Modulation of hepatitis B virus (HBV) expression

• US 9,677,076 B2
• Filed: 07/07/2015
• Issued: 06/13/2017
• Est. Priority Date: 04/21/2011
• Status: Active Grant

• Current Assignee: Glaxo Group Limited (GSK plc)
• Original Assignee: Ionis Pharmaceuticals, Inc.
• Inventors: McCaleb, Michael L., Swayze, Eric E., Freier, Susan M.
• Primary Examiner(s): VIVLEMORE, TRACY ANN
• Application Number:
  US14/793,622
• Publication Number:
  US 20160046945A1
• Time in Patent Office: 707 Days
• Field of Search: None
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C12N 15/1131 against viruses
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/313 Phosphorodithioates
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/3231 having an additional ring, e.g. LNA, ENA
• CPC Class Codes: C12N 2310/3341 5-Methylcytosine
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/344 Position-specific modifications, e.g. on every purine, at the 3'-end
• CPC Class Codes: C12N 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/3525 MOE, methoxyethoxy
• CPC Class Codes: C12N 2320/30 Special therapeutic applications

Abstract

Disclosed herein are antisense compounds and methods for decreasing HBV mRNA, DNA and protein expression. Such methods, compounds, and compositions are useful to treat, prevent, or ameliorate HBV-related diseases, disorders or conditions.

Claims

1. A single stranded modified oligonucleotide consisting of 20 to 30 linked nucleosides and having a nucleobase sequence comprising any of the nucleobase sequences of SEQ ID NOs:

321-331, 333, 352-362, 365-375, 378, 379, 433, 491-497, 511-513, 515, 605-629, 632-634, 650-666, 700-708, 742-746, 770, 771, 774-777, 811, 918,919, 924-926, 928, 947, 948, 950-956, 971, 972, 974-982, 995, 997-1004, 1055-1063, 1067-1105, 1119-1132, 1145, 1147-1161, 1180-1185, 1188-1205, 1207-1223, 1236-1241, 1255-1258, 1271, or 1272, wherein the modified oligonucleotide comprises;

a gap segment consisting of linked deoxynucleosides;

a 5′

wing segment consisting of linked nucleosides; and

a 3′

wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′

wing segment and the 3′

wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

2. The single stranded modified oligonucleotide of claim 1, wherein said modified oligonucleotide is 100% complementary to SEQ ID NO:

1.

3. The single stranded modified oligonucleotide of claim 1, wherein at least one internucleoside linkage is a modified internucleoside linkage.

4. The compound of claim 3, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

5. The single stranded modified oligonucleotide of claim 1, wherein at least one modified sugar is a bicyclic sugar.

6. The single stranded modified oligonucleotide of claim 1, wherein at least one modified sugar comprises a 2′

-O-methoxyethyl group.

7. The single stranded modified oligonucleotide of claim 1, wherein the modified sugar comprises a 2′

-O(CH₂)₂—

OCH₃ group.

8. The single stranded modified oligonucleotide of claim 1, wherein the modified sugar comprises a 4′

-CH(CH₃)—

O-2′

group.

9. The single stranded modified oligonucleotide of claim 1, wherein at least one nucleoside comprises a modified nucleobase.

10. The single stranded modified oligonucleotide of claim 9, wherein the modified nucleobase is a 5-methylcytosine.

11. The single stranded modified oligonucleotide of claim 1, wherein the gap segment consists of 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 linked nucleosides.

12. The single stranded modified oligonucleotide of claim 1, wherein the modified oligonucleotide comprises:

a gap segment consisting of ten linked deoxynucleosides;

a 5′

wing segment consisting of five linked nucleosides; and

a 3′

wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′

wing segment and the 3′

wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

13. A composition comprising the single stranded modified oligonucleotide of claim 1 or salt thereof and at least one of a pharmaceutically acceptable carrier or diluent.

14. A method of preventing, treating, ameliorating, or slowing progression of a HBV-related disease, disorder or condition in an animal comprising administering the single stranded modified oligonucleotide of claim 1 to the animal, thereby preventing, treating, ameliorating, or slowing progression of the HBV-related disease, disorder or condition.

15. The method of claim 14, wherein the disease, disorder or condition is liver disease.

16. The method of claim 14, wherein the disease, disorder or condition is jaundice, liver inflammation, liver fibrosis, inflammation, liver cirrhosis, liver failure, diffuse hepatocellular inflammatory disease, hemophagocytic syndrome, serum hepatitis, HBV viremia, or liver disease-related transplantation.

17. The method of claim 14, wherein administering the single stranded modified oligonucleotide of claim 1 to the animal reduces antigen levels in the animal.

18. The method of claim 17, wherein HBsAG levels are reduced.

19. The method of claim 17, wherein HBeAG levels are reduced.

20. The method of claim 17, wherein the animal is human.

21. The single stranded modified oligonucleotide of claim 12, wherein the modified sugar comprises a 2′

-O-methoxyethyl group.