instead of cyclopentanol. MS: m/e 693.0 (M + ),
- Compound AR00294377 [00523] (15, AR, 65, 145, 18i?)-14-(3-tert-Butyl-ureido)-18-(3,4-dihydro-lH-isoquinoline-2- carbonyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.0 4 ' 6 ]nonadeC ⁇ 7-ene-4-carboxylic acid (Compound AR00294377) was synthesized according to the procedures described in Examples 1-2 and 2-24, except that tert-butyl isocyanate was used to replace cyclopentyl isocyanate in the Example 2-24 procedures. MS m/e 624.1 (M ⁇ +l).
- Example 2-26 Example 2-26:
- Compound AR00320078 [00527] (15, AR, 65, 145, 18i?)-14-(3-tert-Butyl-ureido)-18-(l,3-dihydro-isoindole-2- carbonyloxy)-2, 15-dioxo-3 , 16-diaza-tricyclo [14.3.0.0 4 ' 6 ]nonadec-7-ene-4-carboxylic acid (Compound AR00320078) was synthesized according to the procedures described in Examples 1-2 and 2-24, except that 2,3-dihydro-lH-isoindole was used to replace 1,2,3,4-tetrahydroisoquinoline in Step 4 of Example 1-2, and that tert-butyl isocyanate was used to replace cyclopentyl isocyanate in the Example 2-24 procedures. MS m/e 610.1 (M ⁇ +l).
- Example 2-30 Example 2-30:
- Compound AR00320449 [00529] (15, AR, 6S, US, 18i?)-14-(3-tert-Butyl-ureido)-18-(5-chloro-l,3-dihydro-isoindole-2- carbonyloxy)-2, 15-dioxo-3, 16-diaza-tricyclo [14.3.0.0 4 ' 6 ]nonadec-7-ene-4-carboxylic acid (Compound AR00320449) was synthesized according to the procedures described in Examples 1-2 and 2-24, except that 5-cl ⁇ loro-2,3-dihydro-lH-isoindole was used to replace 1,2,3,4- tetrahydro-isoquinoline in Step 4 of Example 1-2, and that tert-butyl isocyanate was used to replace cyclopentyl isocyanate in the Example 2-24 procedures.
- Compound AR00365381 [00531] (15, AR, 6S, US, 18i?)-14-Cyclopentyloxycarbonylamino-l 8-(5-fluoro-l- methoxymethyl-3 ,4-dihydro- 1 H-isoquinoline-2-carbonyloxy)-2, l-5-dioxo-3 , 16-diaza- tricyclo [14.3.0.0 4 ' 6 ]nonadec-7-ene-4-carboxylic acid (Compound AR00365381) was syntiiesized according to the procedures described in Examples 1-2 and 2-1, except that 5- fluoro-l-methoxymethyl-l,2,3,4-tetrahydro-isoquinolinium chloride was used to replace 1,2,3,4-Tetrahydro-isoquinoline in Step 4 of Example 1-2 instead.
- Compound AR00254906 [00535] (15, 4 ?, 6S, US, 18i?)-3,4-Dihydro-lH-isoquinoline-2-carboxylic acid 14-tert- butoxycarbonylamino-4-methanesulfonylaminocarbonyl-2, 15 -dioxo-3 , 16-diaza- tricyclo[14.3.0.0 4 ' 6 ]nonadec-7-en-18-yl ester (Compound AR00254906) was synthesized according to the procedures described in Example 3-1, except that methyl sulfonamide was used to replace cyclopropyl sulfonamide in the coupling step.
- Compound AR00261409 [00536] (15, AR, 6S, US, 18i?)-3,4-Dihydro-lH-isoquinoline-2-carboxylic acid 4-(butane-l- sulfonylaminocarbonyl)- 14-tert-butoxycarbonylamino-2, 15-dioxo-3 , 16-diaza- tricyclo[14.3.0.0 4 ' 6 ]nonadec-7-en-18-yl ester (Compound AR00261409) was synthesized according to the procedures described in Example 3-1, except that n-butyl sulfonamide was used to replace cyclopropyl sulfonamide in the coupling step.
- Compound AR00294381 [00538] (15, AR, 65, 145, 18 -l,3-Dihydro-isoindole-2-carboxylic acid 14-tert- butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15 -dioxo-3 , 16-diaza- tricyclo[14.3.0.0 4 ' 6 ]nonadec-7-en-18-yl ester (Compound AR00294381) was synthesized according to the procedures described in Examples 1-5 and 3-1.
- Compound AR00298996 [00539] (15, AR, 65, 145, 1 S -S-Fluoro-S ,4-dihydro- lH-isoquinoline-2-carboxylic acid 14-tert- butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15 -dioxo-3 , 16-diaza- tricyclo[14.3.0.0 4 ' 6 ]nonadec-7-en-18-yl ester (Compound AR00298996) was synthesized according to the procedures described in Examples 1-2 and 3-1, except that 5-Fluoro- 1,2,3, 4- tetrahydro-isoquinoline was used to replace 1,2,3, 4-tetrahydro-isoquinoline in Step 4 of Example 1-2.
- Compound AR00298997 [00540] (15, AR, 65, 145, 18i?)-8-TrifluoiOmethyl-3,4-dihydro-lH-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3 ,16- diaza-tricyclo[14.3.0.0 4 ' 6 ]nonadec-7-en-18-yl ester (Compound AR00298997) was synthesized according to the procedures described in Examples 1-2 and 3-1, except that 8-trifluoromethyl- 1,2,3, 4-tetrahydro-isoquinoline was used to replace 1,2,3, 4-tetrahydro-isoquinoline in Step 4 of Example 1-2.
- Compound AR00301746 [00541] (15, AR, 65, 145, 18i?)-7-Chloro-3,4-dihydro-lH-isoquinoline-2-carboxylic acid 14- tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza- tricyclo[14.3.0.0 4 ' 6 ]nonadec-7-en-18-yl ester (Compound AR00301746) was synthesized according to the procedures described in Examples 1-2 and 3-1, except that 7-chloro-l,2,3,4- tetrahydro-isoquinoline was used to replace 1,2,3, 4-tetrahydro-isoquinoline in Step 4 of Example 1-2.
- Compound AR00301747 [00542] (15, AR, 65, 145, 18i?)-6-Trifluoromethyl-3 ,4-dihydro- lHrisoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3 , 16- diaza-tricyclo[14.3.0.0 4 ' 6 ]nonadec-7-en-18-yl ester (Compound AR00301747) was synthesized according to the procedures described in Examples 1-2 and 3-1, except that 6-trifluoromethyl- 1,2,3, 4-tetrahydro-isoquinoline was used to replace 1,2,3, 4-tetrahydro-isoquinoline in Step 4 of Example 1-2.
- Compound AR00301751 [00543] (15, AR, 65, 145, 18i?)-6-Fluoro-3 ,4-dihydro- lH-isoquinoline-2-carboxylic acid 14-tert- butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3 , 16-diaza- tricyclo[14.3.0.0 4 ' 6 ]nonadec-7-en-18-yl ester (Compound AR00301751) was synthesized according to the procedures described in Examples 1-2 and 3-1, except that 6-fluoro-l,2,3,4- tetrahydro-isoquinoline was used to replace 1,2,3, 4-tetrahydro-isoquinoline in Step 4 of Example 1-2.
- Compound AR00304080 [00544] (15, AR, 6S, 145, lS ⁇ -S-Fluoro-S ⁇ -dihydro-lH-isoquinoline ⁇ -carboxylic acid 14-(3- cyclopentyl-ureido)-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza- tricyclo[14.3.0.0 4 ' 6 ]nonadec-7-en-18-yl ester (Compound AR00304080) was synthesized according to the procedures described in Examples 1-2, 2-24 and 3-1, except that 5-fluoro- 1,2,3, 4-tetrahydro-isoquinoline was used to replace 1,2,3, 4-tetrahydro-isoquinoline in Step 4 of Example 1-2.
- Compound AR00311815 [00551] (15, AR, 6S, US, 18i?)-l-Piperidin-l-ylmethyl-3 ,4-dihydro- lH-isoquinoline-2- carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15- dioxo-3,16-diaza-tricyclo[14.3.0.0 4 ' 6 ]nonadec-7-en-18-yl ester (Compound AR00311815) was synthesized according to the procedures described in Examples 1-2 and 3-1, except that 1- Piperidin-1-ylmethyl- 1,2,3, 4-tetrahydro-isoquinoline was used to replace 1,2,3,4-tetrahydroisoquinoline in Step 4 of Example 1-2.
- Compound AR00312024 [00552] (15, 42?, 65, 145, 18i?)-4,4-Spirocyclobutyl-3 ,4-dihydro- lH-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2, 15-dioxo-3 , 16- diaza-tricyclo[14.3.0.0 4 ' 6 ]nonadec-7-en-18-yl ester (Compound AR00312024) was synthesized according to the procedures described in Examples 1-2 and 3-1, except that 4,4- spirocyclobutyl- 1,2,3, 4-tetrahydro-isoquinoline was used to replace 1,2,3,4-tetrahydroisoquinoline in Step 4 of Example 1-2.
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
Claims
Priority Applications (33)
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MXPA06003963A MXPA06003963A (en) | 2003-10-14 | 2004-10-13 | Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of hcv replication. |
SI200431968T SI1680137T1 (en) | 2003-10-14 | 2004-10-13 | Macrocyclic carboxylic acid and acylsulfonamide compound as inhibitor of HCV replication |
RS20060259A RS54573B1 (en) | 2003-10-14 | 2004-10-13 | Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of hcv replication |
DK04795169.4T DK1680137T3 (en) | 2003-10-14 | 2004-10-13 | Macrocyclic carboxylic acid and acylsulfonamide compound as inhibitor of HCV replication |
JP2006535671A JP4584260B2 (en) | 2003-10-14 | 2004-10-13 | Macrocyclic carboxylic acids and acylsulfonamides as HCV replication inhibitors |
BRPI0415373-1A BRPI0415373A (en) | 2003-10-14 | 2004-10-13 | macrocyclic carboxylic acids and acylsulfonamides as hcv replication inhibitors |
NZ546347A NZ546347A (en) | 2003-10-14 | 2004-10-13 | Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of HCV replication |
CN2004800354123A CN1889970B (en) | 2003-10-14 | 2004-10-13 | Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of HCV replication |
RS20110578A RS20110578A3 (en) | 2003-10-14 | 2004-10-13 | Macrocyclic carboxylic acids and acyl sulfonamides as inhibitors of hcv replication |
PL04795169T PL1680137T3 (en) | 2003-10-14 | 2004-10-13 | Macrocyclic carboxylic acid and acylsulfonamide compound as inhibitor of HCV replication |
AU2004281780A AU2004281780B2 (en) | 2003-10-14 | 2004-10-13 | Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of HCV replication |
AP2006003579A AP2287A (en) | 2003-10-14 | 2004-10-13 | Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of HCV replication. |
EA200600732A EA011857B8 (en) | 2003-10-14 | 2004-10-13 | Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of hcv replication |
YUP-2006/0259A RS20060259A (en) | 2003-10-14 | 2004-10-13 | Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of hcv replication |
KR1020067007146A KR100853579B1 (en) | 2003-10-14 | 2004-10-13 | Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of hcv replication |
EP04795169A EP1680137B1 (en) | 2003-10-14 | 2004-10-13 | Macrocyclic carboxylic acid and acylsulfonamide compound as inhibitor of HCV replication |
CA002540858A CA2540858C (en) | 2003-10-14 | 2004-10-13 | Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of hcv replication |
ES04795169T ES2398912T3 (en) | 2003-10-14 | 2004-10-13 | Macrocyclic carboxylic acid and acylsulfonamide compound as an inhibitor of hepatitis C virus replication |
US11/093,884 US7491794B2 (en) | 2003-10-14 | 2005-03-29 | Macrocyclic compounds as inhibitors of viral replication |
TW094109828A TW200611905A (en) | 2004-03-30 | 2005-03-29 | Macrocyclic compounds as inhibitors of viral replication |
IL174704A IL174704A (en) | 2003-10-14 | 2006-03-30 | (1s, 4r, 6s, 14s, 18r)-4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclononadec-7-en-18-yl ester and its use for the manufacture of an anti-hcv infection medicament |
IS8395A IS2876B (en) | 2003-10-14 | 2006-03-31 | Macrocyclic carboxylic acid and acylsulfonamide compounds that inhibit hepatitis C replication |
TNP2006000103A TNSN06103A1 (en) | 2003-10-14 | 2006-04-04 | Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of hcv replication |
AP2011005830A AP2011005830A0 (en) | 2003-10-14 | 2006-04-11 | Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of HCV replication. |
NO20062089A NO343231B1 (en) | 2003-10-14 | 2006-05-09 | Compound and pharmaceutical composition comprising said compound and its use in the treatment of HCV infection. |
HK07100728.2A HK1100164A1 (en) | 2003-10-14 | 2007-01-19 | Macrocyclic carboxylic acid and acylsulfonamide compound as inhibitor of hcv replication |
US12/254,736 US20090286843A1 (en) | 2003-10-14 | 2008-10-20 | Macrocyclic compounds as inhibitors of viral replication |
US12/341,971 US20090105471A1 (en) | 2003-10-14 | 2008-12-22 | Macrocyclic compounds as inhibitors of viral replication |
US12/341,517 US20090111982A1 (en) | 2003-10-14 | 2008-12-22 | Macrocyclic compounds as inhibitors of viral replication |
US12/341,683 US20090111969A1 (en) | 2003-10-14 | 2008-12-22 | Macrocyclic compounds as inhibitors of viral replication |
IL215933A IL215933A0 (en) | 2003-10-14 | 2011-10-25 | Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of hcv replication |
IL215934A IL215934A0 (en) | 2003-10-14 | 2011-10-25 | Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of hcv replication |
HRP20130098TT HRP20130098T1 (en) | 2003-10-14 | 2013-02-05 | Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of hcv replication |
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US51154103P | 2003-10-14 | 2003-10-14 | |
US60/511,541 | 2003-10-14 | ||
US61246004P | 2004-09-22 | 2004-09-22 | |
US60/612,460 | 2004-09-22 |
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EP11160654.7A Previously-Filed-Application EP2407470A3 (en) | 2003-10-14 | 2004-10-13 | Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of HCV replication |
US6444505A Continuation | 2003-10-14 | 2005-02-23 |
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WO2005037214A2 true WO2005037214A2 (en) | 2005-04-28 |
WO2005037214A3 WO2005037214A3 (en) | 2005-11-03 |
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PCT/US2004/033970 WO2005037214A2 (en) | 2003-10-14 | 2004-10-13 | Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of hcv replication |
Country Status (30)
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EP (2) | EP1680137B1 (en) |
JP (3) | JP4584260B2 (en) |
KR (1) | KR100853579B1 (en) |
CN (2) | CN102020697B (en) |
AP (2) | AP2287A (en) |
AR (2) | AR046422A1 (en) |
AU (1) | AU2004281780B2 (en) |
BR (1) | BRPI0415373A (en) |
CA (1) | CA2540858C (en) |
CY (1) | CY1113809T1 (en) |
DK (1) | DK1680137T3 (en) |
EA (1) | EA011857B8 (en) |
EC (2) | ECSP066570A (en) |
ES (1) | ES2398912T3 (en) |
GE (1) | GEP20084560B (en) |
HK (2) | HK1100164A1 (en) |
HR (1) | HRP20130098T1 (en) |
IL (3) | IL174704A (en) |
IS (1) | IS2876B (en) |
MA (1) | MA28152A1 (en) |
MX (1) | MXPA06003963A (en) |
MY (1) | MY144593A (en) |
NO (1) | NO343231B1 (en) |
NZ (1) | NZ546347A (en) |
OA (1) | OA13315A (en) |
PL (1) | PL1680137T3 (en) |
PT (1) | PT1680137E (en) |
RS (3) | RS54573B1 (en) |
TW (2) | TWI375679B (en) |
WO (1) | WO2005037214A2 (en) |
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