Note: Descriptions are shown in the official language in which they were submitted.
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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,
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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.
23:1189-1199; Czaja et al. (1989) Hepatol. 10:795-800; Grossman et al. (1998)
J.
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Gastroenter=ol: Hepatol. 13:1058-1060; Rockey and Chung (1994) J Invest. Med.
42:660-670;
Sakaida et al. (1998) J Hepatol. 28:471-479; Shi et al. (1997) Proc. Natl.
Acad. Sci. USA
94:10663-10668; Baroni et al. (1999) Liver 19:212-219; Lortat-Jacob et al.
(1997) J. Hepatol.
26:894-903; Llorent et al. (1996) J. Hepatol. 24:555-563; U.S. Patent No.
5,082,659; European
Patent Application EP 294,160; U.S. Patent No. 4,806,347; Balish et al. (1992)
J. Infect.
Diseases 166:1401-1403; Katayama et al. (2001) J. Viral Hepatitis 8:180-185;
U.S. Patent No.
5,082,659; U.S. Patent No. 5,190,751; U.S. Patent No. 4,806,347; Wandl et al.
(1992) Br. J.
Haematol. 81:516-519; European Patent Application No. 294,160; Canadian Patent
No.
1,321,348; European Patent Application No. 276,120; Wandl et al. (1992) Sem.
Oncol. 19:88-
94; Balish et al. (1992) J. Infectious Diseases 166:1401-1403; Van Dijk et al.
(1994) Int. J
Cancer 56:262-268; Sundmacher et al. (1987) Current Eye Res. 6:273-276; U.S.
Patent Nos.
6,172,046; 6,245,740; 5,824,784; 5,372,808; 5,980,884; published international
patent
applications WO 96/21468; WO 96/11953; Torre et al. (2001) J Med. Virol.
64:455-459;
Beldcering et al. (2001) J. Hepatol. 34:435-440; Zeuzem et al. (2001)
Gastroenterol. 120:1438-
1447; Zeuzem (1999) J. Hepatol. 31:61-64; Keeffe and Hollinger (1997) Hepatol.
26:101 S-
107S; Wills (1990) Clin. Pharmacokinet. 19:390-399; Heathcote et al. (2000)
New Engl. J
Med. 343:1673-1680; Husa and Husova (2001) Bratisl. Lek Listy 102:248-252;
Glue et al.
(2000) Clin. Pharmacol. 68:556-567; Bailon et al. (2001) Bioconj. Chem. 12:195-
202; and
Neumann et al. (2001) Science 282:103; Zalipsky (1995) Adv. Drug Delivery
Reviews S. 16,
157-182; Mann et al. (2001) Lancet 358:958-965; Zeuzem et al. (2000) New Engl.
J. Med.
343:1666-1672; U.S. Patent Nos. 5,985,265; 5,908,121; 6,177,074; 5,985,263;
5,711,944;
5,382,657; and 5,908,121; Osborn et al. (2002) J Pharmacol. Exp. Therap.
303:540-548;
Sheppard et al. (2003) Nat. Immunol. 4:63-68; Chang et al. (1999) Nat.
Biotechnol. 17:793-
797; Adolf (1995) Multiple Sclerosis 1 Suppl. 1:S44-S47; U.S. Patent No.
5,952,309; Woods et
al. (1993) Am. Fam. Physician Apr;47(5):1171-8.
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
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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.
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[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.
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[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,
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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
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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.
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[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
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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
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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.
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[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
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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
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,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
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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
CA 02566677 2006-11-14
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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.
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[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
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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.
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[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
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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
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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
21
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WO 2005/110455 PCT/US2005/016353
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
22
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WO 2005/110455 PCT/US2005/016353
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
23
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WO 2005/110455 PCT/US2005/016353
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]-
24
CA 02566677 2006-11-14
WO 2005/110455 PCT/US2005/016353
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-
CA 02566677 2006-11-14
WO 2005/110455 PCT/US2005/016353
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-
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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-
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CA 02566677 2006-11-14
WO 2005/110455 PCT/US2005/016353
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:
28
CA 02566677 2006-11-14
WO 2005/110455 PCT/US2005/016353
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.
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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.
CA 02566677 2006-11-14
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[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.
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[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
32
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WO 2005/110455 PCT/US2005/016353
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.
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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.
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WO 2005/110455 PCT/US2005/016353
[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.
CA 02566677 2006-11-14
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[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-
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CA 02566677 2006-11-14
WO 2005/110455 PCT/US2005/016353
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
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CA 02566677 2006-11-14
WO 2005/110455 PCT/US2005/016353
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.
38
CA 02566677 2006-11-14
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[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.
0
11
H3C-O-(CH-)CH2O)n-CH2CH2N H.2+ H.O C-CH2CH2CH-COOH
I
EDAC CkiNI h
H3C-O-(CH'-)CH2C))õ-CH2CH2NH-CO
CI-INII2
(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
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CA 02566677 2006-11-14
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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.
CA 02566677 2006-11-14
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[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
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CA 02566677 2006-11-14
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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
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CA 02566677 2006-11-14
WO 2005/110455 PCT/US2005/016353
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
43
CA 02566677 2006-11-14
WO 2005/110455 PCT/US2005/016353
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
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CA 02566677 2006-11-14
WO 2005/110455 PCT/US2005/016353
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
CA 02566677 2006-11-14
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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
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CA 02566677 2006-11-14
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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.
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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
48
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WO 2005/110455 PCT/US2005/016353
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).
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WO 2005/110455 PCT/US2005/016353
[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.
CA 02566677 2006-11-14
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[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
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WO 2005/110455 PCT/US2005/016353
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.
WO 01/36001
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.
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WO 2005/110455 PCT/US2005/016353
[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.
R2 RI
X' ~
O
II.A II.B
R2 R2
N 0
~
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,
53
CA 02566677 2006-11-14
WO 2005/110455 PCT/US2005/016353
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,
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WO 2005/110455 PCT/US2005/016353
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
NS3
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.
CA 02566677 2006-11-14
WO 2005/110455 PCT/US2005/016353
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
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WO 2005/110455 PCT/US2005/016353
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
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WO 2005/110455 PCT/US2005/016353
- 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:
0
N
l1zN I \
N~
N
(.)H
p
HO OH
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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
WO 02/069903
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.
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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,
2002
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.
CA 02566677 2006-11-14
WO 2005/110455 PCT/US2005/016353
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.
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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
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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
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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,
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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,
CA 02566677 2006-11-14
WO 2005/110455 PCT/US2005/016353
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
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(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.
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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;
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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.
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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
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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
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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,
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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
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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
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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
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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
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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
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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
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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
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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.
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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
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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,
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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
HCV NS3
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
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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
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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
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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
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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
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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,
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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
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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.
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[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
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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.
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[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
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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
HCV NS3
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.
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[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,
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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
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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
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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.
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[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
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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)-
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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,
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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.
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[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.
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[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.
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[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.
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[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.
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[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
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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.
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[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.
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[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
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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.
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[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.
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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.
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[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
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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
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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.
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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
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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.
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[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,
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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
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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
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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
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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
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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)
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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
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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
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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.
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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
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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.
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[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
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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.
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[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
IFN-7
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.
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[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
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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
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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)
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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-
7
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-
7
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
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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
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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.
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