US2019255091A1PendingUtilityA1

RNAi AGENTS FOR HEPATITIS B VIRUS INFECTION

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Assignee: ARROWHEAD PHARMACEUTICALS INCPriority: Aug 4, 2016Filed: Feb 4, 2019Published: Aug 22, 2019
Est. expiryAug 4, 2036(~10.1 yrs left)· nominal 20-yr term from priority
Inventors:Zhen LiRui ZhuChristine I. WooddellBruce D. GivenTao PeiDavid L. LewisLauren J. AlmeidaDavid B. RozemaDarren H. Wakefield
A61P 31/20A61P 1/16A61K 31/7088A61K 9/0019C12N 2310/314C12N 2310/14A61P 31/14C12N 2310/11C12N 2310/315C12N 15/113C12N 15/1131C12N 2310/3515A61K 31/7105A61K 31/675C12N 2310/322C12N 2310/321Y02A50/30A61K 31/713C07H 21/02A61K 47/549A61K 45/06A61P 35/00A61P 31/18A61K 48/00A61P 31/12
64
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Claims

Abstract

Described are compositions and methods for inhibition of Hepatitis B virus gene expression. RNA interference (RNAi) agents for inhibiting the expression of Hepatitis B virus gene are described. The HBV RNAi agents disclosed herein may be targeted to cells, such as hepatocytes, for example, by using conjugated targeting ligands. Pharmaceutical compositions comprising one or more HBV RNAi agents optionally with one or more additional therapeutics are also described. Delivery of the described HBV RNAi agents to infected liver in vivo provides for inhibition of HBV gene expression and treatment of diseases and conditions associated with HBV infection.

Claims

exact text as granted — not AI-modified
1 - 66 . (canceled) 
     
     
         67 . A composition comprising one or more RNAi agents, wherein the one or more RNAi agents comprise:
 (a) an antisense strand comprising a nucleotide sequence of any one of the following:   SEQ ID NO:100, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:171, SEQ ID NO:179 and SEQ ID NO:180; and   (b) a sense strand comprising a nucleotide sequence of any one of the following: SEQ ID NO:229, SEQ ID NO:252, SEQ ID NO:253, SEQ ID NO:273, SEQ ID NO:302 and SEQ ID NO:319.   
     
     
         68 . The composition of  claim 67 , wherein the one or more RNAi agents comprise at least one modified nucleotide or at least one modified inter-nucleoside linkage. 
     
     
         69 . The composition of  claim 68 , wherein substantially all of the nucleotides in the one or more RNAi agents are modified nucleotides. 
     
     
         70 . The composition of  claim 67 , wherein the one or more RNAi agents further comprise a targeting ligand that is conjugated to the one or more RNAi agents. 
     
     
         71 . The composition of  claim 70 , wherein the targeting ligand comprises N-acetyl-galactosamine. 
     
     
         72 . The composition of  claim 71 , wherein the targeting ligand comprises an N-acetyl-galactosamine trimer or an N-acetyl-galactosamine tetramer. 
     
     
         73 . The composition of  claim 72 , wherein the targeting ligand is selected form the group consisting of (NAG13), (NAG13)s, (NAG18), (NAG18)s, (NAG24), (NAG24)s, (NAG25), (NAG25)s, (NAG26), (NAG26)s, (NAG27), (NAG27)s, (NAG28), (NAG28)s, (NAG29), (NAG29)s, (NAG30), (NAG30)s, (NAG31), (NAG31)s, (NAG32), (NAG32)s, (NAG33), (NAG33)s, (NAG34), (NAG34)s, (NAG35), (NAG35)s, (NAG36), (NAG36)s, (NAG37), (NAG37)s, (NAG38), (NAG38)s, (NAG39), and (NAG39)s. 
     
     
         74 . The composition of  claim 73 , wherein the targeting ligand is (NAG25), (NAG25)s, (NAG31), (NAG31)s, (NAG37), or (NAG37)s. 
     
     
         75 . The composition of  claim 70 , wherein the targeting ligand is conjugated to the sense strand of the one or more RNAi agents. 
     
     
         76 . The composition of  claim 70 , wherein the targeting ligand is conjugated to the antisense strand of the one or more RNAi agents. 
     
     
         77 . The composition of  claim 75 , wherein the targeting ligand is conjugated to the 5′ terminus of the sense strand of the one or more RNAi agents. 
     
     
         78 . The composition of  claim 76 , wherein the targeting ligand is conjugated to the 3′ terminus of the antisense strand of the one or more RNAi agents. 
     
     
         79 . The composition of  claim 67 , wherein the sense strand further comprises one or more inverted abasic nucleosides. 
     
     
         80 . The composition of  claim 67  further comprising a pharmaceutically acceptable excipient, carrier, or diluent. 
     
     
         81 . The composition of  claim 67  further comprising an additional RNAi agent, wherein the additional RNAi agent comprises: an antisense strand comprising a nucleotide sequence of any one of the following: SEQ ID NO:140, SEQ ID NO:137, SEQ ID NO:102, SEQ ID NO:162 and SEQ ID NO:188, and a sense strand comprising a nucleotide sequence of any one of the following: SEQ ID NO:248, SEQ ID NO:294, SEQ ID NO:262, SEQ ID NO:271, SEQ ID NO:274, and SEQ ID NO:328. 
     
     
         82 . The composition of  claim 81 , wherein the composition comprises two or more RNAi agents independently selected from the group consisting of: AD04571 (SEQ ID NO: 100 and SEQ ID NO:229), AD04776 (SEQ ID NO: 102 and SEQ ID NO:248), AD04872 (SEQ ID NO: 126 and SEQ ID NO:252), AD04873 (SEQ ID NO: 127 and SEQ ID NO:252), AD04874 (SEQ ID NO: 128 and SEQ ID NO:253), AD04982 (SEQ ID NO: 137 and SEQ ID NO:248), AD05070 (SEQ ID NO:140 and SEQ ID NO:262), AD05148 (SEQ ID NO:140 and SEQ ID NO:271), AD05164 (SEQ ID NO:126 and SEQ ID NO:273) and AD05165 (SEQ ID NO:140 and SEQ ID NO:274). 
     
     
         83 . The composition of  claim 82 , wherein the ratio of the one or more RNAi agents to the additional RNAi agent by weight is in the range of about 1:2 to about 5:1. 
     
     
         84 . The composition of  claim 83 , wherein the ratio of the one or more RNAi agents to the additional RNAi agent by weight is about 2:1 or about 3:1. 
     
     
         85 . The composition of  claim 84 , wherein the one or more RNAi agents comprise an antisense strand comprising SEQ ID NO: 126 and a sense strand comprising SEQ ID NO: 252, the additional RNAi agent comprises an antisense strand comprising SEQ ID NO: 140 and a sense strand comprising SEQ ID NO: 262. 
     
     
         86 . The composition of  claim 84 , wherein the one or more RNAi agents comprise an antisense strand comprising SEQ ID NO: 126 and a sense strand comprising SEQ ID NO: 252, the additional RNAi agent comprises an antisense strand comprising SEQ ID NO:102 and a sense strand comprising SEQ ID NO: 248. 
     
     
         87 . The composition of  claim 84 , wherein the one or more RNAi agents comprise an antisense strand comprising SEQ ID NO: 126 and a sense strand comprising SEQ ID NO: 252, the additional RNAi agent comprises an antisense strand comprising SEQ ID NO:137 and a sense strand comprising SEQ ID NO: 248. 
     
     
         88 . The composition of  claim 82 , wherein the two or more RNAi agents are each independently conjugated to a targeting ligands comprising N-acetyl-galactosamine. 
     
     
         89 . The composition of  claim 85 , wherein the sense strand of the one or more RNAi agents or the additional RNAi agent further comprises one or more inverted abasic nucleosides. 
     
     
         90 . A pharmaceutical composition comprising the composition of  claim 67  and a pharmaceutically acceptable excipient, carrier, or diluent. 
     
     
         91 . A kit comprising the pharmaceutical composition of  claim 90 . 
     
     
         92 . The kit of  claim 91  further comprising a syringe or a vial. 
     
     
         93 . A composition comprising one or more RNAi agents, wherein the one or more RNAi agents comprise:
 (a) an antisense strand comprising a nucleotide sequence of any one of the following: SEQ ID NO:140, SEQ ID NO:102, SEQ ID NO:137, SEQ ID NO:162 and SEQ ID NO:188; and   (b) a sense strand comprising a nucleotide sequence of any one of the following: SEQ ID NO:248, SEQ ID NO:294, SEQ ID NO:262, SEQ ID NO:271, SEQ ID NO:274, and SEQ ID NO:328.   
     
     
         94 . The composition of  claim 93 , wherein the one or more RNAi agents comprise at least one modified nucleotide or at least one modified inter-nucleoside linkage. 
     
     
         95 . The composition of  claim 94 , wherein substantially all of the nucleotides in the one or more RNAi agents are modified nucleotides. 
     
     
         96 . The composition of  claim 93 , wherein the one or more RNAi agents further comprise a targeting ligand that is conjugated to the one or more RNAi agents. 
     
     
         97 . The composition of  claim 96 , wherein the targeting ligand is selected form the group consisting of (NAG13), (NAG13)s, (NAG18), (NAG18)s, (NAG24), (NAG24)s, (NAG25), (NAG25)s, (NAG26), (NAG26)s, (NAG27), (NAG27)s, (NAG28), (NAG28)s, (NAG29), (NAG29)s, (NAG30), (NAG30)s, (NAG31), (NAG31)s, (NAG32), (NAG32)s, (NAG33), (NAG33)s, (NAG34), (NAG34)s, (NAG35), (NAG35)s, (NAG36), (NAG36)s, (NAG37), (NAG37)s, (NAG38), (NAG38)s, (NAG39), and (NAG39)s. 
     
     
         98 . The composition of  claim 96 , wherein the targeting ligand is conjugated to the sense strand of the one or more RNAi agents. 
     
     
         99 . The composition of  claim 96 , wherein the targeting ligand is conjugated to the antisense strand of the one or more RNAi agents. 
     
     
         100 . The composition of  claim 93 , wherein the sense strand further comprises one or more inverted abasic nucleosides. 
     
     
         101 . A pharmaceutical composition comprising the composition of  claim 93  and a pharmaceutically acceptable excipient, carrier, or diluent. 
     
     
         102 . A kit comprising the pharmaceutical composition of  claim 101 . 
     
     
         103 . A method of reducing or inhibiting the expression of at least one Hepatitis B Virus gene in a subject in need thereof, comprising administering to the subject an effective amount of one or more RNAi agents according to  claim 67 . 
     
     
         104 . The method of  claim 103 , wherein the one or more RNAi agents are administered in the amount of about 0.25-5 mg/kg. 
     
     
         105 . The method of  claim 104 , wherein the one or more RNAi agents are formulated for subcutaneous or intravenous injection. 
     
     
         106 . The method of  claim 103  further comprising administering to the subject one or more additional therapeutics. 
     
     
         107 . The method of  claim 106 , wherein the additional therapeutic is lamivudine, tenofovir, tenofovir alafenamide, tenofovir disoproxil, or entecavir. 
     
     
         108 . A method of treating a disease or disorder associated with Hepatitis B Virus infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more RNAi agents according to  claim 67 . 
     
     
         109 . The method of  claim 108 , wherein the one or more RNAi agents are administered in the amount of about 0.25-5 mg/kg. 
     
     
         110 . The method of  claim 109 , wherein the one or more RNAi agents are formulated for subcutaneous or intravenous injection. 
     
     
         111 . The method of  claim 110 , wherein the subject has an infection caused by the Hepatitis B Virus. 
     
     
         112 . The method of  claim 108  further comprising administering to the subject one or more additional therapeutics. 
     
     
         113 . The method of  claim 112 , wherein the additional therapeutic is lamivudine, tenofovir, tenofovir alafenamide, tenofovir disoproxil, or entecavir. 
     
     
         114 . A combination of at least two RNAi agents comprising a first RNAi agent and a second RNAi agent, wherein:
 (a) the first RNAi agent comprising: an antisense strand comprising a nucleotide sequence of any one of the following: SEQ ID NO:100, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:171, SEQ ID NO:179, and SEQ ID NO:180, and a sense strand comprising a nucleotide sequence of any one of the following: SEQ ID NO:229, SEQ ID NO:252, SEQ ID NO:253, SEQ ID NO:273, SEQ ID NO:302, and SEQ ID NO:319; and   (b) the second RNAi agent comprising: an antisense strand comprising a nucleotide sequence of any one of the following: SEQ ID NO:140, SEQ ID NO:102, SEQ ID NO:137, SEQ ID NO:162 and SEQ ID NO:188, and a sense strand comprising a nucleotide sequence of any one of the following: SEQ ID NO:248, SEQ ID NO:294, SEQ ID NO:262, SEQ ID NO:271, SEQ ID NO:274, and SEQ ID NO:328.   
     
     
         115 . The combination of  claim 114 , wherein the first or the second RNAi agent comprises at least one modified nucleotide or at least one modified inter-nucleoside linkage. 
     
     
         116 . The combination of  claim 114 , wherein the first or the second RNAi agent further comprises a targeting ligand that is conjugated to the first or the second RNAi agent. 
     
     
         117 . The combination of  claim 116 , wherein the targeting ligand is selected form the group consisting of (NAG13), (NAG13)s, (NAG18), (NAG18)s, (NAG24), (NAG24)s, (NAG25), (NAG25)s, (NAG26), (NAG26)s, (NAG27), (NAG27)s, (NAG28), (NAG28)s, (NAG29), (NAG29)s, (NAG30), (NAG30)s, (NAG31), (NAG31)s, (NAG32), (NAG32)s, (NAG33), (NAG33)s, (NAG34), (NAG34)s, (NAG35), (NAG35)s, (NAG36), (NAG36)s, (NAG37), (NAG37)s, (NAG38), (NAG38)s, (NAG39), and (NAG39)s. 
     
     
         118 . The combination of  claim 117 , wherein the targeting ligand is conjugated to the 5′ terminus of the sense strand of the one or more RNAi agents. 
     
     
         119 . The combination of  claim 114 , wherein the sense strand in the first or the second RNAi agents further comprises one or more inverted abasic nucleosides. 
     
     
         120 . The combination of  claim 114  further comprising a pharmaceutically acceptable excipient, carrier, or diluent. 
     
     
         121 . The combination of  claim 114 , wherein the ratio of the first RNAi agent to the second RNAi agent by weight is in the range of about 1:2 to about 5:1. 
     
     
         122 . The combination of  claim 114 , wherein the first and the second RNA agents are formulated in a single pharmaceutical composition. 
     
     
         123 . The combination of  claim 114 , wherein the first and the second RNA agents are formulated in separate pharmaceutical compositions. 
     
     
         124 . The combination of  claim 114 , wherein the first and the second RNA agents are formulated for subcutaneous or intravenous injection. 
     
     
         125 . A cell, tissue or non-human organism comprising one or more RNAi agents according to  claim 67 . 
     
     
         126 . A method of preparing an RNAi agent comprising conjugating a targeting group to a reactive group at the 5′- or 3′-terminus of the RNAi agent, wherein:
 the RNAi agent comprises: (a) an antisense strand comprising a nucleotide sequence of any one of the following: SEQ ID NO:100, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:171, SEQ ID NO:179 and SEQ ID NO:180; and (b) a sense strand comprising a nucleotide sequence of any one of the following: SEQ ID NO:229, SEQ ID NO:252, SEQ ID NO:253, SEQ ID NO:273, SEQ ID NO:302 and SEQ ID NO:319; 
 the reactive group at the 5′- or 3′-terminus of the RNAi agent is selected from the group consisting of amine, alkyne, alkyl, abasic nucleoside, ribitol and PEG; and 
 the targeting group comprises N-acetyl-galactosamine. 
 
     
     
         127 . The method of  claim 126 , wherein the reactive group is an amine. 
     
     
         128 . The method of  claim 126 , wherein the targeting group is selected from the group consisting of (NAG13), (NAG13)s, (NAG18), (NAG18)s, (NAG24), (NAG24)s, (NAG25), (NAG25)s, (NAG26), (NAG26)s, (NAG27), (NAG27)s, (NAG28), (NAG28)s, (NAG29), (NAG29)s, (NAG30), (NAG30)s, (NAG31), (NAG31)s, (NAG32), (NAG32)s, (NAG33), (NAG33)s, (NAG34), (NAG34)s, (NAG35), (NAG35)s, (NAG36), (NAG36)s, (NAG37), (NAG37)s, (NAG38), (NAG38)s, (NAG39), and (NAG39)s. 
     
     
         129 . The method of  claim 126 , wherein the sense strand further comprises one or more inverted abasic nucleosides.

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