Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2001-03-29
2003-12-30
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S088000, C514S274000, C544S309000
Reexamination Certificate
active
06670342
ABSTRACT:
FIELD OF 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 compound, in particular a nucleoside or nucleoside analog, that substantially reduces the level of hepatitis B surface antigen. In one nonlimiting embodiment, the nucleoside analog is 2′-fluoro-5-methyl-&bgr;-L-arabinofuranosyl-uridine (also referred to as “L-FMAU”) 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. (1994)
Prog Liver Dis
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. (1994)
Prog Liver Dis
12, 157-75; Rizzetto, M., et al. (1983)
Ann Intern Med
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. & Rizzetto, M. (1992)
Int J Clin Lab Res
22, 211-215; Wright, T. L. & Pereira, B. (1995)
Liver Transplant Surgery
1, 30-42). Chronic disease affects 15 million persons worldwide, about 70,000 of whom are in the U.S. The Centers for Disease Control estimates 1,000 deaths annually in the U.S. due to HDV infection (Alter, M. J. & Hadler, S. C. (1993)
Prog Clin Biol Res
382, 243-50; Alter, M. J. & Mast, E. E. (1994)
Gastroenterol Clin North Am
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. (1987)
Prog Clin Biol Res
234, 277-90; Hoofnagle, J. et al. (1987)
Prog Clin Biol Res
234, 291-8; Rosina, F. et al. (1987)
Prog Clin Biol Res
234, 299-303; Rosina, F. et al. (1991)
Hepatology
13, 1052-6; Farci, P. et al. (1994)
N Engl J Med
330, 88-94; Hadziyannis, S. J. (1991)
J. Hepatol
13 Suppl 1:S21-6; Di Marco, V. et al. (1996)
J Viral Hepat
3, 123-8; Porres, J. C. et al. (1989)
J Hepatol
9, 338-44).
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. (1997)
Gastroenterology
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. (1999)
Hepatology
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. (1998)
N Engl J Med
339, 61-8; Tyrrell, D. et al. (1993)
Hepatology
18, 112A; Nevens, F. et al. (1997)
Gastroenterology
113, 1258-63; Dienstag, J. L. et al. (1995)
N Engl J Med
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. (1997)
Hepatology
24 (Suppl), 1219 (Abstract); Lau, D. T. et al. (1999)
Hepatology
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. (1994)
Prog Liver Dis
12, 157-75). Acyclovir enhances HDV replication in vitro (Smedile, A., et al. (1994)
Prog Liver Dis
12, 157-75). Ribavirin did not significantly affect virological or biochemical parameters and had severe side-effects (Smedile, A., et al. (1994)
Prog Liver Dis
12, 157-75). Synthetic analogs of thymosin have also been ineffective in the treatment of HDV infection (Smedile, A. et al. (1994)
Prog Liver Dis
12, 157-75).
None of the described treatments for HDV infection are generally accepted as effective. 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. (1986)
Nature
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. (1984)
Infect Immun
43, 1000-5; Bonino, F. et al. (1981)
Hepatology
1, 127-31; Bonino, F. et al. (1986)
J Virol
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. (1989)
J Virol
63, 1945-50), but requires HBsAg for packaging and release of HDV virions (Wu, J. C. et al. (1991)
J Virol
65, 1099-104; Ryu, W. S. et al. (1992)
J Virol
66, 2310-2315.), as well as for infectivity (Sureau, C., et al. (1992)
J Virol
66, 1241-5). As a result of the dependence of HDV on HBV, HDV infects individuals only in association with HBV.
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. (1990)
Gastroenterol Jpn
25 (Supp), 38-42; Tennant, B. C. et al. (1988)
Viral Hepatitis and Liver Disease
, 462-464). Experimentally infected woodchucks have also been used extensively for analysis and development of anti-HBV therapeutics. (Zahm, F. E. et al. (1998)
Ital J Gastroenterol Hepatol
30, 510-6; Tennant, B. C. et al. (1998)
Hepatology
28, 179-91; Mason, W. S. et al. (1998)
Virology
245, 18-32; Korba, B. E. et al. (1996)
Hepatology
23, 958-63; Hurwitz, S. et al. (1998)
Antimicrob Agents Chemother
42, 2804-2809; Block, T. M. et al. (1998)
Nat Med
4, 610-4; Cullen, J. M. et al. (1997)
Antimicrob Agents Chemother
41, 2076-82; Fourel, G. et al. (1990)
Nature
347, 294-8; Gangemi, J. et al. (1997)
Antivir Therap
1, 64-70; Genovesi, E. V. et al. (1998)
Antimicrob Agents Chemother
42, 3209-17; Korba, B. E. et al. (2000)
Antiviral Res
45, 19-32; Korba, B. E. et al. (2000)
Antiviral Therapy
55, 95-105; Korba, B. E. et al. (2000)
Antimicrobial Agents and Chemotherapy
44, 19-32. The efficacy of several anti-HBV agents used to experimentally treat chronic WHV infection in woodchucks (araAMP, ribavirin, AZT, ACV, 3TC, famciclovir, FTC, alpha-interferon, fialuridine ganciclovir, thymosin alpha-1, combination therapy with 3TC and alpha-interferon or 3TC and famciclovir) has accurately paralleled the efficacy and_toxicity profiles 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. (1998)
Ital J Gastroenterol Hepatol
30, 510-
Casey John L.
Chu Chung K.
Cote Paul J.
Gerin John L.
Korba Brent E.
Bennett-Paris Joseph M.
Georgetown University
King & Spalding
Knowles Sherry M.
McKenzie Thomas
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