COMBINATION THERAPY FOR TREATING HEPATITIS B VIRUS INFECTIONS
The present disclosure is related to methods for treating hepatitis B infections. The methods comprising administering a subject in need thereof a PAPD5/7 inhibitor and a modified ASO that targets HBV mRNAs.
1 . A method for treating chronic hepatitis B in a human in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound A having the structure:
or a pharmaceutically acceptable salt thereof, and
administering to the subject a therapeutically effective amount of a single-stranded modified oligonucleotide comprising 20 linked nucleosides and having a nucleobase sequence of SEQ ID NO: 1, wherein the modified oligonucleotide comprises:
a gap segment consisting of ten linked deoxynucleosides,
a 5′ wing segment consisting of 5 linked nucleosides, and
a 3′ wing segment consisting of 5 linked nucleosides,
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment,
wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar,
wherein each internucleoside linkage is a phosphorothioate linkage, and wherein each cytosine is a 5-methylcytosine.
2 . The method of claim 1 , wherein Compound A is administered as a free acid.
3 . The method of claim 1 , wherein the single-stranded modified oligonucleotide is bepirovirsen.
4 . The method of claim 1 , wherein the subject is on stable nucleos(t)ide analogue (NA) therapy.
5 . The method of claim 1 , wherein the NA therapy is lamivudine, adefovir, adefovir dipivoxil, telbivudine, entecavir, tenofovir, tenofovir disoproxil fumarate, or tenofovir alafenamide, or a pharmaceutically acceptable salt thereof.
6 . The method of claim 1 , wherein Compound A is administered orally.
7 . The method of claim 6 , wherein Compound A is administered at a dose of about 0.5 mg or 1 mg twice a day.
8 . The method of claim 1 , wherein the modified oligonucleotide is administered by subcutaneous injection.
9 . The method of claim 1 , wherein the modified oligonucleotide is administered at a dose of about 150 mg or 300 mg once weekly.
10 . The method of claim 1 , wherein Compound A and the modified oligonucleotide are administered concomitantly.
11 . The method of claim 10 , wherein Compound A and the modified oligonucleotide are administered concomitantly for about 4 weeks.
12 . The method of claim 10 , wherein the modified oligonucleotide is administered alone for a second treatment period after the concomitant administration.
13 . The method of claim 12 , wherein the second treatment period is about 8-20 weeks.
14 - 17 . (canceled)