Drug – bio-affecting and body treating compositions – Lymphokine – Interleukin
Reexamination Certificate
1999-12-20
2004-02-03
Spector, Lorraine (Department: 1647)
Drug, bio-affecting and body treating compositions
Lymphokine
Interleukin
C424S085700, C424S149100, C424S189100, C514S002600, C514S008100, C514S012200, C514S893000, C514S894000
Reexamination Certificate
active
06685931
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention is directed to the use of interleukin-10 to improve liver histology in patients afflicted with chronic hepatitis C virus infections. In particular, the invention relates to the use of interleukin-10 to reduce hepatic fibrosis in difficult-to-treat patients afflicted with chronic hepatitis C virus infections.
Chronic hepatitis C is an insidious and slowly progressive disease having a significant impact on morbidity and mortality. While many patients who contract hepatitis C will have subclinical or mild disease, HCV infection causes progressive liver damage in the majority of those infected. At least 80% of the individuals who contract HCV will develop chronic infection and hepatitis, a disease state characterized by fluctuating serum transaminase abnormalities and inflammatory with or without fibrosis lesions on liver biopsy. Twenty to fifty percent of these will eventually progress to cirrhosis and 1-2% will develop liver cancer after a 10-20 year period.
Multiple factors influence the hepatitis C virus-host interaction resulting in a unique individual disease pattern. In individuals chronically infected with HCV, there is persistent viremia and liver damage despite the presence of both humoral and cellular responses. The mechanisms responsible for hepatocellular injury are not fully understood. The role of IL-10 in inhibiting liver fibrogenesis has been evaluated in the mouse. Two studies (Louis et al., Heptatology, 1998;28:1607-1615; and Thompson et al., Heptatology, 1998;28:1597-1606) showed that IL-10 knock-out mice develop significantly more severe fibrosis than wild-type mice.
At the present time, the interferon-&agr;-2b/ribavirin combination therapy is the best available treatment option. Sustained virologic response to IFN&agr;-ribavirin combination therapy occurs in about 40-45% of those treated. For those patients who fail interferon-&agr;-2b/ribavirin combination therapy, there is currently no alternative to prevent the progression of liver disease. Thus, a need exists for alternative therapies for the treatment of chronic HCV infection.
SUMMARY OF THE INVENTION
The present invention fulfills this need by providing materials and methods for treating hepatitis C virus infection and liver damage in difficult-to-treat patients.
One aspect of the invention provides a method for improving liver histology in a difficult-to-treat patient afflicted with a chronic hepatitis C virus infection comprising administering an effective amount of an interleukin-10 to such a patient.
Another aspect of the invention provides a method of treating or preventing hepatitis C virus infection in a difficult-to-treat patient afflicted with a chronic hepatitis C virus infection comprising administering an effective amount of an interleukin-10 in association with an effective amount of an an effective amount of an interferon-&agr; to a patient in need of such treating or preventing
Yet another aspect of the invention provides a method of decreasing or preventing liver damage (e.g. fibrosis or cirrhosis) caused by hepatitis C virus in a difficult-to-treat patient afflicted with a chronic hepatitis C virus infection comprising administering an effective amount of interleukin-10 to such a patient to decrease or prevent liver damage (e.g. fibrosis or cirrhosis) caused by the hepatitis C virus.
Still another aspect of the invention provides a method for treating and/or preventing hepatic fibrosis in a difficult-to-treat patient afflicted with a chronic hepatitis C virus infection comprising administering an effective amount of an interleukin-10 to such a patient.
In preferred embodiments of the present invention, there are provided pharmaceutical compositions for treating hepatitis C virus infection in a mammal comprising an effective amount of interleukin-10 and a pharmaceutically acceptable carrier. Optionally, the pharmaceutical composition of the invention may contain at least one other any-viral agent, such as, for example interferon-&agr; and/or ribavirin. In another preferred embodiment of the present invention, the interferon-&agr; is recombinant interferon-&agr;-2b or pegylated interferon-&agr;-2b and the interleukin-10 is recombinant human interleukin-10.
DETAILED DESCRIPTION OF THE INVENTION
The phrase “a difficult-to-treat patient afflicted with chronic hepatitis C virus infection” as used herein means a patient afflicted with chronic hepatitis C virus(“HCV”) infection who has failed to achieve a sustained virologic response after treatment with any type of anti-HCV therapy including, but not limited to, interferon-&agr;, or pegylated interferon-&agr;, alone or in combination with ribavirin, or a non-responder patient to any such anti-HCV therapy as well as a treatment naive patient afflicted with chronic HCV infection with HCV genotype 1A or 1B or a treatment naive patient infected with multiple HCV genotypes including type 1. who has never taken any anti-HCV therapy.
The term “treatment naive patients” afflicted with chronic HCV infection as used herein means patients with HCV who have never been treated with ribavirin or any interferon, including, but not limited to, interferon-&agr; or pegylated interferon-&agr;, alone or in combination with ribavirin.
The term “sustained virologic response” as used herein in reference to difficult-to-treat patients afflicted with chronic HCV infection means there is no detectable HCV-RNA in the serum of patients treated with interferon-&agr;, pegylated interferon-&agr; alone or in combination with ribavirin for at least 24-48 weeks after the end of the combined therapy treatment.
The term “no detectable HCV-RNA” as used herein means that there are fewer than 100 copies/mL of HCV-RNA in the serum as measured by quantative PCR(“qPCR”) testing.
The term “liver histology” as used herein means the minute structure, composition and function of the liver as determined by examination of liver biopsy samples for inter alia, portal inflamrnmation, piecemeal or bridging necrosis, lobular injury, cirrohosis and fibrosis. Evaluation of the biopsies may be performed by a pathologist using the Knodell Histology Activity Score, or the modified Knodell Score (Ishak et al.,J. Hepatol, 1995;22:696-699), or the Metavir scoring system (Bedossa et al., Hepatology,1996;24:289-293). Efficacy of study treatments was assessed by comparing the liver histology, especially the degree of fibrosis and/or inflammatory activity observed at Baseline with that present at the end of treatment in accordance with the present invention.
Elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are known to occur in uncontrolled hepatitis C. A complete response to treatment is generally defined as the normalization of these serum enzymes, particularly ALT (Davis et al., 1989
, New Eng. J. Med
. 321:1501-1506). Interleukin-10 (IL-10) has now been surprisingly found to be effective in normalizing ALT and in reducing hepatic fibrosis.
IL-10 administered as monotherapy in accordance with the present invention has been found not only to reduce hepatic fibrosis, but also to suppress host-mediated immunopathology, a component contributing to the chronic liver damage associated with HCV infection., even though IL-10 monotherapy does not lower or eradicate serum HCV-RNA levels Thus, IL-10 can be used in accordance with the present invention to improve liver function and to modulate the inflammatory response and the fibrosis process responsible for much of the destruction of the liver of difficult-to-treat patients afflicted with chronic HCV infection.
IL-10, as defined herein, include proteins which have an amino acid sequence substantially identical to a known sequence of a mature (i.e., lacking a secretory leader sequence) IL-10 disclosed in U.S. Pat. No. 5,231,012, and has biological activity that is common to native IL-10. For the purposes of this invention, both glycosylated (e.g., produced in eukaryotic cells such as yeast or CHO cells) and unglycosylated (e.g., chemically synthesized or produced in
E. coli
) IL-10 are eq
Davis Gary L.
Grint Paul C.
Nelson David R.
Hoffman Thomas D.
Schering Corporation
Seharaseyon Jegatheesan
Spector Lorraine
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