Galnac conjugated modified oligonucleotides as miR-122 inhibitor having HCV antiviral activity with reduced hyperbilirubinemia side-effect
Described herein are compositions and methods for the inhibition of miR-122 activity. The compositions have certain nucleoside modifications that yield potent inhibitors of miR-122 activity and comprise moieties that facilitate delivery to the liver. The compositions may be administered to subjects infected with hepatitis C virus, as a treatment for hepatitis C virus and related conditions.
1. A compound of the structure:
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , which is a pharmaceutically acceptable salt of the structure.
3. The compound of claim 2 , which is a sodium salt of the structure.
4. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable diluent.
5. The pharmaceutical composition of claim 4 , wherein the pharmaceutically acceptable diluent is an aqueous solution.
6. The pharmaceutical composition of claim 5 , wherein the aqueous solution is a saline solution.
7. A pharmaceutical composition comprising a compound of claim 1 , which is a lyophilized composition.
8. A pharmaceutical composition consisting essentially of a compound of claim 1 in a saline solution.
9. A method of inhibiting the activity of miR-122 in a cell comprising contacting a cell with a compound of claim 1 .
10. A method of treating HCV infection comprising administering to an HCV-infected subject at least one dose of a compound of claim 1 .
11. A method of treating hepatitis C virus (HCV) infection comprising administering at least one dose of a compound of claim 1 and at least one direct-acting antiviral (DAA) to an HCV-infected subject during a treatment period, wherein the duration of the treatment period is 12 weeks or less, and wherein a start dose of the compound is administered at the start of the treatment period and an end dose of the compound is administered at the end of the treatment period, (ii) a start dose of the compound is administered at the start of the treatment period, and the start dose is the only dose of the compound administered during the treatment period, or (iii) an end dose of the compound is administered at the end of the treatment period, and the end dose is the only dose of the compound administered during the treatment period.
12. The method of claim 11 , wherein the duration of the treatment period is 2 to 10 weeks, 4 to 8 weeks, 2 to 6 weeks, or 1 to 4 weeks.
13. The method of claim 10 , where in the HCV-infected subject is infected with genotype 1, genotype 2, genotype 3, genotype 4, genotype 5, or genotype 6.
14. The method of claim 13 , wherein the HCV-infected subject is infected with genotype 1a or with genotype 1b.
15. The method of claim 10 , wherein the HCV-infected subject is determined to be infected with an HCV having one or more resistance-associated polymorphisms.
16. The method of claim 10 , wherein the HCV-infected subject is a treatment-naïve subject.
17. The method of claim 10 , wherein the HCV-infected subject has an HCV-associated disease, which is cirrhosis, liver fibrosis, steatohepatitis, steatosis, or hepatocellular carcinoma; and/or wherein the HCV-infected subject is an HCV-infected subject with renal impairment; and/or wherein the HCV-infected subject is an HCV/HIV co-infected subject.
18. The method of claim 10 , wherein the administering achieves a sustained viral response.
19. The method of claim 11 , wherein the DAA is administered daily.
20. The method of claim 11 , wherein the DAA is selected from a protease inhibitor, a nucleoside polymerase inhibitor, a nucleotide polymerase inhibitor, a non-nucleoside polymerase inhibitor, an NS3B inhibitor, an NS3/4A inhibitor, an NS4A inhibitor, an NS5A inhibitor, an NS5B inhibitor, and a cyclophilin inhibitor.
21. The method of claim 11 , wherein the DAA is selected from one or more of sofosbuvir, ledipasvir, ombitasvir, dasabuvir, glecaprevir, pibrentasvir, elbasvir, grazoprevir, ribavirin, ombitasvir, paritaprevir, ritonavir, boceprevir, vaniprevir, asunaprevir, daclatasvir, simeprevir, mericitabine, tegobuvir, danoprevir, sovaprevir, voxilaprevir, velpatasvir, and GSK2878175.
22. The method of claim 10 , wherein the dose of the compound is less than or equal to 4.0 mg/kg, less than or equal to 3.5 mg/kg, less than or equal to 3.0 mg/kg, less than or equal to 2.5 mg/kg, less than or equal to 2.0 mg/kg, less than or equal to 1.5 mg/kg, less than or equal to 1.0 mg/kg, or less than or equal to 0.5 mg/kg.