HBV ANTISENSE INHIBITORS

• US 20120207709A1
• Filed: 10/15/2010
• Published: 08/16/2012
• Est. Priority Date: 10/16/2009
• Status: Active Grant

• Current Assignee: Glaxo Group Limited (GSK plc)
• Original Assignee: Glaxo Group Limited (GSK plc)
• Inventors: Hamatake, Robert K.
• Granted Patent: US 8,598,334 B2
• Time in Patent Office: Days
• US Class Current: 424/85.7
• CPC Class Codes: A61K 31/7115 Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
• CPC Class Codes: A61K 31/7125 Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Antisense oligomers useful for modulating hepatitis B virus infections, and for the treatment of hepatitis B virus (HBV) and hepatitis B virus-related conditions in animals including humans. More particularly, antisense oligomers with modified nucleotides for treatment of HBV in animals, more particularly antisense oligomers comprising 2′O-4′C-methylene-bridged sugars, or nucleotides with other 2′O-4′C bridged sugars, also known as locked nucleic acids (LNA), for treatment of HBV in animals, and more particularly for treatment of HBV in humans.

Claims

1. An antisense compound comprising a modified antisense oligonucleotide wherein nucleotides in the oligonucleotide are connected by internucleotide linkages having a nucleobase sequence of nucleotides of any of SEQ ID NOs:

14-22,

or a salt, solvate, hydrate or ester thereof.

2. An antisense compound according to claim 1 comprising at least one nucleotide having a modified sugar.

3. An antisense compound according to claim 2 wherein the modified sugar is a LNA having a chemical link between a 2′

- and 4′

-atom of the nucleotide sugar.

4. An antisense compound according to claim 1 wherein the internucleotide linkages are selected from the group consisting of a phosphodiester, phosphotriester, phosphorothioate, phosphorodithioate, H-phosphonate, or alkylphosphonate linkage.

5. An antisense compound according to claim 3, wherein the chemical link is a 2′

O-alkyl-4′

C chemical link and wherein the alkyl is optionally substituted or non-substituted.

6. An antisense compound according to claim 1, wherein the antisense oligomer comprises a sequence that is further selected from any one of SEQ ID NOs 14, 16, 17 or 20.

13. A pharmaceutical formulation for treating hepatitis B virus infection in a mammal comprising an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, solvate, hydrate or ester thereof, and a pharmaceutically acceptable diluent.

16. A method for treating a mammal having a hepatitis B virus infection or a hepatitis B virus-related condition, the method comprising administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need thereof so as to treat the hepatitis B virus infection, or the hepatitis B virus-related condition.

17. A method according to claim 16, wherein the mammal is a human, wherein the hepatitis B virus infection or the hepatitis B virus-related condition is a hepatitis B virus infection from a human hepatitis B virus.

18. A method for treating a mammal having a hepatitis B virus infection according to claim 16, wherein the human hepatitis B virus is selected from any of the human geographical genotypes:

A (Northwest Europe, North America, Central America);

B (Indonesia, China, Vietnam);

C (East Asia, Korea, China, Japan, Polynesia, Vietnam);

D (Mediterranean area, Middle East, India);

E (Africa);

F (Native Americans, Polynesia);

G (United States, France);

or H (Central America).

19. A method according to claim 16, wherein the mammal is a human, and wherein the hepatitis B virus infection or the hepatitis B virus-related condition is a human hepatitis B virus-related condition.

20. A method according to claim 17, wherein the human hepatitis B virus-related condition is selected from any of:

jaundice, liver cancer, liver inflammation, liver fibrosis, liver cirrhosis, liver failure, diffuse hepatocellular inflammatory disease, hemophagocytic syndrome or serum hepatitis.

21. A method according to claim 16, further comprising administering the compound in combination with an additional therapeutic agent, wherein the antisense oligomer and the additional therapeutic agent are administered either together in a single formulation, or administered in separately in different formulations, and wherein the administration of the nucleic acid oligomer and the second therapeutic agent is done concomitantly, or in series.

22. A method according to claim 21, wherein the additional therapeutic agent is selected from an HBV agent, an HCV agent, a chemotherapeutic agent, an antibiotic, an analgesic, a non-steroidal anti-inflammatory (NSAID) agent, an antifungal agent, an antiparasitic agent, an anti-nausea agent, an anti-diarrheal agent, and an immunosuppressant agent.

23. A method according to claim 22, wherein the additional HBV agent is selected from interferon alpha-2b, interferon alpha-2a, and interferon alphacon-1 (pegylated and unpegylated), ribavirin;

an HBV RNA replication inhibitor;

a second antisense oligomer;

an HBV therapeutic vaccine;

an HBV prophylactic vaccine;

lamivudine (3TC);

entecavir;

tenofovir;

telbivudine (LdT);

adefovir; and

an HBV antibody therapy (monoclonal or polyclonal)

24. A method according to claim 22, wherein the additional HCV agent is selected from interferon alpha-2b, interferon alpha-2a, and interferon alphacon-1 (pegylated and unpegylated);

ribavirin;

an HCV RNA replication inhibitor;

an HCV antisense agent;

an HCV therapeutic vaccine;

an HCV protease inhibitor;

an HCV helicase inhibitor; and

an HCV monoclonal or polyclonal antibody therapy.

25. A method for reducing a presence of HBV antigen in a mammal infected with a hepatitis B virus, the method comprising administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need thereof so as to reduce the hepatitis B antigen, compared to the presence of HBV antigen in the mammal before treatment.

26. A method according to claim 25, wherein the mammal is a human, and wherein the hepatitis B virus is a human hepatitis B virus.

27. A method according to claim 25, wherein the human hepatitis B virus is selected from any of the human geographical genotypes:

A (Northwest Europe, North America, Central America);

B (Indonesia, China, Vietnam);

C (East Asia, Korea, China, Japan, Polynesia, Vietnam);

D (Mediterranean area, Middle East, India);

E (Africa);

F (Native Americans, Polynesia);

G (United States, France);

or H (Central America).

29. A method according to claim 25, wherein the HBV antigen is HBsAg.

30. A method according to claim 25, wherein the HBV antigen is HBeAg.

31. A method according to claim 25, wherein the presence of HBV antigen is sufficiently reduced to result in seroconversion, defined as serum HBeAg absence plus serum HBeAb presence if monitoring HBeAg as the determinant for seroconversion, or defined as serum HBsAg absence if monitoring HBsAg as the determinant for seroconversion, as determined by currently available detection limits of commercial ELISA systems.

32. A method according to claim 25, further comprising administering the compound in combination with an additional therapeutic agent, wherein the antisense oligomer and the additional therapeutic agent are administered either together in a single formulation, or administered in separately in different formulations, and wherein the administration of the nucleic acid oligomer and the second therapeutic agent is done concomitantly, or in series.

34. A method according to claim 29, wherein the additional HBV agent is selected from interferon alpha-2b, interferon alpha-2a, and interferon alphacon-1 (pegylated and unpegylated), ribavirin;

an HBV RNA replication inhibitor;

a second antisense oligomer;

an HBV therapeutic vaccine;

an HBV prophylactic vaccine;

lamivudine (3TC);

entecavir;

tenofovir;

telbivudine (LdT);

adefovir; and

an HBV antibody therapy (monoclonal or polyclonal).

35. A method according to claim 29, wherein the additional HCV agent is selected from interferon alpha-2b, interferon alpha-2a, and interferon alphacon-1 (pegylated and unpegylated);

ribavirin;

an HCV RNA replication inhibitor an HCV antisense agent;

an HCV therapeutic vaccine;

an HCV protease inhibitor;

an HCV helicase inhibitor; and

an HCV monoclonal or polyclonal antibody therapy.

36. A method for promoting seroconversion in a mammal infected with a hepatitis B virus, the method comprising:

administering a therapeutically effective amount of a compound according to-claim 1 or a pharmaceutical composition

according to claim 13 to a mammal infected with hepatitis B virus;

monitoring for presence of HBeAg plus HBeAb in a serum sample of the mammal;

or

monitoring for presence of HBsAg in a serum sample of the mammal, such that the absence of HBeAg plus the presence of HBeAb in the serum sample if monitoring HBeAg as the determinant for seroconversion, or the absence of HBsAg in the serum sample if monitoring HBsAg as the determinant for seroconversion, as determined by currently available detection limits of commercial ELISA systems, is indication of seroconversion in the mammal.

37. A method according to claim 16, wherein administration is selected from oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal or intratracheal administration.

38. The compound of claim 1 wherein at least one nucleoside comprises a modified nucleobase.

39. A method for reducing an amount of HBV DNA in a mammal infected with a hepatitis B virus, the method comprising administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need thereof so as to reduce the amount of HBV DNA in the mammal infected with the hepatitis B virus, compared to the amount of HBV DNA in the mammal before treatment.

40. A method according to claim 39, wherein the amount of DNA is reduced 90% compared to amount before administration of the compound.

7. An antisense compound comprising a modified antisense oligonucleotide consisting of from 10 to 100 nucleotides in length connected by internucleotide linkages having a nucleobase sequence comprising from 10 to 30 contiguous nucleotides having a nucleobase sequence that is essentially complementary to any one of SEQ ID NOs. 1-13.

8. An antisense compound according to claim 7 comprising at least one modified nucleotide that is a LNA.

9. An antisense compound according to claim 8 wherein the internucleotide linkages are selected from the group consisting of a phosphodiester, phosphotriester, phosphorothioate, phosphorodithioate, H-phosphonate, or alkylphosphonate linkage.

14. A pharmaceutical formulation for treating hepatitis B virus in a mammal comprising an effective amount of a compound according to claim 7, or a pharmaceutically acceptable salt, solvate, hydrate or ester thereof, and a pharmaceutically acceptable diluent.

15. A pharmaceutical formulation for treating hepatitis B virus infection in a mammal according to claim 14, further comprising a pharmaceutically acceptable carrier.

10-12. -12. (canceled)

28. (canceled)

33. A method according to claim 28, wherein the additional therapeutic agent is selected from an HBV agent, an HCV agent, a chemotherapeutic agent, an antibiotic, an analgesic, a non-steroidal anti-inflammatory (NSAID) agent, an antifungal agent, an antiparasitic agent, an anti-nausea agent, an anti-diarrheal agent, and an immunosuppressant agent.