CA2566677A1

CA2566677A1 - Combination therapy for treating hepatitis virus infection

Info

Publication number: CA2566677A1
Application number: CA002566677A
Authority: CA
Inventors: Osman N. Ozes; Scott D. Seiwert; Lawrence M. Blatt
Original assignee: Individual
Current assignee: Intermune Inc
Priority date: 2004-05-13
Filing date: 2005-05-09
Publication date: 2005-11-24
Also published as: WO2005110455A2; WO2005110455A3

Abstract

The present invention provides methods of treating a viral infection, e.g., a hepatitis C virus (HCV) infection; methods of reducing the incidence of complications associated with HCV infection and cirrhosis of the liver; and methods of reducing viral load, or reducing the time to viral clearance, or reducing morbidity or mortality in the clinical outcomes, in patients suffering from a viral infection, e.g., an HCV infection. The methods generally involve administering to the individual i) a stress-activated protein kinase inhibitor; and ii) a Type I interferon receptor agonist. The present invention provides a method of treating alcoholic liver disease, the method involving administering to an individual in need thereof an effective amount of a stress-activated protein kinase (SAPK) inhibitor, alone or in combination therapy. The present invention further provides methods for treating non-alcoholic steatohepatitis, the method generally involving administering to an individual in need thereof an effective amount of a SAPK
inhibitor, alone or in combination therapy.

Description

COMBINATION THERAPY FOR TREATING HEPATITIS VIRUS INFECTION
CROSS-REFERENCE
[0001] This application claims the benefit of U.S. Provisional Patent Application Nos.
60/571,196, filed May 13, 2004, and 60/571,227, filed May 13, 2004, which applications are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

[0002] The present invention is in the field of hepatic disease, particularly hepatitis C viral infection, alcoholic liver disease, and non-alcoholic steatohepatitis, and use of a stress-activated protein kinase inhibitor to treat hepatitis C viral infection, alcoholic liver disease, and non-alcoholic steatohepatitis.

BACKGROUND OF THE INVENTION

[0003] Hepatitis C virus (HCV) 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 HCV-related, resulting in an estimated 8,000-10,000 deaths each year. HCV-associated end-stage'liver disease is the most frequent indication for liver transplantation among adults.

[0004] Antiviral therapy of chronic hepatitis C has evolved rapidly over the last decade, with significant improvements seen in the efficacy of treatment. Nevertheless, even with combination therapy using pegylated IFN-a plus ribavirin, 40% to 50% of patients fail therapy, i.e., are nonresponders or relapsers. These patients currently have no effective therapeutic alternative. In particular, patients who have advanced fibrosis or cirrhosis on liver biopsy are at significant risk of developing complications of advanced liver disease, including ascites, jaundice, variceal bleeding, encephalopathy, and progressive liver failure, as well as a markedly increased risk of hepatocellular carcinoma.

[0005] The high prevalence of chronic HCV infection has important public health implications for the future burden of chronic liver disease in the United States. Data derived from the National Health and Nutrition Examination Survey (NHANES III) indicate that a large increase in the rate of new HCV infections occurred from the late 1960s to the early 1980s, particularly among persons between 20 to 40 years of age. It is estimated that the number of persons with long-standing HCV infection of 20 years or longer could more than quadruple from 1990 to 2015, from 750,000 to over 3 million. The proportional increase in persons infected for 30 or 40 years would be even greater. Since the risk of HCV-related chronic liver disease is related to the duration of infection, with the risk of cirrhosis progressively increasing for persons infected for longer than 20 years, this will result in a substantial increase in cirrhosis-related morbidity and mortality among patients infected between the years of 1965-1985.

[0006] Alcoholic liver disease (ALD) is a major cause of illness and death, and is the most common liver disease in the United States. It is the fourth leading cause of death in the United States, and results in between 20,000 and 40,000 deaths per year. Women are generally more susceptible to alcohol-induced liver damage than men and develop alcoholic liver disease at a more rapid rate having imbibed less alcohol.

[0007] ALD involves an acute or chronic inflammation of the liver induced by alcohol abuse.
ALD is characterized by fatty liver (steatosis), hepatitis, liver fibrosis, and cirrhosis. Alcoholic hepatitis is characterized histologically by hepatocellular necrosis, alcoholic Mallory's hyaline bodies, and an inflammatory reaction with infiltration by polymorphonuclear leukocytes and lymphocytes. The clinical presentation of alcoholic hepatitis varies with the severity of the disease. Common symptoms are weakness, anorexia, weight loss, nausea, vomiting, and diarrhea. Patients often present with fever, jaundice, and tender hepatomegaly.

[0008] Non-alcoholic steatohepatitis (NASH) is increasingly recognized as a relatively prevalent disorder that can lead to cirrhosis in some individuals. In fact, nearly 20% of patients with histologically proven NASH progress to cirrhosis. NASH can also progress to hepatic insufficiency and hepatocellular carcinoma. Because this disorder is difficult to identify non-invasively, and because its pathogenesis is not well understood, effective rational therapies are lacking.

[0009] There is a need in the art for improved methods for treating viral infections, e.g.
hepatitis C viral infection and for treating ALD and NASH. The present invention addresses this need.
Literature [0010] U.S. Patent Nos. 6,642,204, 6,617,309; U.S. Patent Nos. 6,524,570, 5,908,621, and 6,177,074; U.S. Patent No. 5,382,657; METAVIR (1994) Hepatology 20:15-20;
Brunt (2000) Hepatol. 31:241-246; Alpini (1997) J. Hepatol. 27:371-380; Baroni et al.
(1996) Hepatol.
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SUMMARY UF THE INVENTION

[0011] The present invention provides methods of treating a viral infection, e.g., a hepatitis C
virus (HCV) infection; methods of reducing the incidence of complications associated with HCV infection and cirrhosis of the liver; and methods of reducing viral load, or reducing the time to viral clearance, or reducing morbidity or mortality in the clinical outcomes, in patients suffering from a viral infection, e.g., an HCV infection. The methods generally involve administering to the individual i) a stress-activated protein kinase inhibitor; and ii) a Type I
interferon receptor agonist. The present invention provides a method of treating alcoholic liver disease, the method involving administering to an individual in need thereof an effective amount of a stress-activated protein kinase (SAPK) inhibitor, alone or in combination therapy.
The present invention further provides methods for treating non-alcoholic steatohepatitis, the method generally involving administering to an individual in need thereof an effective amount of a SAPK inhibitor, alone or in combination therapy.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 depicts results indicating that pirfenidone ("Pir") binding to SAPK3 (p38y) is competitive with ATP binding.

[0013] Figure 2 depicts results indicating that SAPK3 K; can be determined from ATP/pirfenidone competitive binding data.

[0014] Figure 3 depicts results indicating that pirfenidone can only bind SAPK3 after the phosphorylation substrate associates with the enzyme.

DEFINITIONS

[0015] As used herein, the terms "treatment," "treating," and the like, refer 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 tenns of a partial or complete cure for a disease and/or adverse affect attributable to the disease. "Treatment," as used herein, covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease or a symptom of a disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it (e.g., including diseases that may be associated with or caused by a primary disease (as in liver fibrosis that can result in the context of chronic HCV infection); (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease.

[0016] 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.

[0017] As used herein, the term "alcoholic hepatitis," refers to an acute or chronic inflammatory lesion of the liver that occurs in the context of chronic alcohol abuse.

[0018] As used herein, the term "alcoholic hepatic fibrosis," used interchangeably herein with "alcoholic liver fibrosis," refers to the growth of scar tissue in the liver that can occur in the context of chronic alcohol abuse.

[0019] The tenn "treatment failure patients" (or "treatment failures") as used herein generally refers to HCV-infected patients who failed to respond to previous therapy for HCV (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 IFN-a monotherapy or IFN-a combination therapy, where the combination therapy may include administration of IFN-a and an antiviral agent such as ribavirin.

[0020] As used herein, the term "a 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.

[0021] As used herein, the term "nucleoside" refers to a compound composed of any pentose or modified pentose moiety attached to a specific positioh of a heterocycle or to the natural position of a purine (9-position) or pyrimidine (1-position) or to the equivalent position in an analog.

[0022] As used herein, the tenn "nucleotide" refers to a phosphate ester substituted on the 5'-position of a nucleoside.

[0023] As used herein, the term "heterocycle" refers to a monovalent saturated or unsaturated carbocyclic radical having at least one hetero atom, such as N, 0, S, Se or P, within the ring, each available position of which can be optionally substituted, independently, with, e.g., hydroxyl, oxo, amino, imino, lower alkyl, bromo, chloro and/or cyano. Included within the term "heterocycle" are purines and pyrimidines.

[0024] As used herein, the term "purine" refers to nitrogenous bicyclic heterocycles.

[0025] As used herein, the term "pyrimidine" refers to nitrogenous monocyclic heterocycles.

[0026] As used herein, the term "L-nucleoside" refers to a nucleoside compound that has an L-ribose sugar moiety.

[0027] As used herein, the term "pirfenidone" refers to 5-methyl-1 -phenyl-2-(1 H)-pyridone.
As used herein, the term "pirfenidone analog" refers to any compound of Formula I. IIA or IIB
below. A "specific pirfenidone analog," and all grammatical variants thereof, refers to, and is limited to, each and every pirfenidone analog shown in Table 1.

[0028] As used herein, the term "a Type II interferon receptor agonist" refers to 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.

[0029] As used herein, the term "HCV enzyme inhibitor" refers to any agent that inhibits an enzymatic activity of an enzyme encoded by HCV. The term "HCV enzyme inhibitor"
includes, but is not limited to, agents that inhibit HCV NS3 protease activity; agents that inhibit HCV NS3 helicase activity; and agents that inhibit HCV NS5B RNA-dependent RNA
polymerase activity.

[0030] As used herein, the terms "HCV NS3 protease inhibitor" and "NS3 protease inhibitor"
refer to any agent that inhibits the protease activity of HCV NS3/NS4A
complex.

[0031] The term "hepatitis virus infection" refers to infection with one or more of hepatitis A, B, C, D, or E'virus, with blood-borne hepatitis viral infection being of particular interest, particularly hepatitis C virus infection.

[0032] The term "sustained viral response" (SVR; also referred to as a "sustained response" or a "durable response"), as used herein, refers to the response of an individual to a treatment regimen for HCV infection, in terms of serum HCV titer. Generally, a "sustained viral response" refers to no detectable HCV RNA (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.

[0033] As used herein, the term "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.

[0034] As used herein, the term "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, 7-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 ainmonia metabolism, hormone metabolism, and lipid metabolism;
detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics; and the like.

[0035] The term "dosing event" as used herein 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. Thus, 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.

[0036] "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.

[0037] "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 interferon receptor agonist, e.g., IFN-a; or a SAPK inhibitor) at a selected or otherwise controllable rate, interval, and/or amount, which is not substantially influenced by the environment of use. "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).

[0038] "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.

[0039] The term "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.

[0040] By "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. Furthermore, "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.

[0041] By "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 (AUC8h,) 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 AUC8hr average is defined as the quotient (q) of the area under the curve of the biological parameter over the entirety of the time course (AUCtotai) divided by the number of 8 hour intervals in the time course (ttotaiiisaays), i.e., q =
(AUCtotat)/ (ttotati/3aays)= For example, in the context of a serum concentration of a drug, 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 (AUC8hr) 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 (AUC8hr average), i.e., the AUC8hr is no more than 20% above or 20%
below the AUC8nr average for the serum concentration of the drug over the time course.

[0042] As used herein, any compound or agent described as "effective for the avoidance or amelioration of side effects induced by a Type I interferon receptor agonist,"
or as "effective for reducing or eliminating the severity or occurrence of side effects induced by a Type I
interferon receptor agonist," or any compound or agent described by language with a meaning similar or equivalent to that of either of the foregoing quoted passages, is/are defined as a compound(s) or agent(s) that when co-administered to a patient in an effective amount along with a given dosing regimen of a subject combination therapy, abates or eliminates the severity or occurrence of side effects experienced by a patient in response to the given dosing regimen of the subject combination therapy, as compared to the severity or occurrence of side effects that would have been experienced by the patient in response to the same dosing regimen of the subject combination therapy without co-administration of the agent.

[0043] In many embodiments, the effective amounts of a Type I interferon receptor agonist and a SAPK inhibitor are synergistic amounts. As used herein, a "synergistic combination" or a "synergistic amount" of a Type I interferon receptor agonist and a SAPK
inhibitor is a combination or amount that is more effective in the therapeutic or prophylactic treatment of a disease 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 Type I interferon receptor agonist when administered at that same dosage as a monotherapy and (ii) the therapeutic or prophylactic benefit of the SAPK inhibitor when administered at the same dosage as a monotherapy.

[0044] Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0045] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the invention, subject to any specifically excluded limit in the stated range.
Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0046] Unless defined otherwise, all teclmical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods arid materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

[0047] It must be noted that as used herein and in the appended claims, the singular forms "a,"
"and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a SAPK inhibitor" includes a plurality of such inhibitors and reference to "the Type I interferon receptor agonist" includes reference to one or more Type I

interferon receptor agonists and equivalents thereof known to those skilled in the art, and so forth. It is furtlier noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely," "only" and the like in connection with the recitation of claim elements, or use of a "negative" limitation.

[0048] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.
Further, the dates of publication provided may be different from the actual publication dates, wliich may need to be independently confirmed.

DETAILED DESCRIPTION OF THE INVENTION

[0049] The present invention provides methods of treating a viral infection, e.g., a hepatitis C
virus (HCV) infection; methods of reducing the incidence of complications associated witli HCV infection and cirrhosis of the liver; and methods of reducing viral load, or reducing the time to viral clearance, or reducing morbidity or mortality in the clinical outcomes, in patients suffering from a viral infection, e.g., an HCV infection. The methods generally involve administering to the individual i) a stress-activated protein kinase inhibitor; and ii) a Type I
interferon receptor agonist. The SAPK inhibitor is an agent other than pirfenidone or a pirfenidone analog. In some embodiments, the methods further involve administering a Type II interferon receptor agonist.

[0050] The present invention provides a method of treating alcoholic liver disease, the method involving administering to an individual in need thereof an effective amount of a stress-activated protein kinase (SAPK) inhibitor, alone or in combination therapy.
The present invention further provides methods for treating non-alcoholic steatohepatitis, the method generally involving administering to an individual in need thereof an effective amount of a SAPK inhibitor, alone or in combination therapy.

TREATMENT METHODS
Viral infection [0051] The present invention provides methods of treating a virus infection, and methods of reducing viral load, or reducing the time to viral clearance, or reducing morbidity or mortality in the clinical outcomes, in patients suffering from a virus infection. The present invention further provides methods of reducing the risk that an individual will develop a pathological viral infection that has clinical sequelae. The methods generally involve a combination therapeutic regimen, wherein a Type I interferon receptor agonist and a stress-activated protein kinase (SAPK) inhibitor are administered to an individual in need thereof. The SAPK inhibitor for use in a subject method is other than pirfenidone or a pirfenidone analog.
Thus, the subject methods specifically exclude the use of pirfenidone or a pirfenidone analog.
Of particular interest in many embodiments is treatment of humans.

[0052] In one aspect, a subject treatment method is prophylactic. Where a subject treatment method is prophylactic, the methods reduce the risk that an individual will develop pathological infection with a virus. In some embodiments, effective amounts of a SAPK
inhibitor and a Type I interferon receptor agonist are any combined dosage that reduces the risk or reducing the probability that an individual will develop a pathological infection with a virus. For example, effective amounts include any combined dosage that reduces the risk that an individual will develop a pathological infection 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 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more, compared to the risk of developing a pathological infection with the virus in the absence of treatment with the combination of agents. Optionally, the subject methods include further administering an amount of a Type II interferon receptor agonist that augments the prophylactic effect of the antiviral treatment received by the individual.

[0053] In other embodiments, effective amounts of a SAPK inliibitor and a Type I interferon receptor agonist are any combined dosage that reduces viral load 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 50%, at least about' 60%, at least about 70%, at least about 80%, at least about 90%, or more, compared to the viral load in the absence of treatment with the combination of agents.
Optionally, the subject methods include fiu-ther administering an amount of a Type II
interferon receptor agonist that augments the viral load reducing effect of the antiviral treatment received by the individual.

[0054] In other embodiments, effective amounts of a SAPK inhibitor and a Type I interferon receptor agonist are any combined dosage that that reduces the time to viral clearance, 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 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more, compared to the time to viral clearance in the absence of treatment with the combination of agents. Optionally, the subject methods include further administering an amount of a Type II interferon receptor agonist that augments the viral clearance effect of the antiviral treatment received by the individual.

[0055] In other embodiments, effective amounts of a SAPK inhibitor and a Type I interferon receptor agonist are any combined dosage that reduces morbidity or mortality due to a virus infection 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 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more, compared to the morbidity or mortality in the absence of treatment with the combination of agents. Optionally, the subject methods include further administering an amount of a Type II interferon receptor agonist that augments the morbidity or mortality reducing effect of the antiviral treatment received by the individual.

[0056] Whether a subject treatment method is effective in reducing the risk of a pathological virus infection, reducing viral load, reducing time to viral clearance, or reducing morbidity or mortality due to a virus infection is readily determined by those skilled in the art. Viral load is readily measured by measuring the titer or level of virus in serum. The number of virus in the serum can be determined using any known assay, including, e.g., a quantitative polymerase chain reaction assay using oligonucleotide primers specific for the virus being assayed.
Whether morbidity is reduced can be determined by measuring any symptom associated with a virus infection, including, e.g., fever, respiratory symptoms (e.g., cough, ease or difficulty of breathing, and the like.) [0057] In other embodiments, the present invention provides a method of reducing viral load, and/or reducing the time to viral clearance, and/or reducing morbidity or mortality in an individual who has been exposed to a virus (e.g., an individual who has come into contact with an individual infected with a virus), the method involving administering an effective amounts of a SAPK inhibitor and a Type I interferon receptor agonist. In these embodiments, therapy is begun from about 1 hour to about 14 days following exposure, e.g., from about 1 hour to about 24 liours, from about 24 hours to about 48 hours, from about 48 hours to about 3 days, from about 3 days to about 4 days, from about 4 days to about 7 days, from about 7 days to about 10 days, or from about 10 days to about 14 days following exposure to the virus.
Optionally, the subject methods include further administering an amount of a Type II
interferon receptor agonist that augments the viral load reducing effect, and/or viral clearance effect, and/or morbidity or mortality reducing effect of the antiviral treatment received by the individual.

[0058] In other embodiments, the present invention provides a method of reducing the risk that an individual who has been exposed to a virus (e.g., an individual who has come into contact with an individual infected with a virus) will develop a pathological virus infection with clinical sequelae, the method involving administering effective amounts of a SAPK inhibitor and a Type I interferon receptor agonist. In these embodiments, therapy is begun from about 1 hour to about 35 days following exposure, e.g., from about 1 hour to about 24 hours, from about 24 hours to about 48 hours, from about 48 hours to about 3 days, from about 3 days to about 4 days, from about 4 days to about 7 days, from about 7 days to about 10 days, from about 10 days to about 14 days, from about 14 days to about 21 days, or from about 21 days to about 35 days following exposure to the virus. Optionally, the subject methods include further administering an amount of a Type II interferon receptor agonist that augments the clinical infection reducing effect of the antiviral treatment received by the individual.
Hepatitis virus infections [00591 The present invention provides methods for treating a hepatitis virus infection, e.g., a hepatitis C virus (HCV) infection. The methods generally involve a combination therapy comprising administering to an individual in need thereof combined effective amounts of i) a Type I interferon receptor agonist; and ii) a SAPK inhibitor, where the combination therapy is effective to decrease viral load in the individual, and to achieve a sustained viral response. In many embodiments, the Type I interferon receptor agonist is IFN-a. Optionally, the subject inetliod further provides administering to the individual an effective amount of a Type II
interferon receptor agonist. Of particular interest in many embodiments is treatment of humans.
[0060] Whether a subject method is effective in treating an HCV infection can be determined by measuring viral load, or by measuring a parameter associated with HCV
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.
[0061] Viral load can be measured by measuring the titer or level of virus in serum. These methods include, but are not limited to, a quantitative polymerase chain reaction (PCR) and a branched DNA (bDNA) test. Quantitative assays for measuring the viral load (titer) of HCV
RNA have been developed. Many such assays are available commercially, including a quantitative reverse transcription PCR (RT-PCR) (Amplicor HCV MonitorTM, Roche Molecular Systems, New Jersey); and a branched DNA (deoxyribonucleic acid) signal amplification assay (QuantiplexTM HCV RNA Assay (bDNA), Chiron Corp., Emeryville, California). See, e.g., Gretch et al. (1995) Ann. Intern. Med. 123:321-329.
[0062] In general, an effective amount of a therapeutic agent that is administered as part of a subject combination therapy is an amount that is effective to reduce viral load to undetectable levels, e.g., to less than about 5000, less than about 1000, less than about 500, or less than about 200 genome copies/mL serum. In some embodiments, an effective amount of a ,c p, .. ...--. .--_ _.- --- therapeutic agent that is administered as part of a subject combination therapy is an amount that is effective to reduce viral load to less than 100 genome copies/mL
serum. In many embodiments, the methods of the invention achieve a sustained viral response, e.g., the viral load is reduced to undetectable levels 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.
[0063] As noted above, whether a subject method is effective in treating an HCV infection can be determined by measuring a parameter associated with HCV infection, such as liver fibrosis.
Methods of determining the extent of liver fibrosis are discussed in detail below. In some embodiments, the level of a serum marker of liver fibrosis indicates the degree of liver fibrosis.
[0064) As one non-limiting example, 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. h1 some embodiments, an effective amount of a therapeutic agent that is administered as part of a subject combination therapy is an amount effective to reduce ALT levels to less than about 45 U/mi serum.
[0065] A therapeutically effective amount of a therapeutic agent that is administered as part of a subject combination therapy 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 lilce, using antibody specific for a given serum marker.
Alcoholic liver disease [0066) The present invention provides methods of treating alcoliolic liver disease, including reducing alcoholic hepatitis, reducing clinical liver fibrosis, reducing the likelihood that liver fibrosis will occur, reducing a parameter associated with liver fibrosis, and reducing liver cirrhosis.
[0067] As used herein, the term "alcoholic liver disease" or "ALD" includes hepatic steatosis, alcoholic hepatitis, hepatic fibrosis, and hepatic cirrhosis, which occur as the result of chronic alcohol abuse. The present invention provides methods of treating ALD, involving administering one or more therapeutic agents, where the monotherapy or combination therapy is effective to ameliorate one or more of hepatic steatosis, alcoholic hepatitis, hepatic fibrosis, and hepatic cirrhosis.
[0068] In some embodiments, the methods involve administering an effective amount of of a SAPK inhibitor in monotherapy. In some embodiments, the methods involve administering an effective amount of a SAPK inhibitor in combination therapy with an effective amount of a Type II interferon receptor agonist. In some of these embodiments, the Type II
interferon receptor agonist is an interferon-gamma (IFN-y). In some embodiments, the methods involve administering an effective amount of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist. In some embodiments, the Type II
interferon receptor agonist is IFN-,y. In some embodiments, the Type I interferon receptor agonist is an interferon-alpha (IFN-a). Any of the above-described embodiments will in some embodiments be modified to include administration of a tumor necrosis factor (TNF) antagonist. Thus, in some embodiments, the methods involve administering effective amounts of a SAPK
inhibitor and a TNF antagonist. In other embodiments, the methods involve administering effective amounts of a SAPK inhibitor, a Type II interferon receptor agonist, and a TNF
antagonist. In other embodiments, the methods involve administering effective amounts of a SAPK
inhibitor, a Type II interferon receptor agonist, a Type I interferon receptor agonist, and a TNF antagonist.
Of particular interest in many embodiments is treatment of humans.
[0069] The SAPK inhibitor for use in a subject method is other than pirfenidone or a pirfenidone analog. Thus, the subject methods specifically exclude the use of pirfenidone or a pirfenidone analog.
[0070] Alcoholic liver fibrosis is a precursor to liver cirrhosis.
Accordingly, the present invention further provides methods of reducing the likelihood that an individual will develop liver cirrhosis. Alcoholic liver fibrosis is a precursor to the complications associated with liver cirrhosis, such as portal hypertension, progressive liver insufficiency, and hepatocellular carcinoma. A reduction in liver fibrosis thus reduces the incidence of such complications.
Accordingly, the present invention further provides methods of reducing the likelihood that an individual will develop complications associated with cirrhosis of the liver.
[0071] An "effective amount" or "effective amounts" of a therapeutic agent(s) (e.g., a SAPK
inhibitor alone or in combination with one or more of: a Type II interferon receptor agonist, a Type I interferon receptor agonist, a TNF antagonist, as mentioned above) is/are any dosage that, administered in monotherapy or in a combined dosage, is effective in reducing liver fibrosis or reduce the rate of progression of alcoholic liver fibrosis; and/or that is effective in reducing the likelihood that an individual will develop alcoholic liver fibrosis; and/or that is effective in reducing a parameter associated with alcoholic liver fibrosis;
and/or that is effective in reducing a disorder associated with cirrhosis of the liver.
[0072] The invention also provides a method for treatment of alcoholic liver fibrosis in an individual comprising one or more therapeutic agents as described above in monotherapy or in combination therapy in amounts that are effective for prophylaxis or therapy of liver fibrosis in the individual, e.g., increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.
[0073] Whether a subject monotherapy or combination therapy is effective in reducing alcoholic liver fibrosis can be determined by any of a number of well-established techniques for measuring liver fibrosis and liver function. Whether liver fibrosis is reduced 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 METAVIR (1994) Hepatology 20:15-20. Based on analysis of the liver biopsy, 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 METAVIR, Knodell, Scheuer, Ludwig, and Ishak scoring systems.
[0074] The METAVIR 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). The definitions of each stage in the METAVIR system are 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.
[0075] 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 IV. Fibrosis. In the Knodell staging system, 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.
Knodell (1981) Hepatol. 1:431.

[0076] In the Scheuer scoring system scores are as follows: score: 0, no fibrosis; score: 1, enlarged, fibrotic portal tracts; score: 2, periportal or portal-portal septa, but intact architecture;
score: 3, fibrosis with architectural distortion, but no obvious cirrhosis;
score: 4, probable or definite cirrhosis. Scheuer (1991) J. Hepatol. 13:372.
[0077] The Ishak scoring system is described in Ishak (1995) J. Hepatol.
22:696-699. Stage 0, No fibrosis; 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.
[0078] The benefit of anti-fibrotic therapy can also be measured and assessed by using the 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.
[0079] In some embodiments, therapeutically effective amounts of a therapeutic agent are any dosage (e.g., a dosage in a subject monotherapy or a combined dosage in a subject combination therapy) that effects a change of one unit or more in the fibrosis stage based on pre- and post-therapy liver biopsies. In particular embodiments, therapeutically effective amounts of a therapeutic agent are any dosage (e.g., a dosage in a subject monotherapy or a combined dosage in a subject combination therapy) reduce liver fibrosis by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.
[0080] Secondary, or indirect, indices of liver function can also be used to evaluate the efficacy of treatment with the subject therapy. 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 liinited to, serum transaminase levels, prothrombin time, bilirubin, platelet count, portal pressure, albumin level, and assessment- of the Child-Pugh score.
[0081] In another embodiment, therapeutically effective amounts of a therapeutic agent are any dosage (e.g., a dosage in a subject monotherapy or a combined dosage in a subject combination therapy) that are 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 in 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.
[0082] 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 a-2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein A, and gamma glutamyl transpeptidase.
[0083] In another embodiment, therapeutically effective amounts of a therapeutic agent are any dosage (e.g., a dosage in a subject monotherapy or a combined dosage in a subject combination therapy) that are 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 in a placebo-treated individual. Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. 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 seruin marker.
[0084] Quantitative tests of functional liver reserve can also be used to assess the efficacy of treatment with the subject therapy. These include: indocyanine green clearance (ICG), galactose elimination capacity (GEC), aminopyrine breath test (ABT), antipyrine clearance, monoethylglycine-xylidide (MEG-X) clearance, and caffeine clearance.
[0085] As used herein, a "complication associated with cirrhosis of the liver"
refers to a disorder that is a sequelae of decompensated liver disease, i.e., or occurs subsequently to and as a result of development of liver fibrosis, and includes, but is 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.

[0086] In another embodiment, therapeutically effective amounts of a therapeutic agent are any dosage (e.g., a dosage in a subject monotherapy or a combined dosage in a subject combination therapy) that is effective in reducing the incidence of (e.g., the likelihood that an individual will develop) 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 in a placebo-treated individual.
[0087] Whether a subject monotherapy or combination therapy is effective in reducing the incidence of a disorder associated with cirrhosis of the liver can readily be determined by those skilled in the art.
[0088] Reduction in liver fibrosis increases liver function. Thus, in another embodiment, therapeutically effective amounts of a therapeutic agent are any dosage (e.g., a dosage in a subject monotherapy or a combined dosage in a subject combination therapy) that is effective in increasing 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, y-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 lilce.
[0089] Whether a liver function is increased is readily ascertainable by those skilled in the art, using well-established tests of liver function. Thus, synthesis of 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.
[0090] Whether 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 range of alanine transaminase is from about 7 to about 56 units per liter 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.
[0091] In another embodiment, therapeutically effective amounts of a therapeutic agent are any dosage (e.g., a dosage in a subject monotherapy or a combined dosage in a subject combination therapy) 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, compared to an untreated individual, or in a placebo-treated individual. For example, in some embodiments, therapeutically effective amounts of a tlzerapeutic agent are any dosage (e.g., a dosage in a subject monotherapy or a combined dosage in a subject combination therapy) that is effective to reduce an elevated level of a serum marker of fiver 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. In other embodiments, therapeutically effective amounts of a therapeutic agent are any dosage (e.g., a dosage in a subject monotherapy or a combined dosage in a subject combination therapy) 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.
Non-alcoholic steatohepatitis [0092] In some aspects, the present invention provides methods of treating NASH. In some embodiments, the methods involve administering an effective amount of a SAPK
inhibitor in monotherapy. In some embodiments, the methods involve administering an effective amount of a SAPK inhibitor in combination therapy with an effective amount of a Type II interferon receptor agonist. In some of these embodiments, the Type II interferon receptor agonist is an IFN-y. In some embodiments, the methods involve administering an effective amount of a SAPK inhibitor, a Type II interferon receptor agonist, and a Type I interferon receptor agonist.
In some embodiments, the Type II interferon receptor agonist is IFN-y. In some embodiments, the Type I interferon receptor agonist is an IFN-a. Any of the above-described embodiments will in some embodiments be modified to include administration of a tumor necrosis factor (TNF) antagonist. Thus, in some einbodiments, the methods involve administering effective amounts of a SAPK inhibitor and a TNF antagonist. In other embodiments, the methods involve administering effective amounts of a SAPK inhibitor, a Type II
interferon receptor agonist, and a TNF antagonist. In other embodiments, the methods involve administering effective amounts of a SAPK inhibitor, a Type II interferon receptor agonist, a Type I
interferon receptor agonist, and a TNF antagonist. Of particular interest in many embodiments is treatment of humans.
[0093] The SAPK inhibitor for use in a subject method is other than pirfenidone or a pirfenidone analog. Thus, the subject methods specifically exclude the use of pirfenidone or a pirfenidone analog.
[0094] An "effective amount" or "effective amounts" of a therapeutic agent(s) (e.g., a SAPK
inhibitor alone or in combination with one or more of: a Type II interferon receptor agonist, a Type I interferon receptor agonist, a TNF antagonist, as mentioned above) is/are any dosage that, administered in monotherapy or in a combined dosage that is effective to reduce at least one sign or symptom or parameter associated with NASH by at least about 10%, at least about 15%, 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, when compared to the level or severity of the sign or symptom or parameter in an individual not treated with the subject monotherapy or combination therapy.
[0095] Symptoms of NASH include elevated alanine transaminase (ALT); elevated aspartate transaminase (AST); enlarged liver; increase in fat content of liver cells (as determined by histological examination of a liver biopsy sample). Thus, therapeutically effective amounts of a therapeutic agent are any dosage (e.g., a dosage in a subject monotherapy or a combined dosage in a subject combination therapy) that is effective to reduce one or more of the level of ALT, the level of AST, liver mass, and fat content of liver cells by at least about 10%, at least about 15%, 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, when compared to the level of ALT, the level of AST, liver mass, or fat content of liver cells in an individual not treated with the subject monotherapy or combination therapy.
[0096] Treatment of NASH increases one or more liver functions. 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, y-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 spla.nchnic and portal hemodynamics; and the like.
[0097] Whether a liver function is increased is readily ascertainable by those skilled in the art, using well-established tests of liver function. Thus, synthesis of 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.
[0098] Whether 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 range of alanine transaminase is from about 7 to about 56 units per liter 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.
[0099] In another embodiment, therapeutically effective amounts of a therapeutic agent are any dosage (e.g., a dosage in a subject monotherapy or a combined dosage in a subject combination therapy) 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. For example, a therapeutically effective amounts of a therapeutic agent are any dosage (e.g., a dosage in a subject monotherapy or a combined dosage in a subject combination therapy) that is 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 amounts of a therapeutic agent are any dosage (e.g., a dosage in a subject monotherapy or a combined dosage in a subject combination therapy) that is 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.
SAPK inhibitors [00100] As discussed above, a SAPK inhibitor suitable for use in a subject combination therapy is an agent other than pirfenidone or a pirfenidone analog.
[00101] SAPK inhibitors that are suitable for use herein inhibit enzymatic activity of a SAPK
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 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, or more, when compared with the enzymatic activity of the SAPK in the absence of the SAPK inhibitor.
[00102] The signal transduction pathways that use mitogen-activated protein kinases (MAPK) have an important role in a variety of cellular responses, including growth, stress-induced gene expression, and compensation for alterations in the environment. The SAPK
group of MAPKs includes the c-Jun N-terminal Kinase (JNK) and p38 kinases. The p38 group of MAPK
includes at least four members, designated p38 or p38a, p38(3, p38y, and p386.
The amino acid sequences of p38a, p38[3, and p38y from various species are known. For example, the amino acid sequences of human p38a, p38(3, and p38y are found under the following GenBank Accession Nos.: 1) Q16539, NP_620583, and NP_001306 provide amino acid sequences of human p38a polypeptides; 2) NP620478, NP_002742, and Q15759 provide amino acid sequences of human p380 polypeptides; and 3) NP_002960, P53778, and JC5252 provide amino acid sequences of human p38y polypeptides.
[00103] In some embodiments, a suitable SAPK inhibitor is an agent that inhibits enzymatic activity of p38a, p38(3, and p38y. In otlier embodiments, a suitable SAPK
inhibitor is an agent that preferentially inhibits the enzymatic activity of p38a and p38(3, i.e., the agent is a stronger inhibitor of the enzymatic activity of p38a and p38[i than that of p38y, e.g., the agent's IC50 against p38a and p38(3 is at least about two-fold lower, or about five-fold lower, or about ten-fold lower, or more, below the agent's IC50 against p38y.
[00104] In other embodiments, a suitable SAPK inhibitor is an agent that preferentially inhibits p38y, i.e., the agent is a stronger inhibitor of the enzymatic activity of p38y than that of p38a and p38(3, e.g., the agent's IC50 against p38y is at least about two-fold lower, or about five-fold lower, or about ten-fold lower, or more, below the agent's IC50 against p38a and p38(3.
[00105] In some embodiments, a SAPK inhibitor is a competitive inhibitor of a SAPK, e.g., a p38a, a p380, or a p38y. In some of these embodiments, a SAPK inhibitor is one that competes with adenosine triphosphate (ATP) for binding to the ATP binding site of p38a, p380, or p38y.
[00106] Stress-activated protein kinase inhibitors that are suitable for use in a subject combination therapy include, but are not limited to, a 2-alkyl imidazole as disclosed in U.S.
Patent No. 6,548,520; any of the 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. 2003/0073 832; pyridyl imidazole compounds disclosed in U.S.
Patent No.
6,288,089; and heteroaryl aminobenzophenones disclosed in U.S. Patent No.
6,432,962. Also suitable for use are compounds disclosed in U.S. Patent No. 6,214,854. Also suitable for use are the heterocyclic compounds discussed in WO 99/61426. Also suitable for use are the SAPK inhibitors discussed in U.S. Patent Publication No. 20030149041.
[00107] Of particular interest in some embodiments is use of any of the following SAPK
inhibitor compounds, or pharmaceutically acceptable salts, or derivatives, or esters, or analogs, thereof:

/ I .
N

O I \ ~
N
[00108] which compound has the IUPAC designation (4-benzyl-piperidin-1-yl)-(1H-indol-5-yl)-methanone. Also suitable for use are any of the following compounds: (4-benzyl-piperidin-1-yl)-(6-chloro-lH-indol-5-yl)-methanone; (4-chloro-lH-indol-5-yl)-[4-(4-fluoro-benzyl)-piperidin-1-yl]-methanone; (4-benzyl-piperidin-1-yl)-(4-methoxy-lH-inol-5-yl)-methanone;
(4-Benzyl-piperidin-l-yl)- { 1-[3-(cyclohexylmethyl-amino)-2-hydroxy-propyl]-1 H-indol-5-yl} -methanone; (4-Benzyl-piperidin-1-yl)-{ 1-[2-hydroxy-3-(4-methyl-piperazin-1-yl)-propyl]-1H-indol-5-yl}-methanone; [1-(3-Benzylamino-2-hydroxy-propyl)-1H-indol-5-yl]-(4-benzyl-piperidin-1-yl)-methanone; (4-Benzyl-piperidin-1-yl)-{ 1-[2-hydroxy-3-(4-methoxy-benzylamino)-propyl]-1H-indol-5-yl}-methanone; (4-Benzyl-piperidin-1-yl)-[1-(2-hydroxy-3-propylamino-propyl)-1H-indol-5-yl]-methanone; (4-Benzyl-piperidin-1-yl)-[1-(pyridine-4-carbonyl)-1H-indol-5-yl]-methanone; 1-[5-(4-Benzyl-piperidine-l-carbonyl)-indol-1-yl]-ethanone; 2-[5-(4-Benzyl-piperidine-l-carbonyl)-indol-1-yl]-N-(4-methoxy-benzyl)-acetamide; 5-(4-Benzyl-piperidine-l-carbonyl)-1H-indole-3-carboxylic acid (2-methoxy-ethyl)-amide; 5-(4-Benzyl-piperidine-l-carbonyl)-1H-indole-3-carboxylic acid (2-methylamino-ethyl)-amide; 5-(4-Benzyl-piperidine-l-carbonyl)-1H-indole-3-carboxylic acid (2-amino-ethyl)-amide; [3-(4-Benzyl-piperidine-l-carbonyl)-1H-indol-5-yl]-(4-benzyl-piperidin-1-yl)-methanone; [3-(4-Benzyl-piperidine-l-carbonyl)-1H-indol-6-yl]-(4-benzyl-piperidin-1-yl)-methanone; 5-(4-Benzyl-piperidine-l-carbonyl)-1H-indole-3-carboxylic acid 4-fluoro-benzylamide; 5-(4-Benzyl-piperidine-l-carbonyl)-1H-indole-3-carboxylicacid[2-(3,5-dimethoxy-phenyl)-ethyl]-a.mide; (4-Benzyl-piperidin-1-yl)-(6-methoxy-1 H-indol-5-yl)-methanone; 1-[5-(4-Benzyl-piperidine-l-carbonyl)-1H-indol-3-yl]-2,2,2-trifluoro-ethanone; 5-(4-Benzyl-piperidine-l-carbonyl)-6-methoxy-lH-indole-3-carboxylic acid (2-dimethylamino-ethyl)-amide; 5-(4-Benzyl-piperidine-l-carbonyl)-1H-indole-3-carboxylic acid;
5-(4-Benzyl-piperidine-1-carbonyl)-1H-indole-3-carboxylic acid (2-dimethylamino-ethyl)-amide; (1H-Benzoimidazol-5-yl)-(4-benzyl-piperidin-1-yl)-inethanone; (1H-Benzoimidazol-5-yl)-[4-(4-fluoro-benzyl)-piperidin-1-yl]-methanone; (4-Benzyl-piperidin-1-yl)-(3-morpholin-4-ylmethyl-1H-indol-5-yl)-methanone; 1-[6-(4-Benzyl-piperidine-l-carbonyl)-1H-indol-3-yl]-2,2,2-trifluoro-ethanone; (4-Benzyl-piperidin-l-yl)-[l-(pyridine-4-carbonyl)-1H-indo1-6-yl]-metlianone; (3-Benzyl-8-aza-bicyclo[3.2.1]oct-8-yl)-(6-methoxy-lH-indol-5-yl)-methanone;
(3 H-Benzoimidazol-5-yl)-(3 -benzyl-8-aza-bicyclo [3 .2.1 ] oct-8-yl)-methanone; [3 -(4-Fluoro-benzyl)-pyrrolidin-1-yl]-(1H-indol-6-yl)-methanone; (1H-Benzoimidazol-5-yl)-[4-(2,6-difluoro-benzyl)-piperazin-1-yl]-methanone; (1H-Benzoimidazol-5-yl)-[4-(4-methylsulfanyl-benzyl)-piperazin-1-yl]-methanone; (1H-Benzoimidazol-5-yl)-[4-(2,3-difluoro-benzyl)-piperazin-1-yl]-methanone; (1H-Benzoimidazol-5-yl)-[4-(3,5-difluoro-benzyl)-piperazin-1-yl]-methanone; (1H-Benzoimidazol-5-yl)-[4-(3-chloro-benzyl)-piperazin-1-yl]-methanone; 4-[4-(1H-Benzoimidazole-5-carbonyl)-piperazin-1-ylmethyl]-benzoic acid methyl ester; (1H-Benzoimidazol-5-yl)-[4-(4-methoxy-benzyl)-piperazin-1-yl]-methanone; (1H-Benzoimidazol-5-yl)-[4-(4-trifluoromethoxy-benzyl)-piperazin-1-yl]-methanone; (1H-Benzoimidazol-5-yl)-[4-(4-methyl-benzyl)-piperazin-1-yl]-methanone; (1H-Benzoimidazol-5-yl)-[4-(2,4-dichloro-benzoyl)-piperazin-1-yl]-methanone; (1H-Benzoimidazol-5-yl)-[4-(3,4-dichloro-benzoyl)-piperazin-1-yl]-methanone; trans-1-[4-(1H-Benzoimidazole-5-carbonyl)-piperazin-1-yl]-3-(3-trifluoromethyl-phenyl)-propenone; (1H-Benzoimidazol-5-yl)-[4-(4-chloro-benzoyl)-piperazin-1-yl]-methanone; (1H-Benzoimidazol-5-yl)-(4-benzoyl-piperazin-1-yl)-methanone;
(1H-Benzoimidazol-5-yl)-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-methanone; (1H-Benzoimidazol-5-yl)-[4-(4-methoxy-benzoyl)-piperazin-l-yl]-methanone; (1H-Benzoimidazol-5-yl)-[4-(3,4-dichloro-phenyl)-piperazin-1--yl]-inethanone; (1H-Benzoimidazol-5-yl)-{4-[(4-chloro-phenyl)-phenyl-methyl]-piperazin-l-yl}-methanone; trans-(1H-Benzoimidazol-5-yl)-[4-(3-phenyl-allyl)-piperazin-1-yl]-methanone; (1H-Benzoimidazol-5-yl)-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl} -methanone; (1 H-Benzoimidazol-5-yl)-[4-(4-chloro-benzyl)-piperazin-1-yl]-methanone; (1H-Benzoimidazol-5-yl)-[4-(2-chloro-benzyl)-piperazin-1-yl]-methanone; (1H-Benzoimidazol-5-yl)-[4-(3,4,5-trimethoxy-benzyl)-piperazin-1-yl]-methanone; (1H-Benzoimidazol-5-yl)-[4-(4-diethylamino-benzyl)-piperazin-1-yl]-methanone;
(1H-Benzoimidazol-5-yl)-(4-biphenyl-4-ylmethyl-piperazin-1-yl)-methanone; (1H-Benzoimidazol-5-yl)-[4-(4-phenoxy-benzyl)-piperazin-1-yl]-methanone; (4-Benzyl-piperidin-1-yl)-(6-methoxy-lH-benzoimidazol-5-yl)-methanone; (4-Benzyl-piperidin-1-yl)-(l-isopropyl-1H-benzoimidazol-5-yl)-methanone; (4-Benzyl-piperidin-1-yl)-(3-isopropyl-3H-benzoimidazol-5-yl)-methanone; (4-Benzyl-piperidin-1-yl)-(l-isopropyl-lH-indol-5-yl)-methanone; [4-(4-Chloro-benzyl)-piperazin-1-yl]-(1-isopropyl-lH-indol-5-yl)-methanone;
(1H-Benzotriazol-5-yl)-(4-benzyl-piperidin-1-yl)-methanone; (4-Benzyl-piperidin-1-yl)-(1-isopropyl-lH-benzotriazol-5-yl)-methanone; [4-(4-Chloro-benzyl)-piperidin-1-yl]-(1H-indol-5-yl)-methanone; [4-(3-Chloro-benzyl)-piperidin-1-yl]-(1H-indol-5-yl)-methanone; [4-(2-Chloro-benzyl)-piperidin-1-yl] -(1 H-indol-5-yl)-methanone; (4-Benzyl-2-methyl-piperidin-l-yl)-(1 H-indol-5-yi)-methanone; (4-Benzyl-piperidin-1-yl)-(4-chloro-1 H-indol-5-yl)-inethanone; (4-Benzyl-piperidin-1-yl)-[7-chloro-l-(pyridine-3-carbonyl)-lH-indol-6-yl]-methanone; (4-Benzyl-piperidin-1-yl)-(5-chloro-lH-indol-6-yl)-methanone; (4-Benzyl-piperidin-1-yl)-(7-chloro-1 H-indol-6-yl)-methanone; 6-(4-Benzyl-piperidine-l-carbonyl)-7-chloro-l-(pyridine-3-carbonyl)-1H-indole-3-carboxylic acid (2-dimethylamino-ethyl)-amide;
(4-Benzyl-piperidin-1-yl)-(1-pyridin-4-ylmethyl-1 H-indol-5-yl)-methanone; (4-Benzyl-piperidin-1-yl)-[6-methoxy-l-(pyridine-3-carbonyl)-1H-indol-5-yl]-methanone;
[5-(4-Benzyl-piperidine-1-carbonyl)-indol-1-yl]-acetic acid methyl ester; 1-[5-(4-Benzyl-piperidine-l-carbonyl)-indol- 1 -yl]-3-isopropylamino-propan- 1 -one; 1-[5-(4-Benzyl-piperidine-l-carbonyl)-indol-1-yl]-3-piperazin-1-yl-propan-1-one; 3-Benzylamino-l-[5-(4-benzyl-piperidine-l-carbonyl)-indol-1-yl]-propan-1-one; 1-[5-(4-Benzyl-piperidine-l-carbonyl)-indol-1-yl]-3-morpholin-4-yl-propan-1-one; 2-[5-(4-Benzyl-piperidine-l-carbonyl)-indol-1-yl]-N-propyl-acetamide; (4-Benzyl-piperidin-1-yl)-[1-(2-diethylamino-ethyl)-6-methoxy-lH-indol-5-yl]-methanone; (4-Benzyl-piperidin-1-yl)-[1-(3-diethylamino-propyl)-1H-indol-5-yl]-methanone;
(4-Benzyl-piperidin-1-yl)-[1-(2-diethylamino-ethyl)-1H-indol-5-yl]-methanone;
(4-Benzyl-piperidin-1-yl)-[6-chloro-l-(3-diethylamino-propyl)-1H-indol-5-yl]-methanone;
[1-(2-Diethylamino-ethyl)-1H-indol-5-yl]-[4-(4-fluoro-benzyl)-piperidin-1-yl]-methanone; (4-Benzyl-piperidin-l-yl),[1-(3-diethylamino-propyl)-6-methoxy-lH-indol-5-yl]-methanone; 5-(4-Benzyl-piperidine-l-carbonyl)-1H-indole-3-carboxylic acid (2-amino-ethyl)-methyl-amide;
5-(4-Benzyl-piperidine-l-carbonyl)-1 H-indole-3 -carboxylic acid [2-(3,4-dimethoxy-phenyl)-ethyl]-amide; (4-Benzyl-piperidin-1-yl)-(3-diethylaminomethyl-lH-indol-5-yl)-methanone; [4-(4-Fluoro-benzyl)-piperidin-1-yl]-(6-methoxy-lH-indol-5-yl)-methanone; (4-Benzyl-piperidin-1-yl)-(1-pyridin-4-yl-lH-indol-5-yl)-methanone; and 4(4-Benzyl-piperidin-l-yl)-(4-chloro-2-methyl-lH-indol-5-yl)-methanone; or pharmaceutically acceptable salts, or derivatives, or esters, or analogs, of any of the foregoing compounds.
[00109] Of particular interest in some einbodiments is use of any of the following SAPK
inhibitor compounds, or pharmaceutically acceptable salts, or derivatives, or esters, or analogs, thereof:

/ N
N\ I
c N CI
~ \
N I
/

[00110] which compound has the IUPAC designation'[2-(2-Chloro-phenyl)-quinazolin-4-yl]-pyridin-4-yl-amine. Also suitable for use are any of the following compounds:
[2-(2,6-Dichloro-phenyl)-quinazolin-4-yl]-pyridin-4-yl-amine; Pyridin-4-yl-(2-o-tolyl-quinazolin-4-yl)-amine; [2-(2-Bromo-phenyl)-quinazolin-4-yl]-pyridin-4-yl-amine; [2-(2-Fluoro-phenyl)-quinazolin-4-yl]-pyridin-4-yl-amine; [2-(2,6-Difluoro-phenyl)-quinazolin-4-yl]-pyridin-4-yl-amine; (2-Phenyl-quinazolin-4-yl)-pyridin-4-yl-amine; [2-(4-Fluoro-phenyl)-quinazolin-4-yl]-pyridin-4-yl-amine; [2-(4-Methoxy-phenyl)-quinazolin-4-yl]-pyridin-4-yl-amine;
[2-(3-Fluoro-phenyl)-quinazolin-4-yl]-pyridin-4-yl-amine; Isopropyl-(2-phenyl-quinazolin-4-yl)-pyridin-4-yl-amine; (4-Methoxy-benzyl)-(2-phenyl-quinazolin-4-yl)-pyridin-4-yl-amine; (2-Phenyl-quinazolin-4-yl)-pyridin-4-ylmethyl-amine; [2-(4-Chloro-phenyl)-quinazolin-4-yl]-pyridin-4-ylmethyl-amine; (2-Phenyl-quinazolin-4-yl)-pyridin-3-yl-amine; (2-Phenyl-quinazolin-4-yl)-pyridin-2-ylmethyl-amine; (2-Phenyl-quinazolin-4-yl)-pyridin-3-ylmethyl-amine;
(2-Phenyl-quinazolin-4-yl)-(2-pyridin-2-yl-ethyl)-amine; (2-Phenyl-quinazolin-4-yl)-pyrimidin-4-yl-amine; (2-Phenyl-quinazolin-4-yl)-pyrimidin-2-yl-amine; Phenyl-(2-phenyl-quinazolin-4-yl)-amine; Benzyl-[2-(3-chloro-phenyl)-quinazolin-4-yl]-amine; 3-(2-Phenyl-quinazolin-4-ylamino)-phenol; 2-(2-Phenyl-quinazolin-4-ylamino)-phenol; 4-(2-Phenyl-quinazolin-4-ylamino)-phenol; (1H-Indol-4-yl)-(2-phenyl-quinazolin-4-yl)-amine; (1H-Indol-5-yl)-(2-phenyl-quinazolin4-y1)-amine; .(4-Metlioxy-phenyl)-(2-phenyl-quinazolin-4-yl)-amine; (3-Methoxy-phenyl)-(2-phenyl-quinazolin-4-yl)-amine; (2-Methoxy-phenyl)-(2-phenyl-quinazolin-4-yl)-a.mine; 2-[4-(2-Phenyl-quinazolin-4-ylamino)-phenyl]-ethanol;
3-(2-Phenyl-quinazolin-4-ylamino)-benzonitrile; (2,5-Difluoro-benzyl)-(2-phenyl-quinazolin-4-yl)-amine;
[4-(2-Butyl)-phenyl]-(2-phenyl-quinazolin-4-yl)-amine; N,N-Dimethyl-N'-(2-phenyl-quinazolin-4-yl)-benzene-1,4-diamine; [2-(2-Chloro-phenyl)-6,7-dimethoxy-quinazolin-4-yl]-pyridin-4-yl-amine; [2-(2-Fluoro-phenyl)-6-nitro-quinazolin-4-yl]-pyridin-4-yl-amine; 2-(2-Fluoro-phenyl)-N4-pyridin-4-yl-quinazoline-4,6-diamine; 2-(2-Fluoro-phenyl)-N4-pyridin-4-yl-quinazoline-4,7-diamine; 2-(2-Fluoro-phenyl)-N6-(3-methoxy-benzyl)-N4-pyridin-4-yl-quinazoline-4,6-diamine; 2-(2-Fluoro-phenyl)-N6-(4-methoxy-benzyl)-N4-pyridin-4-yl-quinazoline-4,6-diamine; N6-Isobutyl-2-(2-fluoro-phenyl)-N4-pyridin-4-yl-quinazoline-4,6-diamine; 2-(2-Fluoro-phenyl)-N6-(4-methylsulfanyl-benzyl)-N4-pyridin-4-yl-quinazoline-4,6-diamine; 4-(4-Pyridylamino)-2-(4-chlorophenyl)quinazoline; 2-Phenyl-4-(2-pyridylamino)-quinazoline; and [2-(2-Fluoro-phenyl)-pyrido[2,3-d]pyrimidin-4-yl]-pyridin-4-yl-amine; or pharmaceutically acceptable salts, or derivatives, or esters, or analogs, of any of the foregoing compounds.
[00111] A further suitable SAPK inhibitor is BIRB796 (1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-e- thoxy)-naphthalen- 1 -yl] -urea); see U.S.
Patent no. 6,319,921.
[00112] BIRB796 has the following structure:

NH
O-zz<
NH
----= C3 N
\..j [00113] Also suitable for use are pharmaceutically active derivatives, analogs, esters, and salts of BIRB796.
[00114] Another suitable SAPK inhibitor is 2(1H)-quinazolinone, as shown below:

N

r- CI
~ ~ I
CI N / F
:0 F
[00115] Also suitable for use are pharmaceutically active derivatives, analogs, esters, and salts of 2(1H)-quinazolinone.
[00116] Methods of measuring SAPK activity are known in the art. See, e.g., U.S. Patent Publication No. 20030149041. One non-limiting example of an assay to measure enzymatic activity of a SAPK is as follows. In a fmal reaction volume of 25 l, SAPK2a (5-10 mU) is incubated with 25 mM Tris pH 7.5, 0.02 mM EGTA, 0.33 mg/ml myelin basic protein, 10 mM
magnesium acetate and [7 33P-ATP] (specific activity approximately 500 cpm/pmol, concentration as required). The reaction is initiated by the addition of the Mg/ATP mix. After incubation for 40 minutes at room temperature, the reaction is stopped by addition of 5 l of a 3% phosphoric acid solution. Ten l of the reaction is then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once more in methanol prior to drying and scintillation counting.
[00117] Another exam.ple of an assay for testing the effect of an agent on p3 8 kinase activity is as follows. A compound to be tested is solubilized in dimethylsulfoxide and diluted into water.
The p38 kinase is diluted to 10 g/ml into a buffer containing 20 mM MOPS, pH
7.0, 25 mM
beta-glycerol phosphate, 2 mg/ml gelatin, 0.5 mM EGTA, and 4 mM DTT. The reaction is carried out by mixing 20 l test compound with 10 l of a substrate cocktail containing 500 g/ml peptide substrate and 0.2 mM APT (+ 200 Ci/ml 'y-32P-ATP) in a 4x assay buffer. The reaction is initiated by the addition of 10 l p38 kinase. Final assay conditions are 25 mM
MOPS, p 7.0, 26.25 mM beta-glycerol phosphate, 80 mM KCl, 22 mM MgC12, 3 mM
MgSO4, 1 mg/ml gelatin, 0.625 mM EGTA, 1 mM DTT, 125 gg/ml peptide substrate, 50 gM
APT, and 2.5 g/rnl enzyme. The reaction is stopped by the addition of 10 10.25 M
phosphoric acid.
Activity is determined by measuring incorporation of radioactivity into the peptide substrate.

Type I Interferon Receptor Agonists [00118] In some embodiments, a subject method comprises administering a SAPK
inhibitor and a Type I interferon receptor agonist. Suitable Type I interferon receptor agonists include an IFN-a; an IFN-(3; an IFN-tau; an IFN-w; antibody agonists specific for a Type I interferon receptor; and any other agonist of Type I interferon receptor, including non-polypeptide agonists.
Interferon-Alpha [00119] Any known IFN-a can be used in the instant invention. The term "interferon-alpha" as used herein refers to a family of related polypeptides that inhibit viral replication and cellular proliferation and modulate immune response. The term "IFN-a" includes naturally occurring IFN-a; synthetic IFN-a; derivatized IFN-a (e.g., PEGylated IFN-a, glycosylated IFN-a, and the like); and analogs of naturally occurring or synthetic IFN-a; essentially any IFN-a that has antiviral properties, as described for naturally occurring IFN-a.
[00120] Suitable alpha interferons include, but are not limited to, naturally-occurring IFN-a (including, but not limited to, naturally occurring IFN-a2a, IFN-a2b);
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. J.; recombinant interferon alpha-2C such as Berofor alpha 2 interferon available from Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield, 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; and 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.
[00121] The term "IFN-a" also encompasses consensus IFN-a. Consensus IFN-a (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. 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.

[00122] Also suitable for use in the present invention are fusion polypeptides comprising an IFN-a and a heterologous polypeptide. Suitable IFN-a fusion polypeptides include, but are not limited to, Albuferon-alphaTM (a fusion product of human albumin and IFN-a;
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-a.
See., e.g., Masci et al. (2003) Curr. Oncol. Rep. 5:108-113.
PEGylated Interferon-Alpha [00123] The term "IFN-a" also encompasses derivatives of IFN-a that are derivatized (e.g., are chemically modified) to alter certain properties such as serum half-life. As such, the term "IFN-a" includes glycosylated IFN-a; IFN-a derivatized with polyethylene glycol ("PEGylated IFN-a"); and the like. PEGylated IFN-a, 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-a encompasses conjugates of PEG and any of the above-described IFN-a 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(M, InterMune, Inc., Brisbane, Calif.).
[00124] Any of the above-mentioned IFN-a polypeptides can be modified with one or more polyethylene glycol moieties, i.e., PEGylated. The PEG molecule of a PEGylated IFN-a polypeptide is conjugated to one or more amino acid side chains of the IFN-a polypeptide. In some embodiments, the PEGylated IFN-a contains a PEG moiety on only one amino acid. In other embodiments, the PEGylated'IFN-a contains a PEG moiety on two or more amino acids, e.g., the IFN-a contains a PEG moiety attached to two, three, four, five, six, seven, eight, nine, or ten different amino acid residues.
[00125] IFN-a 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.
[00126] In some embodiments, the PEGylated IFN-a is PEGylated at or near the amino terminus (N-terminus) of the IFN-a polypeptide, e.g., the PEG moiety is conjugated to the IFN-a polypeptide at one or more amino acid residues from amino acid 1 through amino acid 4, or from amino acid 5 through about 10.
[00127] In other embodiments, the PEGylated IFN-a is PEGylated at one or more amino acid residues from about 10 to about 28.

[00128] In other embodiments, the PEGylated IFN-a is PEGylated at or near the carboxyl terminus (C-terminus) of the IFN-a polypeptide, e.g., at one or more residues from amino acids 156-166, or from amino acids 150 to 155.

[00129] In other embodiments, the PEGylated IFN-a is PEGylated at one or more amino acid residues at one or more residues from amino acids 100-114.
[00130] The polyethylene glycol derivatization of amino acid residues at or near the receptor-binding and/or active site domains of the IFN-a protein can disrupt the functioning of these domains. In certain embodiments of the invention, 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.
[00131] In some embodiments, PEG is attached to IFN-a 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 carbonate (TPC)), a trysylate group, an aldehyde group, an isocyanate group, a vinylsulfone group, a tyrosine group, a cysteine group, a histidine group or a primary amine.
[00132] Methods for making 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.
[00133] Methods for attaching a PEG to an IFN-a polypeptide are known in the art, and any known method can be used. See, for example, by Park et al, Anticancer Res., 1:373-376 (1981); Zaplipsky and Lee, Polyethylene Glycol Chemistry: Biotechnical and Biomedical Applications, J. M. Harris, ed., Plenum Press, NY, Chapter 21 (1992); U.S.
Patent No.
5,985,265; U.S. Pat. No. 5,672,662 (Harris, et al.) and WO 97/03106.
[00134] Pegylated IFN-a, and methods for making same, is discussed in, e.g., U.S. Patent Nos.
5,382,657; 5,981,709; 5,985,265; and 5,951,974. Pegylated IFN-a encompasses conjugates of PEG and any of the above-described IFN-a molecules, including, but not limited to, PEG
conjugated to interferon alpha-2a (Roferon, Hoffman LaRoche, Nutley, N.J.), where PEGylated Roferon is known as Pegasys (Hoffman LaRoche); interferon alpha 2b (Intron, Schering-Plough, Madison, N.J.), 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 CIFN is referred to as PEG-CIFN.
[00135] In many embodiments, the PEG is a monomethoxyPEG molecule that reacts with primary amine groups on the IFN-a 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 :13 3 -140.
[00136] In one non-limiting example, PEG is linked to IFN-a 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-a polypeptide.
[00137] For example, 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-a polypeptide. Such a bond can be formed, e.g., by condensation of an a-methoxy, omega propanoic acid activated ester of PEG
(mPEGspa).
[00138] In some embodiments, the invention employs a PEG-modified CIFN, where the PEG
, moiety is attached to a lysine residue cliosen from 1Ys31, 1Ys50, 1Ys71, 1Ys84, 1Ys1a1, 1Ys12a, 1Ys134 1ys135, and lysl6s In these embodiments, the PEG moiety can be a linear PEG
moiety having an average molecular weight of about 30 kD.
[00139] In other embodiments, the invention einploys a PEG-modified CIFN, where the PEG
moiety is attached to a lysine residue chosen from lys121, 1ys134, lys135, and 1ys16s In these embodiments, the PEG moiety can be a linear PEG moiety having an average molecular weight of about 30 kD.
[00140] As one non-limiting example, one monopegylated CIFN conjugate preferred for use herein has a linear PEG moiety of about 30 kD attaclied 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 lys31,1ys50,1ys71,1ys84, 1ys121, 1ys122, 1yS134, 1yS135, and lys165, and the amide bond is formed by condensation of an a-methoxy, omega propanoic acid activated ester of PEG.

LinkinngQToups [00141] In some embodiments, PEG is attached to IFN-a via a linking group. The linking group is any biocompatible linking group, where "biocompatible" indicates that the compound or group is essentially non-toxic and may be utilized in vivo without causing a significant adverse response in the subject, e.g., injury, sickness, disease, undesirable immune response, or death. PEG can be bonded to the linking group, for example, via an ether bond, an ester bond, a thio ether 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 butanoic acid (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 carbonate (TPC)), a trysylate group, an aldehyde group, an isocyanate group, a vinylsulfone group, a tyrosine group, a cysteine group, a histidine group or a primary amine.
[00142] In many embodiments, the PEG is a monometlioxyPEG molecule that reacts witli primary amine groups on the IFN-a 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 :13 3 -140.
[00143] In one non-limiting example, PEG is linked to IFN-a via an SPA linking group. SPA
esters of PEG, and methods for making sanle, are described in U.S. Patent No.
5,672,662. SPA
linkages provide for linkage to free amine groups on the IFN-a polypeptide.
[00144] For example, 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-a polypeptide. Such a bond can be formed, e.g., by condensation of an a-methoxy, omega propanoic acid activated ester of PEG
(mPEGspa).
[00145] As one non-limiting example, monopegylated CIFN has a linear PEG
moiety of about 301cD 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 lys1a1,1yS134, lys135, and 1ys16s, and the amide bond is formed by condensation of an a-methoxy, omega propanoic acid activated ester of PEG.

[00146] Methods for attaching a PEG molecule to an IFN-a polypeptide are known in the art, and any known method can be used. See, for example, by Park et al, Anticancer Res., 1:373-376 (1981); Zaplipsky and Lee, Polyethylene Glycol Chemistry: Biotechnical and Biomedical Applications, J. M. Harris, ed., Plenum Press, NY, Chapter 21 (1992); and U.S.
Patent No.
5,985,265.
Polyethylene, glycol [00147] Polyethylene glycol suitable for conjugation to an IFN-a polypeptide is soluble in water at room temperature, and has the general formula R(O-CH2-CHa)õO-R, where R is hydrogen or a protective group such as an allcyl 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.
[00148] In many embodiments, PEG has at least one hydroxyl group, e.g., a tenninal 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.
[00149] In other enlbodiments, PEG is derivatized so that it is reactive with free carboxyl groups in the IFN-a polypeptide, e.g., the free carboxyl group at the carboxyl terminus of the IFN-a polypeptide. Suitable derivatives of PEG that are reactive with the free carboxyl group at the carboxyl-terminus of IFN-a include, but are not limited to PEG-amine, and hydrazine derivatives of PEG (e.g., PEG-NH-NH2).
[00150] In other embodiments, PEG is derivatized such that it comprises a terminal thiocarboxylic acid group, -COSH, which selectively reacts with amino groups to generate amide derivatives. Because of the reactive nature of the thio acid, selectivity of certain amino groups over others is achieved. For example, -SH exhibits sufficient leaving group ability in reaction with N-terminal amino group at appropriate pH conditions such that the E-amino groups in lysine residues are protonated and remain non-nucleophilic. On the other hand, reactions under suitable pH conditions may make some of the accessible lysine residues to react with selectivity.
[00151] In other embodiments, the PEG comprises 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.
For example, the N-terminal amino groups may be selectively modified under neutral pH
conditions. However, if the reactivity of the reagent were extreme, accessible-NH2 groups of lysine may also react.

[00152] The PEG can be conjugated directly to the IFN-a polypeptide, or through a linker. In some embodiments, a linker is added to the IFN-a polypeptide, forming a linker-modified IFN-a polypeptide. Such linkers provide various functionalities, e.g., reactive groups such sulfliydryl, amino, or carboxyl groups to couple a PEG reagent to the linker-modified IFN-a polypeptide.
[00153] In some embodiments, the PEG conjugated to the IFN-a polypeptide is linear. In other embodiments, the PEG conjugated to the IFN-a 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.
[00154] PEG having a molecular weiglit 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. For exaniple, PEG suitable for conjugation to IFN-a has a molecular weight of from about 2 kDa 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 kDa, from about 25 kDa to about 30 kDa, from about 30 kDa to about 40 kDa, from about 40 kDa to about 50 kDa, from about 50 kDa to about 60 kDa, from about 60 kDa to about 70 kDa, from about 70 kDa to about 80 kDa, from about 80 kDa to about 90 kDa, or from about 90 kDa to about 100 kDa.
Preparing PEG-IFN-a conlugates [00155] As discussed above, 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-a polypeptide. Conjugation can be carried out in solution or in the solid phase.

N-ternzinal linkage [00156] Methods for attacliing a PEG moiety to an amino acid residue at or near the N-terminus of an IFN-a polypeptide are known in the art. See, e.g., U.S. Patent No.
5,985,265.
[00157] In some embodiments, known methods for selectively obtaining an N-terminally chemically modified IFN-a are used. For example, 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. Under the appropriate reaction conditions, 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 pKa differences between the s-amino groups of the lysine residues and that of the a-amino group of the N-terminal residue of the protein. By such selective derivatization attachment of a PEG moiety to the IFN-a is controlled: the conjugation with the polymer takes place predominantly at the N-terminus of the IFN-a and no significant modification of other reactive groups, such as the lysine side chain amino groups, occurs.
C-terminal linkage [00158] N-terminal-specific coupling procedures such as described in U.S.
Patent No.
5,985,265 provide predominantly monoPEGylated products. However, the purification procedures aimed at removing the excess reagents and minor multiply PEGylated products remove the N-terminal blocked polypeptides. In terms of therapy, such processes lead to significant increases in manufacturing costs. For example, 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. Thus, in some embodiments, N-terminally PEGylated IFN-a is not used;
instead, the IFN-a polypeptide is C-terminally PEGylated.
[00159] An effective synthetic as well as therapeutic approach to obtain mono PEGylated Infergen product is therefore envisioned as follows:
[00160] A PEG reagent that is selective for the C-terminal can be prepared with or without spacers. For example, 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.
[00161] Preparing or obtaining a water-soluble carbodiimide as the condensing agent can be carried out. Coupling IFN-a (e.g., Infergen Alfacon-1 CIFN or consensus interferon) with a water-soluble carbodiimide as the condensing reagent is generally carried out in aqueous inedium 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.
[00162] The reagents selected will depend on process optimization studies. A
non-limiting example of a suitable reagent is EDAC or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide.
The water solubility of EDAC 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 EDAC 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. Most of the synthetic protocols in literature suggest the optimal reaction medium to be in pH range between 4.7 and 6Ø
However the condensation reactions do proceed without significant losses in yields up to pH 7.5. Water may be used as solvent. In view of the contemplated use of Infergen, preferably the medium will be 2-(N-morpholino)ethane sulfonic acid buffer pre-titrated to pH between 4.7 and 6Ø However, 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-a molecule is optimized such that the C-terminal carboxyl residue(s) are selectively PEGylated to yield monoPEGylated derivative(s).
[00163] Even though the use of 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-NH2 which will also condense with the carboxyl group of the IFN-a protein, can also be used. In addition to aqueous phase, 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.
[00164] Additionally, suitable spacers can be added to the C-terminal of the protein. The spacers may have reactive groups such as SH, NH2 or COOH to couple with appropriate PEG
reagent to provide the high molecular weight IFN-a 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-a is extended on a solid phase using a Gly-Gly-Cys-NH2 spacer and then monopegylated in solution using activated dithiopyridyl-PEG
reagent of appropriate molecular weights. Since the coupling at the C-terminus is independent of the blocking at the N-terminus, the envisioned processes and products will be beneficial with respect to cost (a third of the protein is not wasted as in N-terminal PEGylation methods) and contribute to the economy of the therapy to treat chronic hepatitis C
infections, liver fibrosis etc.
[00165] There may be a more reactive carboxyl group of amino acid residues elsewhere in the molecule to react with the PEG reagent and lead to monoPEGylation at that site or lead to multiple PEGylations in addition to the -COOH group at the C-terminus of the IFN-a. It is envisioned that these reactions will be minimal at best owing to the steric freedom at the C-terminal end of the molecule and the steric hindrance imposed by the carbodiimides and the PEG reagents such as in branched chain molecules. It is therefore the preferred mode of PEG
modification for Infergen and similar such proteins, native or expressed in a host system, which may have blocked N-termini to varying degrees to improve efficiencies and maintain higher in vivo biological activity.

[00166] 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. For example, one such reagent could be a branched chain PEG -40kd in molecular weight and this agent could be synthesized as follows:
[00167] OH3C-(CH2CH2O)n-CH2CH2NH2 + Glutamic Acid i.e., HOCO-CH2CH2CH(NH2)-COOH is condensed with a suitable agent e.g., dicyclohexyl carbodiiinide or water-soluble EDC to provide the branched chain PEG agent OH3C-(CH2CH2O)n CH2CHaNHCOCH(NH2)CH2OCH3-(CH2CH2O)õCH2CH2NHCOCH2.

H3C-O-(CH-)CH2O)n-CH2CH2N H.2+ H.O C-CH2CH2CH-COOH
I
EDAC CkiNI h H3C-O-(CH'-)CH2C))õ-CH2CH2NH-CO

(C.H2 )2 t I3C-O-(C::HzC.I-I2O)n-CI1zC II?N:I=I-CO

[00168] This reagent can be used in excess to couple the amino group with the free and flexible carboxyl group of IFN-a to form the peptide bond.
[00169] If desired, PEGylated IFN-a is separated from unPEGylated IFN-a using any known method, including, but not limited to, ion exchange chromatography, size exclusion chromatography, and combinations thereof. For example, where the PEG-IFN-a conjugate is a monoPEGylated IFN-a, 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.
MonoPEG (30 kD, linear)-ylated IFN-a [00170] PEGylated IFN-a that is suitable for use in the present invention includes a monopegylated consensus interferon (CIFN) molecule comprised of a single CIFN
polypeptide and a single polyethylene glycol (PEG) moiety, where the PEG moiety is linear and about 30 in molecular weight and is directly or indirectly linked through a stable covalent linkage to either the N-terminal residue in the CIFN polypeptide or a lysine residue in the CIFN
polypeptide. In some embodiments, the monoPEG (30 kD, linear)-ylated IFN-a is monoPEG
(30 kD, linear)-ylated consensus IFN-a.
[00171] In some embodiments, the PEG moiety is linked to either the alpha-amino group of the N-terminal residue in the CIFN polypeptide or the epsilon-amino group of a lysine residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moietyand either the alpha-amino group of the N-terminal residue or the epsilon-amino group of the lysine residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon-amino group of the lysine residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon-amino group of the lysine residue in the CIFN polypeptide, thereby forming a hydrolytically stable linkage between the PEG moiety and the CIFN polypeptide.
[00172] In some embodiments, the PEG moiety is linked to the N-terminal residue in the CIFN
polypeptid"e. In other embodiments, the PEG moiety is linked to the alpha-amino group of the N-terminal residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the alpha-amino group of the N-terminal residue in the CIFN polypeptide. In still fixrther embodiments, the linkage comprises an amide bond between a'propionyl group of the PEG moiety and the alpha-amino group of the N-terminal residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the alpha-amino group of the N-terminal residue of the CIFN polypeptide.
[00173] In some embodiments, the PEG moiety is linked to a lysine residue in the CIFN
polypeptide. In other embodiments, the PEG moiety is linked to the epsilon-amino group of a lysine residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the lysine group in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the lysine group in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon-amino group of the lysine residue in the CIFN polypeptide.

[00174] In some embodiments, the PEG moiety is linked to a surface-exposed lysine residue in the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the epsilon-amino group of a surface-exposed lysine residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the surface-exposed lysine residue in the CIFN polypeptide. In still fiuther embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the surface-exposed lysine residue in the CIFN
polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon-amino group of the surface-exposed lysine residue in the CIFN polypeptide.
~
[00175] In some embodiments, the PEG moiety is linked to a lysine chosen from lys31, lys50 1ys71, 1ys84, 1ys121, 1ys12a, 1yS134, lysl3s, and 1ys16s of the CIFN
polypeptide. In other embodiments, the PEG moiety is linked to the epsilon-amino group of a lysine chosen from lys31, 1yS50, 1ys71, 1ys84, 1ys121, 1ys122, 1yS134, lyS135, and lys165 of the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG
moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG
moiety and the epsilon-amino group of the chosen lysine residue in the CIFN
polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide.
[00176] In some embodiments, the PEG moiety is linked to a lysine chosen from 1ys121,1ys13a, 1ys135, and 1ys165 of the CIFN polypeptide. In other embodiments, the PEG
moiety is linked to the epsilon-amino group of a lysine chosen from 1ys121,1ys134,1ys135, and lys165 of the CIFN
polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG
lnoiety and the epsilon-amino group of the chosen lysine residue in the CIFN
polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN
polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide.
[00177] In connection with the above-described monopegylated CIFN molecules, the invention contemplates embodiments of each such molecule where the CIFN polypeptide is chosen from interferon alpha-conl, interferon alpha-con2, and interferon alpha-con3, the amino acid sequences of which CIFN polypeptides are disclosed in U.S. Pat. No. 4,695,623.
Populations of IFN-a [00178] In addition, any of the methods of the invention involving administration of IFN-a can employ a PEGylated IFN-a composition that comprises a population of monopegylated IFNa molecules, where the population consists of one or more species of monopegylated IFNa molecules as described above. The composition comprises a population of modified IFN-a polypeptides, each with a single PEG molecule linked to a single amino acid residue of the polypeptide.

[00179] In some of these embodiments, the population comprises a mixture of a first IFN-a polypeptide linked to a PEG molecule at a first amino acid residue; and at least a second IFN-a polypeptide linked to a PEG molecule at a second amino acid residue, wherein the first and second IFN-a polypeptides are the same or different, and wherein the location of the first amino acid residue in the amino acid sequence of the first IFN-a polypeptide is not the same as the location of the second amino acid residue in the second IFN-a polypeptide.
As one non-limiting example, a composition comprises a population of PEG-modified IFN-a polypeptides, the population comprising an IFN-a polypeptide linked at its amino terminus to a linear PEG
molecule; and an IFN-a polypeptide linked to a linear PEG molecule at a lysine residue.
[00180] Generally, a given modified IFN-a species represents from about 0.5%
to about 99.5%
of the total population of monopegylated IFNa polypeptide molecules in a population, e.g, a given modified IFN-a species represents about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or about 99.5% of the total population of monopegylated IFN-a polypeptide molecules in a population. In some embodiments, a composition comprises a population of monopegylated IFN-a polypeptides, which population comprises at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99 10,' IFN-a polypeptides linked to PEG at the same site, e.g., at the N-terminal amino acid.

[00181] In particular embodiments of interest, a composition comprises a population of monopegylated CIFN molecules, the population consisting of one or more species of molecules, where each species of molecules is characterized by a single CIFN
polypeptide linked, directly or indirectly in a covalent linkage, to a single linear PEG
moiety of about 30 kD in molecular weight, and where the linkage is to either a lysine residue in the CIFN
polypeptide, or the N-terminal amino acid residue of the CIFN polypeptide.
[00182] The amino acid residue to which the PEG is attached is in many embodiments the N-terminal amino acid residue. In other embodiments, the PEG moiety is attached (directly or via a linker) to a surface-exposed lysine residue. In additional embodiments, the PEG moiety is attached (directly or via a linker) to a lysine residue chosen from 1ys31,1ys50,1ys71,1ys84, lys121, lys122, lys134, lys135, and lys16s of the CIFN polypeptide. In further embodiments, the PEG moiety is attached (directly or via a linker) to a lysine residue chosen from lysla1,1ys134, lys135, and lys165 of the CIFN polypeptide.

[00183] As an example, a composition comprises a population of monopegylated CIFN
molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN
polypeptide, and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue of a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different. A
composition can further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a lysine residue in the CIFN
polypeptide, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.
[00184] As another example, a composition comprises a population of monopegylated CIFN
molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at the N-terminal anlino acid residue of a first CIFN
polypeptide, and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linlced to a first surface-exposed lysine residue of a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different. A
composition can further comprise at least one additional monopegylated CIFN
polypeptide species of molecules characterized by a PEG moiety linked to a surface-exposed lysine residue in the CIFN polypeptide, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.
[00185] As another example, a composition comprises a population of monopegylated CIFN
molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN
polypeptide, and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue selected from one of 1ys31, lys50, 1ys71, 1ys84, lys121, 1ys122, 1ys134, 1ys135, and lys165 in a second CIFN
polypeptide, where the first and second CIFN polypeptides are the same or different. A subject composition can further comprise a third monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a second lysine residue selected from one of lys31,1ys50,1ys71,1ys84, lys121,1ys122,1ys134,1ys13s, and 1ys16s in a third CIFN polypeptide, where the third CIFN
polypeptide is the same or different from eitlier of the first and second CIFN
polypeptides, where the second lysine residue is located in a position in the amino acid sequence of the third CIFN polypeptide that is not the same as the position of the first lysine residue in the amino acid sequence of the second CIFN polypeptide. A composition may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG
moiety linked to one of 1ys31, 1ys50, 1ys71, 1ys84, lys121, 1ys12a, 1ys134, 1ys135, and 1ys165, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.
[00186] As another example, a composition colnprises a population of monopegylated CIFN
molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN
polypeptide, and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue selected from one of lyslal, lys134,1ys13s, and 1ys16s in a second CIFN polypeptide, where the first and second CIFN
polypeptides are the same or different. A composition can further comprise a third monopegylated CIFN polypeptide species of molecules characterized by a PEG
moiety linked to a second lysine residue selected from one of lys121,1ys134, lys13s, and lysl6s in a third CIFN
polypeptide, where the third CIFN polypeptide is the same or different from either of the first and second CIFN polypeptides, where the second lysine residue is located in a position in the amino acid sequence of the third CIFN polypeptide that is not the same as the position of the first lysine residue in the amino acid sequence of the second CIFN
polypeptide. A composition may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to one of lys1a1,1ys134, 1ys135, and lysl6s, where the location of the linkage site in each additional monopegylated CIFN
polypeptide species is not the same as the location of the linlcage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.
[00187] As another non-limiting example, a composition comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN
polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second lysine residue in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the first lysine is located in a position in the amino acid sequence of the first CIFN
polypeptide that is not the same as the position of the second lysine residue in the amino acid sequence of the second CIFN polypeptide. A composition may further comprise at least one additional monopegylated CIFN species of molecules characterized by a PEG moiety linked to a lysine residue in the CIFN polypeptide, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[00188] As another non-limiting example, a composition comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN
polypeptide species of molecules characterized by a PEG moiety linked at a first lysine residue chosen from 1Ys31, 1Ys50, 1Ys71, 1Ys84, 1Ys121, 1Ys122, 1YS134, 1Ys135, and 1Ys165 in a first CIFN polypeptide;
and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG
, moietY linked at a second lysine residue chosen from 1Ys31, 1Ys50, 1Ys71, 1Ys84, 1Ys121, 1Ys122 1ys134, 1ys135, and 1ys16s in a second CIFN polypeptide, where the first and second CIFN
polypeptides are the same or different, and where the second lysine residue is located in a position in the amino acid sequence of the second CIFN polypeptide that is not the same as the position of the first lysine residue in the first CIFN polypeptide. The composition may further comprise at least one additional monopegylated CIFN polypeptide species of molecules , characterized by a PEG moiety linked to one of 1Ys31, 1Ys50, 1Ys7l, 1Ys84, 1Ys121, 1Ys122, 1Ys134 1ys13s, and 1ys16s, where the location of the linkage site in each additional monopegylated CIFN
polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.
[00189] As another non-limiting example, a composition comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN
polypeptide species of molecules characterized by a PEG moiety linked at a first lysine residue chosen from lys1a1, lyS134, 1ys135, and 1ys165 in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second lysine residue chosen from 1ys121,1yS134, 1ys135~ and lys165 in a second CIFN
polypeptide, where the first and second CIFN polypeptides are the same or different, and where the second lysine residue is located in a position in the amino acid sequence of the second CIFN
polypeptide that is not the same as the position of the first lysine residue in the first CIFN
polypeptide. The composition may further comprise at least one additional monopegylated CIFN
polypeptide species of molecules characterized by a PEG moiety linked to one of 1ys121,1ys134,1ys135, and lyslss, where the location of the linkage site in each additional monopegylated CIFN
polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG lnoiety is a linear PEG moiety having an average molecular weight of about 30 kD.
[00190] As another non-limiting example, a composition comprises a monopegylated population of CIFN molecules, consisting of a first monopegylated CIFN
polypeptide species of molecules characterized by a PEG lnoiety linked to a first surface-exposed lysine residue in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second surface-exposed lysine residue in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the first surface-exposed lysine is located in a position in the amino acid sequence of the first CIFN polypeptide that is not the same as the position of the second surface-exposed lysine residue in the amino acid sequence of the second CIFN polypeptide. A
composition may further comprise at least one additional monopegylated CIFN species of molecules characterized by a PEG moiety linked to a surface-exposed lysine residue in the CIFN
polypeptide, where the location of the linkage site in each additional monopegylated CIFN
polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.
[00191] In connection with each of the above-described populations of monopegylated CIFN
molecules, the invention contemplates embodiments where the molecules in each such population comprise a CIFN polypeptide chosen from interferon alpha-conl, interferon alpha-con2, and interferon alpha-con3.
[00192] The invention further features a product that is produced by the process of reacting CIFN polypeptide with a succinimidyl ester of alpha-methoxy, omega-propionylpoly(ethylene glycol) (mPEGspa) that is linear and about 30 kD in molecular weight, where the reactants are initially present at a molar ratio of about 1:1 to about 1:5 CIFN:mPEGspa, and where the reaction is conducted at a pH of about 7 to about 9, followed by recovery of the monopegylated CIFN product of the reaction. In one embodiment, the reactants are initially present at a molar ratio of about 1:3 CIFN:mPEGspa and the reaction is conducted at a pH of about 8. In another embodiment where the product of the invention is generated by a scaled-up procedure needed for toxicological and clinical investigations, the reactants are initially present in a molar ratio of 1:2 CIFN:mPEGspa and the reaction is conducted at a pH of about 8Ø
[00193] In connection with the above-described product-by-process, the invention contemplates embodiments where the CIFN reactant is chosen from interferon alpha-coni, interferon alpha-con2, and interferon alpha-con3.
IFNN-R
[00194] The term interferon-beta ("IFN-(3") includes IFN-0 polypeptides that are naturally occurring; non-naturally-occurring IFN-0 polypeptides; and analogs and variants of naturally occurring or non-naturally occurring IFN-0 that retain antiviral activity of a parent naturally-occurring or non-naturally occurring IFN-(3.
[00195] Any of a variety of 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-0; IFN-pla, e.g., Avonex (Biogen, Inc.), and Rebif (Serono, SA); IFN-(3lb (Betaseron ; Berlex); and the like.
[00196] The IFN-(3 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-0.
[00197] IFN-0 polypeptides can be produced by any known method. DNA sequences encoding IFN-(3 may be synthesized using standard methods. In many embodiments, IFN-(3 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-P is "recombinant IFN-0." Where the host cell is a bacterial host cell, the IFN-0 is modified to comprise an N-terminal methionine.
[00198] It is to be understood that IFN-0 as described herein may comprise one or more modified amino acid residues, e.g., glycosylations, chemical modifications, and the like.

IFN-tau [00199] The term interferon-tau includes IFN-tau polypeptides that are naturally occurring; non-naturally-occurring IFN-tau polypeptides; and analogs and variants of naturally occurring or non-naturally occurring IFN-tau that retain antiviral activity of a parent naturally-occurring or non-naturally occurring IFN-tau.
[00200] Suitable tau interferons include, but are not limited to, naturally-occurring IFN-tau;
Tauferon (Pepgen Corp.); and the like.
[00201] IFN-tau may comprise an amino acid sequence as set forth in any one of GenBank Accession Nos. P15696; P56828; P56832; P56829; P5683 1; Q29429; Q28595;
Q28594;
S08072; Q08071; Q08070; Q08053; P56830; P28169; P28172; and P28171. The sequence of any known 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).
[00202] 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 enzyines 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.
[00203] The IFN-tau formulation may comprise an N-blocked species, wherein the N-terminal amino acid is acylated witll an acyl group, such as a formyl group, an acetyl group, a malonyl group, and the lilce. Also suitable for use is a consensus IFN-tau.
[00204] 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.
[00205] It is to be understood that IFN-tau as described herein may comprise one or more modified amino acid residues, e.g., glycosylations, chemical modifications, and the like.
IFN-eo [002061 The term interferon-omega ("IFN-o)") includes IFN-(o polypeptides that are naturally occurring; non-naturally-occurring IFN-co polypeptides; and analogs and variants of naturally occurring or non-naturally occurring IFN-co that retain antiviral activity of a parent naturally-occurring or non-naturally occurring IFN-co.
[00207] Any known omega interferon can be delivered by the continuous delivery method of the present invention. Suitable IFN-w include, but are not limited to, naturally-occurring IFN-w; recombinant IFN-o), e.g., Bioined 510 (BioMedicines); and the like.
[00208] IFN-o) may comprise an amino acid sequence as set forth in GenBank Accession No.
NP_002168; or AAA70091. The sequence of any known IFN-co 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).
[00209] 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 fizrther 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.
[00210] The IFN-(o 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-c).

[002111 IFN-co polypeptides can be produced by any known method. DNA sequences encoding IFN-e) may be synthesized using standard methods. In many embodiments, IFN-(o 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-co is "recombinant IFN-c)." Where the host cell is a bacterial host cell, the IFN-co is modified to comprise an N-terminal methionine.
[00212] It is to be understood that IFN-co as described herein may comprise one or more modified amino acid residues, e.g., glycosylations, chemical modifications, and the like.
Type II interferon receptor agonists [00213] In some embodiments, a subject method comprises administering a SAPK
inhibitor, a Type I interferon receptor agonist, and a Type II interferon receptor agonist.
Suitable Type II
interferon receptor agonists include any naturally occurring or non-naturally-occurring ligand of a human Type II interferon receptor that 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.
[00214] A specific example of a Type II interferon receptor agonist is IFN-gamma and variants thereof. While the present invention exemplifies use of an IFN-gamma polypeptide, it will be readily apparent that any Type II interferon receptor agonist can be used in a subject method.
Interferon-Gamma [00215] The nucleic acid sequences encoding IFN-gamma polypeptides may be accessed from public databases, e.g., Genbank, journal publications, and the like. While various mammalian IFN-gamma polypeptides are of interest, for the treatment of human disease, generally the human protein will be used. Human IFN-gamma coding sequence may be found in Genbank, accession numbers X13274; V00543; and NM 000619. The corresponding genomic sequence may be found in Genbank, accession numbers J00219; M37265; and V00536. See, for example. Gray et al. (1982) Nature 295:501 (Genbank X13274); and Rinderknecht et al.
(1984) J. B. C. 259:6790.
[00216] IFN-ylb (Actimmune ; liuman interferon) is a single-chain polypeptide of 140 amino acids. It is made recombinantly in E. coli and is unglycosylated (Rinderknecht et al. 1984, J.
Biol. Chem. 259:6790-6797). Recombinant IFN-gamma as discussed in U.S. Patent No.
6,497,871 is also suitable for use herein.

[00217] The IFN-gamma to be used in the methods of the present invention may be any of natural IFN-gamma, recombinant IFN-gamma and the derivatives thereof so far as they have an IFN-y activity, particularly human IFN-gamma activity. Human IFN-gamma 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. Although IFN-gamma 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). Although the recombinant IFN-gamma produced in E.
coli was originally believed to be 146 amino acids, (commencing at amino acid 20) it was subsequently found that native human IFN-gamma 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. During purification, 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 eulcaryotic expression systems, methionine may be removed.
[00218] For use in the subject methods, any of the native IFN-gamma peptides, modifications and variants thereof, or a combination of one or more peptides may be used.
IFN-gamma 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- gamma 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-y activity, may be used in the present methods.
[00219] The sequence of the IFN-y 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, glutainine); (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).
[00220] 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. IFN-gamma may be modified with one or more polyethylene glycol moieties (PEGylated). In one embodiment, the invention contemplates the use of IFN-gamma 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-gamma polypeptide variants described in any of International Patent Publication Nos.

and WO 02/081507. 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.
[00221] Included for use in the subject invention are 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. For examples, the backbone of the peptide may be cyclized to enhance stability (see, for example, Friedler et al. 2000, J. Biol. Cheni. 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.
[00222] The 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.

[00223] 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. For the most part, the compositions which are used will comprise at least 20% by weiglit 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 [00224] As discussed above, the subject methods specifically exclude the use of pirfenidone (5-methyl-l-phenyl-2-(1 H)-pyridone) or a pirfenidone analog.

Pirfenidone Me Ph O
Pirfenidone analogs I.

X' ~
O
II.A II.B

~
R R O X
X

Descriptions for Substituents Rl, R2, X
[00225] Rl: 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.
[00226] Rl 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.
[00227] R2: alkyl, carbocylic, aryl, heterocyclic. Examples include: methyl, ethyl, propyl, isopropyl, phenyl, 4-nitrophenyl, thienyl and the like.
[00228] 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, lzeteroalkyl, aryl, heteroaryl, halo, nitro, carboxyl, hydroxyl, cyano, amino, thio, alkylamino, haloaryl and the like.
[00229] 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.
[00230] Specific Examples include those shown in Table 1:
Table 1 IA IIB
5-Meth 1-1- 2'- id 1-2-(1H) pyridine, 6-Meth 1-1- hen 1-3- 1H pyridone, 6-Methyl-l- henyl-2-(1H) pyridone, 5-Methyl-1- -tolyl-3-(1H) pyridone, 5-Methyl-3-phenyl-l-(2'-thienyl)-2-(1H) 5-Methyl-l-(2'-naphthyl)-3-(1H) pyridone, pyridone, 5-Meth 1-1- 2'-na hth 1)-2-(1H) pyridone, 5-Meth 1-1- hen 1-3- 1H pyridone, 5-Methyl-l- -tolyl-2-(1H) pyridone, 5-Methyl-1-(5'- uinolyl)-3-(1H) pyridone, 5-Methyl-l-(1'na hthyl)-2-(1H) pyridone, 5-Ethyl-l- henyl-3-(1H) pyridone, 5-Ethyl-1-phenyl-2-(1H) pyridone, 5-Methyl-l-(4'-methoxyphenyl)-3-(1H) pyridone, 5-Meth 1-1- 5'- uinol 1-2- 1H) pyridone, 4-Meth 1-1- hen 1-3- 1H pyridone, 5-Methyl-l-(4'- uinolyl)-2-(1H) pyridone, 5-Methyl-1-(3'- yridyl)-3-(1H) pyridone, 5-Meth 1-1- 4'- id 1-2- 1H pyridone, 5-Meth 1-1- 2'-Thien 1-3- 1H pyridone, 3-Methyl-l- henyl-2-(1H) pyridone, 5-Methyl-l-(2'- yridyl)-3-(1H) pyridone, 5-Methyl-l-(4'-methoxyphenyl)-2-(1H) 5-Methyl-1-(2'-quinolyl)-3-(1H) pyridone, pyridone, 1-Phen 1-2-(1H pyridone, 1-Phen 1-3-(1H) pyridine, 1,3-Di henyl-2-(1H) pyridone, 1-(2'-Furyl)-5-methyl-3-(1H) pyridone, 1,3-Diphenyl-5-methyl-2-(1H) pyridone, 1-(4'-Chlorophenyl)-5-methyl-3-(1H) pyridine.
-Methyl-l-(3' -trifluoromethylphenyl)-2-(1H)- yridone, 3-Ethyl-1- hen 1-2-(1H) pyridone, 5-Meth 1-1- 3'- id 1-2-(1H) pyridone, 5-Methyl-1 -(3-nitro henyl)-2-(1H) yridone, 3 -(4' -Chlorophenyl)-5 -Methyl-l-phenyl-2-(1H) pyridone, 5-Meth 1-1- 2'-Thien 1-2- lI-1) pyridone, 5-Methyl-l-(2'-thiazolyl)-2-(IH) pyridone, 3,6-Dimeth 1-1- hen 1-2-(1 pyridone, 1 -(4' Chlorophenyl)-5 -Methyl-2-(1 H) ridone, 1-(2'-Imidazolyl)-5-Methyl-2-(1H) pyridone, 1-(4'-Nitro hen 1-2- 1H pyridone, 1-(2'-Furyl)-5-Methyl-2-(1H) pyridone, 1 -Phenyl-3 -(4' -chlorophenyl)-2-(1 H) pyridine.

Additional anti-viral therapeutic agents [00231] In some embodiments, a subject method comprises administering to an individual in need thereof a SAPK inhibitor, a Type I interferon receptor agonist; and at least one additional anti-viral therapeutic agent. In some embodiments, a subject method comprises administering to an individual'in rieed thereof a SAPK inhibitor, a Type I interferon receptor agonist, a Type II interferon receptor agonist, and an additional anti-viral therapeutic agent. Additional antiviral therapeutic agents that are suitable for administering in a subject combination therapy include, but are not limited to, thymosin-a; nucleoside analogs such as ribavirin and virainidine; L-nucleosides such as levovirin; amantidine; TNF antagonists; HCV

inhibitors; HCV NS5B inhibitors; alpha-glucosidase inhibitors; inhibitors of inosine monophosphate dehydrogenase (IMPDH); ribozymes that are complementary to viral nucleotide sequences; antisense RNA inhibitors; and the like.
TNF Antagonists [00232] Suitable TNF-a antagonists for use herein include agents that decrease the level of TNF-a synthesis, agents that block or inhibit the binding of TNF-a to a TNF-a receptor (TNFR), and agents that block or inhibit TNFR-mediated signal transduction.
Unless otherwise expressly stated, every reference to a "TNF-a antagonist" or "TNF
antagonist"
lierein will be understood to mean a TNF-a antagonist other than (i) pirfenidone and pirfenidone analogs and (ii) SAPK inhibitors.
[00233] As used herein, the terms "TNF receptor polypeptide" and "TNFR
polypeptide" refer to polypeptides derived from TNFR (from any species) which are capable of binding TNF. Two distinct cell-surface TNFRs have described: Type II TNFR (or p75 TNFR or TNFRII) and 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.
[00234] TNFR polypeptide may be an intact TNFR or a suitable fragment of TNFR.
U.S. Pat.
No. 5,605,690 provides examples of TNFR polypeptides, including soluble TNFR
polypeptides, appropriate for use in the present invention. In many embodiments, the TNFR
polypeptide comprises an extracellular domain of TNFR. In some embodiments, the TNFR
polypeptide is a fusion polypeptide comprising an extracellular domain of TNFR
linked to a constant domain of an immunoglobulin molecule. In other embodiments, the TNFR
polypeptide is a fusion polypeptide comprising an extracellular domain of the p75 TNFR
linked to a constant domain of an IgGl molecule. In some embodiments, when administration to humans is contemplated, an Ig used for fusion proteins is human, e.g., human IgG1.
[00235] Monovalent and multivalent forms of TNFR polypeptides may be used in the present invention. Multivalent forms of TNFR polypeptides possess more than one TNF
binding site.
In some embodiments, the TNFR is a bivalent, or dimeric, form of TNFR. For example, as described in U.S. Pat. No. 5,605,690 and in Mohler et al., 1993, J. Immunol., 151:1548-1561, a chimeric antibody polypeptide with TNFR extracellular domains substituted for the variable domains of either or both of the irnmunoglobulin heavy or liglit chains would provide a TNFR
polypeptide for the present invention. Generally, when such a chimeric TNFR:antibody polypeptide is produced by cells, it forms a bivalent molecule through disulfide linkages between the immunoglobulin domains. Such a chimeric TNFR:antibody polypeptide is referred to as TNFR:Fc.
[00236] In one embodiment, a subject method involves administration of an effective amount of the soluble TNFR ENBREL etanercept. 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 CH1 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.
(1990) Science 248:1019-1023; Mohler et al. (1993) J. Immunol. 151:1548-1561;
U.S. Pat. No.
5,395,760; and U.S. Pat. No. 5,605,690.
[00237] Also suitable for use are monoclonal antibodies that bind TNF-a.
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 sequeiice; 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.

[00238] Examples of suitable monoclonal antibodies include infliximab (REMICADE , Centocor); and adalimumab (HUMIRATM, Abbott) REMICADE is a chimeric monoclonal anti-TNF-a 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-a antibody fused to the constant region of a human IgGl.
Elliott et al.
(1993) Arthritis Rheum. 36:1681-1690; Elliott et al. (1994) Lancet 344:1105-1110; Baert et al.
(1999) Gastroenterology 116:22-28. HUMIRATM is a human, full-length IgGI
monoclonal antibody that was identified using phage display technology. Piascik (2003) J.
Am. Pharm.
Assoc. 43 :327-328.
[00239] Methods to assess TNF antagonist activity are known in the art and exemplified herein.
For example, TNF antagonist activity may be assessed with a cell-based competitive binding assay. In such an 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.
[00240] As another example, 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. In such an assay, 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.
Thymosin-a [00241] Thymosin-a (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-a 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 -Val - Asp - Thr - Ser - Ser - Glu - lle - Thr - Thr - Lys - Asp - Leu - Lys -Glu - Lys - Lys - Glu - Val - Val - Glu - Glu - Ala - Glu - Asn - OH, and having a molecular weight of 3,108 daltons.
The lyopliilized preparation contains 1.6 mg synthetic thymosin-a, 50 mg mannitol, and sodium phosphate buffer to adjust the pH to 6.8.
Ribavirin [00242] Ribavirin, 1-(3-D-ribofuranosyl-lH-1,2,4-triazole-3-carboxamide, is a nucleoside analog available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif., and 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 other therapeutic agent (e.g., a SAPK inhibitor). Of course, other types of administration of both medicaments, as they become available are contemplated, such as by nasal spray, transdermally, by suppository, by sustained release dosage form, etc. Any form of administration will work so long as the proper dosages are delivered without destroying the active ingredient.
[00243] Ribavirin is generally administered in an amount ranging 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.
In some embodiments, ribavirin is administered throughout the entire course of therapy with another agent (e.g., a SAPK inhibitor). In other embodiments, ribavirin is administered only during the first period of time. In still other embodiments, ribavirin is administered only during the second period of time.
Levovirin [00244] Levovirin is the L-enantiomer of ribavirin, and exhibits the property of enhancing a Thl immune response over a Th2 immune response. Levovirin is manufactured by ICN
Pharmaceuticals.
[00245] Levovirin has the following structure:

N
l1zN I \
N~
N

(.)H
p HO OH

Viramidine [00246] Viramidine is a 3-carboxamidine derivative of ribavirin, and acts as a prodrug of ribavirin. It is efficiently converted to ribavirin by adenosine deaminases.
[00247] Viramidine has the following structure:
Ni-I
N
H2N ( \
N
I-1.U
O
I{0 (:)Id Nucleoside analogs [00248] Nucleoside analogs that are suitable for use in a subject combination therapy include, but are not limited to, ribavirin, levovirin, viramidine, isatoribine (ANA245;
Anadys Phannaceuticals, Inc.), ANA97X (Anadys Pharmaceuticals, Inc.); ANA971 (a prodrug of isatoribine; Anadys Pharmaceuticals, Inc.); MN283; 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-(3-L-ribofiaranosyluracil, 1-(3-L-ribofuranosyl-5-fluorouracil, 1-(3-L-ribofuranosylcytosine, 9-(3-L-ribofiiranosyladenine, 9-(3-L-ribofuranosylhypoxanthine, 9-(3-L-ribofuranosylguanine, 9-[i-L-ribofuranosyl-6-thioguanine, 2-amino-a-L-ribofuranl[1',2':4,5]oxazoline, 02,02-anhydro-l-a-L-ribofuranosyluracil, 1-a-L-ribofuranosyluracil, 1-(2,3,5-tri-O-benzoyl-a-ribofuranosyl)-4-thiouracil, 1-a-L-ribofuranosylcytosine, 1-a-L-ribofuranosyl-4-thiouracil, 1-a-L-ribofuranosyl-5-fluorouracil, 2-amino-(3-L-arabinofixrano[1',2':4,5]oxazoline, 02,O2-anhydro-(3-L-arabinofuranosyluracil, 2'-deoxy-(3-L-uridine, 3'S'-Di-O-benzoyl-2'deoxy-4-thio (3-L-uridine, 2'-deoxy-[i-L-cytidine, 2'-deoxy-(3-L-4-thiouridine, 2'-deoxy-(3-L-thymidine, 2'-deoxy-(3-L-5-fluorouridine, 2',3'-dideoxy-(3-L-uridine, 2'-deoxy-[i-L-5-fluorouridine, and 2'-deoxy-(3-L-inosine); a compound as disclosed in U.S. Patent No. 6,423,695 and encompassed by Formula I of U.S.
Patent No.
6,423,695; a compound as disclosed in U.S. Patent Publication No.
2002/0058635, and encompassed by Formula 1 of U.S. Patent Publication No. 2002/0058635; a nucleoside analog as disclosed in WO 01/90121 A2 (Idenix); a nucleoside analog as disclosed in A2 (Biocryst Pharmaceuticals Inc.); a nucleoside analog as disclosed in WO
02/057287 A2 or WO 02/057425 A2 (both Merck/Isis); and the like.

HCV NS3 inhibitors [00249] Suitable HCV non-structural protein-3 (NS3) inhibitors include, but are not limited to, a tri-peptide as disclosed in U.S. Patent Nos. 6,642,204, 6,534,523, 6,420,380, 6,410,531, 6,329,417, 6,329,379, and 6,323,180 (Boehringer-Ingelheim); a compound as disclosed in U.S.
Patent No. 6,143,715 (Boehringer-Ingellieim); a macrocyclic compound as disclosed in U.S.
Patent no. 6,608,027 (Boehringer-Ingelheim); an NS3 inhibitor as disclosed in U.S. Patent Nos.
6,617,309, 6,608,067, and 6,265,380 (Vertex Pharmaceuticals); an azapeptide compound as disclosed in U.S. Patent No. 6,624,290 (Schering); a compound as disclosed in U.S. Patent No.
5,990,276 (Schering); a compound as disclosed in Pause et al. (2003) J. Biol.
Chem.
278:20374-20380; NS3 inhibitor BILN 2061 (Boehringer-Ingelheim; Lamarre et al.
(2002) Hepatology 36:301A; and Lamarre et al. (Oct. 26, 2003) Nature doi:10.1038/nature02099);
NS3 inhibitor VX-950 (Vertex Pharinaceuticals; Kwong et al. (Oct. 24-28, 2003) 54t1i Ann.
Meeting AASLD); NS3 inhibitor SCH6 (Abib et al. (October 24-28, 2003) Abstract 137.
Program and Abstracts of the 54th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). October 24-28, 2003. Boston, MA.); any of the NS3 protease inhibitors disclosed in WO 99/07733, WO 99/07734, WO 00/09558, WO 00/09543, WO
00/59929 or WO 02/060926 (e.g., compounds 2, 3, 5, 6, 8, 10, 11, 18, 19, 29, 30, 31, 32, 33, 37, 38, 55, 59, 71, 91, 103, 104, 105, 112, 113, 114, 115, 116, 120, 122, 123, 124, 125, 126 and 127 disclosed in the table of pages 224-226 in WO 02/060926); an NS3 protease inhibitor as disclosed in any one of U.S. Patent Publication Nos. 2003019067, 20030187018, and 20030186895; and the like.
[00250] Of particular interest in many embodiments are NS3 inhibitors that are specific NS3 inhibitors, e.g., NS3 inhibitors that inhibit NS3 serine protease activity and that do not show significant inhibitory activity against other serine proteases such as human leukocyte elastase, porcine pancreatic elastase, or bovine pancreatic chymotrypsin, or cysteine proteases such as human liver cathepsin B.
NS5B inhibitors [00251] Suitable HCV non-structural protein-5 (NS5; RNA-dependent RNA
polymerase) 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, by Boehringer Ingelheim; a compound as disclosed in U.S. Patent No. 6,440,985 (ViroPharma); a compound as disclosed in WO 01/47883, e.g., JTK-003 (Japan Tobacco); a dinucleotide analog as disclosed in Zhong et al. (2003) Antimicrob. Agents Chemother.

47:2674-268 1; a benzothiadiazine compound as disclosed in Dhanak et al.
(2002) J. Biol Chem. 277(41):38322-7; an NS5B inhibitor as disclosed in WO 02/100846 Al or WO
02/100851 A2 (both Shire); an NS5B 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.
[00252] Of particular interest in many embodiments are NS5 inhibitors that are specific NS5 inhibitors, e.g., NS5 inhibitors that iiiliibit NS5 RNA-dependent RNA
polymerase and that lack significant inhibitory toward other RNA dependent RNA polymerases and toward DNA
dependent RNA polymerases.
Alpha-Glucosidase Inhibitors [00253] Alpha-glucosidase inhibitors are a class of oral medications for type 2 diabetes that decrease'the absorption of carbohydrates from the intestine, resulting in a slower rise in blood glucose throughout the day, especially following meals, in type 2 diabetic patients. Alpha-glucosidase inhibitors suitable for use in a subject combination therapy include, but are not limited to, n-(n-nonyl)-deoxygalactonojirimycin (n,n-DGJ); N-nonyl-deoxynojirimycin (N-nonyl-DNJ); N-butyl-deoxynojirimycin (NB-DNJ); 1-deoxynojirimycin (DNM);
perbutylated-N-butyl-l-deoxynojiromycin (p-N-butyl-DNJ); and 6-0-butanoyl castanospermine;
and the like.
IMPDH inhibitors [00254] IMPDH inhibitors that are suitable for use in a subject combination therapy include, but are not limited to, VX-497 (Merimepodib; (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 Chenzother. 44:859-866); ribavirin (ICN
Pharrnaceuticals); levovirin (Ribapharm; see, e.g., Watson (2002) Curr Opin Investig Drugs 3(5):680-3); viramidine (Ribapharm); and the like.
Ribozyme and antisense [00255] 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.

Side effect management agents [00256] In some embodiments, a subject therapy comprises administering a palliative agent (e.g., an agent that reduces patient discomfort caused by a therapeutic agent), or other agent for the avoidance, treatment, or reduction of a side effect of a therapeutic agent. Such agents are also referred to as "side effect management agents." Suitable side effect management agents include agents for the avoidance, treatment, or reduction of a side effect of a Type I interferon receptor agonist; agents for the avoidance, treatment, or reduction of a side effect of a Type II
interferon receptor agonist; and the like.
[00257] Suitable side effect management agents include agents that are effective in pain management; agents that aineliorate gastrointestinal discomfort; analgesics, anti-inflammatories, antipsychotics, antineurotics, anxiolytics, and hematopoietic agents. In addition, the invention contemplates the use of any compound for palliative care of patients suffering from pain or any other side effect in the course of treatment with a subject therapy.
Exemplary palliative agents include acetaminophen, ibuprofen, and other NSAIDs, H2 blockers, and antacids.
[00258] Analgesics that can be used to alleviate pain in the methods of the invention include non-narcotic analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs) acetaminophen, salicylate, acetyl-salicylic acid (aspirin, diflunisal), ibuprofen, Motrin, Naprosyn, Nalfon, and Trilisate, indomethacin, glucametacine, acemetacin, sulindac, naproxen, piroxicam, diclofenac, benoxaprofen, ketoprofen, oxaprozin, etodolac, ketorolac tromethamine, lcetorolac, nabumetone, and the like, and mixtures of two or more of the foregoing.
[00259] Other suitable analgesics include fentanyl, buprenorphine, codeine sulfate, morphine hydrochloride, codeine, hydromorphone (Dilaudid), levorphanol (Levo-Dromoran), methadone (Dolophine), morphine, oxycodone (in Percodan), and oxymorphone (Numorphan).
Also suitable for use are benzodiazepines including, but not limited to, flurazepam (Dalmane), diazepam (Valium), and Versed, and the like.
Anti-inflammatory agents [00260] Suitable anti-inflammatory agents include, but are not limited to, steroidal anti-inflammatory agents, and non-steroidal anti-inflammatory agents.
[00261] Suitable steroidal anti-inflammatory agents include, but are not limited to, hydrocortisone, hydroxyltriaincinolone, alpha-methyl dexametliasone, dexamethasone-phosphate, beclomethasone dipropionate, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylester, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, conisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, chloroprednisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, triamcinolone, and mixtures of two or more of the foregoing.
[002621 Suitable non-steroidal anti-inflammatory agents, include, but are not limited to, 1) the oxicams, such as piroxicam, isoxicam, tenoxicam, and sudoxicam; 2) the salicylates, such as aspirin, disalcid, benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal; 3) the acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepiract, clidanac, oxepinac, and felbinac; 4) the fenamates, such as mefenamic, meclofenamic, flufenamic, niflumic, and tolfenamic acids; 5) the propionic acid derivatives, such as ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofenic;
and 6) the pyrazoles, such as phenylbutazone, oxyphenbutazone, feprazone, azapropazone, and trimethazone, mixtures of these non-steroidal anti-inflammatory agents may also be employed, as well as the pharmaceutically-acceptable salts and esters of these agents.
[00263] Suitable anti-inflammatory agents include, but are not limited to, Alclofenac;
Alclometasone Dipropionate; Algestone Acetonide; Alpha Amylase; Amcinafal;
Amcinafide;
Amfenac Sodium; Amiprilose Hydrochloride; Anakinra; Anirolac; Anitrazafen;
Apazone;
Balsalazide Disodium; Bendazac; Benoxaprofen; Benzydamine Hydrochloride;
Bromelains;
Broperamole; Budesonide; Carprofen; Cicloprofen; Cintazone; Cliprofen;
Clobetasol Propionate; Clobetasone Butyrate; Clopirac; Cloticasone Propionate;
Cormethasone Acetate;
Cortodoxone; Deflazacort; Desonide; Desoximetasone; -Dexamethasone Dipropionate;
Diclofenac Potassium; Diclofenac Sodium; Diflorasone Diacetate; -Diflumidone Sodium;
Diflunisal; Difluprednate; Diftalone; Dimethyl Sulfoxide; Drocinonide;
Endrysone;
Enlimomab Enolicam Sodium; Epirizole; Etodolac; Etofenamate; Felbinac;
Fenamole;
Fenbufen; Fenclofenac; Fenclorac; Fendosal; Fenpipalone; Fentiazac; Flazalone;
Fluazacort;
Flufenamic Acid; Flumizole; Flunisolide Acetate; Flunixin; Flunixin Meglumine;
Fluocortin Butyl; Fluorometholone Acetate; Fluquazone; Flurbiprofen; Fluretofen;
Fluticasone Propionate; Furaprofen; Furobufen; Halcinonide; Halobetasol Propionate;
Halopredone Acetate; Ibufenac; Ibuprofen; Ibuprofen Aluminum; Ibuprofen Piconol; Ilonidap;
Indomethacin; Indomethacin Sodium; Indoprofen; Indoxole; Intrazole;
Isoflupredone Acetate;
Isoxepac; Isoxicam; Ketoprofen; Lofemizole Hydrochloride; Lornoxicam;
Loteprednol Etabonate; Meclofenamate Sodium; Meclofenamic Acid; Meclorisone Dibutyrate;
Mefenamic Acid; Mesalamine; Meseclazone; Methylprednisolone Suleptanate; Momiflumate;
Nabumetone; Naproxen; Naproxen Sodium; Naproxol; Nimazone; Olsalazine Sodium;
Orgotein; Orpanoxin; Oxaprozin; Oxyphenbutazone; Paranyline Hydrochloride;
Pentosan Polysulfate Sodium; Phenbutazone Sodium Glycerate; Pirfenidone; Piroxicam;
Piroxicam Cinnamate; Piroxicam Olamine; Pirprofen; Prednazate; Prifelone; Prodolic Acid;
Proquazone;
Proxazole; Proxazole Citrate; Rimexolone; Romazarit; Salcolex; Salnacedin;
Salsalate;
Sanguinarium Chloride; Seclazone; Sermetacin; Sudoxicam; Sulindac; Suprofen;
Talmetacin;
Talniflumate; Talosalate; Tebufelone; Tenidap; Tenidap Sodium; Tenoxicam;
Tesicam;
Tesimide; Tetrydamine; Tiopinac; Tixocortol Pivalate; Tolmetin; Tolmetin Sodium;
Triclonide; Triflumidate; Zidometacin; Zomepirac Sodium.
[00264] Antipsychotic and antineurotic drugs that can be used to alleviate psychiatric side effects in the methods of the invention include any and all selective serotonin receptor inhibitors (SSRIs) and other anti-depressants, anxiolytics (e.g. alprazolam), etc. Anti-depressants include, but are not limited to, serotonin reuptake inhibitors such as Celexa , Desyrel , Effexor , Luvox , Paxil , Prozac , Zoloft , and Serzone ; tricyclics such as Adapin , Anafrinil , Elavil , Janimmine , Ludiomil , Pamelor , Tofranil , Vivactil , Sinequan , and Surmontil ; monoamine oxidase inhibitors such as Eldepryl , Marplan , Nardil , and Parnate . Anti-anxiety agents include, but are not limited to, azaspirones such as BuSpar , benzodiazepines such as Ativan , Librium , Tranxene , Centrax , Klonopin , PaxipamV, Serax , Valium , and Xanax ; and beta-blockers such as Inderal and Tenormin .
[00265] Agents that reduce gastrointestinal discomfort such as nausea, diarrhea, gastrointestinal cramping, and the like are suitable palliative agents for use in a subject combination therapy.
Suitable agents include, but are not limited to, antiemetics, anti-diarrheal agents, H2 blockers, antacids, and the like.
[00266] Suitable H2 blockers (histamine type 2 receptor antagonists) that are suitable for use as a palliative agent in a subject therapy include, but are not limited to, Cimetidine (e.g., Tagamet, Peptol, Nu-cimet, -apo-cimetidine; non-cimetidine); Ranitidine (e.g., Zantac, Nu-ranit, Novo-randine, and apo-ranitidine); and Famotidine (Pepcid, Apo-Famotidine, and Novo-Famotidine).
[00267] Suitable antacids include, but are not limited to, aluminum and magnesium hydroxide (Maalox , Mylanta ); aluminum carbonate gel (Basajel ); aluminum hydroxide (Amphojel , AlternaGEL ); calcium carbonate (Tums(l, Titralac ); magnesium hydroxide;
and sodium bicarbonate.
[00268] Antiemetics include, but are not limited to, 5-hydroxytryptophan-3 (5HT3) inhibitors;
corticosteroids such as dexametliasone and methylprednisolone; Marinol (dronabinol);
prochlorperazine; benzodiazepines; promethazine; and metoclopramide cisapride;
Alosetron Hydrochloride; Batanopride Hydrochloride; Bemesetron; Benzquinamide;
Chlorpromazine;
Chlorpromazine Hydrochloride; Clebopride; Cyclizine Hydrochloride;
Dimenhydrinate;
Diphenidol; Diphenidol Hydrochloride; Diphenidol Pamoate; Dolasetron Mesylate;
Domperidone; Dronabinol; Fludorex; Flumeridone; Galdansetron Hydrochloride;
Granisetron;
Granisetron Hydrochloride; Lurosetron Mesylate; Meclizine Hydrochloride;
Metoclopramide Hydrochloride; Metopimazine; Ondansetron Hydrochloride; Pancopride;
Prochlorperazine;
Prochlorperazine Edisylate; Prochlorperazine Maleate; Promethazine Hydrochloride;
Thiethylperazine; Thiethylperaziuie Malate; Thiethylperazine Maleate;
Trimethobenzainide Hydrochloride; Zacopride Hydrochloride..
[00269] Anti-diarrheal agents include, but are not limited to, Rolgamidine, Diphenoxylate hydrocliloride (Lomotil), Metronidazole (Flagyl), Methylprednisolone (Medrol), Sulfasalazine (Azulfidine), and the like.
[00270] Suitable hematopoietic agents that can be used to prevent or restore depressed blood cell populations in the methods of the invention include erythropoietins, such as EPOGENTM
epoetin-alfa, granulocyte colony stimulating factors (G-CSFs), such as NEUPOGENTM
filgrastim, granulocyte-macrophage colony stimulating factors (GM-CSFs), tbrombopoietins, etc.

DOSAGES, FORMULATIONS, AND ROUTES OF ADMINISTRATION
[00271] A therapeutic agent (also referred to herein as an "active agent") used in a subject method (e.g., a SAPK inhibitor, a Type I interferon receptor agonist, a Type II interferon receptor agonist, etc.) is administered to individuals in a formulation with a pharmaceutically acceptable excipient(s). A wide variety of 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. Germaro (2000) "Remington: The Science and Practice of Pharmacy," 20th edition, Lippincott, Williams; & Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C.
Ansel et al., eds., 7th ed., Lippincott, Williams, & Wilkins; and Handbook of Pharmaceutical Excipients (2000) A.H. Kibbe et al., eds., 3d ed. Amer. Pharmaceutical Assoc.
[00272] The pharmaceutically acceptable excipients, such as vehicles, adjuvants, carriers or diluents, are readily available to the public. Moreover, 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.
[00273] In the subject methods, the active agents may be administered to the host using any convenient means capable of resulting in the desired therapeutic effect. Thus, the agents can be incorporated into a variety of formulations for therapeutic administration.
More particularly, 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.
[00274] As such, administration of the agents can be achieved in various ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, subcutaneous, intramuscular, transdermal, intratracheal, etc., administration. In some embodiments, two different routes of administration are used. For example, in some embodiments, IFN-a and/or IFN-7 is administered subcutaneously, and a SAPK inhibitor is administered orally.
[00275] Subcutaneous administration of a therapeutic agent (e.g., a SAPK
inhibitor, a Type I
interferon receptor agonist, a Type II interferon receptor agonist, etc.) can be 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 therapeutic agent to a patient through the port is referred to herein as "a subcutaneous injection port delivery system." In some embodiments, subcutaneous administration is achieved by a combination of devices, e.g., bolus delivery by needle and syringe, followed by delivery using a continuous delivery system.
[00276] In some embodiments, a therapeutic agent (e.g., a SAPK inhibitor, a Type I interferon receptor agonist, a Type II interferon receptor agonist, etc.) is delivered by a continuous delivery system. The term "continuous delivery system" is used interchangeably herein with "controlled delivery system" and encompasses continuous (e.g., controlled) delivery devices (e.g., pumps) in combination with catheters, injection devices, and the like, a wide variety of which are known in the art.
[00277] Mechanical or electromechanical infusion pumps can also be suitable for use with the present invention. Examples of such devices include those described in, for example, U.S. Pat.
Nos. 4,692,147; 4,360,019; 4,487,603; 4,360,019; 4,725,852; 5,820,589;
5,643,207; 6,198,966;
and the like. In general, the present methods of drug delivery can be accomplished using any of a variety of refillable, pump systems. Pumps provide consistent, controlled release over time. Typically, the agent is in a liquid formulation in a drug-impermeable reservoir, and is delivered in a continuous fashion to the individual.
[00278] In one embodiment, the drug delivery system is an at least partially implantable device.
The implantable device can be implanted at any suitable implantation site using methods and devices well known in the art. An inlplantation site is a site within the body of a subject at which a drug delivery device is introduced and positioned. Implantation sites include, but are not necessarily limited to a subdermal, subcutaneous, intramuscular, or other suitable site within a subject's body. Subcutaneous implantation sites are generally preferred because of convenience in implantation and removal of the drug delivery device.
[00279] Drug release devices suitable for use in the invention may be based on any of a variety of modes of operation. For example, the drug release device can be based upon a diffusive system, a convective system, or an erodible system (e.g., an erosion-based system). For example, the drug release device can be an electrochemical pump, osmotic pump, an electroosmotic pump, a vapor pressure pump, or osmotic bursting matrix, e.g., where the drug is incorporated into a polymer and the polymer provides for release of drug formulation concomitant with degradation of a drug-impregnated polymeric material (e.g., a biodegradable, drug-impregnated polymeric material). In other embodiments, the drug release device is based upon an electrodiffusion system, an electrolytic pump, an effervescent pump, a piezoelectric pump, a hydrolytic system, etc.
[00280] Drug release devices based upon a mechanical or electromechanical infusion pump can also be suitable for use with the present invention. Examples of such devices include those described in, for example, U.S. Pat. Nos. 4,692,147; 4,360,019; 4,487,603;
4,360,019;
4,725,852, and the like. In general, the present treatment methods can be accomplished using any of a variety of refillable, non-exchangeable pump systems. Pumps and other convective systems are generally preferred due to their generally more consistent, controlled release over time. Osmotic pumps are particularly preferred due to their combined advantages of more consistent controlled release and relatively small size (see, e.g., PCT
published application no.

WO 97/27840 and U.S. Pat. Nos. 5,985,305 and 5,728,396)). Exemplary osmotically-driven devices suitable for use in the invention include, but are not necessarily limited to, those described in U.S. Pat. Nos. 3,760,984; 3,845,770; 3,916,899; 3,923,426;
3,987,790; 3,995,631;
3,916,899; 4,016,880; 4,036,228; 4,111,202; 4,111,203; 4,203,440; 4,203,442;
4,210,139;
4,327,725; 4,627,850; 4,865,845; 5,057,318; 5,059,423; 5,112,614; 5,137,727;
5,234,692;
5,234,693; 5,728,396; and the like.
[00281] In some embodiments, the drug delivery device is an implantable device. The drug delivery device can be implanted at any suitable implantation site using methods and devices well lcnown in the art. As noted infra, an implantation site is a site within the body of a subject at which a drug delivery device is introduced and positioned. Implantation sites include, but are not necessarily limited to a subdermal, subcutaneous, intramuscular, or other suitable site within a subject's body.
[00282] In some einbodiments, a therapeutic agent is delivered using an implantable drug delivery system, e.g., a system that is programmable to provide for administration of a therapeutic agent. Exemplary programmable, implantable systems include implantable infusion pumps. Exemplary implantable infusion pumps, or devices useful in connection witli such pumps, are described in, for example, U.S. Pat. Nos. 4,350,155;
5,443,450; 5,814,019;
5,976,109; 6,017,328; 6,171,276; 6,241,704; 6,464,687; 6,475,180; and 6,512,954. A further exemplary device that can be adapted for the present invention is the Synchromed infusion pump (Medtronic).
[00283] In pharmaceutical dosage forms, 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.
[00284] For oral preparations, 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.
[00285] 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.
[00286] Furthermore, the agents can be made into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases. An active agent 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.
[00287] Unit dosage forms for oral or rectal adininistration 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 active agents. Similarly, unit dosage forms for injection or intravenous administration may comprise the agent(s) in a composition as a solution in sterile water, normal saline or another pharmaceutically acceptable carrier.
[00288] The term "unit dosage form," as used herein, refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of an active agent calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier or vehicle.
The specifications for the dosage forms for use in the methods 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.
[00289] In connection with each of the methods described herein, the invention provides embodiments in which the therapeutic agent(s) is/are administered to the patient by a controlled drug delivery device. In some embodiments, the therapeutic agent(s) is/are delivered to the patient substantially continuously or continuously by the controlled drug delivery device. Optionally, an implantable infusion pump is used to deliver the therapeutic agent(s) to the patient substantially continuously or continuously by subcutaneous infusion.
[00290] In other embodiments, a therapeutic agent is administered to the patient so as to achieve and maintain a desired average daily serum concentration of the therapeutic agent at a substantially steady state for the duration of the monotherapy or combination therapy.
Optionally, an implantable infusion pump is used to deliver the therapeutic agent to the patient by subcutaneous infusion so as to achieve and maintain a desired average daily serum concentration of the therapeutic agent at a substantially steady state for the duration of the therapeutic agent in monotherapy or combination therapy.

Methods of treating a viral infection [00291] The present invention provides methods of treating a viral infection (e.g., an HCV
infection), the methods generally involving administering to an individual in need thereof effective amounts of a SAPK inhibitor and a Type I interferon receptor agonist. In some embodiments, a subject combination therapy for treating a viral infection (e.g., an HCV
infection) further comprises administering at least one additional anti-viral therapeutic agent.
Additional antiviral therapeutic agents that are suitable for administering in a subject combination therapy include, but are not limited to, a Type II interferon receptor agonist; a TNF antagonist; thymosin-a; ribavirin; levovirin; viramidine; a nucleoside analog; an HCV
NS3 inhibitor; an HCV NS5B inhibitor; an alpha-glucosidase inhibitor;
inhibitors of inosine monophosphate dehydrogenase (IMPDH); ribozymes that are complementary to viral nucleotide sequences; antisense RNA inhibitors; and the like.
SAPK inhibitors and Type I interferon receptor agonists [00292] Effective dosages of a SAPK inhibitor range from about 5 g to about 3000 mg, e.g., from about 5 g to about 10 g, from about 10 g to about 25 .g, from about 25 g to about 50 g, from about 50 g to about 100 g, from about 100 g to about 250 g, from about 250 g to about 500 g, from about 500 g to about 750 g, from about 750 g to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 500 mg, from about 500 mg to about 1000 mg, from about 1000 mg to about 1500 mg, from about 1500 mg to about 2000 mg, from about 2000 mg to about 2500 mg, or from about 2500 mg to about 3000 mg.
[00293] A SAPK inhibitor 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, every other day, daily, twice daily, or in divided daily doses ranging from once daily to 5 times daily.
[00294] A SAPK inhibitor can be administered at any frequency, and 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.
[00295] In some embodiments, where a subject therapy is a combination therapy, a SAPK
inhibitor is administered throughout the entire course of the subject combination therapy (e.g., SAPK inhibitor/Type I interferon receptor agonist combination therapy). In other embodiments, a SAPK inhibitor is administered less than the entire course of the combination therapy, e.g., only during the first phase of the combination therapy, only during the second phase of the combination therapy, or some other portion of the combination therapy treatment regimen.
[00296] In some embodiments, a SAPK inhibitor is administered during the entire course of Type I interferon receptor agonist treatment. In other embodiments, a SAPK
inhibitor is administered for a period of time that is overlapping with that of the Type I
interferon receptor agonist treatment, e.g., the SAPK inhibitor treatment can begin before the Type I interferon receptor agonist treatment begins and end before the Type I interferon receptor agonist treatment ends; the SAPK inhibitor treatment can begin after the Type I
interferon receptor agonist treatment begins and end after the Type I interferon receptor agonist treatment ends;
the SAPK inhibitor treatment can begin after the Type I interferon receptor agonist treatment begins and end before the Type I interferon receptor agonist treatment ends;
or the SAPK
inhibitor treatment can begin before the Type I interferon receptor agonist treatment begins and end after the Type I interferon receptor agonist treatment ends.
[00297] In some embodiments, the invention provides a method for treating a hepatitis C virus infection in an individual in need thereof, the method comprising administering effective amounts of a SAPK inhibitor and a Type I interferon receptor agonist. In some embodiments, the invention provides a method for treating a hepatitis C virus infection in an individual in need thereof, the method comprising administering effective amounts of a SAPK
inhibitor and a Type I interferon receptor agonist, wherein the SAPK inhibitor is one that inhibits enzymatic activity of p38a, p38(3, and p38y.
[00298] In some embodiments, the invention provides a method for treating a hepatitis C virus infection in an individual in need thereof, the method comprising administering effective amounts of a SAPK inhibitor and a Type I interferon receptor agonist, wherein the SAPK
inhibitor is one that inhibits enzymatic activity of p38a, p38(3, or p38,y.
[00299] In some embodiments, the invention provides a method for treating a hepatitis C virus infection in an individual in need thereof, the method comprising administering effective amounts of a SAPK inhibitor and a Type I interferon receptor agonist, wherein the SAPK
inhibitor is one that preferentially inhibits enzymatic activity of p38a and p38(3 (i.e., the agent is a stronger inhibitor of the enzymatic activity of p38a and p38(3 than that of p38y).
[00300] In some embodiments, the invention provides a method for treating a hepatitis C virus infection in an individual in need thereof, the method comprising administering effective amounts of a SAPK inhibitor and a Type I interferon receptor agonist, wherein the SAPK

inhibitor is one that preferentially inhibits enzymatic activity of p38y (i.e., the agent is a stronger inhibitor of the enzymatic activity of p38y than that of p38a or p38(3).
[00301] In some embodiments, the Type I interferon receptor agonist is an IFN-a. Effective dosages of an IFN-a can range from about 1 g to about 30 g, from about 3 gg to about 27 g, from about 1 MU to about 20 MU, from about 3 MU to about 10 MU, from about 90 g to about 180 gg, or from about 18 g to about 90 g.
[00302] Effective dosages of Infergen consensus IFN-a include about 3 g, about 9 g, about 15 g, about 18 g, or about 27 g of drug per dose. Effective dosages of IFN-a2a and IFN-a2b can range from 3 million Units (MU) to 10 MU per dose. Effective dosages of PEGylated IFN-a2a can contain an amount of about 90 g to 180 g, or about 135 g, of drug per dose.
Effective dosages of PEGylated IFN-a2b can contain an amount of about 0.5 g to 1.5 g of drug per kg of body weiglit per dose. Effective dosages of PEGylated consensus interferon (PEG-CIFN) can contain an amount of about 10 g to about 100 g, or about 18 g to about 90 g, or about 27 g to about 60 g, or about 45 g, of CIFN amino acid weight per dose of PEG-CIFN. IFN-a can be administered daily, every other day, once a week, three times a week, every other week, three times per montli, once monthly, substantially continuously or continuously.
[00303] In some embodiments, monoPEG (30 kD, linear)-ylated consensus IFN-a is administered. In some embodiments, monoPEG (30 kD, linear)-ylated consensus IFN-a is administered at a dosing interval of every 7 days. In some embodiments, monoPEG (30 kD, linear)-ylated consensus IFN-a is administered at a dosing interval of every 8 days to every 14 days, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. Effective dosages of monoPEG (30 kD, linear)-ylated 1NFERGEN
consensus IFN-a generally range from about 45 g to about 270 g per dose, e.g., 60 g per dose, 100 g per dose, 150 g per dose, 200 g per dose, etc.
[00304] In some embodiments, a Type I receptor agonist is administered in a first dosing regimen, followed by a second dosing regimen. The first dosing regimen of Type I interferon receptor agonist (also referred to as "the induction regimen ") generally involves administration of a higher dosage of the Type I interferon receptor agonist.
For example, in the case of Infergen consensus IFN-a (CIFN), 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 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.
[00305] The first dosing regimen of the Type I interferon receptor agonist is administered for a first period of time, which time period can be at least about 4 weeks, at least about 8 weeks, or at least about 12 weeks.
[00306] The second dosing regimen of the Type I interferon receptor agonist (also referred to as "the maintenance dose") generally involves administration of a lower amount of the Type I
interferon receptor agonist. For example, in the case of CIFN, the second dosing regimen comprises administering CIFN 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.
[00307] The second dosing regimen of the Type I 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.
[00308] In some embodiments, wliere an "induction"/"maintenance" dosing regimen of a Type I
interferon receptor agonist is administered, a "priming" dose of a Type II
interferon receptor agonist is included. In these embodiments, Type II interferon receptor agonist can be 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 interferon receptor agonist. This period of time is referred to as the "priming" phase.
In some of these embodiments, Type II interferon receptor agonist treatment is continued throughout the entire period of treatment with the Type I interferon receptor agonist. In other embodiments, Type II interferon receptor agonist treatment is discontinued before the end of treatment with the Type I interferon receptor agonist. In some of these embodiments, 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.
[00309] In other embodiments, the Type I interferon receptor agonist is administered in a non-induction (single) dosing regimen. For example, in the case of CIFN, the dose of CIFN is generally in a range of from about 3 g to about 15 gg, or from about 9 g to about 15 g. The dose of Type I 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 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.
[00310] In some embodiments, where a single dosing regimen of a Type I
interferon receptor agonist is administered, a"priming" dose of Type II interferon receptor agonist is included.
For example, a Type II interferon receptor agonist can be 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 interferon receptor agonist.
This period of time is-referred to as the "priming" phase. In some of these embodiments, Type II interferon receptor agonist treatment is continued throughout the entire period of treatment with the Type I interferon receptor agonist. In other embodiments, Type II
interferon receptor agonist treatment is discontinued before the end of treatment with Type I
interferon receptor agonist. In some of these embodiments, the total time of treatment witli 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 Agonists [00311] In some embodiments, a subject method comprises administering a SAPK
inhibitor, a Type I interferon receptor agonist, and a Type II interferon receptor agonist.
In many of these embodiments, the Type II interferon receptor agonist is an IFN-y.

[00312] Effective dosages of IFN-y can range from about 0.5 g/m2 to about 500 g/m2, usually from about 1.5 g/m2 to 200 g/m2, depending on the size of the patient. This activity is based on 106 international units (U) per 50 g of protein. IFN-y can be administered daily, every other day, three times a week, or substantially continuously or continuously.
[003131 In specific embodiments of interest, IFN-y 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-y. In many embodiments of interest, IFN-ylb is administered.
[00314] Where the dosage is 200 g IFN-y per dose, the amount of IFN-y per body weight (assuming a range of body weights of from about 45 kg to about 135 kg) is in the range of from about 4.4 g IFN-y per kg body weight to about 1.48 g IFN-y per kg body weight.
[00315] The body surface area of subject individuals generally ranges from about 1.33 m2 to about 2.50 m2. Thus, in many embodiments, an IFN-y dosage ranges from about 150 gg/m2 to about 20 gg/m2. For example, an IFN-y dosage ranges from about 20 g/m2 to about 30 gg/m2, from about 30 gg/m2 to about 40 g/m2, from about 40 gg/ma to about 50 gg/m2, from about 50 g/m2 to about 60 g/m2; from about 60 g/m2 to about 70 g/m~, from about 70 g/m2 to about 80 g/m2, from about- 80 g/ma to about 90 g/m2, from about 90 g/m2 to about 100 gg/m2, from about 100 g/m~ to about 110 g/ma, from about 110 gg/m2 to about 120 g/m2, from about 120 g/m2 to about 130 g/m2, from about 130 g/m2 to about 140 g/m2, or from about 140 g/m2 to about 150 g/m2. In some embodiments, the dosage groups range from about 25 g/m2 to about 100 g/m2. In other embodiments, the dosage groups range from about 25 g/m2 to about 50 g/m2.
[00316] In many embodiments, multiple doses of an IFN-7 are administered. For example, an IFN-y 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), 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.
[00317] In some embodiments, the IFN-y is Actimmune human IFN-ylb, and is administered subcutaneously tiw in a dosage containing an amount of about 25 g, 50 g, 100 g, 150 g, or 200 g.
TNF Antczgonists [00318] In some embodiments, a subject therapeutic regimen involves modifying any of the above-described regimens by administering a TNF antagonist. Effective dosages of a TNF-a antagonist range from 0.1 g to 40 mg per dose, e.g., from about 0.1 g to about 0.5 gg 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 a.bout 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 gg per dose, from about 30 gg 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 g per dose, from about 70 g to about 80 gg per dose, from about 80 .g per dose to about 100 g per dose, from about 100 g to about 150 gg per dose, from about 150 g to about 200 gg per dose, from about 200 g per dose to about 250 gg per dose, from about 250 g to about 300 g per dose, from about 300 g to about 400 gg per dose, from about 400 g to about 500 g per dose, from about 500 g to about 600 gg per dose, from about 600 gg to about 700 g per dose, from about 700 g to about 800 g per dose, from about 800 g to about 900 gg per dose, from about 900 g to about 1000 g per dose, from about 1 mg to about 10 mg per dose, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.
[00319] In some embodiments, the TNF-a antagonist is ENBREL etanercept.
Effective dosages of etanercept range from about 0.1 g to about 40 mg per dose, from about 0.1 g to about 1 g per dose, from about 1 g to about 10 g per dose, from about 10 g to about 100 .g per dose, from about 100 jig to about 1 mg per dose, from about 1 mg to about 5 mg per dose, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.
[00320] In some embodiments, effective dosages of a TNF-a antagonist are expressed as mg/kg body weight. In these embodiments, effective dosages of a TNF-a antagonist are from about 0.1 mg/lcg body weiglit 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 weigllt, 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/lcg body weight.
[00321] In some embodiments, the TNF-a antagonist is REMICADE infliximab.
Effective dosages of REMICADE range from about 0.1 mg/kg to about 10 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, from about 4.0 mg/kg to about 4.5 mg/kg, from about 4.5 mg/kg to about 5.0 mg/kg, from about 5.0 mg/kg to about 7.5 mg/kg, or from about 7.5 mg/lcg to about 10 mg/kg per dose.
[00322] In some embodiments the TNF-a antagonist is HUMIRATM adalimumab.
Effective dosages of HUMIRATM range 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 gg to about 100 g, from about 100 gg 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, from about 30 mg to about 35 mg, or from about 35 mg to about 40 mg per dose.
[00323] In many embodiments, a TNF-a 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 montlis, or at least one year, and may be administered over longer periods of time. The TNF-a antagonist-can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously.
[00324] In many embodiments, multiple doses of a TNF-a antagonist are administered. For example, a TNF-a antagonist is administered once per month, twice per month, three times per montll, 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 montlis to about four months, from about four montlis 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.
[00325] Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific conipounds, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given 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 coinpound.
Thymosin-a [00326] In some embodiments, a subject therapeutic method involves modifying any of the above-described regimens by administering thymosin-a. Thymosin-a (ZadaxinTM) is generally administered by subcutaneous injection. Thyinosin-a can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously. In many embodiments, thymosin-a is administered twice per week.
[00327] Effective dosages of tliymosin-a range from about 0.5 mg to about 5 mg, e.g., from about 0.5 mg to about 1.0 ing, 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. In particular embodiments, thymosin-a is administered in dosages containing an amount of 1.0 mg or 1.6 mg.
[00328] Thymosin-a 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.
Ribavirin, levovirin, viramidine [00329] In some einbodiments, a subject therapeutic regimen involves modifying any of the above-described regimens by administering ribavirin. Ribavirin 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.
In some embodiments, ribavirin is administered orally in dosages of about 400, about 800, about 1000, or about 1200 mg per day.
[00330] In some embodiments, a subject therapeutic regimen involves modifying any of the above-described regimens by administering 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.
In some embodiments, levovirin is administered orally in dosages of about 400, about 800, about 1000, or about 1200 mg per day.
[00331] In some embodiments, a subject therapeutic regimen involves modifying any of the above-described regimens by administering viramidine. Viramidine 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. In some embodiments, viramidine is administered orally in dosages of about 800, or about 1600 mg per day.
[00332] In many embodiments, multiple doses of a ribavirin, levovirin, viramidine, isatoribine, and/or other nucleoside analogs are administered. For example, a nucleoside 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 (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.
[00333] Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compounds, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily detenninable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.
NS3 inhibitors, NS5B inhibitors [00334] In some embodiments, a subject therapeutic regimen involves modifying any of the above-described regimens for HCV infection by administering an HCV enzyme inhibitor.
Effective dosages of an HCV enzyme inhibitor range from about 10 mg to about 200 mg per dose, e.g., from about 10 mg to about 15 mg per dose, from about 15 ing to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, from about 35 mg to about 40 mg per dose, from about 40 mg per dose to about 45 mg per dose, from about 45 mg per dose to about 50 mg per dose, from about 50 mg per dose to about 60 mg per dose, from about 60 mg per dose to about 70 mg per dose, from about 70 mg per dose to about 80 mg per dose, from about 80 mg per dose to about 90 mg per dose, from about 90 mg per dose to about 100 mg per dose, from about 100 mg per dose to about 125 mg per dose, from about 125 mg per dose to about 150 mg per dose, from about 150 mg per dose to about 175 mg per dose, or from about 175 mg per dose to about 200 mg per dose.
[00335] In some enzbodiments, effective dosages of an HCV enzyme inhibitor are expressed as mg/kg body weight. In these embodiments, effective dosages of an HCV enzyme inhibitor are from about 0.01 mg/lcg body weight to about 100 mg/kg body weight, from about 0.1 mg/kg body weight to about 50 mg/kg body weight, from about 0.1 mg/kg body weiglit to about 1 mg/kg body weight, from about 1 mg/kg body weight to about 10 mg/kg body weigh, from about 10 mg/kg body weight to about 100 mg/kg body weight, from about 5 mg/lcg body weight to about 400 mg/kg body weight, from about 5 mg/kg body weight to about 50 mg/kg body weight, from about 50 mg/kg body weight to about 100 mg/kg body weight, from about 100 mg/kg body weight to about 200 mg/kg body weight, from about 200 mg/kg body weight to about 300 mg/kg body weight, or from about 300 mg/kg body weight to about 400 mg/kg body weight.
[00336] In many embodiments, an HCV enzyme inhibitor 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 HCV enzyme inhibitor can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously.
[00337] In many embodiments, multiple doses of an HCV enzyme inhibitor are administered.
For example, an HCV enzyme iitliibitor 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 (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 nlonths 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.
[00338] Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compounds, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given 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 compound.
Combination regimens for treating a viral infection [00339] The present invention provides methods of treating a viral infection, e.g., an HCV
infection, by administering a combination of a SAPK inhibitor and a Type I
interferon receptor agonist. In some embodiments, a subject combination therapy fiuther comprises administering at least one additional anti-viral therapeutic agent.

Combination therapy comprising administering a SAPK inhibitor and a Type I
interferon receptor agonist [003401 In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a SAPK inhibitor; and ii) a Type I interferon receptor agonist, in the treatment of a viral infection, e.g., an HCV infection, in a patient, comprising co-administering to the patient a) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 g/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 g to about 1000 mg per day, or about 100 g to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and b) 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, or once monthly, or per day continuously or substantially continuously; for the desired treatment duration, to achieve a sustained viral response.
[00341] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a SAPK inhibitor; and ii) a Type I interferon receptor agonist, in the treatment of a viral infection, e.g., an HCV infection, in a patient, comprising co-administering to the patient a) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 g/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 g to about 1000 mg per day, or about 100 g to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and b) a dosage of PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 10 g to about 100 g, or about 45 gg to about 60 g, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly; for the desired treatment duration, to achieve a sustained viral response.
[00342] In some enlbodiments, the invention provides a combination therapy method using combined effective amounts of i) a SAPK inhibitor; and ii) a Type I interferon receptor agonist, in the treatment of a viral infection, e.g., an HCV infection, in a patient, comprising co-administering to the patient a) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 g/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 g to about 1000 mg per day, or about 100 g to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and b) a dosage of IFN-a 2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-a 2a, -2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously; for the desired treatment duration, to achieve a sustained viral response.
[00343] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a SAPK inhibitor; and ii) a Type I interferon receptor agonist, in the treatment of a viral infection, e.g., an HCV infection, in a patient, comprising co-administering to the patient a) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 g/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 .g to about 1000 mg per day, or about 100 g to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and b) a dosage of PEGASYS
peginterferon alfa-2a containing an amount of about 90 g to about 360 g, or about 180 g, of drug per dose of PEGASYS subcutaneously qw, qow, three times per month, or monthly; for the desired treatment duration, to achieve a sustained viral response.
[00344] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a SAPK inhibitor; and ii) a Type I interferon receptor agonist, in the treatment of a viral infection, e.g., an HCV infection, in a patient, comprising co-administering to the patient a) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 g/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 g to about 1000 mg per day, or about 100 g to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and b) a dosage of PEG-INTRON
peginterferon alfa-2b contaiiiing an amount of about 0.75 g to about 3.0 g, or about 1.0 g to about 1.5 gg, of drug per kilogram of body weight per dose of PEG-INTRON , subcutaneously qw, qow, tliree times per month, or monthly; for the desired treatment duration, to achieve a sustained viral response.
[00345] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a SAPK inhibitor; and ii) a Type I interferon receptor agonist, in the treatment of a viral infection, e.g., an HCV infection, in a patient, comprising co-administering to the patient a) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 g/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 g to about 1000 mg per day, or about 100 gg to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and b) a dosage of mono PEG(30 kD, linear)-ylated consensus IFN-a containing an amount of from about 100 g to about 200 g, or about 150 gg, of drug per dose of mono PEG(3010, linear)-ylated consensus IFN-a, subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or once monthly; for the desired treatment duration, to achieve a sustained viral response.
[00346] Any of the above-described treatment regimens can be further modified to include administration of an additional anti-viral agent.
[00347] For example, in some embodiments, any of the above-described treatment regimens for HCV infection is modified to include administering a dosage of-an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of 0.01 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.
[00348] As another example, in some embodiments, any of the above-described treatment regimens for HCV infection is modified to include administering a dosage of an protease inhibitor containing an amount of 0.01 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.
[00349] As another example, in some embodiments, any of the above-described treatment regimens for viral infection is modified to include administering a dosage of ribavirin or a derivative thereof, in an amount of about 400 mg, 800 mg, 1000 mg, or 1200 mg orally daily, optionally in two or more divided doses per day, for the desired treatment duration.
[00350] As another example, in some einbodiments, any of the above-described treatment regimens for viral infection is modified to include administering a dosage of levovirin, in an amount of about 400 mg, 800 mg, 1000 mg, or 1200 mg orally daily, optionally in two or more divided doses per day, for the desired treatment duration.
[00351] As another example, in some embodiments, any of the above-described treatment regimens for viral infection is modified to include administering a dosage of viramidine in an ainount of from about 800 mg to about 1600 mg orally daily, optionally in two or more divided doses per day, for the desired treatment duration.
[00352] As another example, in some embodiments, any of the above-described treatment regimens is modified to include administering a dosage of ZadaxinTM containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration.
[00353] As another example, in some embodiments, any of the above-described regimens for viral infection is modified to include administering a dosage of a TNF
antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.
Combination therapy comprising administering a SAPK inhibitor, a Type I
interferon receptor agonist, and a Type II interferon receptor agonist [003541 In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a SAPK inhibitor, and iii) a Type I interferon receptor agonist in the treatment of a viral infection, e.g., an HCV
infection, in a patient, the method comprising co-administering to the patient a) a dosage of IFN-y containing an amount of from about 25 g to about 500 g subcutaneously qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; b) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 g/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 g to about 1000 mg per day, or about 100 g to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and c) a dosage of an IFN-a selected from (i) 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 continuously or substantially continuously (ii) PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 10 g to about 100 gg, or about 45 g to about 60 g, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-a 2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS containing an amount of about 90 g to about 360 g, or about 180 g, of drug per dose of PEGASYS subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRON containing an amount of about 0.75 g to about 3.0 g, or about 1.0 g to about 1.5 g, of drug per kilogram of body weight per dose of PEG-INTRON
subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG(30 kD, linear)-ylated consensus IFN-a containing an amount of from about 100 gg to about 200 gg, or about 150 g, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-a subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly for the desired treatment duration, to treat the viral infection.
[003551 In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a SAPK inhibitor, and iii) a Type I interferon receptor agonist in the treatment of a viral infection, e.g., an HCV
infection, in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-y containing an amount of from about 25 g/m2 to about 100 g/m2, or a fixed dosage of IFN-y containing an amount of from about 50 g to about 200 g, administered subcutaneously tiw for the desired treatment duration; b) a dosage of a SAPK
inhibitor, in a weight-based dosage in the range from about 10 g/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 g to about 1000 mg per day, or about 100 g to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and c) a dosage of an IFN-a selected from (i) 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 continuously or substantially continuously (ii) PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 10 g to about 100 g, or about 45 g to about 60 g, of CIFN amino acid weight per dose of PEG-CIFN
subcutaneously qw, qow, three times per montli, or monthly (iii) IFN-a 2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS containing an amount of about 90 g to about 360 g, or about 180 g, of drug per dose of PEGASYS subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRON containing an amount of about 0.75 g to about 3.0 g, or about 1.0 g to about 1.5 g, of drug per kilogram of body weight per dose of PEG-INTRON subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG(30 kD, linear)-ylated consensus IFN-a containing an amowit of from about 100 g to about 200 gg, or about 150 gg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-a subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for the desired treatment duration, to treat the viral infection.
[00356] In another embodiment, the invention provides a method using an effective amount of a consensus IFN-a, IFN-y and a SAPK inhibitor compound in the treatment of a viral infection, e.g., an HCV infection, in a patient. In general, an effective amount of a consensus interferon (CIFN) and IFN-y suitable for use in the methods of the invention is provided by a dosage ratio of 1 gg CIFN: 10 g IFN-y, where both CIFN and IFN-y are unPEGylated and unglycosylated species.
[00357] In one embodiment, the invention provides any of the above-described methods modified to use an effective amount of INFERGEN consensus IFN-a and IFN-y in the treatment of a viral infection, e.g., an 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-y containing an amount of about 10 g to about 300 g of drug per dose of IFN-y, 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.
[00358] In another embodiment, the invention provides any of the above-described methods modified to use an effective amount of INFERGEN consensus IFN-a and IFN-y in the treatment of a viral infection, e.g., an 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 montl-Ay, or per day substantially continuously or continuously, in combination with a dosage of IFN-y containing an amount of about 10 g to about 100 g of drug per dose of IFN-y, 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.
[00359] In another embodiment, the invention provides any of the above-described methods modified to use an effective amount of INFERGEN consensus IFN-a and IFN-y in the treatment of a viral infection, e.g., an HCV infection, in a patient comprising administering to the patient a dosage of INFERGEN contaiiiing 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-y containing an amount of about 10 g to about 50 g of drug per dose of IFN-y, 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.
[00360] In another embodiment, the invention provides any of the above-described methods modified to use an effective amount of INFERGEN consensus IFN-a and IFN-y in the treatment of a viral infection, e.g., an HCV 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-y containing an amount of about 90 gg to about 100 g of drug per dose of IFN-y, 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.
[00361] In another embodiment, the invention provides any of the above-described methods modified to use an effective amount of INFERGEN consensus IFN-a and IFN-y in the treatment of a viral infection, e.g., an HCV 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-y containing an amount of about 200 gg to about 300 g of drug per dose of IFN-y, 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.
[00362] In another embodiment, the invention provides any of the above-described methods modified to use an effective amount of PEGylated consensus IFN-a and IFN-y in the treatment of a viral infection, e.g., an HCV infection, in a patient comprising administering to the patient a dosage of PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 10 g to about 100 g of CIFN amino acid weiglit per dose of PEG-CIFN, subcutaneously qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN-y containing an amount of about 100 g to about 1,000 g of drug per week in divided doses administered subcutaneously qd, qod, tiw, biw, or administered substantially continuously or contiiiuously, for the desired duration of treatment.
[00363] In another embodiment, the invention provides any of the above-described methods modified to use an effective amount of PEGylated consensus IFN-a and IFN-y in the treatment of a viral infection, e.g., an HCV infection, in a patient comprising administering to the patient a dosage of PEGylated consensus IFN-a (PEG-CIFN) containing an aniount of about 40 g to about 80 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-y containing an amount of about 100 g to about 600 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.
[00364] In general, an effective amount of IFN-a 2a or 2b or 2c and IFN-y suitable for use in the methods of the invention is provided by a dosage ratio of 1 million Units (MU) IFN-a 2a or 2b or 2c: 30 g IFN-y, where both IFN-a 2a or 2b or 2c and IFN-y are unPEGylated and unglycosylated species.
[00365] In another embodiment, the invention provides any of the above-described methods modified to use an effective amount of IFN-a 2a or 2b or 2c and IFN-y in the treatment of a viral infection, e.g., an HCV infection, in a patient comprising administering to the patient a dosage of IFN-a 2a, 2b or 2c containing an amount of about 1 MU to about 20 MU
of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of IFN-y containing an amount of about 30 g to about 600 g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, for the desired duration of treatment.
[00366] In another embodiment, the invention provides any of the above-described methods modified to use an effective amount of IFN-a 2a or 2b or 2c and IFN-y in the treatment of a viral infection, e.g., an HCV infection, in a patient comprising administering to the patient a dosage of IFN-a 2a, 2b or 2c containing an amount of about 3 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of IFN-y containing an amount of about 100 g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, for the desired duration of treatment.
[00367] In another embodiment, the invention provides any of the above-described methods modified to use an effective amount of IFN-a 2a or 2b or 2c and IFN-y in the treatment of a viral infection, e.g., an HCV infection, in a patient comprising administering to the patient a dosage of IFN-a 2a, 2b or 2c containing an amount of about 10 MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, in combination with a dosage of IFN-y containing an amount of about 300 g of drug per dose of IFN-y, subcutaneously qd, qod, tiw, biw, or per day substantially continuously or continuously, for the desired duration of treatment.
[00368] In another embodiment, the invention provides any of the above-described methods modified to use an effective amount of PEGASYS PEGylated IFN-a2a and IFN-y in the treatment of a viral infection, e.g., an HCV 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-y containing an amount of about 100 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.
[00369] In another embodiment, the invention provides any of the above-described methods modified to use an effective amount of PEGASYS PEGylated IFN-a2a and IFN-y in the treatment of a viral infection, e.g., an HCV 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-y containing an amount of about 100 g to about 600 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.
[00370] In another embodiment, the invention provides any of the above-described methods modified to use an effective amount of PEG-INTRON PEGylated IFN-a2b and IFN-y in the treatment of a viral infection, e.g., an HCV 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 biw, qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN-y containing an amount of about 100 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.
[00371] In another embodiment, the invention provides any of the above-described methods modified to use an effective amount of PEG-INTRON PEGylated IFN-a2b and IFN-y in the treatment of a viral infection, e.g., an HCV infection, in a patient comprising administering to the patient a dosage of PEG-INTRON containing an amount of about 1.0 g to about 1.5 g of drug per kilograin of body weight per dose of PEG-INTRON , subcutaneously biw, qw, qow, three times per month, or monthly, in combination with a total weekly dosage of IFN-y containing an amount of about 100 g to about 600 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.
[00372] In another embodiment, the present invention provides any of the above-described methods modified to comprise administering to an individual having an HCV
infection an effective a.inount of a SAPK inhibitor; and a regimen of 9 g or 15 g INFERGEN consensus IFN-a administered subcutaneously qd or tiw, and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, 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.
[00373] In another embodiment, 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 a SAPK inhibitor; and a regimen of 9 g or 15 g INFERGEN
consensus IFN-a administered subcutaneously qd or tiw; 50 g Actimmune human IFN-ylb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, 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.
[00374] In another embodiment, 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 a SAPK inhibitor; and a regimen of 9 g or 15 g INFERGEN
consensus IFN-a administered subcutaneously qd or tiw; 100 g Actimmune human IFN-ylb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this einbodiment, 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.
[00375] In another embodiment, 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 a SAPK inhibitor; and a regimen of 9 g or 15 g INFERGEN
consensus IFN-a adininistered subcutaneously qd or tiw; and 50 g Actimmune human IFN-ylb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[00376] In another embodiment, the present invention provides any of the above-described methods modified to coinprise administering to an individual having an HCV
infection an effective amount of a SAPK inhibitor; and a regimen of 9 g or 15 g INFERGEN
consensus IFN-a administered subcutaneously qd or tiw; and 100 g Actimmune human IFN-y1b administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[00377] In another embodiment, 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 a SAPK inhibitor; and a regimen of 9 g or 15 g INFERGEN
consensus IFN-a administered subcutaneously qd or tiw; 25 g Actimnlune human IFN-71b administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, 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.

[00378] In another embodiment, 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 a SAPK inhibitor; and a regimen of 9 g or 15 g INFERGEN
consensus IFN-a administered subcutaneously qd or tiw; 200 g Actimmune human IFN-ylb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, 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.
[00379] In another embodiment, 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 a SAPK inhibitor; and a regimen of 9 gg or 15 g INFERGEN
consensus IFN-a administered subcutaneously qd or tiw; and 25 g Actimmune human IFN-ylb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[00380] In another embodiment, the present invention provides any of the above-described methods inodified to comprise administering to an individual having an HCV
infection an effective amount of an SAPK inhibitor; and a regimen of 9 g or 15 gg INFERGEN

consensus IFN-a administered subcutaneously qd or tiw; and 200 g Actimmune human IFN-ylb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[00381] In another embodiment, 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 a SAPK inhibitor; and a regimen of 100 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days, every 8 days, or qw, and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
In this embodiment, ribavirin is administered in an ainount of 1000 mg for individuals weighing less than 75 kg, and 1200 mg for individuals weighing 75 kg or more.
[00382] In another embodiment, 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 a SAPK inhibitor; and a regimen of 100 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days, every 8 days, or qw; 50 g Actimmune hunian IFN-ylb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, 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.
[00383] In another embodiment, 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 a SAPK inhibitor; and a regimen of 100 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days, every 8 days, or qw; 100 g Actimmune human IFN-ylb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, 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.
[00384] In another embodiment, 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 a SAPK inhibitor; and a regimen of 100 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days, every 8 days, or qw; and 50 g Actimmune human IFN-ylb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[00385] In another embodiment, the present invention provides any of the above-described methods modified to comprise administering to an individual having an HCV
infection an effective aniount of a SAPK inhibitor; and a regimen of 100 gg monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days, every 8 days, or qw; and 100 g Actimmune hunlan IFN-y1b administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[00386] In another embodiment, 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 a SAPK inhibitor; and a regimen of 150 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days, every 8 days, or qw, and ribaviriri administered orally qd, where the duration of therapy is 48 weeks.
In this embodiment, 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.
[00387] In another embodiment, 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 a SAPK inhibitor; and a regimen of 150 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days, every 8 days, or qw; 50 gg Actimmune human IFN-ylb administered subcutaneously tiw; and ribavirin adnlinistered orally qd, where the duration of therapy is 48 weeks. In this embodiment, 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.

[00388] In another embodiment, 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 a SAPK inhibitor; and a regimen of 150 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days, every 8 days, or qw; 100 g Actiinmune human IFN-,ylb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, 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.
[00389] In another embodiment, 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 a SAPK inhibitor; and a regimen of 150 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days, every 8 days, or qw; and 50 g Actimmune human IFN--ylb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[00390] In another embodiment, 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 a SAPK inhibitor; and a regimen of 150 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days, every 8 days, or qw; and 100 g Actimmune human IFN-ylb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[00391] In another embodiment, 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 a SAPK inhibitor; and a regimen of 200 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days, every 8 days, or qw, and ribavirin administered orally qd, where the duration of therapy is 48 weeks.
In this embodiment, 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.
[00392] In another embodiment, 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 a SAPK inhibitor; and a regimen of 200 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days, every 8 days, or qw; 50 g Actimmune human IFN-ylb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, 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.
[00393] In another embodiment, 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 a SAPK inhibitor; and a regimen of 200 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days, every 8 days, or qw; 100 g Actimmune human IFN-ylb administered subcutaneously tiw; and ribavirin administered orally qd, where the duration of therapy is 48 weeks. In this embodiment, 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.
[00394] In anotlier embodiment, 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 a SAPK inhibitor; and a regimen of 200 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days, every 8 days, or qw; and 50 gg Actimmune human IFN-ylb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[00395] In another embodiment, 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 a SAPK inhibitor; and a regimen of 200 g monoPEG(30 kD, linear)-ylated consensus IFN-a administered subcutaneously every 10 days, every 8 days, or qw; and 100 g Actimmune human IFN-ylb administered subcutaneously tiw, where the duration of therapy is 48 weeks.
[00396] Any of the above-described treatment regimens can be further modified to include administration of an additional anti-viral agent.
[00397] For example, in some embodiments, any of the above-described treatment regimens for HCV infection is modified to include administering a dosage of an HCV NS5B RNA-'dependent RNA polymerase inhibitor containing an amount of 0.01 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.
[00398] As another example, in some embodiments, any of the above-described treatment regimens for HCV infection is modified to include administering a dosage of an protease inhibitor containing an amount of 0.01 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.

[00399] As another example, in some embodiments; any of the above-described treatment regimens for viral infection is modified to include administering a dosage of ribavirin or a derivative thereof, in an amount of about 400 mg, 800 mg, 1000 mg, or 1200 mg orally daily for the desired treatment duration.
[00400] As anotlier example, in some einbodiments, any of the above-described treatment regimens for viral infection is modified to include administering a dosage of levovirin, in an amount of about 400 mg, 800 mg, 1000 mg, or 1200 mg orally daily for the desired treatment duration.
[00401] As another example, in some embodiments, any of the above-described treatment regimens for viral infection is modified to include administering a dosage of viramidine in an ainount of from about 800 mg to about 1600 mg orally daily for the desired treatment duration.
[00402] As another example, in some embodiments, any of the above-described treatment regimens is modified to include administering a dosage of ZadaxinTM containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration.
[00403] As another example, any of the above-described regimens for viral infection is modified to include administering a dosage 'of a TNF antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.

[00404] As non-limiting examples, any of the above-described methods featuring an IFN-a regimen can be modified to replace the subject IFN-a regimen with a regimen of monoPEG
(30 kD, linear)-ylated consensus IFN-a comprising administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a 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.
[00405] As non-limiting examples, any of the above-described methods featuring an IFN-a regimen can be modified to replace the subject IFN-a regimen with a regimen of monoPEG
(30 kD, linear)-ylated consensus IFN-a comprising administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a 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.
[00406] As non-limiting examples, any of the above-described methods featuring an IFN-a regimen can be modified to replace the subject IFN-a regimen with a regimen of monoPEG
(30 kD, linear)-ylated consensus IFN-a, comprising administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a 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.
[00407] As non-limiting examples, any of the above-described methods featuring an IFN-a regimen can be modified to replace the subject IFN-a regimen with a regimen of INFERGENO
interferon alfacon-1 comprising administering a dosage of INFERGENO interferon alfacon-1 contaiiiing an amount of 9 g of drug per dose, subcutaneously once daily or three times per week for the desired treatment duration.
[00408] As non-limiting examples, any of the above-described methods featuring an IFN-a regimen can be modified to replace the subject IFN-a regimen with a regimen of INFERGENO
interferon alfacon-1 comprising administering a dosage of INFERGENO 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.
[00409] As non-limiting examples, any of the above-described methods featuring an IFN-y regimen can be modified to replace the subject IFN-y regimen with a regimen of IFN-y comprising administering a dosage of IFN-y containing an amount of 25 g of drug per dose, subcutaneously three times per week for the desired treatment duration.
[00410] As non-limiting examples, any of the above-described methods featuring an IFN-y regimen can be modified to replace the subject IFN-y regimen with a regimen of IFN-y comprising administering a dosage of IFN-y containing an amount of 50 g of drug per dose, subcutaneously three times per week for the desired treatment duration.
[00411] ' As non-limiting examples, any of the above-described methods featuring an IFN-y regimen can be modified to replace the subject IFN-y regimen with a regimen of IFN-y comprising administering a dosage of IFN-y containing an amount of 100 g of drug per dose, subcutaneously three times per week for the desired treatment duration.
[00412] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising:
(a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a 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-y containing an amount of 50 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00413] As non-limiting examples, 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.
[00414] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising:
(a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a 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-y containing an amount of 100 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00415] . As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising:
(a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a 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 IFN-y containing an amount of 50 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00416] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising:
(a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a 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 IFN-y containing an amount of 100 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00417] . As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising:
(a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 200 g of drug per dose, subcutaneously once weekly, once every 8 days, or once every 10 days; and (b) adininistering a dosage of IFN-y containing an amount of 50 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00418] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising:
(a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a 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-y containing an amount of 100 jig of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00419] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN=y combination regimen with an IFN-a and IFN-y 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-y containing an amount of 25 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00420] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-,y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen withan IFN-a and IFN-y 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-y containing an amount of 50 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00421] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y 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-y containing an amount of 100 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00422] As non-limiting examples, any of the above=described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y combination regimen comprising:
(a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 9 gg of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-y containing an amount of 25 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00423] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-,y combination regimen comprising:
(a) adininistering 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-y containing an amount of 50 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00424] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-,y combination regimen comprising:
(a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 9 gg of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-y containing an amount of 100 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00425] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y 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-y containing an amount of 25 Rg of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00426] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y 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-y containing an amount of 50 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00427] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-,y 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-y - containing an amount of 100 gg of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00428] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y 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-y containing an amount of 25 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00429] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y 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-y containing an amount of 50 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00430] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y 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-y containing an amount of 100 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00431] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen can be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y and TNF
antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 100 gg of drug per dose, subcutaneously once weeldy, once every 8 days, or once every 10 days; (b) administering a dosage of IFN-y 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.
[00432] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen can be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y and TNF
antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 100 g of drug per dose, subcutaneously once weelcly, once every 8 days, or once every 10 days; (b) administering a dosage of IFN-7 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.
[00433] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen can be modified to replace the subject IFN-a, IFN-,y and TNF antagonist combination regimen with an IFN-a, IFN-y and TNF
antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a 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-y 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.
[00434] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen can be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y and TNF
antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a 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-7 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 weeldy or once every other week; for the desired treatment duration.
[00435] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen can be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y and TNF
antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a 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-y 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 weelcs thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.
[00436] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen can be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y and TNF
antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a 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-y 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.

[00437] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen can be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y 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-y 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.
[00438] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen can be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y 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-y 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 ainount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 ing 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.
[00439] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen can be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y 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 weelc;
(b) administering a dosage of IFN-y 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 tliereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.

[00440] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen can be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y 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-y 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.
[00441] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen can be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-,y 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-y 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.
[00442] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen can be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y 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-y containing an ainount 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.

[00443] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen can be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y 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-y 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.
[00444] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen can be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y and TNF
antagonist combina'tion 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-y 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.
[00445] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen can be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y 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-y 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.

[00446] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen can be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y 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-y 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 ing 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 weelcly or once every other week; for the desired treatment duration.
[00447] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen can be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y and TNF
antagonist coinbination 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) adininistering a dosage of IFN-y 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) inflixiniab 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 weelc; for the desired treatment duration.
[00448] As non-limiting examples, any of the above-described methods featuring an IFN-a, IFN-y and TNF antagonist combination regimen can be modified to replace the subject IFN-a, IFN-y and TNF antagonist combination regimen with an IFN-a, IFN-y and TNF
antagonist combination regimen comprising: (a) administering a dosage of INFERGEN
interferon alfacon-1 containing an amount of 15 gg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-y containing an amount of 100 gg 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.

[00449] As non-limiting examples; any of the above-described methods featuring an IFN-a and TNF antagonist combination regimen can be modified to replace the subject IFN-a and TNF
antagonist combination regimen with an IFN-a and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a 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 weelcs thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weeldy or once every other week; for the desired treatment duration.
[00450] As non-limiting examples, any of the above-described methods featuring an IFN-a and TNF antagonist combination regimen can be modified to replace the subject IFN-a and TNF
antagonist combination regimen with an IFN-a and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a 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.
[00451] As non-limiting examples, any of the above-described methods featuring an IFN-a and TNF antagonist combination regimen can be modified to replace the subject IFN-a and TNF
antagonist combination regimen with an IFN-a and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a 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 weelcs thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.
[00452] As non-limiting examples, any of the above-described methods featuring an IFN-a and TNF antagonist combination regimen can be modified to replace the subject IFN-a and TNF
antagonist combination regimen with an IFN-a 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 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.
[00453] As non-limiting examples, any of the above-described methods featuring an IFN-a and TNF antagonist combination regimen can be modified to replace the subject IFN-a and TNF
antagonist combination regimen with an IFN-a 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 weelc, (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 thereafte'r or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.
[004541 As non-limiting examples, any of the above-described methods featuring an IFN-,y and TNF antagonist combination regimen can be modified to replace the subject IFN-7 and TNF
antagonist combination regimen with an IFN-y and TNF antagonist combination regimen comprising: (a) administering a dosage of IFN-y 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.
[00455] As non-limiting examples, any of the above-described methods featuring an IFN-y and TNF antagonist combination regimen can be modified to replace the subject IFN-y and TNF
antagonist combination regimen with an IFN-y and TNF antagonist combination regimen comprising: (a) administering a dosage of IFN-y 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 arnount 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.

[00456] - As non-limiting examples, any of the above-described methods featuring an IFN-y and TNF antagonist combination regimen can be modified to replace the subject IFN-y and TNF
antagonist combination regimen with an IFN-y and TNF antagonist combination regimen comprising: (a) administering a dosage of IFN-y 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.
[00457] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a can be modified to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a 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.
[00458] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a can be modified to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a 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.
[00459] As non-limiting examples, 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.
[00460] As non-limiting examples, 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.
[00461] As non-limiting examples, any of the above-described methods feauturing an NS3 inhibitor regimen can be modified to replace the subject NS3 inhibitor regimen with an NS3 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.

[00462] As non-limiting examples, any of the above-described methods feauturing an NS3 inhibitor regimen 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.
[00463] As non-limiting examples, any of the above-described methods feauturing an NS3 inhibitor regimen 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.
[00464] As non-limiting examples, any of the above-described methods feauturing an NS3 inhibitor regimen 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.
[00465] As non-limiting examples, 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.
[00466] As non-limiting examples, 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 0.1 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.
[00467] As non-limiting examples, 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 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.
[00468] As non-limiting examples, 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 drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration.
[00469] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a can be modified to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a with a regimen of peginterferon alfa-2a comprising administering a dosage of peginterferon alfa-2a containing an amount of 90 g to 360 g, of drug per dose, subcutaneously once weekly for the desired treatment duration.
[00470] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a can be modified to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a with a regimen of peginterferon alfa-2b comprising administering a dosage of peginterferon alfa-2b containing an amount of 0.5 g to 2.0 g, of drug per kilogram of body weight per dose, subcutaneously once or twice weekly for the desired treatment duration.
[00471] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (301kD, linear)-ylated consensus IFN-a comprising administering an amount of monoPEG (30 kD, linear)-ylated consensus IFN-a once weekly or once every 8 days can be modified to administer the amount of monoPEG (30 kD, linear)-ylated consensus IFN-a once every 10 days for the desired treatment duration.
[00472] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a SAPK 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 the SAPK inhibitor compound.
[00473] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a SAPK 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 SAPK inhibitor compound.
[00474] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen witli a SAPK 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 SAPK inhibitor compound.

[00475] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a SAPK 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 SAPK inhibitor compound.
Side effect management agent [00476] Any subject monotherapy or combination therapy can be modified to include administration of a side effect management agent. Thus, the subject invention provides any of the above-described treatment methods, modified to include administering an effective amount of a side effect management agent for the desired treatment duration. In many embodiments, side effect management agents are selected from one or more of acetaminophen, ibuprofen, and other NSAIDs, H2 blockers, and antacids.
[00477] Side effects of Type I interferon receptor agonist treatment include, but are not limited to, fever, malaise, tachycardia, chills, headache, arthralgia, myalgia, myelosuppression, suicide ideation, platelet suppression, neutropenia, lymphocytopenia, erythrocytopenia (anemia), and anorexia. In some embodiments, an effective amount of a palliative agent reduces a side effect induced by treatment with a Type I interferon receptor agonist 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%, or more, compared to the rate of occurrence or the degree or extent of the side effect when the Type I interferon receptor agonist is administered without the palliative agent. For example, if a fever is experienced with the Type I interferon receptor agonist therapy, then the body temperature of an individual treated with the Type I interferon receptor agonist therapy and palliative agent according to the instant invention is reduced by at least 0.5 degree Fahrenheit, and in some enibodiinents is within the normal range, e.g., at or near 98.6 F.
[00478] Side effects of pirfenidone or a pirfenidone analog include gastrointestinal disturbances and discomfort. Gastrointestinal disturbances include nausea, diarrhea, gastrointestinal cramping, and the like. In some embodiments, an effective amount of a palliative agent reduces a side effect induced by treatment with a pirfenidone or a pirfenidone analog 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%, or more, compared to the rate of occurrence or the degree or extent of the side effect when the pirfenidone or pirfenidone analog is administered without the palliative agent.

Patient identification [00479] In certain embodiments, the specific regimen of drug therapy used in treatment of the HCV patient is selected according to certain disease parameters exhibited by the patient, such as the iiiitial viral load, genotype of the HCV infection in the patient, liver histology and/or stage of liver fibrosis in the patient.
[00480] Thus, in some embodiments, 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.
[00481] In other embodiments, the invention provides any of the above-described methods for HCV in which the subject metliod is modified to treat a non-responder patient, where the patient receives a 48 week course of therapy.
[00482] In other embodiments, 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.
[00483] In other embodiments, 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 naive patient infected with HCV genotype 1, where the patient receives a 48 week course of therapy.
[00484] In other embodiments, 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 naive patient infected with HCV genotype 4, where the patient receives a 48 week course of therapy.
[00485] In other embodiments, 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 naive 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 106 HCV genome copies per mL
serum, and where the patient receives a 48 week course of therapy.
[00486] In one embodiment, 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) adininistering 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.

[00487] In another embodiment, 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 40 weeks to about 50 weeks, or about 48 weeks.
[00488] In another embodiment, 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.
[00489] In another embodiment, 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.
[00490] In another embodiment, 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.
[00491] In another embodiment, 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.
[00492] In another embodiment, 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.
[00493] In another embodiment, 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.
[00494] In another embodiment, 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 weelcs to about 48 weeks.
[00495] In another embodiment, the invention provides any of the above-described methods for the treatinent 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 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.
[00496] In another embodiment, 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) adininistering 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.
[00497] In another embodiment, 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 about 20 weeks to about 24 weeks.
[00498] In another embodiment, 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.
[00499] In another embodiment, 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.
[00500] In another embodiment, 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.
[00501] In another embodiment, 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 a.n 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 at least about 24 weeks and up to about 48 weeks.

SUBJECTS SUITABLE FOR TREATMENT
[00502] Individuals who are to be treated according to the methods of the invention for treating a viral infection include individuals who have been clinically diagnosed as infected with HCV.
Individuals who are infected with HCV are identified as having HCV RNA in their blood, and/or having anti-HCV antibody in their serum.
[00503] Individuals who are clinically diagnosed as infected with HCV include naive individuals (e.g., individuals not previously treated for HCV, particularly those who have not previously received IFN-a-based and/or ribavirin-based therapy) and 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-a monotherapy, a previous IFN-a and ribavirin combination therapy, or a previous pegylated IFN-a and ribavirin combination therapy); and relapsers (i.e., individuals who were previously treated for HCV, e.g., who received a previous IFN-a monotherapy, a previous IFN-a and ribavirin combination therapy, or a previous pegylated IFN-a and ribavirin combination therapy, whose HCV titer decreased, arid subsequently increased).
[00504] In particular embodiments of interest, individuals have an HCV titer of at least about 105, at least about 5 x 105, or at least about 106, or at least about 2 x 106, genome copies of HCV per milliliter of serum. The patient may be infected with any HCV genotype (genotype 1, including la and Ib, 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.
[00505] Also of interest 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-a-based therapies or who cannot tolerate IFN-a-based therapies, or who have a contraindication to such therapies. In particular embodiments of interest, 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. In other embodiments, 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. In still other embodiments, 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.).
ALD monotherapy and combination therapy [00506] The present invention provides methods for treating ALD. In some embodiments, the invention provides methods of treating ALD, comprising administering to an individual in need thereof an effective amount of a SAPK inhibitor. In other embodiments, the invention provides methods of treating ALD, comprising administering to an individual in need thereof effective amounts of a SAPK inhibitor and a Type II interferon receptor agonist, e.g., IFN-y.
In otlzer embodiments, the invention provides methods of treating ALD, comprising administering to an individual in need thereof effective amounts of a SAPK
inhibitor, a Type II
interferon receptor agonist, and a Type I interferon receptor agonist. Any of these embodiments can be further modified to include administration of an effective amount of a TNF antagonist.
SAPK inhibitor monotherapy for treating ALD
[00507] In one aspect, the present invention provides SAPK inhibitor monotherapy for the treatment of alcoholic liver disease.
[00508] In one embodiment, the invention provides a method using an effective amount of a SAPK inhibitor in the treatment of alcoholic liver disease in a patient comprising administering to the patient a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about g/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 g to about 1000 mg per day, or about 100 g to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration, for the desired treatment duration.
SAPK inhibitof and Type II interferon receptor agonist combination therapy for treating ALD
[005091 In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a SAPK inhibitor, and ii) a Type II
interferon receptor agonist in the treatment of ALD in a patient, the method comprising co-administering to the patient a) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 g/Icg/day to about 10 mg/kg/day, or a fixed dosage of about 100 g to about 1000 mg per day, or about 100 jig to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and b) a dosage of IFN-y containing an amount of from about 25 g to about 500 g subcutaneously qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to treat the ALD.

[005101 In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a SAPK inhibitor, and ii) a Type II
interferon receptor agonist in the treatment of ALD in a patient, the method comprising co-administering to the patient a) a SAPK inhibitor, in a weight-based dosage in the range from about 10 g/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 g to about 1000 mg per day, or about 100 g to about 1 mg per day, or about 1 ing to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and b) a dosage of Actimmune human IFN-ylb containing an amount of about 25 g, 50 g, 100 g, 150 g, or 200 g, administered subcutaneously tiw, to treat the ALD.
SAPK inhibitor and TNF antagonist in combination therapy for the treatment of ALD
[00511] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a SAPK inhibitor, and ii) a TNF antagonist in the treatment of ALD in a patient, the method comprising co-administering to the patient a) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 g/kg/day to about 10 mg/lcg/day, or a fixed dosage of about 100 g to about 1000 mg per day, or about 100 g to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and b) a dosage of a TNF antagonist containing an amount of from about 0.1 g to 40 mg administered subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration, to treat the ALD.
[005121 In some embodiments, the invention provides a combination therapy method using combined effective ainounts of i) a SAPK inhibitor, and ii) a TNF antagonist in the treatment of ALD in a patient, the method comprising co-administering to the patient a) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 g/kg/day to about 10 ing/kg/day, or a fixed dosage of about 100 g to about 1000 mg per day, or about 100 g to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and b) a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE
in an amount of about 3 mg/kg to about 10 mg/lcg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIR.ATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration, to treat the ALD.
[00513] The subject invention provides any of the above-described treatment methods, modified to include administering an effective amount of a side effect management agent for the desired treatment duration. In many embodiments, side effect management agents are selected from one or more of acetaminophen, ibuprofen, and otlier NSAIDs, H2 blockers, and antacids.
SAPK inhibitor, Type II interfeNon receptor agonist, and TNF antagonist in combination therapy to treat ALD
[00514] In some embodiments, the invention provides a combination therapy method involving administering a SAPK inhibitor, a Type II interferon receptor agonist, and a TNF antagonist.
[005151 In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a SAPK inhibitor, ii) a TNF antagonist, and iii) a Type II
interferon receptor agonist in the treatnlent of ALD in a patient, the method comprising co-administering to the patient a) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 g/kg/day to about 10 mg/lcg/day, or a fixed dosage of about 100 g to about 1000 mg per day, or about 100 g to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; b) a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per inonth, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an ainount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and c) a dosage of Actimmune human IFN-ylb containing an amount of about 25 g, 50 g, 100 g, 150 g, or 200 g, administered subcutaneously tiw, to treat the ALD.
SAPK inhibitor, Type II inte~feron receptor agonist, and Type I interferon receptor agonist in combination therapy to treat ALD
[00516] In some embodiments, the invention provides a conibination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a SAPK inhibitor, and iii) a Type I interferon receptor agonist in the treatment of ALD in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-y containing an amount of from about 25 g/m2 to about 100 g/m2, or a fixed dosage of IFN-y containing an amount of from about 50 g to about 200 g, administered subcutaneously tiw for the desired treatment duration; b) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 g/kg/day to about 10 mg/lcg/day, or a fixed dosage of about 100 gg to about 1000 mg per day, or about 100 g to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and c) a dosage of an IFN-a selected from (i) INFERGEN containing an amount of about 1 gg 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 continuously or substantially continuously (ii) PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 10 g to about 100 g, or about 45 g to about 60 g, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-a 2a, 2b or 2c containing an amount of about 3 MU to about MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS containing an amount of about 90 g to about 360 g, or about 180 g, of drug per dose of PEGASYS
subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRON containing an amount of about 0.75 g to about 3.0 g, or about 1.0 gg to about 1.5 g, of drug per kilogram of body weight per dose of PEG-INTRON subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG(30 kD, linear)-ylated consensus IFN-a containing an amount of from about 100 g to about 200 g, or about 150 g, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-a subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for the desired treatment duration, to treat the ALD.
[00517] As non-limiting examples, any of the above-described treatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II
interferon receptor agonist regimen with a regimen of IFN-y comprising administering a dosage of IFN-y containing an amount of 25 g of drug per dose, subcutaneously three times per week for the desired treatment duration.
[00518] As non-limiting examples, any of the above-described treatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II
interferon receptor agonist regimen with a regimen of IFN-y comprising administering a dosage of IFN-7 I containing an amount of 50 g of drug per dose, subcutaneously three times per weelc for the desired treatment duration.
[00519] As non-limiting examples, any of the above-described treatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II
interferon receptor agonist regimen with a regimen of IFN-y comprising administering a dosage of IFN-y containing an amount of 100 g of drug per dose, subcutaneously three times per week for the desired treatment duration.
[00520] As non-limiting examples, any of the above-described treatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II
interferon receptor agonist regimen with a regimen of IFN-y comprising administering a dosage of IFN-y containing an amount of 200 g of drug per dose, subcutaneously three times per week for the desired treatment duration.
[00521] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 100 g of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 200 g of drug per dose, subcutaneously three times per week;
for the desired treatment duration.
[005221 As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 100 g of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 100 g of drug per dose, subcutaneously three times per week;
for the desired treatment duration.
[00523] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 100 g of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 50 g of drug per dose, subcutaneously three times per week;
for the desired treatment duration.
[00524] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 150 g of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 50 g of drug per dose, subcutaneously three times per week;
for the desired treatment duration.
[00525] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 150 g of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 100 g of drug per dose, subcutaneously three times per week;
for the desired treatment duration.
[00526] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regiinen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 150 g of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 200 g of drug per dose, subcutaneously three times per week;
for the desired treatment duration.
[00527] . As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 200 g of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing aii amount of 50 g of drug per dose, subcutaneously three times per week;
for the desired treatment duration.
[00528] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 200 g of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 100 g of drug per dose, subcutaneously three times per week;
for the desired treatment duration.
[00529] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen witll an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 200 g of drug per dose; subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 200 g of drug per dose, subcutaneously three times per week;
for the desired treatment duration.
[00530] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-,y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-,y 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-,y containing an amount of 200 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00531) As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace tlie, subject IFN-a and IFN-,y combination regimen with an IFN-a and IFN-y 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-y containing an amount of 50 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00532] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-,y combination regimen can be modified to replace the subject IFN-a and IFN-,y combination regimen with an IFN-a and IFN-,y regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 9 g of drug per dose, subcuta.neously three times per week; and (b) administering a dosage of IFN-,y containing an amount of 100 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00533] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-,y combination regimen can be modified to replace the subject IFN-a and IFN-'y combination regimen with an IFN-a and IFN-,y 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-y containing an amount of 200 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00534] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-,y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with, an IFN-a and IFN-y 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-y containing an amount of 50 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00535] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-,y coinbination 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--y containing an amount of 100 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00536] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-7 combination regimen can be modified to replace the subject IFN-a and IFN-,[
combination regimen with an IFN-a and IFN-,y 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-y containing an amount of 200 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00537] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y 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-y containing an amount of 50 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00538] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of INFERGEN interferon alfacon-1 containing an amount of 15 jig of drug per dose, subcutaneously three times per weelc; and (b) administering a dosage of IFN-y containing an amount of 100 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00539] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y 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-y containing an amount of 200 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00540] As non-liiniting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN--y combination regimen with an IFN-a and IFN-y 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-y containing an amount of 50 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00541] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y 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-y containing an amount of 100 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00542] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a can be modified to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a with a regimen of peginterferon alfa-2a comprising administering a dosage of peginterferon alfa-2a containing an amount of 90 g to 360 g, or 180 g, of drug per dose, subcutaneously once weekly for the desired treatment duration.
[00543] '' As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a can be modified to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a with a regimen of peginterferon alfa-2b comprising adniinistering a dosage of peginterferon alfa-2b containing an amount of 0.5 g to 2.0 g, or 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.
[00544] Any of the above-described treatment methods featuring a SAPK
inhibitor, a Type II
interferon receptor agonist, and a Type I interferon receptor coinbination regimen can be modified to include administering a TNF antagonist, comprising administering a dosage of a TNF-a antagonist selected from: (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.
Variations [00545] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a SAPK 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 the SAPK inhibitor compound.
[00546] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a SAPK 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 SAPK inhibitor compound.
[00547] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a SAPK 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 SAPK inhibitor compound.
[00548] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a SAPK 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 SAPK inhibitor compound.
[00549] The subject invention provides any of the above-described treatment methods, modified to include administering an effective ainount of a side effect management agent for the desired treatment duration. In many embodiments, side effect management agents are selected from one or more of acetaminophen, ibuprofen, and other NSAIDs, H2 blockers, and antacids.

NASH monotherapy and combination therapy [00550] The present invention provides methods for treating NASH. In some embodiments, the invention provides methods of treating NASH, comprising administering to an individual in need thereof an effective amount of a SAPK inhibitor. In other embodiments, the invention provides methods of treating NASH, comprising administering to an individual in need thereof effective amounts of a SAPK inhibitor and a Type II interferon receptor agonist, e.g., IFN-y.
In other embodiments, the invention provides methods of treating NASH, comprising administering to an individual in need thereof effective amounts of a SAPK
inhibitor, a Type II
interferon receptor agonist, and a Type I interferon receptor agonist. Any of these embodiments can be further modified to include administration of an effective amount of a TNF antagonist.
SAPK inhibitor monotherapy for treating NASH
[00551] In one aspect, the present invention provides SAPK inhibitor monotherapy for the treatinent of alcoholic liver disease.
[00552] In one embodiment, the invention provides a method using an effective amount of a SAPK inhibitor in the treatment of alcoholic liver disease in a patient comprising administering to the patient a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about g/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 g to about 1000 mg per day, or about 100 g to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration, for the desired treatment duration.
SAPK inhibitor and Type II interferon receptor agonist combination therapy for treating NASH
[00553] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a SAPK inhibitor, and ii) a Type II
interferon receptor agonist in the treatment of NASH in a patient, the method comprising co-administering to the patient a) a dosage of a SAPK inliibitor, in a weight-based dosage in the range from about 10 g/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 g to about 1000 mg per day, or about 100 g to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and b) a dosage of IFN-y containing an amount of from about 25 g to about 500 g subcutaneously qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to treat the NASH.
[00554] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a SAPK inhibitor, and ii) a Type II
interferon receptor agonist in the treatment of NASH in a patient, the method comprising co-administering to the patient a) a SAPK inhibitor, in a weight-based dosage in the range from about 10 g/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 gg to about 1000 mg per day, or about 100 g to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and b) a dosage of Actimmune human IFN-ylb containing an amount of about 25 g, 50 g, 100 g, 150 g, or 200 g, administered subcutaneously tiw, to treat the NASH.
SAPK inhibitor and TNF antagonist in combination therapy for the treatment ofNASH
[00555] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a SAPK inhibitor, and ii) a TNF antagonist in the treatment of NASH in a patient, the method comprising co-administering to the patient a) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 g/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 g to about 1000 mg per day, or about 100 g to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and b) a dosage of a TNF antagonist contaiv.iing an amount of from about 0.1 g to 40 mg administered subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration, to treat the NASH.
[00556] In some embodiments, the invention provides a combination therapy method using coinbined effective amounts of i) a SAPK inhibitor, and ii) a TNF antagonist in the treatment of NASH in a patient, the method comprising co-administering to the patient a) a dosage of a SAPK inhibitor, in a weiglit-based dosage in the range from about 10 g/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 g to about 1000 mg per day, or about 100 g to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and b) a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE
in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration, to treat the NASH.

[00557] The subject invention provides any of the above-described treatment methods, modified to include administering an effective amount of a side effect management agent for the desired treatment duration. In many embodiments, side effect management agents are selected from one or more of acetaminophen, ibuprofen, and other NSAIDs, H2 blockers, and antacids.
SAPK inhibitor, Type II interferon receptor agonist, and TNF antagonist in combination therapy to treat NASH
[005581 In some embodiments, the invention provides a combination therapy method involving administering a SAPK inhibitor, a Type II interferon receptor agonist, and a TNF antagonist.
[005591 In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a SAPK inhibitor, ii) a TNF antagonist, and iii) a Type II
interferon receptor agonist in the treatment of NASH in a patient, the method comprising co-administering to the patient a) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 g/lcg/day to about 10 mg/kg/day, or a fixed dosage of about 100 g to about 1000 mg per day, or about 100 g to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; b) a dosage of a TNF-a antagonist selected from the group consisting of (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and c) a dosage of Actimmune human IFN-ylb containing an amount of about 25 gg, 50 g, 100 g, 150 g, or 200 g, administered subcutaneously tiw, to treat the NASH.
SAPK inhibitor, Type II interferon receptor agonist, and Type I interferon receptor agonist in combination therapy to treat NASH
[00560] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a SAPK inhibitor, and iii) a Type I interferon receptor agonist in the treatment of NASH in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-y containing an amount of from about 25 g/m2 to about 100 g/m2, or a fixed dosage of IFN-y containing an amount of from about 50 g to about 200 g, administered subcutaneously tiw for the desired treatment duration; b) a dosage of a SAPK inhibitor, in a weight-based dosage in the range from about 10 g/kg/day to about 10 mg/kg/day, or a fixed dosage of about 100 g to about 1000 mg per day, or about 100 g to about 1 mg per day, or about 1 mg to about 10 mg per day, or about 10 mg to about 100 mg per day, or about 100 mg to about 1000 mg per day, administered orally for the desired treatment duration; and c) a dosage of an IFN-a selected from (i) 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 continuously or substantially continuously (ii) PEGylated consensus IFN-a (PEG-CIFN) containing an amount of about 10 g to about 100 g, or about 45 g to about 60 g, of CIFN ainino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-a 2a, 2b or 2c containing an amount of about 3 MU to about MU of drug per dose of IFN-a 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYSO containing an amount of about 90 g to about 360 g, or about 180 g, of drug per dose of PEGASYS
subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRON containing an amount of about 0.75 g to about 3.0 g, or about 1.0 g to about 1.5 g, of drug per kilogram of body weight per dose of PEG-INTRON subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG(30 kD, linear)-ylated consensus IFN-a containing an amount of from about 100 gg to about 200 g, or about 150 g, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-a subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for the desired treatment duration, to treat the NASH.
[00561] As non-limiting examples, any of the above-described treatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II
interferon receptor agonist regimen with a regimen of IFN-y comprising administering a dosage of IFN-y containing an amount of 25 g of drug per dose, subcutaneously three times per weelc for the desired treatment duration.
[00562] As non-limiting examples, any of the above-described treatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II
interferon receptor agonist regimen with a regimen of IFN-y comprising administering a dosage of IFN-y containing an amount of 50 g of drug per dose, subcutaneously three times per week for the desired treatment duration.
[00563] As non-limiting examples, any of the above-described treatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II
interferon receptor agonist regimen with a regimen of IFN-y comprising administering a dosage of IFN-y containing an amount of 100 g of drug per dose, subcutaneously three times per week for the desired treatment duration.

[00564] - As non-limiting examples, any of the above-described treatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II
interferon receptor agonist regimen with a regimen of IFN-y comprising administering a dosage of IFN-y containing an amount of 200 g of drug per dose, subcutaneously three times per weelc for the desired treatment duration.
[00565] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-,y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 100 gg of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 200 g of drug per dose, subcutaneously three times per week;
for the desired treatment duration.
[00566] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-,y combination regimen can be modified to replace the subject IFN-a and combination regimen witli an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 100 g of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an ainount of 100 g of drug per dose, subcutaneously three times per week;
for the'desired treatment duration.
[00567] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 100 g of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an ainount of 50 g of drug per dose, subcutaneously three times per week;
for the desired treatment duration.
[00568] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 150 g of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 50 g of drug per dose, subcutaneously three times per week;
for the desired treatment duration.

[00569] As non-limiting examples,- any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 150 gg of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 100 gg of drug per dose, subcutaneously three times per week;
for the desired treatment duration.
[00570] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 150 gg of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 200 g of drug per dose, subcutaneously three times per week;
for the desired treatment duration.
[00571] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 200 g of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 50 g of drug per dose, subcutaneously three times per week;
for the desired treatment duration.
[00572] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y coinbination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 200 g of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y containing an amount of 100 g of drug per dose, subcutaneously three times per week;
for the desired treatment duration.
[00573] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-a containing an amount of 200 g of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-y-containing anamount of 200 g of drug per dose, subcutaneously three times per week;
for the desired treatment duration.
[00574] As non-limiting exainples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y 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=y containing an amount of 200 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00575] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-,y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y 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-y containing an amount of 50 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00576] As non-liuniting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y 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-y containing an amount of 100 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00577] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-,y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y 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-y containing an amount of 200 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00578] As non-limiting exainples, any of the above-described methods featuring an IFN-a and IFN-,y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y 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-y containing an amount of 50 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00579] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-,y combination regimen with an IFN-a and IFN-y 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-y containing an amount of 100 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00580] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y 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-y containing an amount of 200 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00581] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y 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-y containing an amount of 50 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00582] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y regimen comprising: (a) administering a dosage of 1NFERGEN 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-y containing an amount of 100 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.
[00583] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-y combination regimen with an IFN-a and IFN-y 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-y containing an amount of 200 g of drug per dose, subcutaneously three times per week;for the desired treatment duration.

[00584] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-combination regimen with an IFN-a and IFN-y 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-y containing an amount of 50 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00585] As non-limiting examples, any of the above-described methods featuring an IFN-a and IFN-y combination regimen can be modified to replace the subject IFN-a and IFN-combination regimen with an IFN-a and IFN-y 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-y containing an amount of 100 g of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00586] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a can be modified to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a with a regimen of peginterferon alfa-2a comprising administering a dosage of peginterferon alfa-2a containing an amount of 90 g to 360 gg, or 180 g, of drug per dose, subcutaneously once weekly for the desired treatment duration.
[00587] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a can be modified to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN-a with a regimen of peginterferon alfa-2b comprising administering a dosage of peginterferon alfa-2b containing an amount of 0.5 g to 2.0 g, or 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.
[00588] Any of the above-described treatment methods featuring a SAPK
inhibitor, a Type II
interferon receptor agonist, and a Type I interferon receptor combination regimen can be modified to include administering a TNF antagonist, comprising administering a dosage of a TNF-a antagonist selected from: (i) ENBREL in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRATM in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration.
Variations [00589] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a SAPK 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 the SAPK inhibitor compound.
[00590] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a SAPK 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 SAPK inhibitor compound.
[00591] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inhibitor regimen with a SAPK 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 SAPK inhibitor compound.
[00592] As non-limiting examples, any of the above-described methods can be modified to replace the subject SAPK inliibitor regimen with a SAPK 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 treatinent duration with the SAPK inhibitor compound.
[00593] The subject invention provides any of the above-described treatment methods, modified to include administering an effective amount of a side effect management agent for the desired treatment duration. In many embodiments, side effect management agents are selected from one or more of acetaminophen, ibuprofen, and otlier NSAIDs, H2 blockers, and antacids.
SUBJECTS SUITABLE FOR TREATMENT
[00594] Subjects suitable for treatment with a subject method for treating ALD
include individuals who have been diagnosed with ALD. The subject treatment methods for ALD are suitable for the treatment of any stage of ALD in a patient. For example, the subject methods can be employed in the treatment of hepatic steatosis, alcoholic hepatitis, hepatic fibrosis, or hepatic cirrhosis, or any combination thereof, that occurs in a patient suffering from ALD.
[00595] Subjects suitable for treatment with a subject method for treating NASH include individuals who have been diagnosed with NASH.

EXAMPLES
[00596] The following examples are put forth so as to provide thoseof ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed.
Efforts have been made to ensure accuracy with respect to numbers used (e.g.
amounts, temperature, etc.) but some experimental errors and deviations should be accounted for.
Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric.
Standard abbreviations may be used, e.g., bp, base pair(s); kb, kilobase(s);
pl, picoliter(s); s or sec, second(s); min, minute(s); h or hr, hour(s); aa, amino acid(s); kb, kilobase(s); bp, base pair(s); nt, nucleotide(s); i.m., intramuscular(ly); i.p., intraperitoneal(ly); s.c., subcutaneous(ly);
and the like.
Example 1: Analysis of pirfenidone inhibition of p38y [00597] Pirfenidone inhibition of p38y (SAPK3) was analyzed. The results are depicted in Figures 1-3. The results indicate that: 1) pirfenidone does not inhibit SAPK3 by aggregation or any other non-specific molecular effect; 2) pirfenidone is a competitive inhibitor of ATP; 3) pirfenidone binds SAPK3 only after the phosphorylation substrate binds. Since it is known that ATP can only bind after the phosphorylation substrate binds, the results imply that pirfenidone binds directly to the ATP binding site.

[00598] While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims

1. A method of treating a hepatitis C virus (HCV) infection in an individual, the method comprising administering to an individual in need thereof i) a stress-activated protein kinase (SAPK) inhibitor other than pirfenidone or a pirfenidone analog; and ii) an interferon-a (IFN-.alpha.) in amounts effective to achieve a sustained viral response.

2. A method of treating non-alcoholic steatohepatitis, the method comprising administering to an individual in need thereof an effective amount of a stress-activated protein kinase (SAPK) inhibitor other than pirfenidone or a pirfenidone analog.

3. A method of treating alcoholic liver disease, the method comprising administering to an individual in need thereof an effective amount of a stress-activated protein kinase (SAPK) inhibitor other than pirfenidone or a pirfenidone analog.

4. The method of any of claims 1-3, wherein the SAPK inhibitor inhibits enzymatic activity of a p38.alpha., a p38C.beta., or a p38.gamma..

5. The method of claim 4, wherein the SAPK inhibitor is a competitive inhibitor.

6. The method of claim 5, wherein the SAPK inhibitor competes with ATP for binding to the ATP binding site of p38.alpha., p38.beta., or p38.gamma..

7. The method of claim 1, wherein the IFN-.alpha. is INFERGEN® consensus IFN-.alpha..

8. The method of claim 1, wherein the IFN-.alpha. is pegylated.

9. The method of claim 8, wherein the pegylated IFN-.alpha. is selected from the group consisting of peginterferon alfa-2a, peginterferon alfa-2b, and monoPEG
(30 kD, linear)-ylated consensus IFN-.alpha..

10. The method of claim 2 or 3, further comprising administering an amount of an interferon-.gamma. (IFN-.gamma.) effective to augment the treatment received by the individual.

11. The method of claim 10, wherein the IFN-.gamma. is Actimmune® IFN-.gamma..

12. The method of claim 10, further comprising administering an amount of an interferon-.alpha. (IFN-.alpha.) effective to augment treatment received by the individual.

13. The method of claim 12, wherein the IFN-.alpha. is a consensus IFN-.alpha..

14. The method of claim 13, wherein the IFN-.alpha. is INFERGEN® consensus IFN-.alpha..

15. The method of claim 12, wherein the IFN-.alpha. is IFN-.alpha. 2a, 2b or 2c.

16. The method of claim 15, wherein the IFN-.alpha. is pegylated.

17. The method of claim 8 or 12, wherein the IFN-.alpha. is PEGylated consensus IFN-.alpha..

18. The method of any of claims 1 or 4-9, further comprising administering an amount of an interferon-.gamma. (IFN-.gamma.) that augments the sustained viral response (SVR) to the antiviral treatment received by the individual.

19. The method of claim 18, wherein the IFN-.gamma. is Actimmune® IFN-.gamma..

20. The method of any one of claims 1 or 4-9 or 18 or 19, further comprising administering an HCV NS3 protease inhibitor that augments the sustained viral response (SVR) to the antiviral treatment received by the individual.

21. The method of any one of claims 1 or 4-9 or 18-20, further comprising administering an HCV NS5B RNA-dependent RNA polymerase inhibitor that augments the sustained viral response (SVR) to the antiviral treatment received by the individual.

22. The method of any one of claims 1 or 4-9 or 18-21, wherein the method further comprises administering to the individual an amount of a nucleoside analog that augments the sustained viral response (SVR) to the antiviral treatment received by the individual.

23. The method of claim 22, wherein the nucleoside analog is ribavirin, levovirin, viramidine or isatoribine.

24. The method of any of claims 1 or 4-9 or 18-23, further comprising administering an amount of a TNF antagonist that augments the sustained viral response (SVR) to the antiviral treatment received by the individual.

25. The method of claim 2 or 3, further comprising administering to the individual an amount of a TNF antagonist effective to augment the treatment received by the individual.

26. The method of claim 24 or 25, wherein the TNF antagonist is etanercept, infliximab or adalimumab.

27. The method of any of claims 1-26, wherein the individual is a human.