(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2005/0031585 A1
`(43) Pub. Date:
`Feb. 10, 2005
`HSu
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`US 2005003 1585A1
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`(54)
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`(76)
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`METHOD FOR TREATING HEPATITIS C
`VIRUS INFECTION IN TREATMENT
`FAILURE PATIENTS
`
`Inventor: Henry H. Hsu, Hillsborough, CA (US)
`Correspondence Address:
`BOZICEVIC, FIELD & FRANCIS LLP
`1900 UNIVERSITY AVE
`SUTE 200
`EAST PALO ALTO, CA 94.303 (US)
`Appl. No.:
`10/490,456
`PCT Fed:
`Sep. 20, 2002
`
`PCT No.:
`
`PCT/US02/30006
`
`Related U.S. Application Data
`Provisional application No. 60/326,100, filed on Sep.
`28, 2001.
`
`Publication Classification
`
`A61K 38/21
`5
`51) Int. C.7
`; A61K 31/7056
`1) Int. Cl.' ......................
`(52) U.S. Cl. ............................................. 424/85.7; 514/43
`
`(57)
`
`ABSTRACT
`
`The present invention provides methods for treating indi
`viduals having a hepatitis C virus (HCV) infection, which
`individuals have failed to respond to therapy with an IFN-C.
`other than consensus interferon (CIFN), or who, following
`cessation of therapy with an IFN-C. other than CIFN, have
`Suffered relapse. The methods generally involve a treatment
`regimen comprising administering a first dosing regimen of
`CIFN, followed by a second dosing regimen of CIFN.
`Ribavirin is administered with at least the Second dosing
`regimen.
`
`APOTEX ET AL. - EXHIBIT 1066
`Apotex Inc. et al. v. Novartis AG
`IPR2017-00854
`
`

`

`US 2005/0031585 A1
`
`Feb. 10, 2005
`
`METHOD FOR TREATING HEPATITIS C VIRUS
`INFECTION IN TREATMENT FAILURE PATIENTS
`
`FIELD OF THE INVENTION
`0001. This invention is in the field of treating viral
`infections, and in particular, treating hepatitis C virus infec
`tion.
`
`BACKGROUND OF THE INVENTION
`0002 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 annu
`ally, 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.
`0003) The high prevalence of chronic HCV infection has
`important public health implications for the future burden of
`chronic liver disease in the United States. Data derived from
`the National Health and Nutrition Examination Survey
`(NHANES III) indicate that a large increase in the rate of
`new HCV infections occurred from the late 1960s to the
`early 1980s, particularly among persons between 20 to 40
`years of age. It is estimated that the number of perSons with
`long-standing HCV infection of 20 years or longer could
`more than quadruple from 1990 to 2015, from 750,000 to
`over 3 million. The proportional increase in perSons infected
`for 30 or 40 years would be even greater. Since the risk of
`HCV-related chronic liver disease is related to the duration
`of infection, with the risk of cirrhosis progressively increas
`ing 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.
`0004 Antiviral therapy of chronic hepatitis C has
`evolved rapidly over the last decade, with Significant
`improvements Seen in the efficacy of treatment. Neverthe
`less, even with combination therapy using pegylated IFN-C.
`plus ribavirin, 40% to 50% of patients fail therapy. These
`patients are generally referred to as “treatment failure'
`patients, and include both non-responders (patients in whom
`Viral titer remains high even during therapy) and relapsers
`(patients in whom Viral titers drop initially during therapy,
`but Subsequently rise either during therapy or after treatment
`has ended). These patients currently have no effective thera
`peutic alternative. In particular, patients who have advanced
`fibrosis or cirrhosis on liver biopsy are at Significant risk of
`developing complications of advanced liver disease, includ
`ing ascites, jaundice, variceal bleeding, encephalopathy, and
`progressive liver failure, as well as a markedly increased risk
`of hepatocellular carcinoma.
`0005 Type I interferons are cytokines that exhibit both
`antiviral and antiproliferative activity. Type I interferons
`include interferon-C. (IFN-C) and interferon-B. IFN-O.
`includes naturally occurring IFN-O, and derivatives having
`the amino acid Sequence of a naturally occurring IFN-C,
`
`such as in PEGylated IFN-C. Naturally occurring IFN-C. that
`have been used in anti-viral therapies includes IFN-C2a,
`IFN-C2b. Derivatives of naturally occurring IFN-O, e.g.,
`PEGylated IFN-C.’s, have also been used in antiviral therapy.
`0006 Consensus IFN-C.’s (IFN-con; IFN alfacon; CIFN)
`are forms of non-naturally occurring type I IFN-C. Consen
`sus interferon alphas include IFN-con, IFN-con, and IFN
`cons. In vitro Studies comparing the relative antiviral, anti
`proliferative, and natural killer cell activities of recombinant
`CIFN with either leukocyte or other recombinant type-one
`interferons demonstrate that CIFN displays significantly
`higher activity when compared on a mass basis. Others have
`reported that CIFN, when used in the treatment of diseases
`Susceptible to treatment by alpha interferons, does not cause
`the same degree of Side effects in patients as do the alpha
`interferons. It has also been reported that 3 to 5 times higher
`doses of CIFN can be used, leading to enhanced therapeutic
`benefit, with Substantially no corresponding increase in the
`frequency or Severity of undesirable side effects. Some
`success has been reported in the use of CIFN monotherapy
`to treat patients that failed to respond to IFN-C therapy.
`0007 Even in view of the therapies currently available,
`there remains a need for improved therapies for treatment
`failure patients. The present invention addresses this need.
`0008 Literature
`0009 U.S. Pat. No. 5,980,884. U.S. Pat. No. 5,372,808.
`Aliaga, S. et al., Farmacia Clinica (Spain) 14(5):324-331
`(June 1997); Bailly, F. et al., Nephrol. Dial. Transplant.
`11(Suppl. 4):56-57 (1996); Bizollon, T. et al., Hepatol.
`26:500-504 (1997); Brillanti, S. et al., J. Hepatol.
`23(Suppl.2):13-16 (1995); Camps, J. et al., J. Hepatol.
`19:408-412 (1993); Davis et al., Hepatol. 26(Suppl.
`1): 122S-127S (September 1997); Davis, G. L., Gastroen
`terol. Clin. N. Amer. 23(3):603-613 (1994); Dusheiko, G. M.
`et al., Br. Med. J. 312:357-364 (1996); Fried, M. W., Med.
`Clin. N. Anmer. 80(5):957-972 (1996); Lindsay, K., Hepatol.
`26(Suppl. 1):71S-77S (September 1997); Mazzaferro, V. et
`al., Transplant. Proc. 29:519-521 (1997); McHutchison, J.,
`Hepatol. 26(2):505-506 (August 1997); Merican, M. I.,
`Med. J. Malaysia 47(3):158-169 (1992); Poupon, R. and
`Serfaty, L., Bull. Acad. Natle. Med. 180(6):1279-1289
`(1996); Reichard, O., Scand. J. Infect. Dis. (Suppl.95): 1-56
`(1994); Saracco, G. and Rizzetto, M., Drugs 53(1):74-85
`(1997); Schalm, S. W. and Brouwer, J. T., Scand. J. Gas
`troenterol. 223:46-49 (1997); Schalm, S. W. et al., Dig. Dis.
`Sci. 41(12): 131S-134S (December 1996); Scotto, G. et al.,
`Ital. J. Gastroenterol. 28:505-511 (1996); Scotto, G. et al.,
`J. Chemother. 7(1):58-61 (1995); Theodor, E. and Regev, A.,
`Harefuah 132(6):402-403,447 (1997); Thomas, H. C. et al.,
`Drugs 52(Suppl. 2):1-8 (1996); Tillmann, H. and Manns,
`M., Kidney Blood Press. Res. 19(3-4):215-219 (1996); Tong,
`M. et al., J. Gastroenterol. Hepatol. 9:587-591 (1994);
`Trepo, C. et al., Nephrol. Dial. Transplant. 11(Suppl. 4):62
`64 (1996); Weiss, R. and Oostrom-Ram, T., Vet. Microbiol.
`20:255-265 (1989); Chemello, L. et al., J. Hepatol.
`23(Suppl. 2):8-12 (1995); Main, J., J. Hepatol. 23(Suppl.
`2):32-36 (1995); Schalm, S. W. et al., J. Hepatol. 26:961
`966 (May 1997); Sherlock, S., J. Hepatol. 23(Suppl. 2):3-7
`(1995); Braconier, J. et al., Scand. J. Infect. Dis. 27:325-329
`(1995); Brillanti, S. et al., Gastroenterol. 107:812-817
`(1994); Chemello, L. et al., J. Hepatol. 21(Suppl. 1):s12
`Abstract No. GS 5/29 (1994); Cohen, J., Science 285:26-30
`
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`US 2005/0031585 A1
`
`Feb. 10, 2005
`
`(2 Jul. 1999); Lai, M-Y. et al., Gastroenterol. 111: 1307-1312
`(1996); McHutchison, J. G. et al., N. Eng. J. Med.
`339(21): 1485-1491 (1998); Poynard, T. et al., The Lancet
`352(9138): 1426-1432 (1998; Schvarez, R. et al., J. Hepatol.
`23(Suppl. 2):17-21 (1995); and Schvarcz, R. et al., J. Med.
`Virol. 46(1):43-47 (1995)
`0010 Melian and Plosker (2001) Drugs 61:1-31; Heath
`cote et al. (1998) Hepatol. 27:1136-1143; Heathcote et al.
`(1999) Hepatol. 30:562-566; Sjögren et al. (Apr. 30, 2000)
`35" Annual Meeting of the European Association for the
`Study of the Liver Rotterdam; Chow et al. (1998) Hepatol.
`27:1144-1148; Chemello et al. (1997) C. Gastroenterol.
`113:1654-1659; Davis et al. (1998) N. Engl. J. Med.
`339:1493-1499; Kaiser et al. (Apr. 20, 2001) 36" Annual
`Meeting of the European Association for the Study of the
`Liver, Prague; Sjögren (Apr. 20, 2001) 36" Annual Meeting
`of the European Association for the Study of the Liver,
`Prague.
`
`SUMMARY OF THE INVENTION
`0.011 The present invention provides methods for treat
`ing individuals having a hepatitis C virus (HCV) infection,
`which individuals have failed to respond to therapy with an
`IFN-C other than consensus interferon (CIFN), or who,
`following cessation of therapy with an IFN-O. other than
`CIFN, have suffered relapse. The methods generally involve
`a treatment regimen comprising administering a first dosing
`regimen of CIFN, followed by a second dosing regimen of
`CIFN. Ribavirin is administered with at least the second
`dosing regimen.
`0012. In one aspect, the invention features a method for
`treating a hepatitis C virus infection in an individual. The
`methods generally involve delivery of CIFN and ribavirin,
`where CIFN is administered in a therapeutic regimen com
`prising a first dosing regimen of CIFN, followed by a Second
`dosing regimen of CIFN, where the lowest average daily
`serum concentration of CIFN achieved by the first dosing
`regimen is greater than the highest average daily Serum
`concentration of CIFN achieved by the second dosing regi
`men. Ribavirin is administered during administration of at
`least the last dosing event of the Second dosing regimen, and
`may be administered with additional dosing events continu
`ous with the last dosing event during which ribavirin is
`administered. The individual treated has failed previous
`IFN-C-based therapy, e.g., the individual has either failed to
`respond to IFN-C therapy other than CIFN therapy, or,
`following cessation of IFN-C. therapy other than CIFN
`therapy, has Suffered a relapse.
`Definitions
`0013 The term “treatment failure patients” (or “treat
`ment 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 (e.g., in whom an initial viral
`response (IVR) was observed), but in whom the therapeutic
`response was not maintained (referred to as "relapsers”).
`The previous therapy generally can include treatment with
`IFN-O. monotherapy, or IFN-C combination therapy, where
`the IFN-C combination therapy may include administration
`of IFN-O. and an antiviral agent such as ribavirin.
`0014) The terms “non-CIFN IFN-C therapy,” and “IFN-O.
`therapy other than CIFN,” as used interchangeably herein in
`
`the context of previous IFN-C. therapy, refer to any IFN-C-
`based therapy, other than therapy that includes administra
`tion of CIFN, including IFN-O. monotherapy and IFN-C.
`combination therapy (e.g., IFN-O. and an antiviral Such as
`ribavirin).
`0.015 The terms “non-CIFN IFN-o” and “IFN-C other
`than CIFN,” used interchangeably herein, refer to IFN-C. that
`is not consensus CIFN and includes, but is not limited to,
`IFN-C2a, IFN-C2b; IFN-C2C, recombinant forms of natu
`rally-occurring IFN-C, mixtures of naturally occurring
`IFN-C. (e.g., IFN-On1 and IFN-On3); and derivatives, e.g.,
`PEGylated derivatives, of the foregoing. The term specifi
`cally excludes consensus IFN-O, as defined below.
`0016. The term “consensus IFN-O.” (used interchange
`ably herein with “CIFN" and “IFN-alpha con”), as used
`herein referS Specifically to a Synthetic interferons including
`IFN-con, IFN-con, IFN-con, and derivatives thereof, e.g.,
`PEGylated derivatives. PEGylated derivatives of CIFN can
`be produced according to methods in the art (See, e.g., U.S.
`Pat. Nos. 5,985,265; 5,382,657; 5,559,213; and 6,177,074).
`0017. The term “early viral response,” used interchange
`ably with “initial viral response” (“IVR”) refers to the drop
`in viral titer within about 24 hours, about 48 hours, about 2
`days, or about 1 week after the beginning of treatment for
`HCV infection.
`0.018. 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 patients
`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.
`0019 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 terms 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.
`0020. 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, with humans being of particular inter
`eSt.
`0021. 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,
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`Feb. 10, 2005
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`vary. It is also to be understood that the terminology used
`herein is for the purpose of describing particular embodi
`ments only, and is not intended to be limiting, Since the
`scope of the present invention will be limited only by the
`appended claims.
`0022. Where a range of values is provided, it is under
`stood 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.
`0023. Unless defined otherwise, all technical and scien
`tific 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 and 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 mate
`rials in connection with which the publications are cited.
`0024. 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 dose' includes
`a plurality of such doses and reference to “the method”
`includes reference to one or more methods and equivalents
`thereof known to those skilled in the art, and so forth.
`0.025 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 ante
`date such publication by virtue of prior invention. Further,
`the dates of publication provided may be different from the
`actual publication dates which may need to be independently
`confirmed.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`0026. The present invention provides methods of treating
`hepatitis C virus (HCV) infection in individuals having an
`HCV infection and have failed treatment, e.g., individuals
`who have failed to respond to IFN-O. therapy other than
`consensus interferon (CIFN) therapy; or who, during or
`following cessation of IFN-C. therapy other than CIFN
`therapy, have Suffered a relapse. The methods generally
`involve administration of CIFN and an antiviral agent such
`as ribavirin as follows: 1) administering a first dosing
`regimen of CIFN, optionally with a dosing regimen of
`ribavirin; 2) followed by a second dosing regimen of CIFN
`and a dosing regimen of ribavirin. The lowest average daily
`serum concentration of CIFN achieved by the first dosing
`regimen is higher than the highest average daily Serum
`concentration of CIFN achieved by the second dosing regi
`men. The first and Second dosing regimen of ribavirin may
`be the same or different.
`
`0027. The first dosing regimen of CIFN (also referred to
`as “the induction regimen”) generally involves administra
`tion of CIFN at about 9 tug, about 15 lug, about 18 lug, or
`about 27 lug. The first dosing regimen can encompass a
`Single dosing event, or at least two or more dosing events.
`0028. The first dosing regimen of CIFN can be adminis
`tered daily, every other day, three times a week, or Substan
`tially continuously So as to achieve a desired average daily
`serum concentration of CIFN.
`0029. The first dosing regimen of CIFN (which may be
`administered in combination with an antiviral Such as rib
`avirin) 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.
`0030) The first dosing regimen of CIFN (optionally
`administered with ribavirin) is effective to reduce viral titer
`to a low viral titer, e.g., a reduction of at least about 0.5 log,
`at least about 1.0 log, at least about 1.5 log, at least about 2.0
`log, at least about 2.5 log, at least about 3.0 log, at least
`about 3.5 log, at least about 4.0 log, at least about 4.5 log,
`or at least about 5 log, compared to the pre-treatment viral
`titer, is achieved by the end of the first dosing regimen.
`0031) The second dosing regimen of CIFN (also referred
`to as “the maintenance dose”) generally involves adminis
`tration of at least about 3 ug, at least about 9 ug, at least
`about 15 lug, or at least about 18 lug of CIFN. The second
`dosing regimen can encompass a Single dosing event, or at
`least two or more dosing events.
`0032. The second dosing regimen of CIFN can be admin
`istered daily, every other day, three times a week, or Sub
`Stantially continuously So as to achieve a desired average
`daily serum concentration of CIFN.
`0033. The second dosing regimen of CIFN (in combina
`tion with ribavirin) is effective to reduce viral titer still
`further, e.g., to undetectable levels, e.g., to from about 500
`genome copies per ml Serum, to less than or about 200
`genome copies per ml Serum, or to less than or about 100
`genome copies per ml Serum.
`0034. The second dosing regimen of CIFN is adminis
`tered for at least about 8 weeks, at least about 12 weeks, at
`least about 20 weeks, at least about 24 weeks, or at least
`about 48 weeks.
`0035) The treatment regimen described above (i.e., the
`first and Second dosing regimens) effects a durable response
`(also referred to as a “Sustained response'), e.g., no detect
`able HCV RNA is found in the patient's serum for a period
`of at least about one month, at least about two months, at
`least about three months, at least about four months, at least
`about five months, or at least about Six months following
`cessation of a treatment regimen as described herein.
`0036 CIFN is administered in combination with an anti
`Viral agent. The antiviral agent can be administered Simul
`taneously in Separate formulations, Simultaneously in the
`Same formulation; administered in Separate formulations
`and within about 48 hours, within about 36 hours, within
`about 24 hours, within about 16 hours, within about 12
`hours, within about 8 hours, within about 4 hours, within
`about 2 hours, within about 1 hour, within about 30 minutes,
`or within about 15 minutes or less. Where the CIFN and the
`antiviral agent are delivered as Separate formulations, the
`
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`Feb. 10, 2005
`
`CIFN and the antiviral agent may be delivered by the same
`or different routes. The antiviral agent may be delivered in
`the same or different dosing regimen as the CIFN.
`0037. In one embodiment, patients are treated with a
`combination of CIFN and ribavirin. Ribavirin, 1-3-D-ribo
`furanosyl-1H-1,2,4-triazole-3-carboxamide, available from
`ICN Pharmaceuticals, Inc., Costa Mesa, Calif., is described
`in the Merck Index, compound No. 8199, Eleventh Edition.
`Its manufacture and formulation is described in U.S. Pat.
`No. 4,211,771. The invention also contemplates use of
`derivatives of ribavirin (see, e.g., U.S. Pat. No. 6,277,830).
`The ribavirin may be administered orally in capsule or tablet
`form, or in the same or different administration form and in
`the same or different route as the CIFN. 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.
`0.038
`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.
`0039. In some embodiments, ribavirin is administered
`throughout the entire course of CIFN therapy. Ribavirin is
`administered with at least the last dosing regimen, and may
`be administered with the last dosing regimen and any
`additional dosing regimen within the treatment regimen
`continuous with the last dosing regimen. For example,
`where the treatment regimen includes four dosing events,
`ribavirin is administered with the fourth dose, and may
`optionally be administered with the third and fourth doses,
`the Second, third, and fourth doses, or with the first, Second,
`third and fourth doses.
`0040 Exemplary,
`non-limiting treatment regimens
`include the following.
`0041 Treatment Regimen 1A: 15 lug CIFN/day for eight
`weeks, followed by 9 tug CIFN/day for 16 weeks to 40
`weeks. Ribavirin is administered 1000-1200 mg per day
`throughout the treatment regimen.
`0.042 Treatment Regimen 1B: 15 lug CIFN/day for eight
`weeks, followed by 9 tug CIFN/day for 16 weeks to 40
`weeks. Ribavirin is administered 1000-1200 mg per day for
`the last 16-40 weeks.
`0.043 Treatment Regimen 2A: 15 lug CIFN/day for eight
`weeks, followed by 15ug CIFN three times per week (TIW)
`for 16-40 weeks. Ribavirin is administered 1000-1200 mg
`per day throughout the treatment regimen.
`0044) Treatment Regimen 2B: 15 lug CIFN/day for eight
`weeks, followed by 15ug CIFN three times per week (TIW)
`for 16-40 weeks. Ribavirin is administered 1000-1200 mg
`per day for the last 16-40 weeks.
`0045 Treatment Regimen 3A: 27 ug CIFN/day for four
`weeks, followed by 18 lug CIFN/day for eight weeks,
`followed by 9 tug CIFN day for 12 weeks, followed by 9 ug
`
`CIFN TIW for 24 weeks. Ribavirin is administered 1000
`1200 mg per day throughout the treatment regimen.
`0046 Treatment Regimen 3B: 27 ug CIFN/day for four
`weeks, followed by 18 lug CIFN/day for eight weeks,
`followed by 9 tug CIFN day for 12 weeks, followed by 9 ug
`CIFN TIW for 24 weeks Ribavirin is administered 1000
`1200 mg per clay beginning with the eight week course of
`18 tug CIFN/day and continued for the remainder of the
`treatment regimen.
`0047 Treatment Regimen 3C: 27 ug CIFN/day for four
`weeks, followed by 18 lug CIFN/day for eight weeks,
`followed by 9 tug CIFN/day for 12 weeks, followed by 9 ug
`CIFN TIW for 24 weeks Ribavirin is administered 1000
`1200 mg per day beginning with the 12 week course of 9 tug
`CIFN/day and continued for the remainder of the treatment
`regimen.
`0048 Treatment Regimen 3D: 27 ug CIFN/day for four
`weeks, followed by 18 lug CIFN/day for eight weeks,
`followed by 9 tug CIFN day for 12 weeks, followed by 9 ug
`CIFN TIW for 24 weeks Ribavirin is administered 1000
`1200 mg per day beginning with the 24 week course of 9 tug
`CIFN/TIW and continued for the remainder of the treatment
`regimen.
`0049 Treatment Regimen 4A: 18 lug CIFN/day for four
`weeks, followed by 9 tug CIFN/day for 20 weeks, followed
`by 9 tug CIFNTIW for 24 weeks. Ribavirin is administered
`1000-1200 mg per day throughout the treatment regimen.
`0050 Treatment Regimen 4B: 18 lug CIFN/day for four
`weeks, followed by 9 tug CIFN/day for 20 weeks, followed
`by 9 tug CIFNTIW for 24 weeks. Ribavirin is administered
`1000-1200 mg per day beginning with the 20 week course
`of 9 tug CIFN/day and continued throughout the treatment
`regimen.
`0051) Treatment Regimen 4C: 18 lug CIFN/day for four
`weeks, followed by 9 tug CIFN/day for 20 weeks, followed
`by 9 tug CIFNTIW for 24 weeks. Ribavirin is administered
`1000-1200 mg per day beginning with the 24 week course
`of 9 tug CIFNTIW and continued throughout the treatment
`regimen.
`0.052 Treatment Regimen 5A: 9 tug CIFN/day for 8-12
`weeks, followed by 9 tug CIFN three times a week for the
`balance of the treatment period (e.g., 36 to 40 weeks),
`wherein the treatment period is a total of 48 weeks. Ribavi
`rin is administered 1000-1200 mg per day throughout the
`treatment regimen.
`0053 Treatment Regimen 5B: 9 ug CIFN/day for 8-12
`weeks, followed by 9 ug CIFN three times a week (TIW) for
`the balance of the treatment period (e.g., 36 to 40 weeks),
`wherein the treatment period is a total of 48 weeks. Ribavi
`rin is administered 1000-1200 mg per day beginning with
`administration of the treatment course of 9 tug CIFN three
`times a week and continued throughout the remainder of the
`treatment regimen.
`0054 Guidance for dosage regimens is found in the art.
`See, e.g., Kaiser et al. (Apr. 20, 2001) 36" Annual Meeting
`of the European Association for the Study of the Liver,
`Prague; Sjögren (Apr. 20, 2001) 36" Annual Meeting of the
`European ASSociation for the Study of the Liver, Prague;
`Sjögren (Apr. 30, 2001) 35" Annual Meeting of the Euro
`
`

`

`US 2005/0031585 A1
`
`Feb. 10, 2005
`
`pean Association for the Study of the Liver, Rotterdam; and
`Balmon Melian and Plosker (2001) Drugs 61:1-31; and U.S.
`Pat. No. 5,980,884.
`0055) IFN-Alpha
`0056. The instant methods involve administering to a
`“treatment-failure' patient an amount of CIFN and ribavirin
`effective to reduce viral titer and to effect a Sustained viral
`response. Treatment failure patients include non-responders
`and relapsers who previously underwent treatment with
`IFN-O. other than CIFN. Such previous treatments include
`treatment with non-CIFN IFN-O. monotherapy, and non
`CIFN IFN-C combination therapy (e.g., non-CIFN IFN-O.
`plus ribavirin).
`0057 The term “non CIFN interferon-alpha” as used
`herein refers to IFN-C. proteins, other than CIFN, that inhibit
`Viral replication and cellular proliferation and modulate
`immune response. The term “non CIFN interferon-alpha”
`includes: (1) any naturally occurring IFN-C.; (2) recombi
`nant interferon alpha-2b Such as Intron-A interferon avail
`able from Schering Corporation, Kenilworth, N.J.; (3)
`recombinant interferon alpha-2a Such as Roferon interferon
`available from Hoffmann-La Roche, Nutley, N.J.; (4) recom
`binant interferon alpha-2C such as Berofor alpha 2 inter
`feron available from Boehringer Ingelheim Pharmaceutical,
`Inc., Ridgefield, Conn.; (5) interferon alpha-n1, a purified
`blend of natural alpha interferons Such as Sumiferon avail
`able from Sumitomo, Japan or as Wellferon interferon
`alpha-n1 (INS) available from the Glaxo-Wellcome Ltd.,
`London, Great Britain; (6) 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.
`0058. The term “non-CIFN IFN-O” also encompasses
`derivatives of non-CIFN IFN-C that are derivatized to alter
`certain properties Such as Serum half-life. AS Such, the term
`“non-CIFN IFN-O." includes glycosylated non-CIFN IFN-O;
`non-CIFN IFN-Cl derivatized with polyethylene glycol
`(“PEGylated IFN-C.”); and the like. PEGylated IFN-C, and
`methods for making Same, are discussed in, e.g., U.S. Pat.
`Nos. 5,382,657; 5,981,709; 5,824,784; 5,985,265; and
`5,951,974. PEGylated IFN-C encompasses conjugates of
`PEG and any of the above-described IFN-O. molecules,
`including, but not limited to, PEG conjugated to interferon
`alpha-2a (Roferon, Hoffman La-Roche, Nutley, N.J.), inter
`feron alpha 2b (Intron, Schering-Plough, Madison, N.J.),
`interferon alpha-2c (Berofor Alpha, Boehringer Ingelheim,
`Ingelheim, Germany).
`0059) The term “consensus IFN-C” (also referred to as
`“CIFN" and “IFN-con”) includes CIFN such as those
`described in U.S. Pat. Nos. 4,897,471 and 4,695,623 (e.g.,
`Examples 7, 8 or 9 thereof) and the specific product avail
`able from Amgen, Inc., (InfergenE), Amgen, Thousand Oaks,
`Calif.). The term encompasses but is not limited to the amino
`acid sequences designated IFN-con, IFN-con and IFN
`cons which are disclosed in U.S. Pat. Nos. 4,695,623 and
`4,897,471. DNA sequences encoding IFN-con can be syn
`thesized as described in the aforementioned patents or other
`Standard methods.
`0060 Additional Therapeutic Agents
`0061 CIFN therapy according to the invention can be
`carried out in conjunction with therapy for diseases and
`
`disorders other than HCV that an individual having an HCV
`may Suffer from. Such diseases include human immunode
`ficiency virus (HIV) infection; disorders include disorders
`associated with HIV infection, and include, but are not
`limited to, fungal infections, respiratory tract infections,
`infections of the eye, Kaposi's Sarcoma, and the like.
`0062 CIFN can be administered together with (i.e.,
`Simultaneously in Separate formulations, Simultaneously in
`the same formulation; administered in Separate formulations
`and within about 48 hours, within about 36 hours, within
`about 24 hours, within about 16 hours, within about 12
`hours, within about 8 hours, within about 4 hours, within
`about 2 hours, within about 1 hour, within about 30 minutes,
`or within about 15 minutes or less) one or more additional
`therapeutic agents. Therapeutic agents that can be adminis
`tered in combination therapy include, but are not limited to,
`anti-inflammatory, anti-Viral, anti-fungal, anti-mycobacte
`rial, antibiotic, amoebicidal, trichomonocidal, analgesic,
`anti-neoplastic, anti-hypertensives, anti-microbial and