Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-05-29
2003-07-22
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S046000, C514S047000, C514S048000, C514S049000, C514S050000, C514S894000
Reexamination Certificate
active
06596700
ABSTRACT:
FIELD OF THE INVENTION
This invention is in the area of methods and compositions for the treatment of a host infected with hepatitis delta virus (also referred to as “HDV”) that includes administering an effective amount of a defined &bgr;-L-2′-deoxy-nucleoside or a pharmaceutically acceptable salt or prodrug thereof.
BACKGROUND OF THE INVENTION
Type D hepatitis, the most severe form of viral hepatitis, is caused by infection with hepatitis D (delta) virus (HDV), a sub-viral satellite of hepatitis B virus (HBV) (Smedile, A. et al.
Prog Liver Dis
1994, 12, 157-75). Compared with other agents of viral hepatitis, acute HDV infection is more often associated with fulminant hepatitis, a rapidly progressive, often fatal form of the disease in which massive amounts of the liver are destroyed. Chronic type D hepatitis is typically characterized by necroinflammatory lesions, similar to chronic HBV infection, but is more severe, and frequently progresses rapidly to cirrhosis and liver failure, accounting for the disproportionate association of chronic HDV infection with terminal liver disease (Smedile, A. et al.
Prog Liver Dis
1994, 12, 157-75; Rizzetto, M. et al.
Ann Intern Med
1983, 98, 437-41). Although HDV infection affects fewer individuals than HBV alone, the resulting acute or chronic liver failure is a common indication for liver transplantation in Europe as well as North America (Smedile, A. and Rizzetto, M.
Int J Clin Lab Res
1992, 22, 211-215; Wright, T. L. and Pereira, B.
Liver Transplant Surgery
1995, 1, 30-42). Chronic disease affects 15 million persons worldwide, about 70,000 of whom are in the U.S. The Center for Disease Control estimates 1,000 deaths annually in the U.S. due to HDV infection (Alter, M. J. and Hadler, S. C.
Prog Clin Biol Res
1993, 382, 243-50; Alter, M. J. and Mast, E. E.
Gastroenterol Clin North Am
1994, 23, 437-55).
There is currently no generally accepted effective therapy for type D hepatitis, and liver transplantation is the only option for the associated end-stage liver disease. Although interferon alpha has been moderately successful in treating some cases of type D hepatitis, the need for better treatment options is indicated by the very high doses required, variable responses, frequent relapse after cessation of treatment, and difficulties in drug administration (Thomas, H. C. et al.
Prog Clin Biol Res
1987, 234, 277-90; Hoofnagle, J. et al.
Prog Clin Biol Res
1987, 234, 291-8; Rosina, F. et al.
Prog Clin Biol Res
1987, 234, 299-303; Rosina, F. et al.
Hepatology
1991, 13, 1052-6; Farci, P. et al.
N Engl J Med
1994, 330, 88-94; Hadziyannis, S. J.
J Hepatol
1991, 13(Suppl 1), S21-6; Di Marco, V. et al.
J Viral Hegat
1996, 3, 123-8; Porres, J. C. et al.
J Hepatol
1989, 9, 338-44).
The HDV virion is composed of a ribonucleoprotein core and an envelope. The core contains HDV-RNA, and hepatitis delta antigen (HDAg), which is the only protein encoded by this virus (Wang, K. S. et al.
Nature
1986, 323, 508-14). The envelope is formed by the surface antigen protein (hepatitis B surface antigen, or HBsAg) of the helper virus, hepatitis B (Bonino, F.
Infect Immun
1984, 43, 1000-5; Bonino, F. et al.
Hepatology
1981, 1, 127-31; Bonino, F. et al.
J Virol
1986, 58, 945-50). The envelope is the sole helper function provided by HBV. HDV is able to replicate its RNA within cells in the absence of HBV (Kuo, M. Y. et al.
J Virol
1989, 63, 1945-50), but requires HBsAg for packaging and release of HDV virions (Wu, J. C. et al.
J Virol
1991, 65, 1099-104; Ryu, W. S. et al.
J Virol
1992, 66, 2310-2315.), as well as for infectivity (Sureau, C., et al.
J Virol,
1992, 66, 1241-5). As a result of the dependence of HDV on HBV, HDV infects individuals only in association with HBV.
Lamivudine (&bgr;-L-2′,3′-dideoxy-3′-thiacytidine, 3TC) is a synthetic nucleoside shown to be effective in treating HIV and HBV infection. See U.S. Pat. No. 5,539,116 to Liotta et al. Lamivudine is known to cause sustained suppression of HBV replication during treatment (Nevens, F. et al.
Gastroenterology
1997, 113, 1258-1263). However, lamivudine does not improve disease activity or lower HDV-RNA levels in patients with chronic delta hepatitis (Lau, D. T. et al.
Hepatology
1999, 30, 546-9). Lamivudine was recently approved in the U.S. and several other countries for treatment of chronic HBV infection. Prolonged treatment of chronic HBV carriers with lamivudine leads to decreased levels of HBV in serum and improved liver histology (Lai, C. L. et al.
N Engl J Med
1998, 339, 61-8; Tyrrell, D. et al.
Hepatology
1993, 18, 112A; Nevens, F. et al.
Gastroenterology
1997, 113, 1258-63; Dienstag, J. L. et al.
N Engl J Med
1995, 333, 1657-61). Despite the dramatic effects on HBV, lamivudine treatment of patients chronically infected with both HBV and HDV has little effect on circulating levels of HDV; more importantly, there is no improvement in disease activity even though HBV levels are suppressed (Honkoop, P. et al.
Hepatology
1997
,
24
(Suppl), 1219 (Abstract); Lau, D. T. et al.
Hepatology
1999, 30, 546-9).
Additional forms of treatment have been tried. For example, suramin in vitro blocks the entry of the virion into hepatocytes, but it is too toxic to be acceptable for long term use in humans (Smedile, A. et al.
Prog Liver Dis
1994, 12, 157-75). Acyclovir enhances HDV replication in vitro (Smedile, A. et al.
Prog Liver Dis
1994, 12, 157-75). Ribavirin did not significantly affect virological or biochemical parameters and had severe side-effects (Smedile, A. et al.
Prog Liver Dis
1994, 12, 157-75). Synthetic analogs of thymosin have also been ineffective in the treatment of HDV infection (Smedile, A. et al.
Prog Liver Dis
1994, 12, 157-75).
None of the described treatments for HDV infection are generally accepted as effective.
Because the woodchuck hepatitis virus (WHV) is closely related to HBV (ca. 85% nucleic acid homology), it has been widely used as a model for HBV infection and disease in its natural host, the eastern woodchuck (
M. monax
) (Gerin, J. L.
Gastroenterol Jpn
1990, 25, Supp, 38-42; Tennant, B. C. et al.
Viral Hepatitis and Liver Disease
1988, 462-464). Experimentally infected woodchucks have also been used extensively for analysis and development of anti-HBV therapeutics (Zahm, F. E. et al.
Ital J Gastroenterol Hepatol
1998, 30, 510-6; Tennant, B. C. et al.
Hepatology
1998, 28, 179-91; Mason, W. S. et al.
Virology
1998, 245, 18-32; Korba, B. E. et al.
Hepatology
1996, 23, 958-63; Hurwitz, S. et al.
Antimicrob Agents Chemother
1998, 42, 2804-2809; Block, T. M. et al.
Nat Med
1998, 4, 610-4; Cullen, J. M. et al.
Antimicrob Agents Chemother
1997, 41, 2076-82; Fourel, G. et al.
Nature
1990, 347, 294-8; Gangemi, J. et al.
Antivir Therap
1997, 1, 64-70; Genovesi, E. V. et al.
Antimicrob Agents Chemother
1998, 42, 3209-17; Korba, B. E. et al.
Antiviral Res
2000, 45, 19-32; Cote, P. J. et al.
Hepatology
2000, 31, 190-200; Korba, B. E. et al.
Antiviral Therapy
2000, 5(2), 95-104; Korba, B. E. et al.
Antimicrobial Agents and Chemotherapy
2000, 44(6), 1757-60; Korba, B. E. et al.
Antimicrobial Agents and Chemotherapy
2000, 44(7), 1964-1969). The efficacy of several anti-HBV agents used to experimentally treat chronic WHV infection in woodchucks (araAMP, ribavirin, AZT, ACV, 3TC, famciclovir, FTC) has accurately paralleled the efficacy of these agents administered to HBV patients treated in the course of clinical trials. The similar efficacy observed in WHV infected woodchucks and HBV infected persons treated with anti-HBV agents demonstrates that the woodchuck animal model can be predictive for anti-HBV therapies in man (Zahm, F. E. et al.
Ital J Gastroenterol Hepatol
1998, 30, 510-6; Tennant, B. C. et al.
Hepatology
1998, 28, 179-91; Mason, W. S. et al.
Virology
1998, 245, 18-32; Hurwitz, S. J. et al.
Antimicrob Agents Chemother
1998, 42(11), 2804-2809; Fourel, G. et al.
Nature
1990, 347, 294-8; Gangemi, J. et al.
Antivir Therap
1997, 1, 64-70; Genovesi,
Bryant Martin L.
Sommadossi Jean-Pierre
Idenix Pharmaceuticals Inc.
King & Spalding
Knowles Sherry M.
Lewis Patrick
Wilson James O.
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