Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-02
2003-03-04
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S264110, C514S263370, C514S262100, C514S261100
Reexamination Certificate
active
06528515
ABSTRACT:
This invention is in the area of methods for the treatment of hepatitis B virus (also referred to as “HBV”) that includes administering to a host in need thereof, an effective combination of nucleosides which have known anti-hepatitis B activity.
HBV is second only to tobacco as a cause of human cancer. The mechanism by which HBV induces cancer is unknown, although it is postulated that it may directly trigger tumor development, or indirectly trigger tumor development through chronic inflammation, cirrhosis, and cell regeneration associated with the infection.
Hepatitis B virus has reached epidemic levels worldwide. After a two to three month incubation period in which the host is unaware of the infection, HBV infection can lead to acute hepatitis and liver damage, that causes abdominal pain, jaundice, and elevated blood levels of certain enzymes. HBV can cause fulminant hepatitis, a rapidly progressive, often fatal form of the disease in which massive sections of the liver are destroyed.
Patients typically recover from acute hepatitis. In some patients, however, high levels of viral antigen persist in the blood for an extended, or indefinite, period, causing a chronic infection. Chronic infections can lead to chronic persistent hepatitis. Patients infected with chronic persistent HBV are most common in developing countries. By mid-1991, there were approximately 225 million chronic carriers of HBV in Asia alone, and worldwide, almost 300 million carriers. Chronic persistent hepatitis can cause fatigue, cirrhosis of the liver, and hepatocellular carcinoma, a primary liver cancer.
In western industrialized countries, high risk groups for HBV infection include those in contact with HBV carriers or their blood samples. The epidemiology of HBV is very similar to that of acquired immune deficiency syndrome (AIDS), which accounts for why HBV infection is common among patients with AIDS or AIDS related complex. However, HBV is more contagious than HIV.
However, more recently, vaccines have also been produced through genetic engineering and are currently used widely. Unfortunately, vaccines cannot help those already infected with HBV. Daily treatments with &agr;-interferon, a genetically engineered protein, has also shown promise, but this therapy is only successful in about one third of treated patients. Further, interferon cannot be given orally.
A number of synthetic nucleosides have been identified which exhibit activity against HBV. The (−)-enantiomer of BCH-189, known as 3TC, claimed in U.S. Pat. No. 5,539,116 to Liotta, et al., has been approved by the U.S. Food and Drug Administration for the treatment of hepatitis B. See also EPA 0 494 119 A1 filed by BioChem Pharma, Inc.
&bgr;2-Hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (“FTC”), claimed in U.S. Pat. Nos. 5,814,639 and 5,914,331 to Liotta, et al., exhibits activity against HBV. See Furman, et al., “The Anti-Hepatitis B Virus Activities, Cytotoxicities, and Anabolic Profiles of the (−) and (+) Enantiomers of cis-5-Fluoro-1-[2-(Hydroxymethyl)-1,3-oxathiolane-5-yl]Cytosine”
Antimicrobial Agents and Chemotherapy
, December 1992, page 2686-2692; and Cheng, et al.,
Journal of Biological Chemistry
, Volume 267(20), 13938-13942 (1992).
U.S. Pat. Nos. 5,565,438, 5,567,688 and 5,587,362 (Chu, et al.) disclose the use of 2′-fluoro-5-methyl-&bgr;-L-arabinofuranolyluridine (L-FMAU) for the treatment of hepatitis B and Epstein Barr virus.
U.S. Pat. No. 5,767,122 to Emory University and The University of Georgia Research Foundation, Inc. discloses and claims enantiomerically pure &bgr;-D-dioxolanyl nucleosides of the formula:
wherein R is NH
2
, OH, Cl, or H. A method for treating HBV infection using a combination of DAPD and FTC is claimed in U.S. Pat. No. 5,684,010 to Raymond F. Schinazi.
Penciclovir (2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)butyl]-6H-purin-6-one; PCV) has established activity against hepatitis B. See U.S. Pat. Nos. 5,075,445 and 5,684,153.
Adefovir (9-[2-(phosphonomethoxy)ethyl]adenine, also referred to as PMEA or [[2(6-amino-9H-purin-9-yl)ethoxy]methylphosphonic acid), also has established activity against hepatitis B. See for example U.S. Pat. Nos. 5,641,763 and 5,142,051.
Yale University and The University of Georgia Research Foundation, Inc. disclose the use of L-FDDC (5-fluoro-3′-thia-2′,3′-dideoxycytidine) for the treatment of hepatitis B virus in WO 92/18517.
von Janta-Lipinski et al. disclose the use of the L-enantiomers of 3′-fluoro-modified &bgr;-2′-deoxyribonucleoside 5′-triphosphates for the inhibition of hepatitis B polymerases (J. Med. Chem., 1998, 41,2040-2046). Specifically, the 5′-triphosphates of 3′-deoxy-3′-fluoro-&bgr;-L-thymidine (&bgr;-L-FTTP), 2′,3′-dideoxy-3′-fluoro-&bgr;-L-cytidine (&bgr;-L-FdCTP), and 2′,3′-dideoxy-3′-fluoro-&bgr;-L-5-methylcytidine (&bgr;-L-FMethCTP) were disclosed as effective inhibitors of HBV DNA polymerases.
It has been recognized that drug-resistant variants of HBV can emerge after prolonged treatment with an antiviral agent. Drug resistance most typically occurs by mutation of a gene that encodes for an enzyme used in the viral lifecycle, and most typically in the case of HBV, DNA polymerase. Recently, it has been demonstrated that the efficacy of a drug against HBV infection can be augmented by administering the compound in combination with a second, and perhaps third, antiviral compound that induces a different mutation from that caused by the principle drug. Alternatively, the pharmacokinetics, biodistribution, or other parameter of the drug can be altered by such combination therapy. In general, combination therapy induces multiple simultaneous stresses on the virus.
United U.S. Pat. No. 5,808,040 discloses that L-FMAU can be administered in combination with FTC, 3TC, carbovir, acyclovir, interferon, AZT, DDI (2′,3′-dideoxyinosine), DDC (2′,3′-dideoxycytidine), L-DDC, L-F-DDC, and D4T.
United U.S. Pat. No. 5,674,849 discloses the use of a nucleoside in combination with an oligonucleotide for the treatment of a viral disease.
U.S. Pat. No. 5,684,010 discloses a method for the treatment of hepatitis B that includes administering in combination or alternation a compound of the formula:
wherein R is NH
2
, OH, or Cl, with FTC, 3TC, carbovir, or interferon.
WO 98/23285 discloses a method for the treatment or prophylaxis of hepatitis B virus infections in a human or animal patient which comprises administering to the patient effective or prophylactic amounts of penciclovir (or a bioprecursor thereof such as famciclovir) and alpha-interferon.
In light of the fact that hepatitis B virus has reached epidemic levels worldwide, and has severe and often tragic effects on the infected patient, there remains a strong need to provide new effective treatments for humans infected with the virus that have low toxicity to the host.
Therefore, it is an object of the present invention to provide new methods for the treatment of human patients or other hosts infected with hepatitis B virus and related conditions comprising administering a synergistically effective amount of a combination of anti-HBV agents.
SUMMARY OF THE INVENTION
It has been discovered that certain combinations of agents with hepatitis B activity are synergistic, and thus can provide enhanced benefits to the patient when administered in an effective combination or alternation dosage pattern.
In one preferred embodiment of the present invention, a method for treating HBV infection and related conditions in humans is disclosed, comprising administering a synergistically effective amount of &bgr;-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC), preferably substantially in the form of the (−)-optical isomer, or a pharmaceutically acceptable salt, ester or prodrug thereof with Penciclovir (2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)butyl]-6H-purin-6-one, also referred to as “PCV”). Fam
Barry David W.
Furman Phillip A.
Painter, III George R.
Rousseau Franck
King & Spalding LLP
Knowles, Esq. Sherry M.
Sullivan, Esq. Clark G.
Travers Russell
Triangle Pharmaceuticals, Inc.
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