Use of Oligonucleotides in Individuals with Renal Dysfunction - Patent application

Abstract

The present disclosure relates to a method for the treatment of Hepatitis B in a subject, comprising an RNAi component, wherein the subject has a level of renal dysfunction.

Description

[Technical field]

[0001] The present disclosure relates to a method for the treatment of Hepatitis B in a subject, where the subject has a level of renal dysfunction. [Background technology]

[0002] Hepatitis B virus (HBV), a member of the Hepadnaviridae family, is a non-cytopathic hepatic DNA virus that exclusively infects the liver of humans and great apes (e.g., chimpanzees, orangutans, bonobos, and gorillas). Primary infection of adult humans with HBV causes acute hepatitis with symptoms of organ inflammation, fever, jaundice, and increased blood liver transaminases. Approximately 10-20% of adult patients do not overcome the viral infection and suffer from chronic disease progression over many years, increasing the risk of developing chronic hepatitis B virus (CHB) infection and developing cirrhosis or liver cancer. Perinatal vertical transmission from mothers with CHB to their newborns also causes chronic hepatitis in approximately 80% of cases. All patients with CHB are at increased risk of progression to cirrhosis and hepatocellular carcinoma (HCC), depending on host and viral factors (Lampertico et al., J Hepatol., 2017, 67(2):370-398).

[0003] Among people with chronic HBV infection, patients with renal dysfunction are at higher risk of progressing to end-stage disease. Renal diseases resulting from HBV infection are membranous (MN), membranoproliferative glomerulonephritis (MPGN), polyarteritis nodosa (PAN), and mesangial proliferative glomerulonephritis (MesPGN) (Kamimura et al., Diseases 2018, 6(52):1-8). Renal dysfunction is common, especially in HBV patients with cirrhosis. A condition called hepatorenal syndrome (HRS) is characterized by renal dysfunction in HBV patients brought about by advanced cirrhosis in HBV patients. Current treatments for CHB, such as nucleoside / nucleotide analogs (NAs), often worsen renal dysfunction in patients.

[0004] There is a need to safely treat individuals with Hepatitis B virus infection, including those with impaired renal and / or hepatic function, to produce a functional cure (FC) such that patients have (still) undetectable serum HBsAg and HBV DNA 6 months (or longer) after the end of treatment. FC essentially places CHB patients in a similar state to patients who have recovered from acute HBV infection, i.e., a state of viral latency maintained by HBV-specific T cells, and has been shown to improve survival and health-related quality of life by preventing disease progression, including the development of advanced decompensated cirrhosis and HCC. Summary of the Invention

[0005] Provided herein is a method for treating Hepatitis B virus (HBV) infection in a subject, for enhancing an immune response in a subject having a Hepatitis B virus (HBV) infection, for reducing viral replication in a subject having a Hepatitis B virus (HBV) infection, for reducing expression of one or more Hepatitis B virus (HBV) polypeptides, more particularly one or more polypeptides selected from HBsAg and HBeAg, in a subject in need thereof, and / or for increasing targeted killing of hepatocytes containing integrated viral DNA or extrachromosomal DNA in a subject having a Hepatitis B virus (HBV) infection, comprising administering to a subject: (i) a first RNAi agent comprising an antisense strand comprising the nucleotide sequence of any one of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7, and a complementary sense strand (in some embodiments, the complementary sense strand comprises the nucleotide sequence of any one of SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, and SEQ ID NO:15); and (ii) a second RNAi agent comprising an antisense strand comprising the nucleotide sequence of any one of SEQ ID NO:8 and SEQ ID NO:9, and a complementary sense strand (in some embodiments, the complementary sense strand comprises the nucleotide sequence of any one of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, and SEQ ID NO:19). The method includes administering an effective amount of a pharmaceutical composition comprising an RNAi component having the formula:

[0006] In particular, the present disclosure provides a method for treating Hepatitis B virus (HBV) infection in a subject with renal dysfunction, for enhancing immune response in a subject with Hepatitis B virus (HBV) infection and renal dysfunction, for reducing viral replication in a subject with Hepatitis B virus (HBV) infection and renal dysfunction, for reducing expression of one or more Hepatitis B virus (HBV) polypeptides, more particularly one or more polypeptides selected from HBsAg and HBeAg, in a subject with renal dysfunction in need thereof, and / or for increasing targeted killing of hepatocytes containing integrated viral DNA or extrachromosomal DNA in a subject with Hepatitis B virus (HBV) infection and renal dysfunction, comprising administering an RNAi component as described above. In some such embodiments, the subject with renal dysfunction also has liver dysfunction.

[0007] In some embodiments, the present disclosure provides a method for treating Hepatitis B virus (HBV) infection in a subject with severe renal dysfunction or end-stage renal disease (ESRD), comprising administering an RNAi component as described above. In some such embodiments, the subject is also undergoing dialysis. In some embodiments, the subject with severe renal dysfunction or ESRD also has liver dysfunction. In some embodiments, the subject has ESRD, undergoes dialysis, and has liver dysfunction. In another embodiment, the subject has ESRD, is not undergoing dialysis, and has liver dysfunction.

[0008] In some embodiments, the subject has both renal and hepatic impairment, the subject has a Child-Pugh score of 7-9 (Class B), indicating significant functional liver impairment. In some embodiments, the subject has a Child-Pugh score of 10-15 (Class C), indicating decompensated disease. In some embodiments, the subject has a Child score of 7-9 or 10-15, the subject also suffers from renal impairment. In some embodiments, the subject with renal and hepatic impairment has a glomerular filtration rate [GFR] of less than 90 mL / min. In another embodiment, the subject with renal and hepatic impairment is undergoing dialysis.

[0009] In some embodiments, the subject with renal and hepatic dysfunction may have compensated cirrhosis. In another embodiment, the subject with renal and hepatic dysfunction may have decompensated cirrhosis.

[0010] In certain embodiments, the method or use according to the embodiments of the present application further comprises one or more additional agents for treating HBV, particularly CHB. The additional agent may be, for example, a nucleoside / nucleotide analog (NA). In some embodiments, the nucleoside analog is entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide, lamivudine, telbivudine or a combination thereof. The additional agent may also be, for example, a NAP, including but not limited to, REP2006, REP2031, REP2055, STOPS™ (S-antigen transport inhibitory oligonucleotide polymer), and those disclosed in International Publication Nos. 200424919; 201221985; and 202097342, and U.S. Patent Nos. 7,358,068; 8,008,269; 8,008,270; and 8,067,385. The additional agent may also be one or more capsid assembly modulators (CAMs). The method or combination for use according to the embodiments of the present application may further include one or more interferons, such as interferon alpha or lambda, preferably pegylated interferon, more preferably pegylated interferon alpha-2a or pegylated interferon lambda-1a. In some embodiments, the RNAi components of the present disclosure may be administered with both a NA and a CAM.

[0011] In some embodiments, the present disclosure provides a method of treating HBV in a subject with impaired renal function, comprising: (i) a first RNAi agent comprising an antisense strand comprising the nucleotide sequence of SEQ ID NO:2 and a complementary sense strand (e.g., a sense strand comprising the nucleotide sequence of SEQ ID NO:11); and (ii) a second RNAi agent comprising an antisense strand comprising the nucleotide sequence of SEQ ID NO:8 and a complementary sense strand (e.g., a sense strand comprising the nucleotide sequence of SEQ ID NO:16). or (i) a first RNAi agent comprising an antisense strand comprising a nucleotide sequence that is at least 70% homologous to SEQ ID NO:2 and a complementary sense strand comprising a nucleotide sequence that is at least 80% homologous to SEQ ID NO:11; and (ii) a second RNAi agent comprising an antisense strand comprising a nucleotide sequence that is at least 70% identical to the sequence of SEQ ID NO:8, and a complementary sense strand comprising a nucleotide sequence that is at least 80% identical to SEQ ID NO:16. RNAi components including The method includes subcutaneously administering to a subject a pharmaceutical composition comprising about 100 mg to about 200 mg (e.g., about 100 mg, about 125 mg, about 150 mg, or about 200 mg) of Methods are provided wherein the molar ratio of the first RNAi agent to the second RNAi agent is about 2: 1. In some such embodiments, the subject also has impaired liver function.

[0012] In some embodiments, the present disclosure provides a method of treating HBV in a subject with cirrhosis and impaired renal function, comprising: (i) a first RNAi agent comprising an antisense strand comprising the nucleotide sequence of SEQ ID NO:2 and a complementary sense strand (e.g., a sense strand comprising the nucleotide sequence of SEQ ID NO:11); and (ii) a second RNAi agent comprising an antisense strand comprising the nucleotide sequence of SEQ ID NO:8 and a complementary sense strand (e.g., a sense strand comprising the nucleotide sequence of SEQ ID NO:16). or (i) a first RNAi agent comprising an antisense strand comprising a nucleotide sequence that is at least 70% homologous to SEQ ID NO:2 and a complementary sense strand comprising a nucleotide sequence that is at least 70% homologous to SEQ ID NO:11; and (ii) a second RNAi agent comprising an antisense strand comprising a nucleotide sequence that is at least 70% identical to the nucleotide sequence of SEQ ID NO:8, and a complementary sense strand comprising a nucleotide sequence that is at least 70% identical to SEQ ID NO:16. RNAi components including The method includes subcutaneously administering to a subject a pharmaceutical composition comprising about 100 mg to about 200 mg (e.g., about 100 mg, about 125 mg, about 150 mg, or about 200 mg) of Methods are provided wherein the molar ratio of the first RNAi agent to the second RNAi agent is about 2: 1. In some such embodiments, the subject has hepatorenal syndrome (HRS).

[0013] In some embodiments, the present disclosure provides a method of treating HBV in a subject with impaired renal function, comprising: (i) a first RNAi agent comprising an antisense strand comprising the nucleotide sequence of SEQ ID NO:2 and a complementary sense strand (e.g., a sense strand comprising the nucleotide sequence of SEQ ID NO:11); and (ii) a second RNAi agent comprising an antisense strand comprising the nucleotide sequence of SEQ ID NO:8 and a complementary sense strand (e.g., a sense strand comprising the nucleotide sequence of SEQ ID NO:16). or (i) a first RNAi agent comprising an antisense strand comprising a nucleotide sequence that is at least 70% homologous to SEQ ID NO:2 and a complementary sense strand comprising a nucleotide sequence that is at least 70% homologous to SEQ ID NO:11; and (ii) a second RNAi agent comprising an antisense strand comprising a nucleotide sequence that is at least 70% identical to the sequence of SEQ ID NO:8, and a complementary sense strand comprising a nucleotide sequence that is at least 70% identical to SEQ ID NO:16. RNAi components including administering to a subject a pharmaceutical composition comprising: The molar ratio of the first RNAi agent to the second RNAi agent is about 2:1, and the C of the first component is max is about 1,500 ng / mL to about 4,000 ng / mL, and the C max In some embodiments, the C of the first component is about 200 ng / mL to about 1,000 ng / mL. max is about 2,000ng / mL to about 3,000ng / mL, and the C of the second component maxis about 400 ng / mL to about 800 ng / mL. In some such embodiments, the subject with renal dysfunction also has liver dysfunction. In some such embodiments, the subject with renal dysfunction has liver cirrhosis. In some such embodiments, the subject has hepatorenal syndrome (HRS).

[0014] In some embodiments, the present disclosure provides a method of treating HBV in a subject with impaired renal function, comprising: (i) a first RNAi agent comprising an antisense strand comprising the nucleotide sequence of SEQ ID NO:2 and a complementary sense strand (e.g., a sense strand comprising the nucleotide sequence of SEQ ID NO:11); and (ii) a second RNAi agent comprising an antisense strand comprising the nucleotide sequence of SEQ ID NO:8 and a sense strand comprising a complementary nucleotide sequence (e.g., a sense strand comprising the sequence of SEQ ID NO:16). or (i) a first RNAi agent comprising an antisense strand comprising a nucleotide sequence that is at least 70% homologous to SEQ ID NO:2 and a complementary sense strand comprising a nucleotide sequence that is at least 70% homologous to SEQ ID NO:11; and (ii) a second RNAi agent comprising an antisense strand comprising a nucleotide sequence that is at least 70% identical to the sequence of SEQ ID NO:8, and a complementary sense strand comprising a nucleotide sequence that is at least 70% identical to SEQ ID NO:16. RNAi components including administering to a subject a pharmaceutical composition comprising: The molar ratio of the first RNAi agent to the second RNAi agent is about 2:1, and the AUC ∞ is about 20,000 ng.h / mL to about 50,000 ng.h / mL, and the AUC ∞ In some embodiments, the AUC of the first component is about 3,000 ng.h / mL to about 12,000 ng.h / mL. ∞ is about 30,000 ng.h / mL to about 40,000 ng.h / mL, and the AUC of the second component ∞is about 5,000 ng.h / mL to about 10,000 ng.h / mL. In some such embodiments, the subject with renal dysfunction has liver dysfunction. In some such embodiments, the subject with renal dysfunction has liver cirrhosis. In some such embodiments, the subject has hepatorenal syndrome (HRS).

[0015] In some embodiments disclosed above, the first RNAi comprises an antisense strand comprising a nucleotide sequence at least 80% homologous to SEQ ID NO:2 and a complementary sense strand comprising a nucleotide sequence at least 80% homologous to SEQ ID NO:11. In some embodiments, the first RNAi comprises an antisense strand comprising a nucleotide sequence at least 85% homologous to SEQ ID NO:2 and a complementary sense strand comprising a nucleotide sequence at least 85% homologous to SEQ ID NO:11. In some embodiments, the first RNAi comprises an antisense strand comprising a nucleotide sequence at least 90% homologous to SEQ ID NO:2 and a complementary sense strand comprising a nucleotide sequence at least 90% homologous to SEQ ID NO:11. In some embodiments, the first RNAi comprises an antisense strand comprising a nucleotide sequence at least 95% homologous to SEQ ID NO:2 and a complementary sense strand comprising a nucleotide sequence at least 95% homologous to SEQ ID NO:11.

[0016] In some embodiments disclosed above, the second RNAi comprises an antisense strand comprising a nucleotide sequence at least 80% homologous to SEQ ID NO:8 and a complementary sense strand comprising a nucleotide sequence at least 80% homologous to SEQ ID NO:16. In some embodiments, the second RNAi comprises an antisense strand comprising a nucleotide sequence at least 85% homologous to SEQ ID NO:8 and a complementary sense strand comprising a nucleotide sequence at least 85% homologous to SEQ ID NO:16. In some embodiments, the second RNAi comprises an antisense strand comprising a nucleotide sequence at least 90% homologous to SEQ ID NO:8 and a complementary sense strand comprising a nucleotide sequence at least 90% homologous to SEQ ID NO:16. In some embodiments, the second RNAi comprises an antisense strand comprising a nucleotide sequence at least 95% homologous to SEQ ID NO:8 and a complementary sense strand comprising a nucleotide sequence at least 95% homologous to SEQ ID NO:16.

[0017] In some embodiments disclosed above, the first RNAi comprises an antisense strand comprising a nucleotide sequence at least 80% homologous to SEQ ID NO:2 and a complementary sense strand comprising a nucleotide sequence at least 80% homologous to SEQ ID NO:11, and the second RNAi comprises an antisense strand comprising a nucleotide sequence at least 80% homologous to SEQ ID NO:8 and a complementary sense strand comprising a nucleotide sequence at least 80% homologous to SEQ ID NO:16. In some embodiments disclosed above, the first RNAi comprises an antisense strand comprising a nucleotide sequence at least 90% homologous to SEQ ID NO:2 and a complementary sense strand comprising a nucleotide sequence at least 90% homologous to SEQ ID NO:11, and the second RNAi comprises an antisense strand comprising a nucleotide sequence at least 90% homologous to SEQ ID NO:8 and a complementary sense strand comprising a nucleotide sequence at least 90% homologous to SEQ ID NO:16. In some embodiments disclosed above, the first RNAi comprises an antisense strand comprising a nucleotide sequence that is at least 95% homologous to SEQ ID NO:2 and a complementary sense strand comprising a nucleotide sequence that is at least 95% homologous to SEQ ID NO:11, and the second RNAi comprises an antisense strand comprising a nucleotide sequence that is at least 95% homologous to SEQ ID NO:8 and a complementary sense strand comprising a nucleotide sequence that is at least 95% homologous to SEQ ID NO:16.

[0018] In some embodiments, the disclosed method further comprises administering to the subject an additional agent for treating the infection caused by HBV. In some embodiments, the additional agent is a nucleoside / nucleotide analog (NA). In some such embodiments, the NA is entecavir (ETV), lamivudine or telbivudine (LDT). In some embodiments, the NA is adefovir or tenofovir (TDF). In certain embodiments, the NA is orally administered under a dosing regimen that provides the subject with an effective amount of the drug. For example, the NA may be administered to the subject once a day. In some embodiments, the NA is administered at a dose lower than that typically administered to a subject with HBV infection. For example, the NA may be administered at a dose lower than the recommended dose reflected in the approved label of the NA. Reducing the dose of the NA limits the nephrotoxicity often associated with these drugs.

[0019] Another general aspect of the present application is a combination or kit for use to treat HBV infection, such as chronic HBV infection (CHB), with or without viral co-infection, e.g., with or without co-infection with HDV and / or HCV and / or HIV, more particularly with or without at least co-infection with HDV, and / or for treating chronic HDV infection (CHD) in a subject in need thereof, comprising: (i) a first RNAi agent comprising an antisense strand comprising the nucleotide sequence of any one of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7, and a complementary sense strand (e.g., a sense strand comprising the nucleotide sequence of any one of SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, and SEQ ID NO:15); and (ii) a second RNAi agent comprising an antisense strand comprising the nucleotide sequence of any one of SEQ ID NO:8 and SEQ ID NO:9, and a sense strand comprising a complementary nucleotide sequence (e.g., a sense strand comprising the nucleotide sequence of any one of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, and SEQ ID NO:19). The present invention relates to a combination or kit comprising a pharmaceutical composition comprising an RNAi component having the formula:

[0020] In some embodiments, the combination or kit is for use in a subject with a Hepatitis B Virus (HBV) infection, more particularly with chronic HBV infection (CHB), with or without viral co-infection, to enhance immune response, reduce viral replication, and / or reduce expression of one or more Hepatitis B Virus (HBV) polypeptides, more particularly with one or more polypeptides selected from HBsAg and HBeAg.

[0021] In some embodiments, the combination or kit further comprises an additional agent for treating an infection caused by HBV.

[0022] Also provided herein is an effective amount of an RNAi component, and optionally an additional agent for treating an infection caused by HBV, such as a nucleoside / nucleotide analog or a nucleic acid polymer (NAP), in the manufacture of a medicament for treating HBV infection in a subject, for enhancing an immune response in a subject having HBV infection, for reducing viral replication in a subject having HBV infection, for reducing expression of one or more HBV polypeptides, more particularly one or more polypeptides selected from HBsAg and HBeAg, and / or for increasing targeted killing of hepatocytes containing integrated viral DNA or extrachromosomal DNA in a subject having HBV infection.

[0023] In some embodiments, the RNAi components are administered to the subject over the same treatment period for up to 2 years, up to 1 year, up to 6 months, or any time between 1 month and 2 years.

[0024] In another embodiment, the treatment comprises a first phase that is administered prior to a second phase, a) the first phase involves administering to the subject an RNAi component, thereby reducing HBsAg to a level low enough to allow restoration of T cell function, preferably to a serum HBsAg level of less than 1000, 100, 10 or 1 IU / mL; b) The second phase involves administering an additional compound or drug effective in treating the hepatitis infection.

[0025] In certain embodiments, the second phase does not include administering an RNAi component to the subject. In another embodiment, the second phase further includes administering an RNAi component to the subject. The first phase of treatment can last for about 1-24 months, e.g., 1-12 months, 1-3 months, 4-6 months, 7-9 months, 10-12 months, or any period therebetween. The second phase of treatment can last for about 1-24 months, e.g., 1-12 months, 4-6 months, 7-9 months, 10-12 months, 13-18 months, 19-24 months, or any period therebetween.

[0026] In some embodiments, the RNAi component is administered subcutaneously or intravenously, preferably subcutaneously, in an amount of about 40-1000 mg per dose, more particularly about 40-250 mg per dose, such as about 100-200 mg per dose, more particularly about 200 mg per dose, and is administered weekly, every 2 weeks, every 4 weeks, monthly, every 2 months or every 3 months, preferably every 4 weeks or monthly.

[0027] In some embodiments, the subject exhibits one or more of the following characteristics during or after treatment with a combination according to an embodiment of the present application: a) a reduction in HBV replication as measured by serum HBV DNA levels, preferably undetectable serum HBV DNA levels; b) a reduction in the expression of one or more HBV polypeptides, preferably a reduction in the expression of HBsAg as measured in serum HBsAg levels, preferably an undetectable serum HBsAg level; c) enhancement of HBV-specific T cell responses; d) disappearance of HBeAg or seroconversion of HBeAg if the subject was HBeAg positive prior to treatment; and e) HBsAg seroconversion and more particularly two or more of features a) through e), more particularly at least features a), b) and c), and more particularly all of features a) through d).

[0028] In some embodiments, the embodiments of the present application are for use in treating subjects who are co-infected with CHB and another chronic infection with at least one of Hepatitis D virus (HDV); Hepatitis C virus (HCV); or Human Immunodeficiency Virus (HIV). This combination can be used in a method of reducing serum levels of HDV RNA in subjects who are chronically co-infected with both HBV and HDV; a method of normalizing alanine aminotransferase (ALT) levels in subjects who are chronically co-infected with HBV and HDV; or a method of eradicating HDV infection in subjects who are chronically co-infected with HBV and HDV.

[0029] In any of the methods, the RNAi agent comprises at least one modified nucleotide or at least one modified internucleoside bond.In another variation, at least 90% or substantially all of the nucleotides in the first and second RNAi agent are modified nucleotides.In a further variation, the first or second RNAi agent further comprises a targeting ligand that is conjugated to the first or second RNAi agent.In one embodiment, the targeting ligand comprises N-acetyl-galactosamine. In a detailed embodiment, the targeting ligand is (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), (NAG31), (NAG32), (NAG33), (NAG34), (NAG35), (NAG36), (NAG37), (NAG38), (NAG39), (NAG39), (NAG30), (NAG31), (NAG32), (NAG33), (NAG34), (NAG35), (NAG36), (NAG37), (NAG38), (NAG39), (NAG39), (NAG39), (NAG30), (NAG31), (NAG32), (NAG33), (NAG34), (NAG34), (NAG35 ... 0)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. In one variation, the targeting ligand is (NAG25), (NAG25)s, (NAG31), (NAG31)s, (NAG37) or (NAG37)s. In another variation, the targeting ligand is conjugated to the sense strand of the first or second RNAi agent. In another variation, the targeting ligand is conjugated to the 5' end of the sense strand of the first or second RNAi agent.In yet another variation, the first and second RNAi agents independently comprise a duplex selected from the group consisting of an antisense strand comprising SEQ ID NO:1 and a sense strand comprising SEQ ID NO:10; an antisense strand comprising SEQ ID NO:2 and a sense strand comprising SEQ ID NO:11; an antisense strand comprising SEQ ID NO:3 and a sense strand comprising SEQ ID NO:11; an antisense strand comprising SEQ ID NO:4 and a sense strand comprising SEQ ID NO:12; an antisense strand comprising SEQ ID NO:8 and a sense strand comprising SEQ ID NO:16; an antisense strand comprising SEQ ID NO:8 and a sense strand comprising SEQ ID NO:17; an antisense strand comprising SEQ ID NO:2 and a sense strand comprising SEQ ID NO:13; and an antisense strand comprising SEQ ID NO:8 and a sense strand comprising SEQ ID NO:18. In a detailed variation, the first and second RNAi agents are each independently conjugated to a targeting ligand comprising N-acetyl-galactosamine, and the first and second RNAi agents independently comprise a duplex selected from the group consisting of an antisense strand comprising SEQ ID NO:2 and a sense strand comprising SEQ ID NO:11; an antisense strand comprising SEQ ID NO:4 and a sense strand comprising SEQ ID NO:12; an antisense strand comprising SEQ ID NO:8 and a sense strand comprising SEQ ID NO:16; an antisense strand comprising SEQ ID NO:2 and a sense strand comprising SEQ ID NO:13; and an antisense strand comprising SEQ ID NO:8 and a sense strand comprising SEQ ID NO:18. In yet another variation, the molar ratio of the first RNAi agent to the second RNAi agent is about 1:2 to about 5:1. In another variation, the molar ratio of the first RNAi agent to the second RNAi agent is about 2:1. In certain embodiments, the first and second RNAi agents are each independently conjugated to (NAG37)s, the first RNAi agent comprises an antisense strand comprising SEQ ID NO:2 and a sense strand comprising SEQ ID NO:11, and the second RNAi agent comprises an antisense strand comprising SEQ ID NO:8 and a sense strand comprising SEQ ID NO:16.

[0030] Further aspects, features and advantages of the present invention will be apparent from the following disclosure, including the detailed description of the invention and its preferred embodiments, as well as the appended claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] definition Listed below are definitions of various terms used in this specification. These definitions apply to the terms as they are used throughout the specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0032] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry and peptide chemistry are those well known and commonly employed in the art.

[0033] As used herein, the articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. Furthermore, use of the term "including" is not limiting, as are other forms such as "include," "includes," "included," etc.

[0034] As used herein and in the claims, the term "comprising" can include the embodiments "consisting of" or "consisting essentially of." The terms "comprise," "include," "having," "has," "can," "contain," and variations thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the specified components / steps and permit the presence of other components / steps. However, such descriptions should also be construed as describing compositions or processes as "consisting of" and "consisting essentially of" the recited compounds, which permits the presence of only the specified compounds, along with any pharma- ceutically acceptable carriers, and excludes other compounds.

[0035] As used herein, approximation may be applied to modify any quantitative expression that may vary without resulting in a change in the basic function to which it relates. Thus, a value modified by a term such as "substantially" may not be limited to the exact value specified in some cases. At least in some cases, the approximation may correspond to the precision of the instrument that measures the value.

[0036] As used herein, the term "treatment" or "treating" is defined as the application or administration of a therapeutic agent, i.e., a compound provided herein (alone or in combination with another pharmaceutical agent), to a subject (e.g., a human patient), or the application or administration of a therapeutic agent to a tissue or cell line (e.g., for diagnostic or ex vivo applications) isolated from a patient with HBV infection, particularly chronic HBV infection, symptoms of HBV infection, or the likelihood of developing HBV infection, with the goal of curing, curing, mitigating, palliating, altering, relieving, ameliorating, improving, or affecting HBV infection, symptoms of HBV infection, or the likelihood of developing HBV infection. Such treatments may be specifically tailored or modified based on knowledge gained from the field of pharmacogenetics.

[0037] As used herein, the terms "patient," "individual," or "subject" refer to a human or non-human mammal. Non-human mammals include mammals such as, for example, farm animals and pets, e.g., sheep, cows, pigs, dogs, cats, and mice. Preferably, the patient, subject, or individual is a human.

[0038] As used herein, "treatment naive" means a patient, individual or subject who has not previously received treatment with a drug (investigational or approved) for HBV infection, particularly a nucleoside analog drug, a nucleotide analog drug or an interferon drug.

[0039] Alternatively, the patient, individual or subject treated according to the method of the present disclosure may be "treatment-experienced". As used herein, "treatment-experienced" refers to a patient, individual or subject who has previously undergone at least one previous course of HBV antiviral therapy, particularly a nucleoside or nucleotide treatment. Particular nucleosides or nucleotides include entecavir or a pharma- ceutically acceptable salt or solvate thereof, such as entecavir monohydrate, or tenofovir or a salt or prodrug thereof, such as tenofovir alafenamide or tenofovir disoproxil fumarate.

[0040] As used in reference to the methods of treatment and use of the compounds and pharmaceutical compositions thereof described herein, an individual "in need thereof" can be an individual who has been diagnosed with or previously treated for the condition to be treated. Typically, in the case of the step of administering a compound provided herein, the method further contemplates the step of identifying an individual or subject in need of the particular treatment to be administered or having the particular condition to be treated.

[0041] As used herein, the term "pharmaceutical acceptable" means a material, such as a carrier or diluent, that does not destroy the biological activity or properties of a compound and is relatively non-toxic, i.e., the material may be administered to an individual without producing undesired biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0042] As used herein, the term "pharmaceutical acceptable salt" refers to derivatives of the disclosed compounds, where the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutical acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutical acceptable salts provided herein include conventional non-toxic salts of the parent compound, for example, formed from non-toxic inorganic or organic acids. The pharmaceutical acceptable salts provided herein can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water, in an organic solvent, or in a mixture of the two (generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred). Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0043] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound provided herein and pharma- ceutical acceptable carrier.The pharmaceutical composition facilitates the administration of the compound to a patient or subject.There are multiple techniques of administering the compound in the art, including but not limited to intravenous administration, oral administration, aerosol administration, parenteral administration, ophthalmic administration, pulmonary administration and topical administration.

[0044] As used herein, the term "pharmaceutical acceptable carrier" refers to a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent or encapsulating material, which is involved in carrying or transporting the compound provided herein in or to a patient so that the compound can perform its intended function. Typically, such constructs are carried or transported from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compound provided herein, and not harmful to the patient. Some examples of materials which may function as pharma- ceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository wax; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic compatible substances used in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carriers" also include any coatings that are compatible with the activity of the compounds provided herein and are physiologically acceptable to the patient, antibacterial and antifungal agents, absorption delaying agents, and the like. Supplementary active compounds may be incorporated into the compositions. "Pharmaceutically acceptable carriers" may further include pharmaceutically acceptable salts of the compounds provided herein.Other additional ingredients that may be included in the pharmaceutical compositions provided herein are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, ed., Mack Publishing Co., 1985, Easton, Pa.), which is incorporated herein by reference.

[0045] The term "tablet" as used herein refers to an orally administrable, single-dose solid dosage form, which can be produced by compressing a drug substance or a pharma- ceutically acceptable salt thereof with suitable excipients (e.g., fillers, disintegrants, lubricants, glidants, and / or surfactants) by conventional tableting processes. Tablets can be produced using conventional granulation methods, such as wet or dry granulation, optionally with milling of granules followed by compression, and optionally with coating. Tablets can also be produced by spray drying.

[0046] As used herein, the terms "effective amount," "pharmacologically effective amount," and "therapeutically effective amount" refer to a nontoxic but sufficient amount of an agent to produce a desired biological result. That result may be reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. The appropriate therapeutic amount in any individual case may be determined by one of skill in the art through routine experimentation.

[0047] The terms "combination", "therapeutic combination", "pharmaceutical combination" or "combination product" as used herein mean a non-fixed combination or kit of parts for combined administration, where two or more therapeutic agents can be administered independently, either simultaneously or separately within a time interval, particularly such that the combination partners can exhibit a synergistic, e.g., synergistic, effect.

[0048] As used herein, an "adverse event (AE)" refers to any untoward medical occurrence in a subject administered an investigational drug, e.g., an RNAi component disclosed herein or a pharmaceutical formulation thereof, and does not necessarily refer only to events that have a clear causal relationship to the relevant investigational drug.

[0049] As used herein, the term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon having the specified number of carbon atoms (i.e., C1-C6 alkyl means alkyl having 1-6 carbon atoms), including straight and branched chains. In embodiments, C1-C6 alkyl groups are provided herein. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl. Other examples of C1-C6 alkyl include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl.

[0050] As used herein, the term "alkoxy" means an alkyl (a chain of carbon and hydrogen) group single-bonded to an oxygen, such as a methoxy or ethoxy group.

[0051] As used herein, the term "amino" refers to functional groups having the formula -NH2, -NH(alkyl), and -N(alkyl)2, where alkyl is as defined herein.

[0052] As used herein, the term "amide" means a functional group having the formula -C(O)N(R)2 or -N(R)C(O)alkyl, where a carbon atom is double bonded to an oxygen atom and R is, independently at each occurrence, hydrogen or alkyl.

[0053] As used herein, the term "ester" means a functional group having the formula -C(O)alkoxy, COalkyl, -OC(O)alkyl, where a carbon atom is doubly bonded to an oxygen atom and single bonded to an alkoxy group as defined herein.

[0054] As used herein, the terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably fluorine, chlorine or bromine, and more preferably fluorine or chlorine.

[0055] As used herein, the term "nitrile" refers to the functional group --CN in which a carbon is triple bonded to a nitrogen.

[0056] As used herein, the term "heterocycle" refers to a saturated or partially saturated molecule, including tetrahydrofuran, oxetane, dioxane, or other cyclic ethers. Heterocycle also includes bridged or spirocyclic bicyclic structures, where each ring in the bicycle has 3-8 atoms and contains 0, 1, or 2 N, O, or S atoms. The term "heterocyclyl" includes cyclic esters (i.e., lactones) and cyclic amides (i.e., lactams), and specifically includes, but is not limited to, epoxyzyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl (i.e., oxanyl), pyranyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1,3-oxazinanyl, 1,3-thiazinanyl, 2-azabicyclo[2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 6-azabicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 4-azabicyclo[3.1.1]heptanyl, 5-azabicyclo[3.1.1]hexanyl, 6-azabicyclo[3.1.1]heptanyl, 7-azabicyclo[3.1.1]heptanyl, 8-azabicyclo[3.1.1]heptanyl, 9-azabicyclo[3.1.1]heptanyl, 10-azabicyclo[3.1.1]heptanyl, 11-azabicyclo[3.1.1]heptanyl, 12-azabicyclo[3.1.1]heptanyl, 13-azabicyclo[3.1.1]heptanyl, 14-azabicyclo[3.1.1]heptanyl, 15-azabicyclo[3.1.1]heptanyl, 16-azabicyclo[3.1.1]hept ]heptanyl, 2-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 3-oxa-7-azabicyclo[3.3.1]nonanyl, 3-oxa-9-azabicyclo[3.3.1]nonanyl, 2-oxa-5 -azabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.5]nonanyl, 3-oxaspiro[5.3]nonanyl and 8-oxabicyclo[3.2.1]octanyl.

[0057] It will be understood that when a carbon is in the (R)-configuration, this means that said carbon is an asymmetric carbon. As one skilled in the art will recognize, a symmetric carbon that is not a stereocenter cannot be in the (R)- or (S)-configuration. Only asymmetric carbons can be in said configurations. Thus, the R bonded to the amine at the 4-position of the quinazoline is 3 It will be understood that the carbon is an asymmetric carbon.

[0058] Whenever a substituent is represented on a chemical structure, "---" represents the bond to the remainder of the molecule. Lines drawn through a particular ring of a ring system (e.g., "---") indicate that the bond may be attached to any of the suitable ring atoms.

[0059] HBV infections that may be treated according to the disclosed methods include HBV genotype A, B, C, and / or D infections. However, in embodiments, the disclosed methods may treat any HBV genotype ("pan-genotype treatment"). HBV genotyping may be performed using methods known in the art, for example, INNO-LIPA® HBV Genotyping (Innogenetics NV, Ghent, Belgium).

[0060] As used herein, the term "level of renal sufficiency" refers to the level of renal (kidney) function in an individual. As used herein, the level of renal sufficiency in an individual includes no renal dysfunction, mild renal dysfunction, moderate renal dysfunction, severe renal dysfunction, and end-stage renal disease (ESRD). The term renal dysfunction includes mild renal dysfunction, moderate renal dysfunction, severe renal dysfunction, and end-stage renal disease (ESRD).

[0061] As used herein, "no renal dysfunction" means that an individual has normal renal function. The level of renal function, renal function sufficiency or renal dysfunction can be determined using any method known in the art or described herein. For terms such as "mild renal dysfunction", "moderate renal dysfunction", "severe renal dysfunction" and "end-stage renal disease (ESRD)", the cutoffs that define these levels of renal function sufficiency depend on the test that is carried out to determine the level of renal function sufficiency.

[0062] Depending on the technique used and the interpretation of the medical practitioner, various thresholds or cutoffs may be used to determine the level of renal function sufficiency of an individual. When determining the level of renal function sufficiency of an individual, several variables may be considered, including, for example, whether the individual is obese, the race of the individual, the sex of the individual, and the age of the individual. Recommendations regarding classification of renal function sufficiency are known in the art. These recommendations may change over time as newer techniques or better formulas are used to more accurately determine the renal function of an individual. Regarding the method of determining the level of renal function sufficiency of an individual, in some embodiments, the level of renal function sufficiency is determined by the serum creatinine level of the individual. In some embodiments, the method of determining the level of renal function sufficiency of an individual is not specified. In some embodiments, the individual is asked about the level of renal function sufficiency, either verbally or on paper.

[0063] The level of renal function sufficiency of an individual may include, for example, no renal dysfunction (i.e., normal renal function), mild renal dysfunction, moderate renal dysfunction, severe renal dysfunction, and ESRD. In some embodiments, the level of renal function sufficiency is not specified.

[0064] An individual's level of renal function sufficiency may be determined only when the individual visits a medical professional. In some embodiments, to determine an individual's level of renal function sufficiency, the individual is asked a series of questions, verbally or in writing. The questions may include asking about risk factors associated with renal function sufficiency. Risk factors associated with an individual's level of renal function sufficiency may include, for example, whether the individual has diabetes, hypertension, gout, coronary artery disease, congestive heart failure, severe liver disease, or a history of kidney surgery. Other risk factors associated with kidney dysfunction may include, for example, older age (e.g., over 60 years old), male sex, use of nephrotoxic drugs such as furosemide, chemotherapy or HIV infection, protein in urine, or a single kidney.

[0065] In some embodiments, tests are administered to an individual to determine the individual's level of renal function sufficiency. For example, a medical professional may prescribe a urine test or a blood panel test for the individual. Urine tests may include, for example, a timed urine collection or a 24-hour urine collection. Urine may be analyzed for levels of protein, glucose, ketone bodies, or abnormal debris called urinary casts, or the levels of certain markers, such as creatinine, may be determined. A blood panel may be analyzed for markers, such as, for example, creatinine, blood urea nitrogen (BUN), and electrolytes.

[0066] In some embodiments, patients with renal dysfunction also have liver dysfunction. Liver dysfunction is a state in which the normal function of the liver is reduced. Liver dysfunction can be acute, which develops rapidly, or chronic. Chronic liver dysfunction, or cirrhosis, can occur due to many causes, such as excessive alcohol intake, hepatitis, autoimmune disease, genetic or metabolic, or it can be idiopathic. Liver damage is generally irreversible, and treatment consists of preventing progression and treating symptoms. In severe cases, liver transplantation is the only option. Liver dysfunction may not show noticeable symptoms, or it may be characterized by symptoms such as decreased blood clotting ability (coagulopathy) and brain dysfunction (encephalopathy), fluid accumulation in the abdominal cavity, increased risk of infection, hypogonadism, changes in liver size, jaundice, and increased sensitivity to drugs. The Child-Pugh score is a system that evaluates the prognosis of liver dysfunction (such as the intensity of treatment required and the need for liver transplantation) in chronic liver diseases, mainly cirrhosis. It provides a prediction of increased severity of liver disease.

[0067] The Child-Pugh group, Child-Pugh classification, etc. are rankings of the level of liver dysfunction based on the Child-Pugh score. If the Child-Pugh score is 5 to 6, it is classified as Child-Pugh class A (mild liver dysfunction), and the expected two-year survival rate is 85%. If the Child-Pugh score is 7 to 9, it is classified as Child-Pugh class B (moderate liver dysfunction), and the expected two-year survival rate is 57%. If the Child-Pugh score is 10 to 15, it is classified as Child-Pugh class C (severe liver dysfunction), and the expected two-year survival rate is 35%.

[0068] Child-Pugh score is a score based on five clinical measures of liver dysfunction, including total bilirubin, serum albumin, PT INR, ascites and hepatic encephalopathy levels.Each measure is rated 1, 2 or 3, and the sum of the five measures is the Child-Pugh score.Child-Pugh score can be used to classify liver dysfunction by dividing subjects into Child-Pugh groups.

[0069] The level of liver function sufficiency of an individual can include, for example, no liver dysfunction (i.e., normal liver function), mild liver dysfunction, moderate liver dysfunction, and severe liver dysfunction. In some embodiments, the level of liver function sufficiency is not specified.

[0070] As used herein, unless otherwise specified, the term "isolated form" means that the compound is present in a form separated from any biological environment (e.g., plasma, blood, gastric fluid, urine, cerebrospinal fluid, etc.).

[0071] In particular embodiments of the present application, a therapeutically effective amount refers to an amount of a composition or therapeutic combination that is sufficient to achieve one, two, three, four or more of the following effects: (i) reducing or ameliorating the severity of HBV infection or symptoms associated therewith, (ii) shortening the duration of HBV infection or symptoms associated therewith, (iii) preventing the progression of HBV infection or symptoms associated therewith, (iv) causing regression of HBV infection or symptoms associated therewith, (v) preventing the onset or onset of HBV infection or symptoms associated therewith, (vi) preventing the onset or onset of HBV infection or symptoms associated therewith, (vii) preventing the onset or onset of HBV infection or symptoms associated therewith, (viii) preventing the onset or onset of HBV infection or symptoms associated therewith, (viii) preventing the onset or onset of HBV infection or symptoms associated therewith, (viiii ... ) treating or re-treating chronic HBV infection or symptoms associated therewith that recur after a functional cure has been achieved, (vii) preventing the recurrence of HBV infection or symptoms associated therewith, (viii) reducing hospitalization of a subject with HBV infection, (ix) shortening the length of hospitalization of a subject with HBV infection, (x) increasing the survival rate of a subject with HBV infection, (xi) eliminating HBV infection in a subject, (xii) inhibiting or reducing HBV replication in a subject, and / or (xiii) enhancing or improving the prophylactic or therapeutic effect of another therapy.

[0072] A therapeutically effective amount may also be an amount of compound sufficient to reduce HBsAg levels consistent with progression to clinical seroconversion; achieve sustained HBsAg clearance associated with a reduction in infected liver cells by the subject's immune system; induce a population of HBV antigen-specific activated T cells; and / or achieve sustained elimination of HBsAg during or after treatment, thereafter preferably sustained for at least six months after the end of treatment, and most preferably for life.

[0073] As used herein, the terms and phrases "in combination," "in combination with," "co-delivery," and "administered with" in the context of administration of two or more therapies or components to a subject refer to the simultaneous or subsequent administration of two or more therapies or components, such as two vectors, e.g., DNA plasmids, peptides, or therapeutic combinations, and adjuvants. "Concurrent administration" or "administered simultaneously" refers to the administration of two or more therapies or components within the same treatment period, e.g., at least within the same day. When two components are "administered together," "administered in combination," or "administered within the same treatment period," they can be administered sequentially in separate compositions within a short time period. "Overlapping administration" refers to the administration of two or more therapies or components with at least one overlapping treatment period, but not within the same overall treatment period. "Subsequent administration" can be the administration of two or more therapies or components in sequence during different treatment periods. The use of the term "in combination with" does not limit the order in which the therapies or components are administered to a subject. For example, a first therapy or component (e.g., an RNAi component) may be administered prior to (e.g., 5 minutes to 1 hour before), in conjunction with or simultaneously with, or subsequent to (e.g., 5 minutes to 1 hour after) administration of a second therapy or component. In another embodiment, the first therapy or component (e.g., an RNAi component) and the second therapy or component, or a stereoisomer or tautomeric form thereof, a pharma- ceutically acceptable salt thereof, or a solvent thereof, are administered in separate compositions, such as two separate compositions.

[0074] RNAi component In one aspect, the RNAi component comprises one or more RNAi agents. Each RNAi agent disclosed herein comprises at least a sense strand and an antisense strand. The sense strand and the antisense strand may be partially, substantially or fully complementary to one another. The sense strand and the antisense strand of the RNAi agents described herein may each be 16-30 nucleotides in length. In some embodiments, the sense strand and the antisense strand are independently 17-26 nucleotides in length. In some embodiments, the sense strand and the antisense strand are independently 19-26 nucleotides in length. In some embodiments, the sense strand and the antisense strand are independently 21-26 nucleotides in length. In some embodiments, the sense strand and the antisense strand are independently 21-24 nucleotides in length. The sense strand and the antisense strand may be either the same length or different lengths. The HBV RNAi agents disclosed herein are designed to include an antisense strand sequence that is at least partially complementary to a sequence in the HBV genome that is conserved across the majority of known serotypes of HBV. Upon delivery to a cell expressing HBV, the RNAi agents described herein inhibit the expression of one or more HBV genes in vivo or in vitro.

[0075] The RNAi agent comprises a sense strand (also referred to as passenger strand) that comprises a first sequence, and an antisense strand (also referred to as guide strand) that comprises a second sequence. The sense strand of the HBV RNAi agent described herein comprises a core extension that has at least about 85% identity to the nucleotide sequence of at least 16 consecutive nucleotides in HBV mRNA. In some embodiments, the sense strand core nucleotide extension that has at least about 85% identity to the sequence in HBV mRNA is 16, 17, 18, 19, 20, 21, 22 or 23 nucleotides in length. The antisense strand of the HBV RNAi agent comprises a nucleotide sequence that has at least about 85% complementarity to the sequence in HBV mRNA and the corresponding sense strand over the core extension of at least 16 consecutive nucleotides. In some embodiments, the antisense strand core nucleotide sequence having at least about 85% complementarity to a sequence in HBV mRNA or the corresponding sense strand is 16, 17, 18, 19, 20, 21, 22 or 23 nucleotides in length.

[0076] In some embodiments, the RNAi component comprises a first RNAi agent comprising an antisense strand comprising the nucleotide sequence of any one of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7 and a complementary sense strand (e.g., a sense strand comprising the nucleotide sequence of any one of SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, and SEQ ID NO:15), or a second RNAi agent comprising an antisense strand comprising the nucleotide sequence of any one of SEQ ID NO:8 and SEQ ID NO:9 and a complementary sense strand (e.g., a sense strand comprising the nucleotide sequence of any one of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, and SEQ ID NO:19). In some embodiments, the RNAi component comprises a first RNAi agent comprising an antisense strand comprising the nucleotide sequence of any one of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7 and a complementary sense strand (e.g., a sense strand comprising the nucleotide sequence of any one of SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, and SEQ ID NO:15), and a second RNAi agent comprising an antisense strand comprising the nucleotide sequence of any one of SEQ ID NO:8 and SEQ ID NO:9 and a complementary sense strand (e.g., a sense strand comprising the nucleotide sequence of any one of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, and SEQ ID NO:19).

[0077] In some embodiments, the first and second RNAi agents disclosed herein comprise any of the sequences in Table 1.

[0078] [Table 1]

[0079] Targeting Group In some embodiments, the RNAi agent is delivered to the target cell or tissue by using any oligonucleotide delivery technique known in the art.Nucleic acid delivery methods include, but are not limited to, by encapsulation in liposomes, by iontophoresis, or by incorporation into other vehicles such as hydrogels, cyclodextrins, biodegradable nanocapsules and bioadhesive microspheres, proteinaceous vectors or dynamic polyconjugates (DPCs) (see, for example, WO 2000 / 053722, WO 2008 / 0022309, WO 2011 / 104169 and WO 2012 / 083185, each of which is incorporated herein by reference).In some embodiments, the HBV RNAi agent is delivered to the target cell or tissue by covalently linking the RNAi agent to a targeting group.In some embodiments, the targeting group can include a cell receptor ligand, such as an asialoglycoprotein receptor (ASGPr) ligand. In some embodiments, the ASGPr ligand comprises or consists of a galactose derivative cluster. In some embodiments, the galactose derivative cluster comprises an N-acetyl-galactosamine trimer or an N-acetyl-galactosamine tetramer. In some embodiments, the galactose derivative cluster is an N-acetyl-galactosamine trimer or an N-acetyl-galactosamine tetramer.

[0080] The targeting group may be attached to the 3' or 5' end of the sense strand or antisense strand of the HBV RNAi agent. In some embodiments, the targeting group is attached to the 3' or 5' end of the sense strand. In some embodiments, the targeting group is attached to the 5' end of the sense strand. In some embodiments, the targeting group is attached to the RNAi agent via a linker.

[0081] In some embodiments, the RNAi component comprises a combination or mixture of a first and a second RNAi agent having different nucleotide sequences. In some embodiments, the first and the second RNAi agent are each separately and independently bound to a targeting group. In some embodiments, the first and the second RNAi agent are each bound to a targeting group consisting of N-acetyl-galactosamine. In some embodiments, when the first and the second RNAi agent are included in the composition, each of the RNAi agents is bound to the same targeting group. In some embodiments, when the first and the second RNAi agent are included in the composition, each of the RNAi agents is bound to a different targeting group, for example, a targeting group having a different chemical structure.

[0082] In some embodiments, the targeting group is linked to the first and second RNAi agents without the use of additional linkers. In some embodiments, the targeting group is designed with a linker that is easily present to facilitate linking to the first or second RNAi agent. In some embodiments, when the first and second RNAi agents are included in the composition, the first and second RNAi agents can be linked to the targeting group using the same linker. In some embodiments, when the first and second RNAi agents are included in the composition, the first and second RNAi agents are linked to the targeting group using different linkers.

[0083] Examples of targeting and linking groups are shown in Table 2. The non-nucleotide group may be covalently attached to the 3' and / or 5' end of either the sense strand and / or the antisense strand. In some embodiments, the first or second RNAi agent contains a non-nucleotide group attached to the 3' and / or 5' end of the sense strand. In some embodiments, the non-nucleotide group is attached to the 5' end of the first or second RNAi agent sense strand. The non-nucleotide group may be directly or indirectly attached to the first or second RNAi agent via a linker / linking group. In some embodiments, the non-nucleotide group is attached to the first or second RNAi agent via a labile, cleavable or reversible bond or linker.

[0084] The targeting and binding groups include the following, the chemical structures of which are shown below in Table 2: (PAZ), (NAG13), (NAG13)s, (NAG18), (NAG18)s, (NAG24), (NAG24)s, (NAG25), (NAG25)s, (NAG26), (NAG26)s, (NAG27), (NAG27)s, (NAG28), (NAG28)s, (NAG 29), (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), (NAG39)s. Each sense and / or antisense strand can have any of the targeting or binding groups listed above, as well as other targeting or binding groups conjugated to the 5' and / or 3' ends of the sequence.

[0085] [Table 2] JPEG2024527380000003.jpg213170JPEG2024527380000004.jpg179170JPEG2024527380000005.jpg176170 JPEG2024527380000006.jpg194170JPEG2024527380000007.jpg180170JPEG2024527380000008.jpg209170 JPEG2024527380000009.jpg189170JPEG2024527380000010.jpg215170JPEG2024527380000011.jpg185170 JPEG2024527380000012.jpg223170JPEG2024527380000013.jpg178170JPEG2024527380000014.jpg231166

[0086] Modified Nucleotides In some embodiments, the first or second RNAi agent contains one or more modified nucleotides. As used herein, a "modified nucleotide" is a nucleotide other than a ribonucleotide (2'-hydroxyl nucleotide). In some embodiments, at least 50% (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99% or 100%) of the nucleotides are modified nucleotides. As used herein, modified nucleotides include, but are not limited to, deoxyribonucleotides, nucleotide mimics, abasic nucleotides (represented herein as Ab), 2'-modified nucleotides, 3'-3' linked (inverted) nucleotides (represented herein as invdN, invN, invn, invAb), non-natural base-containing nucleotides, bridged nucleotides, peptide nucleic acids (PNAs), 2',3'-seconucleotide mimics (unlocked nucleobase analogs, herein referred to as NUNA or NNA). UNA ), locked nucleotides (represented herein as NLNA or N LNA3'-O-methoxy (2' internucleoside linked) nucleotides (represented herein as 3'-OMen), 2'-F-arabinonucleotides (represented herein as NfANA or Nf ANA 2'-Modified nucleotides (i.e., nucleotides having a group other than a hydroxyl group at the 2' position of the 5-membered ring sugar) include, but are not limited to, 2'-O-methyl nucleotides (represented herein as lowercase "n" in nucleotide sequences), 2'-deoxy-2'-fluoro nucleotides (represented herein as Nf, also represented as 2'-fluoro nucleotides), 2'-deoxy nucleotides (represented herein as dN), 2'-methoxyethyl (2'-O-2-methoxylethyl) nucleotides (represented herein as NM or 2'-MOE), 2'-amino nucleotides, and 2'-alkyl nucleotides. Not all positions in a given compound need be uniformly modified. Conversely, two or more modifications can be incorporated into the first or second RNAi agent or even into a single nucleotide.The sense strand and antisense strand of RNAi agent can be synthesized and / or modified by methods known in the art.The modification at one nucleotide is independent of the modification at another nucleotide.

[0087] Modified nucleobases include synthetic and natural nucleobases, such as 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and O-6 substituted purines (e.g., 2-aminopropyladenine, 5-propynyluracil or 5-propynylcytosine), 5-methylcytosine (5-me-C), 5-hydroxymethylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-alkyl (e.g., 6-methyl, 6-ethyl, 6-isopropyl or 6-n-butyl) derivatives of adenine and guanine, 2-alkyl (e.g., 2-methyl, 2-ethyl, 2-isopropyl or 2-n-butyl) and other alkyl derivatives of adenine and guanine, 2-thiouracil, These include 2-thiothymine, 2-thiocytosine, 5-halouracil, cytosine, 5-propynyluracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-sulfhydryl, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo (e.g., 5-bromo), 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and adenine, 8-azaguanine and adenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine and adenine.

[0088] In some embodiments, all or at least 90% of the nucleotides of the first or second RNAi agent are modified nucleotides.As used herein, the RNAi agent in which at least 90% of the nucleotides present are modified nucleotides is an RNAi agent that has 4 or less (i.e., 0, 1, 2, 3 or 4) nucleotides that are ribonucleotides in both sense and antisense strands.As used herein, the sense strand in which at least 90% of the nucleotides present are modified nucleotides is a sense strand that has 2 or less (i.e., 0, 1 or 2) nucleotides that are ribonucleotides in the sense strand.As used herein, the antisense strand in which at least 90% of the nucleotides present are modified nucleotides is an antisense strand that has 2 or less (i.e., 0, 1 or 2) nucleotides that are ribonucleotides in the sense strand.In some embodiments, one or more nucleotides of the RNAi agent are ribonucleotides.

[0089] Modified Internucleoside Linkages In some embodiments, one or more nucleotides of the first or second RNAi agent are linked by a non-standard bond or backbone (i.e., a modified internucleoside bond or a modified backbone). In some embodiments, the modified internucleoside bond is a non-phosphate-containing covalent internucleoside bond. Modified internucleoside linkages or backbones include, but are not limited to, 5'-phosphorothioate groups (represented herein as a lower case "s"), chiral phosphorothioates, thiophosphates, phosphorodithioates, phosphotriesters, aminoalkyl-phosphotriesters, alkyl phosphonates (e.g., methyl phosphonates or 3'-alkylene phosphonates), chiral phosphonates, phosphinates, phosphoramidates (e.g., 3'-amino phosphoramidate, aminoalkyl phosphoramidate or thionophosphoramidate), thionoalkyl-phosphonates, thionoalkyl phosphotriesters, morpholino linkages, boranophosphates with normal 3'-5' linkages, 2'-5' linked analogs of boranophosphates, or boranophosphates with inverted polarity in which adjacent pairs of nucleoside units are linked 3'-5' to 5'-3' or 2'-5' to 5'-2'. In some embodiments, the modified internucleoside linkage or backbone is deficient in phosphorus atom. Modified internucleoside linkages that are deficient in phosphorus atom include, but are not limited to, short chain alkyl or cycloalkyl intersugar linkages, mixed heteroatom and alkyl or cycloalkyl intersugar linkages, or one or more short chain heteroatom or heterocyclic intersugar linkages. In some embodiments, modified internucleoside backbone includes, but is not limited to, siloxane backbone, sulfide backbone, sulfoxide backbone, sulfone backbone, formacetyl and thioformacetyl backbone, methyleneformacetyl and thioformacetyl backbone, alkene-containing backbone, sulfamic acid backbone, methyleneimino and methylenehydrazino backbone, sulfonic acid and sulfonamide backbone, amide backbone, and other backbone with mixed N, O, S and CH2 moieties.

[0090] In some embodiments, the sense strand of the first or second RNAi agent may contain 1, 2, 3, 4, 5, or 6 phosphorothioate linkages, the antisense strand of the first or second RNAi agent may contain 1, 2, 3, 4, 5, or 6 phosphorothioate linkages, or both the sense strand and the antisense strand may independently contain 1, 2, 3, 4, 5, or 6 phosphorothioate linkages. In some embodiments, the sense strand of the first or second RNAi agent may contain 1, 2, 3, or 4 phosphorothioate linkages, the antisense strand of the first or second RNAi agent may contain 1, 2, 3, or 4 phosphorothioate linkages, or both the sense strand and the antisense strand may independently contain 1, 2, 3, or 4 phosphorothioate linkages.

[0091] In some embodiments, the first or second RNAi agent sense strand contains at least two phosphorothioate internucleoside linkages. In some embodiments, the at least two phosphorothioate internucleoside linkages are between nucleotides at positions 1-3 from the 3' end of the sense strand. In some embodiments, the at least two phosphorothioate internucleoside linkages are between nucleotides at positions 1-3, 2-4, 3-5, 4-6, 4-5 or 6-8 from the 5' end of the sense strand. In some embodiments, the first or second RNAi agent antisense strand contains four phosphorothioate internucleoside linkages. In some embodiments, the four phosphorothioate internucleoside linkages are between nucleotides at positions 1-3 from the 5' end of the sense strand and between nucleotides at positions 19-21, 20-22, 21-23, 22-24, 23-25, or 24-26 from the 5' end of the sense strand. In some embodiments, the first or second RNAi agent contains at least two phosphorothioate internucleoside linkages in the sense strand and three or four phosphorothioate internucleoside linkages in the antisense strand.

[0092] In some embodiments, the first or second RNAi agent contains one or more modified nucleotides and one or more modified internucleoside linkages. In some embodiments, a 2'-modified nucleoside is combined with a modified internucleoside linkage.

[0093] In some embodiments, the modified antisense strand sequence comprising an RNAi component has one of the sequences shown in Table 3. Table 3 shows the modified sequences of the antisense strand and their underlying unmodified sequences. In some embodiments, the modified sense strand sequence comprising an RNAi component has one of the sequences shown in Table 4. Table 4 shows the modified sequences of the sense strand and their underlying unmodified sequences.

[0094] [Table 3] JPEG2024527380000016.jpg254163JPEG2024527380000017.jpg254163JPEG2024527380000018.jpg53166

[0095] [Table 4] JPEG2024527380000020.jpg254163JPEG2024527380000021.jpg231166

[0096] In some embodiments, the first and second RNAi agents disclosed herein comprise any of the modified sequences in Table 5.

[0097] [Table 5] JPEG2024527380000023.jpg120170

[0098] Of note, the sense strands in Tables 4 and 5 contain a targeting group (NAG25, NAG25s, NAG37 or NAG37s) at the 5' end. It will be understood that the present disclosure also includes sense strands having sequences as shown in Tables 4 and 5, but without a targeting group at the 5' end, or with a targeting group other than NAG25, NAG25s, NAG37 or NAG37s, as disclosed herein. It will be further understood that both the antisense strand and / or the sense strand as shown in Table 3 can be modified at either the 5' end or the 3' end with a targeting group as disclosed herein.

[0099] In some embodiments, the first RNAi agent comprises SEQ ID NO:5 and SEQ ID NO:14. In some embodiments, the first RNAi agent comprises SEQ ID NO:6 and SEQ ID NO:14. In some embodiments, the first RNAi agent comprises SEQ ID NO:7 and SEQ ID NO:15. In some embodiments, the first RNAi agent comprises SEQ ID NO:1 and SEQ ID NO:10, 11 or 13. In some embodiments, the first RNAi agent comprises SEQ ID NO:2 and SEQ ID NO:10, 11 or 13. In some embodiments, the first RNAi agent comprises SEQ ID NO:3 and SEQ ID NO:10, 11 or 13. In some embodiments, the first RNAi agent comprises SEQ ID NO:4 and SEQ ID NO:12. In some embodiments, the second RNAi agent comprises SEQ ID NO:9 and SEQ ID NO:19. In some embodiments, the second RNAi agent comprises SEQ ID NO:8 and SEQ ID NO:16, 17 or 18.

[0100] In some embodiments, the RNAi components include a first RNAi agent that comprises SEQ ID NO:5 and SEQ ID NO:14, and a second RNAi agent that comprises SEQ ID NO:9 and SEQ ID NO:19. In some embodiments, the RNAi components include a first RNAi agent that comprises SEQ ID NO:6 and SEQ ID NO:14, and a second RNAi agent that comprises SEQ ID NO:9 and SEQ ID NO:19. In some embodiments, the RNAi components include a first RNAi agent that comprises SEQ ID NO:7 and SEQ ID NO:15, and a second RNAi agent that comprises SEQ ID NO:9 and SEQ ID NO:19.

[0101] In some embodiments, the RNAi components include a first RNAi agent comprising SEQ ID NO:1 and SEQ ID NO:10, 11 or 13, and a second RNAi agent comprising SEQ ID NO:8 and SEQ ID NO:16, 17 or 18. In some embodiments, the RNAi components include a first RNAi agent comprising SEQ ID NO:2 and SEQ ID NO:10, 11 or 13, and a second RNAi agent comprising SEQ ID NO:8 and SEQ ID NO:16, 17 or 18. In some embodiments, the RNAi components include a first RNAi agent comprising SEQ ID NO:3 and SEQ ID NO:10, 11 or 13, and a second RNAi agent comprising SEQ ID NO:8 and SEQ ID NO:16, 17 or 18. In some embodiments, the RNAi components include a first RNAi agent comprising SEQ ID NO:4 and SEQ ID NO:12, and a second RNAi agent comprising SEQ ID NO:8 and SEQ ID NO:16, 17 or 18.

[0102] In some embodiments, the RNAi components include a first and a second RNAi agent in a molar ratio of about 1:1, 2:1, 3:1, 4:1, or 5:1. In some embodiments, the two HBV RNAi agents are administered in a molar ratio of about 2:1.

[0103] In some embodiments, the first and second RNAi agents are each independently conjugated to (NAG37)s, the first RNAi agent comprises an antisense strand that comprises SEQ ID NO:2 and a sense strand that comprises SEQ ID NO:11, and the second RNAi agent comprises an antisense strand that comprises SEQ ID NO:8 and a sense strand that comprises SEQ ID NO:16.

[0104] In some embodiments, one of the RNAi agents comprising an RNAi component is represented by the following structure (an antisense strand comprising SEQ ID NO:8 and a sense strand comprising SEQ ID NO:16), shown as a sodium salt:

[0105] [ka]

[0106] In some embodiments, one of the RNAi agents comprising an RNAi component is represented by the following structure (an antisense strand comprising SEQ ID NO:8 and a sense strand comprising SEQ ID NO:18), shown as a sodium salt:

[0107] [ka]

[0108] In some embodiments, one of the RNAi agents that comprises an RNAi component is represented by the following structure (the antisense strand comprises SEQ ID NO:8 and the sense strand comprises SEQ ID NO:16), shown as the free acid:

[0109] [ka]

[0110] In some embodiments, one of the RNAi agents comprising an RNAi component is represented by the following structure (an antisense strand comprising SEQ ID NO: 120 and a sense strand comprising SEQ ID NO: 234), shown as a sodium salt:

[0111] [ka]

[0112] In some embodiments, one of the RNAi agents comprising an RNAi component is represented by the following structure (an antisense strand comprising SEQ ID NO:3 and a sense strand comprising SEQ ID NO:13), shown as a sodium salt:

[0113] [ka]

[0114] In some embodiments, one of the RNAi agents that comprises an RNAi component is represented by the following structure (with the antisense strand comprising SEQ ID NO:2 and the sense strand comprising SEQ ID NO:11), shown as the free acid:

[0115] [ka]

[0116] In some embodiments, one of the RNAi agents that includes an RNAi component is represented by the following structure (the antisense strand comprises SEQ ID NO:2 and the sense strand comprises SEQ ID NO:13), shown as the free acid:

[0117] [ka]

[0118] In some embodiments, one of the RNAi agents that comprises an RNAi component is represented by the following structure (with the antisense strand comprising SEQ ID NO:2 and the sense strand comprising SEQ ID NO:11), shown as the free acid:

[0119] [ka]

[0120] The combinations described herein may be used in any of the methods or kits described below.

[0121] Compositions and Administration Also provided herein is one or more compositions that include an RNAi component.

[0122] Suitable compositions may include all compositions that are commonly employed for systemic administration of drugs. To prepare the pharmaceutical compositions of the present invention, an effective amount of a specific compound (optionally further in the form of a salt) as an active ingredient is combined in a uniform mixture with a pharma- ceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are preferably in a unit dosage form suitable for administration, particularly oral, rectal, transdermal or parenteral injection. For example, when preparing a composition in oral dosage form, any of the usual pharmaceutical media, such as water, glycols, oils, alcohols, etc., may be used for oral liquid preparations, such as suspensions, syrups, elixirs, emulsions and solutions; solid carriers, such as starches, sugars, kaolin, lubricants, binders, disintegrants, etc., may be used for powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules are the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are used. For parenteral compositions, the carrier usually comprises at least mostly sterile water, although other ingredients, for example, to aid solubility, may be included. Injectable solutions may be prepared, for example, in which the carrier comprises saline, glucose solution, or a mixture of saline and glucose solution. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents, and the like may be used. Also included are solid form preparations that are intended to be converted to liquid form preparations immediately prior to use. In compositions suitable for transdermal administration, the carrier may optionally comprise a penetration enhancer and / or a suitable wetting agent, optionally combined in minor proportions with suitable additives of any nature, which additives do not cause significant adverse effects on the skin. The compounds of the present invention may also be administered by oral inhalation or insufflation in the form of a solution, suspension, or dry powder, using any delivery system known in the art.

[0123] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate the above-mentioned pharmaceutical composition in unit dosage form.The term "unit dosage form" used herein means a physically separate unit suitable for unit dosage, each unit containing a predetermined amount of active ingredient calculated to produce desired therapeutic effect together with necessary pharmaceutical carrier.The example of such unit dosage form includes tablets (including split tablets or coated tablets), capsules, pills, suppositories, powder packets, wafers, injection solutions or suspensions, etc., and their separate composites.

[0124] The first and second RNAi agents of the RNAi components that target or reduce HBsAg can be formulated in the same or separate pharmaceutical compositions.The HBV RNAi agents in the same or separate compositions can be formulated with the same or different excipients and carriers.The HBV RNAi agents in the same or separate compositions can be administered via the same or different administration routes.

[0125] Any suitable pharmaceutical composition comprising the first and / or second RNAi agent of RNAi components and pharmaceutically acceptable carrier can be used in the present invention in view of the present disclosure.The pharmaceutical composition can comprise any RNAi component described herein or known in the art.One or more pharmaceutically acceptable excipients (including vehicles, carriers, diluents and / or delivery polymers) can be mixed with the first and / or second RNAi agent of RNAi components to form a pharmaceutical composition suitable for in vivo delivery to humans.

[0126] The HBV RNAi agents disclosed herein can be administered via any suitable parenteral route in pharmaceutical compositions appropriately prepared for a particular route.That is, the pharmaceutical compositions described herein can be administered by injection, for example, intravenously, intramuscularly, subcutaneously or intraperitoneally.In some embodiments, the pharmaceutical compositions described herein are preferably administered via subcutaneous injection.

[0127] The pharmaceutical composition comprising the HBV RNAi agent described herein can be delivered to a cell, a group of cells, a tumor, a tissue or a subject using oligonucleotide delivery techniques known in the art.Generally, any suitable method (in vitro or in vivo) recognized in the art for delivering nucleic acid molecules can be adapted for use with the compositions described herein.For example, the pharmaceutical composition comprising at least one of the first and second RNAi agents of the RNAi components described herein can be delivered by systemic administration via parenteral routes, including subcutaneous, intravenous, intraperitoneal and intramuscular administration.In certain embodiments, the composition is administered by subcutaneous or intravenous infusion or injection.

[0128] As used herein, a pharmaceutical composition or medicament comprises a pharmacologically effective amount of at least one of the therapeutic compounds described and a pharma- ceutically acceptable carrier. The pharma- ceutically acceptable carrier may include one or more pharma- ceutically acceptable excipients. A pharma- ceutically acceptable excipient, also referred to herein as an "excipient," is a substance other than an active pharmaceutical ingredient that is intentionally included in a drug delivery system. An excipient does not exert or is not intended to exert a therapeutic effect at the intended dose. An excipient may act to a) aid in the processing of the drug delivery system during manufacture, b) protect, support or enhance the stability, bioavailability or patient acceptability of the API, c) aid in product identification, and / or d) enhance other properties of either the overall safety, efficacy, delivery of the API during storage or use. A pharma- ceutically acceptable excipient may or may not be an inert substance.

[0129] Excipients include, but are not limited to, absorption enhancers, anti-adhesives, anti-foaming agents, antioxidants, binders, buffers, carriers, coatings, colorants, delivery enhancers, delivery polymers, dextrans, dextrose, diluents, emulsifiers, bulking agents, humectants, oils, polymers, preservatives, saline, salts, solvents, sugars, suspending agents, sustained release matrices, isotonicity agents, and vehicles.

[0130] Suitable pharmaceutical compositions for injectable use include sterile aqueous solutions (if water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ) or phosphate buffered saline. Suitable carriers should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating agent such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols, such as mannitol, sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0131] Sterile injectable solution can be prepared by incorporating the active compound in the required amount in a suitable solvent with one or combination of the above-listed components, and then optionally sterilizing by filtration.Generally, dispersion is prepared by incorporating active compound into a sterile vehicle that contains a basic dispersion medium and other components that are required from the above-listed components.In the case of sterile powder for preparing sterile injectable solution, the preparation method includes vacuum drying and freeze-drying, which produces the powder of active ingredient and any additional desired ingredient from its solution that has been previously sterilized by filtration.

[0132] The active compound can be prepared with a carrier that will protect the compound against rapid excretion from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid.The method of preparing such formulations will be clear to those skilled in the art.Liposomal suspensions can also be used as pharmaceutically acceptable carriers.These can be prepared according to the method known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0133] TLR8 agonist and / or HBV RNAi agent can be formulated in a composition in unit dosage form for ease of administration and uniformity of dosage.Unit dosage form means a physically separate unit suitable as a unit dosage for the subject to be treated, each unit containing a predetermined amount of active compound calculated to produce desired therapeutic effect together with required pharmaceutical carrier.The specification of the unit dosage form of the present disclosure is determined by and directly depends on the inherent characteristics of active compound and the therapeutic effect of the subject to be achieved, and the inherent limitations in the field of the formulation of such active compound for individual treatment.

[0134] Pharmaceutical compositions can contain other additional components that are generally found in pharmaceutical compositions. Such additional components include, but are not limited to, antipruritic agents, astringents, local anesthetics or anti-inflammatory agents (e.g., antihistamines, diphenhydramine, etc.). It is also envisioned that cells, tissues or isolated organs expressing or containing the RNAi agents defined herein can be used as "pharmaceutical compositions". As used herein, "pharmacologically effective amount", "therapeutically effective amount" or simply "effective amount" refers to the amount of RNAi agent that produces pharmacological, therapeutic or preventive results.

[0135] The amount administered will also depend on factors such as the patient's general health, the relative biological availability of the compound being delivered, the drug formulation, the presence and type of excipients in the formulation, and the route of administration, etc. Also, the initial dosage administered may be increased beyond an upper level in order to rapidly achieve the desired blood or tissue level, or the initial dosage may be less than optimal.

[0136] For the treatment of disease or for forming a medicament or composition for the treatment of disease, the pharmaceutical compositions described herein containing an HBV RNAi agent may be combined with excipients, additional therapeutic agents or treatments, such as, but not limited to, additional or alternative RNAi agents, small molecule drugs, antibodies, antibody fragments and / or vaccines.

[0137] When added to pharma- ceutically acceptable excipients and / or adjuvants, the described HBV RNAi agents can be packaged into kits, containers, packs, or dispensers.The pharmaceutical compositions described herein can be packaged in pre-filled syringes or vials.

[0138] Subjects were classified according to renal function. The degree of renal impairment was based on CLCR, as determined by the CKD-EPI equation. Patients with normal renal function had an estimated glomerular filtration rate (eGFR) of 90 milliliters per minute per 1.73 meters squared (mL / min / 1.73 m ). 2 ) or greater. Patients must have stable renal function, defined as: (a) for subjects with impaired renal function: less than 20 percent (%) change in serum creatinine concentration from Screening to Day -1; (b) for healthy subjects: less than 0.2 milligrams per deciliter (mg / dL) change in serum creatinine concentration from Screening to Day -1.

[0139] For patients with renal impairment, patients had renal impairment based on eGFR as follows: (a) eGFR between 90 and 60 mL / min / 1.73 m for subjects in the mild renal impairment cohort;2 (b) subjects in the moderately impaired cohort with eGFR between 30 and 59 mL / min / 1.73 m 2 (c) subjects with ESRD requiring hemodialysis with an eGFR of 30 mL / min / 1.73 m 2 Less than 100 mg / kg. Concomitant medications to treat underlying disease states or medical conditions associated with impaired renal function are permitted. Subjects must be on a stable dose of medication and / or treatment regimen for at least 2 months prior to dosing and throughout the duration of the study.

[0140] In some embodiments, the subject is suffering from renal failure. In some embodiments, the subject is suffering from renal failure. 2 In some embodiments, the subject has an estimated glomerular filtration rate (eGFR) of 60-90 mL / min / 1.73 m 2 In some embodiments, the subject has an estimated glomerular filtration rate (eGFR) of 30-59 mL / min / 1.73 m 2 In some embodiments, the subject has an estimated glomerular filtration rate (eGFR) of 30 mL / min / 1.73 m 2 In some embodiments, the subject has end stage renal disease.

[0141] The present application also provides methods of making the compositions and therapeutic combinations of the present application.

[0142] In another embodiment, the kit further comprises a package insert, including but not limited to appropriate instructions regarding preparation and administration of the formulation, side effects of the formulation, and other relevant information. The instructions may be in any suitable format, including but not limited to instructions on printed matter, videotape, computer readable disk, optical disk, or internet-based instructions.

[0143] In another aspect, a kit is provided for treating an individual suffering from or susceptible to a condition described herein, comprising a first container containing a dosage of the composition or formulation as disclosed herein, and a package insert for use.The container can be any of those known in the art, and can be suitable for storing and delivering intravenous formulations.In certain embodiments, the kit further comprises a second container that contains pharma- ceutically acceptable carriers, diluents, adjuvants, etc., for preparing the formulation to be administered to an individual.

[0144] In another aspect, kits can also be provided that contain a sufficient dosage of a composition described herein (including a pharmaceutical composition thereof) to provide effective treatment to an individual for an extended period of time, such as 1-3 days, 1-5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 1 cycle, 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles or more, in some embodiments, a cycle of treatment is about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months, about 21 months, or about 24 months.

[0145] In some embodiments, the kits may include multiple doses and may be packaged in sufficient quantities for storage and use in pharmacies, such as hospital pharmacies and compounding pharmacies. In certain embodiments, the kits may include a dosage of at least one composition as disclosed herein.

[0146] Treatment regimen Any of the compositions and therapeutic combinations of the present application described herein may be used in the combination treatment regimens or treatment methods of the present application.

[0147] In some embodiments of the present application, an effective amount of the RNAi component is administered to a subject in the range of about 25-600 mg per dose. In some embodiments, the effective amount of the RNAi component is about 25-50 mg, about 50-75 mg, about 75-100 mg, about 100-150 mg, about 150-200 mg, about 200-250 mg, about 250-300 mg, about 300-400 mg, about 400-500 mg, or about 500-600 mg per dose. In some embodiments, the effective amount of the RNAi component is about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg per dose. In some embodiments, the effective amount of the RNAi component is about 25 mg, about 35 mg, about 40 mg, about 50 mg, about 100 mg, or about 200 mg per dose. The effective amount of RNAi components can be administered once a month (Q1M), once every four weeks (Q4W), every other month, or any period therebetween.As used herein, unless otherwise specified, the dose of RNAi components or agents refers to the dose of the RNAi components or agents themselves, not the dose of the composition that may contain the RNAi components or agents.For example, when an RNAi conjugate, such as an RNAi-(NAG37)s conjugate, is administered, the dose of RNAi components or agents refers to the amount of the RNAi components or agents of the conjugate.The dose of RNAi components refers to the total amount of the first and second RNAi agents of the RNAi components.

[0148] In some embodiments, the first and second HBV RNAi agents of the RNAi components are administered in a molar ratio of about 1:1, 2:1, 3:1, 4:1 or 5:1. In some embodiments, the first and second HBV RNAi agents of the RNAi components are administered to the subject in a molar ratio of about 2:1.

[0149] In some embodiments, the two HBV RNAi agents are administered in a molar ratio of about 2:1, about 3:1, about 1:1, about 4:1, about 5:1, or about 1:2 in a total amount of about 25-75 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a molar ratio of about 2:1, about 3:1, about 1:1, about 4:1, about 5:1, or about 1:2 in a total amount of about 35-40 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a molar ratio of about 2:1, about 3:1, about 1:1, about 4:1, about 5:1, or about 1:2 in a total amount of about 50-125 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a molar ratio of about 2:1, about 3:1, about 1:1, about 4:1, about 5:1, or about 1:2 in a total amount of about 75-150 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a molar ratio of about 2:1, about 3:1, about 1:1, about 4:1, about 5:1, or about 1:2 in a total amount of about 100-200 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a molar ratio of about 2:1, about 3:1, about 1:1, about 4:1, about 5:1, or about 1:2 in a total amount of about 150-250 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a molar ratio of about 2:1, about 3:1, about 1:1, about 4:1, about 5:1, or about 1:2 in a total amount of about 200-300 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a molar ratio of about 2:1, about 3:1, about 1:1, about 4:1, about 5:1, or about 1:2 in a total amount of about 300-400 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a molar ratio of about 2:1, about 3:1, about 1:1, about 4:1, about 5:1, or about 1:2 in a total amount of about 50-100 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a molar ratio of about 2:1 in a total amount of about 25-400 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a molar ratio of about 2:1 in a combined amount of about 25-75 mg per dose administration.In some embodiments, the two HBV RNAi agents are administered in a molar ratio of about 2:1 in a total amount of about 35-40 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a molar ratio of about 2:1 in a total amount of about 50-125 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a molar ratio of about 2:1 in a total amount of about 75-150 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a molar ratio of about 2:1 in a total amount of about 100-200 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a molar ratio of about 2:1 in a total amount of about 125-225 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a molar ratio of about 2:1 in a total amount of about 150-250 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a molar ratio of about 2:1 in a total amount of about 200-300 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a molar ratio of about 2:1 in a total amount of about 300-400 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a molar ratio of about 2:1 in a total amount of about 100 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a molar ratio of about 2:1 in a total amount of about 25 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a molar ratio of about 2:1 in a total amount of about 35 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a molar ratio of about 2:1 in a total amount of about 40 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a total amount of about 50 mg per dose administration and in a molar ratio of about 2:1. In some embodiments, the two HBV RNAi agents are administered in a total amount of about 75 mg per dose administration and in a molar ratio of about 2:1. In some embodiments, the two HBV RNAi agents are administered in a total amount of about 200 mg per dose administration and in a molar ratio of about 2:1.

[0150] In some embodiments, the first RNAi agent is administered in an amount of about 3-650 mg per dose administration and the second RNAi agent is administered in an amount of about 2-325 mg per dose administration. In some embodiments, the first RNAi agent is administered in an amount of about 15-150 mg per dose administration and the second RNAi agent is administered in an amount of about 5-75 mg per dose administration. In some embodiments, the first RNAi agent is administered in an amount of about 35-265 mg per dose administration. In some embodiments, the first RNAi agent is administered in an amount of about 50-75 mg per dose administration. In some embodiments, the first RNAi agent is administered in an amount of about 15-75 mg per dose administration. In some embodiments, the second RNAi agent is administered in an amount of about 20-125 mg per dose administration. In some embodiments, the second RNAi agent is administered in an amount of about 25-50 mg per dose administration. In some embodiments, the second RNAi agent is administered in an amount of about 5-40 mg per dose administration. In some embodiments, the first RNAi agent is administered in an amount of about 17 mg per dose administration and the second RNAi agent is administered in an amount of about 8 mg per dose administration. In some embodiments, the first RNAi agent is administered in an amount of about 23 mg per dose administration and the second RNAi agent is administered in an amount of about 12 mg per dose administration. In some embodiments, the first RNAi agent is administered in an amount of about 27 mg per dose administration and the second RNAi agent is administered in an amount of about 13 mg per dose administration. In some embodiments, the first RNAi agent is administered in an amount of about 33 mg per dose administration and the second RNAi agent is administered in an amount of about 17 mg per dose administration. In some embodiments, the first RNAi agent is administered in an amount of about 67 mg per dose administration and the second RNAi agent is administered in an amount of about 33 mg per dose administration.

[0151] In some embodiments, the two RNAi agents are administered in a combined dose of 25-400 mg per dose administration. In one embodiment, the two RNAi agents are administered in a combined dose of 25-400 mg, with the first RNAi agent administered with the second RNAi agent in a 1:1 molar ratio. In one embodiment, the dose of each of the first and second RNAi agents is in an amount of about 12 mg for a combined dose of about 25 mg. In one embodiment, the dose of each of the first and second RNAi agents is in an amount of about 17 mg for a combined dose of about 35 mg. In one embodiment, the dose of each of the first and second RNAi agents is in an amount of about 20 mg for a combined dose of about 40 mg. In one embodiment, the dose of each of the first and second RNAi agents is in an amount of about 25 mg for a combined dose of about 50 mg. In one embodiment, the dose of each of the first and second RNAi agents is in an amount of about 50 mg for a combined dose of about 100 mg. In one embodiment, the dose of each of the first and second RNAi agents is about 100mg for a total dose of about 200mg.In one embodiment, the dose of each of the first and second RNAi agents is about 150mg for a total dose of about 300mg.In one embodiment, the dose of each of the first and second RNAi agents is about 200mg for a total dose of about 400mg.

[0152] In one embodiment, the two RNAi agents are administered at a total dose of 25-400 mg per dose, with the first RNAi agent being administered with the second RNAi agent at a molar ratio of 2:1. In one embodiment, for a total dose of about 25 mg, the dose of the first RNAi agent is in an amount of about 16 mg, and the dose of the second RNAi agent is in an amount of about 8 mg. In one embodiment, for a total dose of about 35 mg, the dose of the first RNAi agent is in an amount of about 24 mg, and the dose of the second RNAi agent is in an amount of about 12 mg. In one embodiment, for a total dose of about 40 mg, the dose of the first RNAi agent is in an amount of about 27 mg, and the dose of the second RNAi agent is in an amount of about 13 mg. In one embodiment, for a total dose of about 50 mg, the dose of the first RNAi agent is in an amount of about 33 mg, and the dose of the second RNAi agent is in an amount of about 17 mg. In one embodiment, for a total dose of about 100mg, the dose of the first RNAi agent is about 65mg, and the dose of the second RNAi agent is about 35mg. In one embodiment, for a total dose of about 200mg, the dose of the first RNAi agent is about 133mg, and the dose of the second RNAi agent is about 67mg. In one embodiment, for a total dose of about 300mg, the dose of the first RNAi agent is about 200mg, and the dose of the second RNAi agent is about 100mg. In one embodiment, for a total dose of about 400mg, the dose of the first RNAi agent is about 270mg, and the dose of the second RNAi agent is about 135mg.

[0153] In one embodiment, the two RNAi agents are administered at a total dose of 25-400 mg per dose, with the first RNAi agent being administered with the second RNAi agent at a molar ratio of 3:1. In one embodiment, for a total dose of about 25 mg, the dose of the first RNAi agent is in an amount of about 18 mg, and the dose of the second RNAi agent is in an amount of about 6 mg. In one embodiment, for a total dose of about 35 mg, the dose of the first RNAi agent is in an amount of about 27 mg, and the dose of the second RNAi agent is in an amount of about 9 mg. In one embodiment, for a total dose of about 40 mg, the dose of the first RNAi agent is in an amount of about 30 mg, and the dose of the second RNAi agent is in an amount of about 10 mg. In one embodiment, for a total dose of about 50 mg, the dose of the first RNAi agent is in an amount of about 36 mg, and the dose of the second RNAi agent is in an amount of about 12 mg. In one embodiment, for a total dose of about 100mg, the dose of the first RNAi agent is about 75mg, and the dose of the second RNAi agent is about 25mg. In one embodiment, for a total dose of about 200mg, the dose of the first RNAi agent is about 150mg, and the dose of the second RNAi agent is about 50mg. In one embodiment, for a total dose of about 300mg, the dose of the first RNAi agent is about 225mg, and the dose of the second RNAi agent is about 75mg. In one embodiment, for a total dose of about 400mg, the dose of the first RNAi agent is about 300mg, and the dose of the second RNAi agent is about 100mg.

[0154] In some embodiments, the first and second RNAi agents are administered in a combined amount of about 25-400 mg per dose. In some embodiments, the first and second RNAi agents are administered in a combined amount of about 25-50 mg, 50-75 mg, 75-100 mg, 100-125 mg, 125-150 mg, 150-175 mg, 175-200 mg, 200-225 mg, 225-250 mg, 250-275 mg, 275-300 mg, 300-325 mg, 325-350 mg, 350-375 mg, , 375-400mg, 25-75mg, 50-100mg, 100-150mg, 150-200mg, 200-250mg, 250-300mg, 300-350mg, 350-400mg, 25-100mg, 50-150mg, 100-200mg, 150-250mg, 200-300mg, 300-400mg, 25-200mg or 200-400mg total dose. In some embodiments, the first RNAi agent and the second RNAi agent are administered in a total amount of about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg or about 400 mg per dose. In some embodiments, the first RNAi agent and the second RNAi agent are administered in a total amount of about 50 mg, about 75 mg, about 100 mg or about 125 mg per dose. In some embodiments, the first RNAi agent and the second RNAi agent are administered in a total amount of about 25 mg, about 35 mg, about 40 mg or about 200 mg per dose.

[0155] In some embodiments, the two HBV RNAi agents are administered in a total amount of about 1-10 mg / kg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a total amount of about 1-5 mg / kg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a total amount of about 1-1.5 mg / kg, about 1.5-2.0 mg / kg, about 2.0-2.5 mg / kg, about 2.5-3.0 mg / kg, about 3.0-3.5 mg / kg, about 3.5-4.0 mg / kg, about 4.0-4.5 mg / kg, about 4.5-5.0 mg / kg, about 5.0-5.5 mg / kg, about 5.5-6.0 mg / kg, about 6.0-6.5 mg / kg, about 6.5-7.0 mg / kg per dose administration. / kg, about 7.0-7.5 mg / kg, about 7.5-8.0 mg / kg, about 8.0-8.5 mg / kg, about 8.5-9.0 mg / kg, about 9.0-9.5 mg / kg, about 9.5-10 mg / kg, about 1-2.5 mg / kg, about 2.5-5.0 mg / kg, about 5.0-7.5 mg / kg, about 7.5-10 mg / kg, about 1-5.0 mg / kg, or about 5.0-10 mg / kg.

[0156] In some embodiments, the first RNAi agent is administered in an amount of about 0.6-7 mg / kg per dose administration and the second RNAi agent is administered in an amount of about 0.3-5 mg / kg per dose administration. In some embodiments, the second RNAi agent is administered in an amount of about 0.5-2.5 mg / kg per dose administration. In some embodiments, the second RNAi agent is administered in an amount of about 0.3-1.5 mg / kg per dose administration. In some embodiments, the first RNAi agent is administered in an amount of about 0.6-5 mg / kg per dose administration. In some embodiments, the first RNAi agent is administered in an amount of about 1-2.5 mg / kg per dose administration.

[0157] In some embodiments, the two RNAi agents are administered about 1-18 weeks apart. In some embodiments, the two RNAi agents are administered about 1 week apart, about 2 weeks apart, about 3 weeks apart, about 4 weeks apart, about 5 weeks apart, about 6 weeks apart, about 7 weeks apart, about 8 weeks apart, about 9 weeks apart, about 10 weeks apart, about 11 weeks apart, about 12 weeks apart, about 13 weeks apart, about 14 weeks apart, about 15 weeks apart, about 16 weeks apart, about 17 weeks apart, or about 18 weeks apart. In some embodiments, the two RNAi agents are administered about 1-6 months apart. In some embodiments, the two RNAi agents are administered about 1 month apart, about 2 months apart, about 3 months apart, about 4 months apart, about 5 months apart, or about 6 months apart. In some embodiments, the two RNAi agents are administered about 4 weeks apart or about 1 month apart. In some embodiments, the two RNAi agents are administered once a month.

[0158] In some embodiments, the first and second RNAi agents are administered for a duration of about 1-12 months. In some embodiments, the first and second RNAi agents are administered for a duration of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months. In some embodiments, the first and second RNAi agents are administered for a duration of about 1-18 weeks. In some embodiments, the first RNAi agent and the second RNAi agent are administered for a duration of at least about 1 week, at least about 5 weeks, at least about 10 weeks, at least about 15 weeks, at least about 20 weeks, at least about 25 weeks, at least about 30 weeks, at least about 35 weeks, at least about 40 weeks, at least about 45 weeks, at least about 50 weeks, at least about 55 weeks, at least about 60 weeks, at least about 65 weeks, at least about 70 weeks, at least about 75 weeks, at least about 80 weeks, at least about 90 weeks, or at least 96 weeks.

[0159] In some embodiments, the first and second RNAi agents are administered in a total dose of 25-600 mg, more particularly 25-400 mg per dose administration. In one embodiment, the first and second RNAi agents are administered in a total dose of 25-600 mg, more particularly 25-400 mg, and the first RNAi agent is administered with the second RNAi agent in a 1:1 molar ratio. In one embodiment, the dose of the first RNAi agent administered with the second RNAi agent is in an amount of about 12 mg for a total dose of about 25 mg. In one embodiment, the dose of each of the first and second RNAi agents is in an amount of about 17 mg for a total dose of about 35 mg. In one embodiment, the dose of each of the first and second RNAi agents is in an amount of about 20 mg for a total dose of about 40 mg. In one embodiment, the dose of each of the first and second RNAi agents is about 25 mg for a total dose of about 50 mg. In one embodiment, the dose of each of the first and second RNAi agents is about 50 mg for a total dose of about 100 mg. In one embodiment, the dose of each of the first and second RNAi agents is about 100 mg for a total dose of about 200 mg. In one embodiment, the dose of each of the first and second RNAi agents is about 150 mg for a total dose of about 300 mg. In one embodiment, the dose of each of the first and second RNAi agents is about 200 mg for a total dose of about 400 mg.

[0160] In one embodiment, the first and second RNAi agents are administered at a total dose of 25-600 mg, more particularly 25-400 mg per dose, and the second RNAi agent is administered with the first RNAi agent in a molar ratio of 1:2. In one embodiment, for a total dose of about 25 mg, the dose of the first RNAi agent is in an amount of about 16 mg and the dose of the second RNAi agent is in an amount of about 8 mg. In one embodiment, for a total dose of about 35 mg, the dose of the second RNAi agent is in an amount of about 12 mg and the dose of the first RNAi agent is in an amount of about 24 mg. In one embodiment, for a total dose of about 40 mg, the dose of the first RNAi agent is in an amount of about 27 mg and the dose of the second RNAi agent is in an amount of about 13 mg. In one embodiment, for a total dose of about 50 mg, the dose of the first RNAi agent is in an amount of about 33 mg and the dose of the second RNAi agent is in an amount of about 17 mg. In one embodiment, for a total dose of about 100mg, the dose of the second RNAi agent is about 35mg, and the dose of the first RNAi agent is about 65mg. In one embodiment, for a total dose of about 200mg, the dose of the second RNAi agent is about 67mg, and the dose of the first RNAi agent is about 133mg. In one embodiment, for a total dose of about 300mg, the dose of the second RNAi agent is about 100mg, and the dose of the first RNAi agent is about 200mg. In one embodiment, for a total dose of about 400mg, the dose of the second RNAi agent is about 135mg, and the dose of the first RNAi agent is about 270mg.

[0161] In one embodiment, the first and second RNAi agents are administered at a total dose of 25-600 mg, more particularly 25-400 mg per dose, and the second RNAi agent is administered with the first RNAi agent in a molar ratio of 1:3. In one embodiment, for a total dose of about 25 mg, the dose of the first RNAi agent is in an amount of about 18 mg and the dose of the second RNAi agent is in an amount of about 6 mg. In one embodiment, for a total dose of about 35 mg, the dose of the second RNAi agent is in an amount of about 9 mg and the dose of the first RNAi agent is in an amount of about 27 mg. In one embodiment, for a total dose of about 40 mg, the dose of the first RNAi agent is in an amount of about 30 mg and the dose of the second RNAi agent is in an amount of about 10 mg. In one embodiment, for a total dose of about 50 mg, the dose of the first RNAi agent is in an amount of about 36 mg and the dose of the second RNAi agent is in an amount of about 12 mg. In one embodiment, for a total dose of about 100mg, the dose of the second RNAi agent is about 25mg, and the dose of the first RNAi agent is about 75mg. In one embodiment, for a total dose of about 200mg, the dose of the second RNAi agent is about 50mg, and the dose of the first RNAi agent is about 150mg. In one embodiment, for a total dose of about 300mg, the dose of the second RNAi agent is about 75mg, and the dose of the first RNAi agent is about 225mg. In one embodiment, for a total dose of about 400mg, the dose of the second RNAi agent is about 100mg, and the dose of the first RNAi agent is about 300mg.

[0162] In some embodiments, about 1 mg / kg (mpk) of the first RNAi agent and about 1 mg / kg of the second RNAi agent are administered to the subject in need thereof. In some embodiments, about 1.5 mg / kg of the first RNAi agent and about 1.5 mg / kg of the second RNAi agent are administered to the subject in need thereof. In some embodiments, about 2.0 mg / kg of the first RNAi agent and about 1.0 mg / kg of the second RNAi agent are administered to the subject in need thereof. In some embodiments, about 3.0 mg / kg of the first RNAi agent and about 1.0 mg / kg of the second RNAi agent are administered to the subject in need thereof. In some embodiments, about 3.2 mg / kg of the first RNAi agent and about 0.8 mg / kg of the second RNAi agent are administered to the subject in need thereof. In some embodiments, about 2.7 mg / kg of the first RNAi agent and about 1.3 mg / kg of the second RNAi agent are administered to the subject in need thereof. In some embodiments, about 4.0 mg / kg of the first RNAi agent and about 1.0 mg / kg of the second RNAi agent are administered to a subject in need thereof. In some embodiments, about 3.3 mg / kg of the first RNAi agent and about 1.7 mg / kg of the second RNAi agent are administered to a subject in need thereof. In some embodiments, about 0.05 to about 5 mg / kg of the first RNAi agent and about 0.05 to about 5 mg / kg of the second RNAi agent are administered to a subject in need thereof. In some embodiments, about the first RNAi agent and about the second RNAi agent are administered separately (e.g., in separate injections). In some embodiments, each dose of the first RNAi agent and each dose of the second RNAi agent are administered together (e.g., in the same injection). In some embodiments, each dose of the first RNAi agent and each dose of the second RNAi agent are prepared in a single pharmaceutical composition.

[0163] In some embodiments, the RNAi component is administered to the subject once a month at a dose of about 40-350 mg, such as about 40-250 mg, more particularly 40-200 mg, more particularly 100 mg or 200 mg, more particularly 200 mg.

[0164] In some embodiments, the first and second RNAi agents are each independently conjugated to (NAG37)s, the first RNAi agent comprises an antisense strand comprising SEQ ID NO:2 and a sense strand comprising SEQ ID NO:11, and the second RNAi agent comprises an antisense strand comprising SEQ ID NO:8 and a sense strand comprising SEQ ID NO:16.

[0165] In certain embodiments, the combinations of the present application are used to reduce viral replication as measured by serum HBV DNA in subjects with CHB, and the subjects are not already suppressed with NUC. In certain embodiments, the combinations of the present application are used to reduce the expression of one or more HBV polypeptides, such as HBsAg, in the serum of subjects with CHB. In another embodiment, the combinations of the present application are used to produce an enhanced HBV-specific T cell response in subjects with CHB, which may be enhanced in a quantitative and / or qualitative manner.

[0166] The methods according to embodiments of the present application further include administering to a subject in need thereof another immunogenic agent (such as another natural immune modulator or therapeutic vaccine) or another antiviral agent against HBV (such as a nucleoside analog or other direct antiviral compound) in combination with the composition of the present application.

[0167] In some embodiments, the method further comprises administering to the subject a nucleoside analog. In some embodiments, the nucleoside analog is entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide, lamivudine, telbivudine, or a combination thereof. In some embodiments, the nucleoside analog is entecavir and is administered in an amount of about 0.01-5 mg, about 0.01-0.05 mg, about 0.05-0.1 mg, about 0.1-0.5 mg, about 0.5-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, or about 4-5 mg. In some embodiments, the nucleoside analog is entecavir and is administered in an amount of about 0.5 mg. In some embodiments, the nucleoside analog is tenofovir disoproxil fumarate and is administered in an amount of about 100-500 mg, about 100-150 mg, about 150-200 mg, about 200-250 mg, about 250-300 mg, 300-400 mg, about 400-500 mg. In some embodiments, the nucleoside analog is tenofovir disoproxil fumarate and is administered in an amount of about 300 mg. In some embodiments, the nucleoside analog is tenofovir alafenamide and is administered in an amount of about 5-100 mg, about 5-25 mg, about 25-50 mg, about 50-75, or about 75-100 mg. In some embodiments, the nucleoside analog is tenofovir alafenamide and is administered in an amount of about 25 mg. In some embodiments, the nucleoside analog is lamivudine and is administered in an amount of about 50-600 mg, about 100-500 mg, about 150-400 mg, about 200-350 mg, or about 250-300 mg. In some embodiments, the nucleoside analog is lamivudine and is administered in an amount of 150 mg or 300 mg. In some embodiments, the nucleoside analog is telbivudine and is administered in an amount of about 300-600 mg, about 300-400 mg, about 400-500 mg, or about 500-600 mg. In some embodiments, the nucleoside analog is telbivudine and is administered in an amount of 600 mg. In some embodiments, the patient is exposed to the nucleoside analog prior to receiving the combination therapy.In some embodiments, the patient has been administered the nucleoside analog for at least one month, at least three months, at least six months, or at least one year prior to receiving the combination therapy.

[0168] In some embodiments, the method comprises the steps of: a subunit vaccine comprising one or more HBV-derived peptides, polypeptides or proteins, optionally conjugated to a carrier molecule, which subunit vaccine optionally further comprises one or more adjuvants and / or one or more delivery systems, which may also provide adjuvant activity; a recombinant viral vaccine comprising one or more viral vectors encoding one or more HBV-derived peptides, polypeptides or proteins, optionally further encoding one or more cytokines to provide adjuvant activity; Nucleic acid based vaccines comprising one or more DNA molecules, such as DNA plasmids, encoding one or more HBV derived peptides, polypeptides or proteins, and optionally further encoding one or more cytokines to provide adjuvant activity, wherein the DNA molecules are administered by intramuscular injection using delivery systems such as liposomes and nanoparticles, administered to a subject using an electroporation device, or coated onto gold particles and administered into the dermis using a jet delivery device; A nucleic acid-based vaccine comprising one or more RNA molecules, such as mRNA or a self-amplifying mRNA or RNA replicon, encoding one or more HBV-derived peptides, polypeptides or proteins, and optionally further encoding one or more cytokines to provide adjuvant activity, wherein the RNA molecules are administered, for example, by intramuscular delivery in a lipid nanoparticle delivery system. The method further comprises administering to the subject one or more HBV-specific therapeutic vaccines selected from the group consisting of:

[0169] In some embodiments, the combinations of the present application further comprise a peptide, polypeptide or protein derived from HBV, including one or more, preferably all, of HBV core antigen, pol antigen and surface antigen, or a nucleic acid molecule encoding a peptide, polypeptide or protein derived from HBV. Preferably, the HBV surface antigen includes one or more, preferably all, of small (S), medium (M) and large (L) envelope proteins. Examples of HBV-derived peptides, polypeptides or proteins, or coding sequences thereof, useful in the methods or combinations of the present application include, but are not limited to, those described in U.S. Patent Application Publication No. 2019 / 0185828, the entire contents of which are incorporated herein by reference.

[0170] In some alternative embodiments, the combinations of the present application further comprise at least one other active ingredient, such as one or more of an antiviral agent, an immunomodulatory agent, and a capsid assembly modulator (CAM) in the form of a small molecule, an antibody, a polypeptide, a protein, or a nucleic acid, including, but not limited to, one or more of the following: immune checkpoint inhibitors (e.g., anti-PD-1, anti-TIM-3, etc.), other Toll-like receptor agonists, RIG-I agonists, IL-15 superagonists (Altor Bioscience), mutated IRF3 and IRF7 genetic adjuvants, STING agonists (Aduro), FLT3L genetic adjuvants, IL-12 genetic adjuvants, IL-7-hyFc; CAR-T (S-CAR cells) that bind to HBV env; CAMs; cccDNA inhibitors, and interferon alpha receptor ligands.

[0171] In some other embodiments, the combinations of the present application may be administered in combination with one or more other HBV antiviral agents, such as HBV polymerase inhibitors (e.g., entecavir and tenofovir); immunomodulators; Toll-like receptor 7 modulators; Toll-like receptor 8 modulators; Toll-like receptor 3 modulators; hyaluronidase inhibitors; IL-10 modulators; HBsAg inhibitors; Toll-like receptor 9 modulators; cyclophilin inhibitors; HBV prophylactic vaccines; HBV therapeutic vaccines; HBV viral entry inhibitors; antisense oligonucleotides targeting viral mRNA, more particularly anti-HBV antisense oligonucleotides; short interfering RNA (siRNA), more particularly anti-HBV siRNA; endonuclease modulators; ribonucleotide reductase inhibitors; HBV E antigen inhibitors; HBV antibodies targeting the surface antigen of the Hepatitis B virus; HBV antibodies; CCR2 chemokine antagonists; thymosin agonists; cytokines such as IL-12; capsid assembly modulators (CAMs), nucleoprotein inhibitors (HBV core or capsid protein inhibitors); nucleic acid polymers (NAPs); retinoic acid inducible gene I stimulators; NOD2 stimulators; HBV replication inhibitors; PI3K inhibitors; cccDNA inhibitors; immune checkpoint inhibitors such as PD-L1 inhibitors, PD-1 inhibitors, TIM-3 inhibitors, TIGIT inhibitors, Lag3 inhibitors and CTLA-4 inhibitors; agonists of costimulatory receptors expressed on immune cells (more particularly T cells) such as CD27, CD28; BTK inhibitors; other agents for treating HBV; IDO inhibitors; arginase inhibitors and KDM5 inhibitors.

[0172] method In some embodiments, the RNAi components include (i) a first RNAi agent comprising an antisense strand comprising the nucleotide sequence of any one of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7, and a sense strand comprising the nucleotide sequence of any one of SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, and SEQ ID NO:15, and (ii) a second RNAi agent comprising an antisense strand comprising the nucleotide sequence of any one of SEQ ID NO:8 and SEQ ID NO:9, and a sense strand comprising the nucleotide sequence of any one of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, and SEQ ID NO:19.

[0173] In some embodiments, the first RNAi agent comprises SEQ ID NO:5 and SEQ ID NO:14. In some embodiments, the first RNAi agent comprises SEQ ID NO:6 and SEQ ID NO:14. In some embodiments, the first RNAi agent comprises SEQ ID NO:7 and SEQ ID NO:15. In some embodiments, the first RNAi agent comprises SEQ ID NO:1 and SEQ ID NO:10, 11 or 13. In some embodiments, the first RNAi agent comprises SEQ ID NO:2 and SEQ ID NO:10, 11 or 13. In some embodiments, the first RNAi agent comprises SEQ ID NO:3 and SEQ ID NO:10, 11 or 13. In some embodiments, the first RNAi agent comprises SEQ ID NO:4 and SEQ ID NO:12. In some embodiments, the second RNAi agent comprises SEQ ID NO:9 and SEQ ID NO:19. In some embodiments, the second RNAi agent comprises SEQ ID NO:8 and SEQ ID NO:16, 17 or 18.

[0174] In some embodiments, the RNAi components include a first RNAi agent that comprises SEQ ID NO:5 and SEQ ID NO:14, and a second RNAi agent that comprises SEQ ID NO:9 and SEQ ID NO:19. In some embodiments, the RNAi components include a first RNAi agent that comprises SEQ ID NO:6 and SEQ ID NO:14, and a second RNAi agent that comprises SEQ ID NO:9 and SEQ ID NO:19. In some embodiments, the RNAi components include a first RNAi agent that comprises SEQ ID NO:7 and SEQ ID NO:15, and a second RNAi agent that comprises SEQ ID NO:9 and SEQ ID NO:19.

[0175] In some embodiments, the RNAi components include a first RNAi agent comprising SEQ ID NO:1 and SEQ ID NO:10, 11 or 13, and a second RNAi agent comprising SEQ ID NO:8 and SEQ ID NO:16, 17 or 18. In some embodiments, the RNAi components include a first RNAi agent comprising SEQ ID NO:2 and SEQ ID NO:10, 11 or 13, and a second RNAi agent comprising SEQ ID NO:8 and SEQ ID NO:16, 17 or 18. In some embodiments, the RNAi components include a first RNAi agent comprising SEQ ID NO:3 and SEQ ID NO:10, 11 or 13, and a second RNAi agent comprising SEQ ID NO:8 and SEQ ID NO:16, 17 or 18. In some embodiments, the RNAi components include a first RNAi agent comprising SEQ ID NO:4 and SEQ ID NO:12, and a second RNAi agent comprising SEQ ID NO:8 and SEQ ID NO:16, 17 or 18.

[0176] In some embodiments, the RNAi components include a first RNAi agent that comprises SEQ ID NO:2 and SEQ ID NO:11, and a second RNAi agent that comprises SEQ ID NO:16 and SEQ ID NO:8.

[0177] In some embodiments, the two HBV RNAi agents are administered in a ratio of about 1:1, 2:1, 3:1, 4:1 or 5:1. In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1.

[0178] In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1, about 3:1, about 1:1, about 4:1, about 5:1, or about 1:2 in a total amount of about 25-75 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1, about 3:1, about 1:1, about 4:1, about 5:1, or about 1:2 in a total amount of about 35-40 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1, about 3:1, about 1:1, about 4:1, about 5:1, or about 1:2 in a total amount of about 50-125 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1, about 3:1, about 1:1, about 4:1, about 5:1, or about 1:2 in a total amount of about 75-150 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1, about 3:1, about 1:1, about 4:1, about 5:1, or about 1:2 in a total amount of about 100-200 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1, about 3:1, about 1:1, about 4:1, about 5:1, or about 1:2 in a total amount of about 150-250 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1, about 3:1, about 1:1, about 4:1, about 5:1, or about 1:2 in a total amount of about 200-300 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1, about 3:1, about 1:1, about 4:1, about 5:1, or about 1:2 in a total amount of about 300-400 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1, about 3:1, about 1:1, about 4:1, about 5:1, or about 1:2 in a total amount of about 50-100 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1 in a total amount of about 25-400 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1 in a total amount of about 25-75 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1 in a total amount of about 35-40 mg per dose administration.In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1 in a total amount of about 50-125 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1 in a total amount of about 75-150 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1 in a total amount of about 100-200 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1 in a total amount of about 125-225 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1 in a total amount of about 150-250 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1 in a total amount of about 200-300 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1 in a total amount of about 300-400 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1 in a total amount of about 100 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1 in a total amount of about 25 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1 in a total amount of about 35 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1 in a total amount of about 40 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1 in a total amount of about 50 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1 in a total amount of about 75 mg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a ratio of about 2:1 in a total amount of about 200 mg per dose administration.

[0179] In some embodiments, the first RNAi agent is administered in an amount of about 3-650 mg per dose administration and the second RNAi agent is administered in an amount of about 2-325 mg per dose administration. In some embodiments, the first RNAi agent is administered in an amount of about 15-150 mg per dose administration and the second RNAi agent is administered in an amount of about 5-75 mg per dose administration. In some embodiments, the first RNAi agent is administered in an amount of about 35-265 mg per dose administration. In some embodiments, the first RNAi agent is administered in an amount of about 50-75 mg per dose administration. In some embodiments, the first RNAi agent is administered in an amount of about 15-75 mg per dose administration. In some embodiments, the second RNAi agent is administered in an amount of about 20-125 mg per dose administration. In some embodiments, the second RNAi agent is administered in an amount of about 25-50 mg per dose administration. In some embodiments, the second RNAi agent is administered in an amount of about 5-40 mg per dose administration. In some embodiments, the first RNAi agent is administered in an amount of about 17 mg per dose administration and the second RNAi agent is administered in an amount of about 8 mg per dose administration. In some embodiments, the first RNAi agent is administered in an amount of about 23 mg per dose administration and the second RNAi agent is administered in an amount of about 12 mg per dose administration. In some embodiments, the first RNAi agent is administered in an amount of about 27 mg per dose administration and the second RNAi agent is administered in an amount of about 13 mg per dose administration. In some embodiments, the first RNAi agent is administered in an amount of about 33 mg per dose administration and the second RNAi agent is administered in an amount of about 17 mg per dose administration. In some embodiments, the first RNAi agent is administered in an amount of about 67 mg per dose administration and the second RNAi agent is administered in an amount of about 33 mg per dose administration.

[0180] In some embodiments, the two RNAi agents are administered in a total dose of 25-400 mg per dose administration. In one embodiment, the two RNAi agents are administered in a total dose of 25-400 mg, with the first RNAi agent being administered with the second RNAi agent in a 1:1 ratio. In one embodiment, the dose of each of the first and second RNAi agents is in an amount of about 12 mg for a total dose of about 25 mg. In one embodiment, the dose of each of the first and second RNAi agents is in an amount of about 17 mg for a total dose of about 35 mg. In one embodiment, the dose of each of the first and second RNAi agents is in an amount of about 20 mg for a total dose of about 40 mg. In one embodiment, the dose of each of the first and second RNAi agents is in an amount of about 25 mg for a total dose of about 50 mg. In one embodiment, the dose of each of the first and second RNAi agents is in an amount of about 50 mg for a total dose of about 100 mg. In one embodiment, the dose of each of the first and second RNAi agents is about 100mg for a total dose of about 200mg.In one embodiment, the dose of each of the first and second RNAi agents is about 150mg for a total dose of about 300mg.In one embodiment, the dose of each of the first and second RNAi agents is about 200mg for a total dose of about 400mg.

[0181] In one embodiment, the two RNAi agents are administered at a total dose of 25-400 mg per dose, with the first RNAi agent being administered with the second RNAi agent in a 2:1 ratio. In one embodiment, for a total dose of about 25 mg, the dose of the first RNAi agent is in an amount of about 16 mg, and the dose of the second RNAi agent is in an amount of about 8 mg. In one embodiment, for a total dose of about 35 mg, the dose of the first RNAi agent is in an amount of about 24 mg, and the dose of the second RNAi agent is in an amount of about 12 mg. In one embodiment, for a total dose of about 40 mg, the dose of the first RNAi agent is in an amount of about 27 mg, and the dose of the second RNAi agent is in an amount of about 13 mg. In one embodiment, for a total dose of about 50 mg, the dose of the first RNAi agent is in an amount of about 33 mg, and the dose of the second RNAi agent is in an amount of about 17 mg. In one embodiment, for a total dose of about 100mg, the dose of the first RNAi agent is about 65mg, and the dose of the second RNAi agent is about 35mg. In one embodiment, for a total dose of about 200mg, the dose of the first RNAi agent is about 133mg, and the dose of the second RNAi agent is about 67mg. In one embodiment, for a total dose of about 300mg, the dose of the first RNAi agent is about 200mg, and the dose of the second RNAi agent is about 100mg. In one embodiment, for a total dose of about 400mg, the dose of the first RNAi agent is about 270mg, and the dose of the second RNAi agent is about 135mg.

[0182] In one embodiment, the two RNAi agents are administered at a total dose of 25-400 mg per dose, with the first RNAi agent being administered with the second RNAi agent in a ratio of 3:1. In one embodiment, for a total dose of about 25 mg, the dose of the first RNAi agent is in an amount of about 18 mg, and the dose of the second RNAi agent is in an amount of about 6 mg. In one embodiment, for a total dose of about 35 mg, the dose of the first RNAi agent is in an amount of about 27 mg, and the dose of the second RNAi agent is in an amount of about 9 mg. In one embodiment, for a total dose of about 40 mg, the dose of the first RNAi agent is in an amount of about 30 mg, and the dose of the second RNAi agent is in an amount of about 10 mg. In one embodiment, for a total dose of about 50 mg, the dose of the first RNAi agent is in an amount of about 36 mg, and the dose of the second RNAi agent is in an amount of about 12 mg. In one embodiment, for a total dose of about 100mg, the dose of the first RNAi agent is about 75mg, and the dose of the second RNAi agent is about 25mg. In one embodiment, for a total dose of about 200mg, the dose of the first RNAi agent is about 150mg, and the dose of the second RNAi agent is about 50mg. In one embodiment, for a total dose of about 300mg, the dose of the first RNAi agent is about 225mg, and the dose of the second RNAi agent is about 75mg. In one embodiment, for a total dose of about 400mg, the dose of the first RNAi agent is about 300mg, and the dose of the second RNAi agent is about 100mg.

[0183] In some embodiments, the first and second RNAi agents are administered in a combined amount of about 25-400 mg per dose. In some embodiments, the first and second RNAi agents are administered in a combined amount of about 25-50 mg, 50-75 mg, 75-100 mg, 100-125 mg, 125-150 mg, 150-175 mg, 175-200 mg, 200-225 mg, 225-250 mg, 250-275 mg, 275-300 mg, 300-325 mg, 325-350 mg, 350-375 mg, , 375-400mg, 25-75mg, 50-100mg, 100-150mg, 150-200mg, 200-250mg, 250-300mg, 300-350mg, 350-400mg, 25-100mg, 50-150mg, 100-200mg, 150-250mg, 200-300mg, 300-400mg, 25-200mg or 200-400mg total dose. In some embodiments, the first RNAi agent relative to the second RNAi agent is administered in a total amount of about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg or about 400 mg per dose administration. In some embodiments, the first RNAi agent and the second RNAi agent are administered in a total amount of about 50 mg, about 75 mg, about 100 mg or about 125 mg per dose administration. In some embodiments, the first RNAi agent and the second RNAi agent are administered in a total amount of about 25 mg, about 35 mg, about 40 mg or about 200 mg per dose administration.

[0184] In some embodiments, the two HBV RNAi agents are administered in a total amount of about 1-10 mg / kg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a total amount of about 1-5 mg / kg per dose administration. In some embodiments, the two HBV RNAi agents are administered in a total amount of about 1-1.5 mg / kg, about 1.5-2.0 mg / kg, about 2.0-2.5 mg / kg, about 2.5-3.0 mg / kg, about 3.0-3.5 mg / kg, about 3.5-4.0 mg / kg, about 4.0-4.5 mg / kg, about 4.5-5.0 mg / kg, about 5.0-5.5 mg / kg, about 5.5-6.0 mg / kg, about 6.0-6.5 mg / kg, about 6.5-7.0 mg / kg per dose administration. / kg, about 7.0-7.5 mg / kg, about 7.5-8.0 mg / kg, about 8.0-8.5 mg / kg, about 8.5-9.0 mg / kg, about 9.0-9.5 mg / kg, about 9.5-10 mg / kg, about 1-2.5 mg / kg, about 2.5-5.0 mg / kg, about 5.0-7.5 mg / kg, about 7.5-10 mg / kg, about 1-5.0 mg / kg, or about 5.0-10 mg / kg.

[0185] In some embodiments, the first RNAi agent is administered in an amount of about 0.6-7 mg / kg per dose administration and the second RNAi agent is administered in an amount of about 0.3-5 mg / kg per dose administration. In some embodiments, the second RNAi agent is administered in an amount of about 0.5-2.5 mg / kg per dose administration. In some embodiments, the second RNAi agent is administered in an amount of about 0.3-1.5 mg / kg per dose administration. In some embodiments, the first RNAi agent is administered in an amount of about 0.6-5 mg / kg per dose administration. In some embodiments, the first RNAi agent is administered in an amount of about 1-2.5 mg / kg per dose administration.

[0186] In some embodiments, the two RNAi agents are administered about 1-18 weeks apart. In some embodiments, the two RNAi agents are administered about 1 week apart, about 2 weeks apart, about 3 weeks apart, about 4 weeks apart, about 5 weeks apart, about 6 weeks apart, about 7 weeks apart, about 8 weeks apart, about 9 weeks apart, about 10 weeks apart, about 11 weeks apart, about 12 weeks apart, about 13 weeks apart, about 14 weeks apart, about 15 weeks apart, about 16 weeks apart, about 17 weeks apart, or about 18 weeks apart. In some embodiments, the two RNAi agents are administered about 1-6 months apart. In some embodiments, the two RNAi agents are administered about 1 month apart, about 2 months apart, about 3 months apart, about 4 months apart, about 5 months apart, or about 6 months apart. In some embodiments, the two RNAi agents are administered about 4 weeks apart or about 1 month apart. In some embodiments, the two RNAi agents are administered once a month.

[0187] In some embodiments, the first and second RNAi agents are administered for a duration of about 1-12 months. In some embodiments, the first and second RNAi agents are administered for a duration of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months. In some embodiments, the first and second RNAi agents are administered for a duration of about 1-18 weeks. In some embodiments, the first RNAi agent and the second RNAi agent are administered for a duration of at least about 1 week, at least about 5 weeks, at least about 10 weeks, at least about 15 weeks, at least about 20 weeks, at least about 25 weeks, at least about 30 weeks, at least about 35 weeks, at least about 40 weeks, at least about 45 weeks, at least about 50 weeks, at least about 55 weeks, at least about 60 weeks, at least about 65 weeks, at least about 70 weeks, at least about 75 weeks, at least about 80 weeks, at least about 90 weeks, or at least 96 weeks.

[0188] In some embodiments, the first and second RNAi agents are administered in a combined dose of 25-400 mg per dose administration. In one embodiment, the first and second RNAi agents are administered in a combined dose of 25-400 mg, with the first RNAi agent administered with the second RNAi agent in a 1:1 ratio. In one embodiment, the dose of the first RNAi agent administered with the second RNAi agent is in an amount of about 12 mg for a combined dose of about 25 mg. In one embodiment, the dose of each of the first and second RNAi agents is in an amount of about 17 mg for a combined dose of about 35 mg. In one embodiment, the dose of each of the first and second RNAi agents is in an amount of about 20 mg for a combined dose of about 40 mg. In one embodiment, the dose of each of the first and second RNAi agents is in an amount of about 25 mg for a combined dose of about 50 mg. In one embodiment, the dose of each of the first and second RNAi agents is about 50mg for a total dose of about 100mg. In one embodiment, the dose of each of the first and second RNAi agents is about 100mg for a total dose of about 200mg. In one embodiment, the dose of each of the first and second RNAi agents is about 150mg for a total dose of about 300mg. In one embodiment, the dose of each of the first and second RNAi agents is about 200mg for a total dose of about 400mg.

[0189] In one embodiment, the first and second RNAi agents are administered at a total dose of 25-400 mg per dose, and the second RNAi agent is administered with the first RNAi agent in a 1:2 ratio. In one embodiment, for a total dose of about 25 mg, the dose of the first RNAi agent is in an amount of about 16 mg, and the dose of the second RNAi agent is in an amount of about 8 mg. In one embodiment, for a total dose of about 35 mg, the dose of the second RNAi agent is in an amount of about 12 mg, and the dose of the first RNAi agent is in an amount of about 24 mg. In one embodiment, for a total dose of about 40 mg, the dose of the first RNAi agent is in an amount of about 27 mg, and the dose of the second RNAi agent is in an amount of about 13 mg. In one embodiment, for a total dose of about 50 mg, the dose of the first RNAi agent is in an amount of about 33 mg, and the dose of the second RNAi agent is in an amount of about 17 mg. In one embodiment, for a total dose of about 100mg, the dose of the second RNAi agent is about 35mg, and the dose of the first RNAi agent is about 65mg. In one embodiment, for a total dose of about 200mg, the dose of the second RNAi agent is about 67mg, and the dose of the first RNAi agent is about 133mg. In one embodiment, for a total dose of about 300mg, the dose of the second RNAi agent is about 100mg, and the dose of the first RNAi agent is about 200mg. In one embodiment, for a total dose of about 400mg, the dose of the second RNAi agent is about 135mg, and the dose of the first RNAi agent is about 270mg.

[0190] In one embodiment, the first and second RNAi agents are administered at a total dose of 25-400 mg per dose, and the second RNAi agent is administered with the first RNAi agent in a ratio of 1:3. In one embodiment, for a total dose of about 25 mg, the dose of the first RNAi agent is in an amount of about 18 mg, and the dose of the second RNAi agent is in an amount of about 6 mg. In one embodiment, for a total dose of about 35 mg, the dose of the second RNAi agent is in an amount of about 9 mg, and the dose of the first RNAi agent is in an amount of about 27 mg. In one embodiment, for a total dose of about 40 mg, the dose of the first RNAi agent is in an amount of about 30 mg, and the dose of the second RNAi agent is in an amount of about 10 mg. In one embodiment, for a total dose of about 50 mg, the dose of the first RNAi agent is in an amount of about 36 mg, and the dose of the second RNAi agent is in an amount of about 12 mg. In one embodiment, for a total dose of about 100mg, the dose of the second RNAi agent is about 25mg, and the dose of the first RNAi agent is about 75mg. In one embodiment, for a total dose of about 200mg, the dose of the second RNAi agent is about 50mg, and the dose of the first RNAi agent is about 150mg. In one embodiment, for a total dose of about 300mg, the dose of the second RNAi agent is about 75mg, and the dose of the first RNAi agent is about 225mg. In one embodiment, for a total dose of about 400mg, the dose of the second RNAi agent is about 100mg, and the dose of the first RNAi agent is about 300mg.

[0191] In some embodiments, about 1 mg / kg (mpk) of the first RNAi agent and about 1 mg / kg of the second RNAi agent are administered to the subject in need thereof. In some embodiments, about 1.5 mg / kg of the first RNAi agent and about 1.5 mg / kg of the second RNAi agent are administered to the subject in need thereof. In some embodiments, about 2.0 mg / kg of the first RNAi agent and about 1.0 mg / kg of the second RNAi agent are administered to the subject in need thereof. In some embodiments, about 3.0 mg / kg of the first RNAi agent and about 1.0 mg / kg of the second RNAi agent are administered to the subject in need thereof. In some embodiments, about 3.2 mg / kg of the first RNAi agent and about 0.8 mg / kg of the second RNAi agent are administered to the subject in need thereof. In some embodiments, about 2.7 mg / kg of the first RNAi agent and about 1.3 mg / kg of the second RNAi agent are administered to the subject in need thereof. In some embodiments, about 4.0 mg / kg of the first RNAi agent and about 1.0 mg / kg of the second RNAi agent are administered to a subject in need thereof. In some embodiments, about 3.3 mg / kg of the first RNAi agent and about 1.7 mg / kg of the second RNAi agent are administered to a subject in need thereof. In some embodiments, about 0.05 to about 5 mg / kg of the first RNAi agent and about 0.05 to about 5 mg / kg of the second RNAi agent are administered to a subject in need thereof. In some embodiments, about the first RNAi agent and about the second RNAi agent are administered separately (e.g., in separate injections). In some embodiments, each dose of the first RNAi agent and each dose of the second RNAi agent are administered together (e.g., in the same injection). In some embodiments, each dose of the first RNAi agent and each dose of the second RNAi agent are prepared in a single pharmaceutical composition.

[0192] In some embodiments, the RNAi component is administered to the subject once a month at a dose of about 40-350 mg, such as about 40-250 mg, more particularly 40-200 mg, more particularly 100 mg or 200 mg, more particularly 200 mg.

[0193] In some embodiments, the method further comprises administering a nucleoside analog. In some embodiments, the nucleoside analog is entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide, lamivudine, telbivudine, or a combination thereof. In some embodiments, the nucleoside analog is entecavir and is administered in a once daily dose in an amount of about 0.01-5 mg, about 0.01-0.05 mg, about 0.05-0.1 mg, about 0.1-0.5 mg, about 0.5-1 mg, about 1-2 mg, about 2-3 mg, about 3-4 mg, or about 4-5 mg. In some embodiments, the nucleoside analog is entecavir and is administered in a once daily dose in an amount of about 0.5 mg. In some embodiments, the nucleoside analog is tenofovir disoproxil fumarate and is administered in a once daily dose in an amount of about 100-500 mg, about 100-150 mg, about 150-200 mg, about 200-250 mg, about 250-300 mg, 300-400 mg, about 400-500 mg. In some embodiments, the nucleoside analog is tenofovir disoproxil fumarate and is administered in a once daily dose in an amount of about 300 mg. In some embodiments, the nucleoside analog is tenofovir alafenamide and is administered in a once daily dose in an amount of about 5-100 mg, about 5-25 mg, about 25-50 mg, about 50-75, or about 75-100 mg. In some embodiments, the nucleoside analog is tenofovir alafenamide and is administered in a once daily dose in an amount of about 25 mg. In some embodiments, the nucleoside analog is lamivudine and is administered in a once daily dose in an amount of about 50-600 mg, about 50-300 mg, about 100-300 mg, about 100-500 mg, about 150-400 mg, about 200-350, or about 250-300 mg. In some embodiments, the nucleoside analog is lamivudine and is administered in a once daily dose in an amount of 100 mg, 150 mg, or 300 mg. In some embodiments, the nucleoside analog is telbivudine and is administered in a once daily dose in an amount of about 300-800 mg, about 400-700 mg, about 300-600 mg, about 300-400 mg, about 400-500 mg, or about 500-600 mg.In some embodiments, the nucleoside analog is telbivudine and is administered in a dose of 600mg once a day.In some embodiments, the patient is exposed to the nucleoside analog prior to combination therapy.In some embodiments, the patient is administered the nucleoside analog for at least 1 month, at least 3 months, at least 6 months or at least 1 year prior to receiving combination therapy.

[0194] In one embodiment, the method further comprises administering a nucleic acid polymer (NAP). The NAP may be selected from, for example, REP2139 or REP2165. REP2139 is an (A,5'MeC) 20 where each linkage is phosphorothioated and each ribose is 2'O methylated (this is disclosed in WO2016 / 04525 as SEQ ID NO: 10, the contents of which are incorporated herein by reference in their entirety). REP2165 has the sequence (A,5'MeC) 20 wherein each linkage is phosphorothioated and all riboses are 2'O methylated except for the adenosines at positions 11, 21 and 31, where the ribose is 2'OH (this is disclosed as SEQ ID NO: 13 in WO2016 / 04525).

[0195] NAPs can also be other exemplary nucleic acid polymers, including, but not limited to, REP2006, REP2031, REP2055, STOPS™ (S-antigen transport inhibiting oligonucleotide polymer), and those disclosed in International Publication Nos. WO 200424919; WO 201221985; and WO 202097342 and U.S. Pat. Nos. 7,358,068; 8,008,269; 8,008,270; and 8,067,385, the contents of each of which are incorporated herein by reference in their entirety.

[0196] In some embodiments, the patient is screened for HBeAg status prior to administration of the combination therapy. In some embodiments, the patient is HBeAg positive. In some embodiments, the patient is HBeAg negative. In some embodiments, the patient is screened for immune tolerance prior to administration of the combination therapy.

[0197] In some embodiments, the HBsAg level in the patient increases from baseline on day 1 by at least about log 10 0.5, approximately log 10 0.75, approximately log 10 1, about log 10 1.25, approximately log 10 1.5, approximately log 10 1.75, approximately log 10 2 or about log 10 In some embodiments, the HBeAg level in the patient is reduced by at least about log 2.5 from baseline on day 1. 10 0.5, approximately log 10 0.75, approximately log 10 1, about log 10 1.25, approximately log 10 1.5, approximately log 10 1.75, approximately log 10 2 or about log 10 In some embodiments, the HBcrAg level in the patient is reduced by at least about log 2.5 from baseline on Day 1. 10 0.5, approximately log 10 0.75, approximately log 10 1, about log 10 1.25, approximately log 10 1.5, approximately log 10 1.75, approximately log 10 2 or about log 10 In some embodiments, the HBV DNA level in the patient is reduced by at least about log 2.5 from baseline on day 1. 10 0.5, approximately log 10 1, about log 10 1.5, approximately log 10 2, about log 103, about log 10 4, about log 10 5 or about log 10 In some embodiments, the HBV RNA level in the patient is reduced by at least about log 7.5 from baseline on Day 1. 10 0.5, approximately log 10 0.75, approximately log 10 1, about log 10 1.25, approximately log 10 1.5, approximately log 10 1.75, approximately log 10 2 or about log 10 Reduced by 2.5.

[0198] For drugs that are substantially eliminated by renal excretion, renal impairment may alter their PK or pharmacodynamics (PD) to such an extent that a dosing regimen established in subjects with normal renal function may require adjustment in subjects with renal impairment. Thus, the degree of renal impairment must be considered when prescribing dosing regimens for these subjects. The guidance on studies in patients with renal impairment from the Committee for Medicinal Products for Human Use (CHMP) of the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) states that PK studies in subjects with renal impairment are recommended when renal impairment is likely to significantly alter the PK of the drug and / or its active or toxic metabolites. Even for drugs that are primarily eliminated by hepatic metabolism, studies in renal impairment should still be considered unless the therapeutic index is relatively wide.

[0199] The level of renal function sufficiency can be measured in several ways. For example, it can be measured by estimating an individual's creatinine clearance (CLCR) using serum creatinine values ​​according to the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) formula. An individual is considered to have a creatinine clearance rate of 90 mL / min / 1.73 m 2 If the individual has this level or higher, they are classified as having normal renal function, and so on up to the point where they require hemodialysis (end stage renal disease (ESRD)).

[0200] [Table 6]

[0201] In certain embodiments, the subject has previously been determined to be free of renal dysfunction.

[0202] In a further embodiment, the subject has previously been determined to have renal dysfunction. More particularly, the subject has been determined to have mild, moderate or severe renal dysfunction. In yet a further embodiment, the subject suffers from renal dysfunction or ESRD. In another embodiment, the subject suffers from ESRD and is not undergoing hemodialysis. In a further embodiment, the subject suffers from ESRD that requires hemodialysis.

[0203] In embodiments of the method of treating HBV infection provided herein, the patient, individual or subject in need thereof is a patient with chronic HBV infection, with or without underlying hepatitis. In some embodiments, the patient has chronic HBV infection. In another embodiment, the patient suffers from HBV-induced disease. In some embodiments, the HBV-induced disease is cirrhosis, liver failure or hepatocellular carcinoma. In another embodiment, the patient is a treatment-naïve patient. More particularly, the patient is a treatment-naïve patient with chronic HBV infection. In a further embodiment, the patient is HBeAg positive. In a further embodiment, the patient is treatment-naïve and HBeAg positive.

[0204] In one embodiment, the method further comprises administering to the subject at least one additional therapeutic agent selected from a nucleoside analog, in particular tenofovir or a pharmaceutically acceptable salt or prodrug thereof, or entecavir or a pharmaceutically acceptable salt or solvate thereof.In an embodiment of the method, the nucleoside analog is selected from the group consisting of entecavir monohydrate, tenofovir disoproxil fumarate and tenofovir alafenamide.In an embodiment of the method, the nucleoside analog is entecavir monohydrate.In an embodiment of the method, the nucleoside analog is tenofovir disoproxil fumarate.In a further embodiment of the method, the nucleoside analog is tenofovir alafenamide.

[0205] In an embodiment of this method, tenofovir disoproxil fumarate is administered in an amount of 60-600 mg. In another embodiment of this method, tenofovir disoproxil fumarate is administered in an amount of 300 mg. In yet another embodiment of this method, entecavir monohydrate is administered in an amount of 0.1-1 mg. In yet another embodiment of this method, entecavir monohydrate is administered in an amount of 0.5 mg. In another embodiment of this method, tenofovir alafenamide is administered in an amount of 25 mg.

[0206] In one embodiment, the method includes the use of HBV combination drugs, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, Toll-like receptor (TLR) modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, Hepatitis B surface antigen (HBsAg) inhibitors, cytotoxic T-lymphocyte associated protein 4 (ipi4) inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors, antisense oligonucleotides targeting viral mRNA, short interfering RNA (siRNA) and ddRNAi endonuclease modulators, ribonucleotide reductase inhibitors, HBV The method further comprises administering to the subject at least one additional therapeutic agent selected from the group consisting of E antigen inhibitors, covalently closed circular DNA (cccDNA) inhibitors, phagesoid X receptor agonists, HBV antibodies, CCR2 chemokine antagonists, thymosin agonists, cytokines, nuclear protein modulators, retinoic acid-inducible gene I stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors, indoleamine-2,3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors, PD-L1 inhibitors, recombinant thymosin alpha-1, Bruton's tyrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replication inhibitors, arginase inhibitors, and other HBV drugs. EXAMPLES

[0207] An open-label, parallel-group, single-dose, PK study of a single 200 mg dose of RNAi components (first and second RNAi agents present in a 2:1 molar ratio) was conducted in men and women aged 18 to 80 years (inclusive) with moderate to severe renal impairment / ESRD, not undergoing dialysis, and with no other major comorbidities, with healthy subjects with normal renal function as the control group. The study design follows current recommendations in the US FDA guidance (FDA Guidance 2020) and EMA guideline (EMA Guideline 2015) for the PK evaluation of pharmaceutical products in subjects with renal impairment.

[0208] The following PK parameters will be evaluated:

[0209] [Table 7]

[0210] Study design After signing the study informed consent document, subjects will be screened for study eligibility. To assess renal function eligibility, two serum creatinine samples (with a minimum of 7 days between samples) must be collected by day 1 for calculation of estimated glomerular filtration rate (eGFRcr) using serum creatinine. A previous sample collected within 3 months prior to the screening visit at the same laboratory may be used as the first sample. eGFRcr is calculated based on serum creatinine value using the online calculator on the CKD-EPI website (http: / / ckdepi.org / equations / gfr-calculator / ), and the CKD-EPIcr result is used to obtain eGFR (unit: mL / min). Any underlying disease causing renal dysfunction (e.g., renal vascular disease, diabetic nephropathy, etc.) will be recorded.

[0211] The average of the two eGFRcr values ​​is used to determine renal function, as shown in the table below.

[0212] [Table 8]

[0213] The study is a parallel-group design comparing subjects with moderate renal impairment or severe renal impairment / ESRD not undergoing dialysis with healthy subjects with normal renal function. Group 1: 8 subjects with moderate renal dysfunction (eGFRcr ≥ 30 mL / min and < 60 mL / min) Group 2: 8 subjects with severe renal dysfunction or ESRD (eGFRcr < 30 mL / min) not undergoing dialysis Group 3: 8-16 healthy subjects with normal renal function (eGFRcr ≥ 90 mL / min)

[0214] A total of 24-32 subjects are planned to be enrolled. Eight subjects with moderate renal impairment based on eGFRcr (≥30 mL / min and <60 mL / min, group 1) and eight subjects with severe renal impairment / ESRD not on dialysis (<30 mL / min, group 2) will be enrolled in parallel. Up to 16 case-matched healthy participants with normal renal function (group 3) will be enrolled in parallel.

[0215] An individual matching procedure is used to demographically match subjects with normal renal function in terms of age, weight, and sex with subjects enrolled in the renal impairment group. For each subject in the moderate renal impairment or severe renal impairment / ESRD not on dialysis group, a healthy subject with normal renal function of the same sex, similar age (within ±10 years) and similar weight at screening (within ±10 kg) is enrolled in the control group (group 3). Subjects with normal renal function may be used to match up to two subjects with renal impairment, including one with moderate renal impairment and one with severe renal impairment / ESRD (not on dialysis).

[0216] For Groups 1 and 2 (subjects with moderate renal impairment and severe renal impairment / ESRD not on dialysis, respectively), further enrollment into the study will be paused after four subjects in each group have completed the Day 4 post-dose evaluation. After evaluation of the safety data from the first four subjects, SET will confirm enrollment of the next four subjects into each group. For Group 3 (healthy subjects with normal renal function), this enrollment strategy is not required.

[0217] The study consists of a screening phase (within 28 days prior to study drug administration), an open-label treatment phase (Days -1 to 4) with a single dose on Day 1 and 4 days of PK sampling, and an EOS / follow-up evaluation on Day 14. Subjects who withdraw from the study before completion of scheduled PK evaluations will have an EOS evaluation performed before discharge. The total study duration for an individual subject is approximately 42 days (including screening and EOS / follow-up evaluations).

[0218] Subjects will be confined to the study center from the morning of Day -1 until completion of 72-hour PK blood and urine sample collection on Day 4. Subjects will return to the study center on Day 14 for follow-up evaluations. Subject safety will be monitored throughout the study.

[0219] In addition, samples for PPB determination were collected from all subjects in each group, pre- and post-dose plasma samples on day 1 at C max The samples were taken 6 hours before and after the test.

[0220] [Table 9] JPEG2024527380000036.jpg252163JPEG2024527380000037.jpg194163

[0221] Exclusion criteria Candidates who meet any of the following criteria will be excluded from participating in this study.

[0222] [Table 10] JPEG2024527380000039.jpg249159JPEG2024527380000040.jpg20161

[0223] Study Endpoints The objectives of this study and the endpoints measured are shown in Table 8.

[0224] [Table 11]

Claims

A medicament for use in treating chronic HBV infection in a subject in need thereof, comprising: wherein the medicament comprises: (i) a first RNAi agent comprising an antisense strand having the structure: asGfsasAfafuUfgAfAfAfafaGfuCfcasc (SEQ ID NO: 2) and a sense strand having the structure: (NAG37)s(invAb)sgugga cuuCfUfCfucaauuuucus(invAb) (SEQ ID NO: 11); and (ii) a second RNAi agent comprising an antisense strand having the structure: usAfscsCfafuUfuAfugfcCfufcAfgcsg (SEQ ID NO: 8) and a sense strand having the structure: (NAG37)s(invAb)scgcug uagGfCfAfuuaaauggus(invAb) (SEQ ID NO: 16) comprising an RNAi component having, wherein (NAG37)s has the following structure: 【Chemical 1】 having, a, g, c and u are 2'-O-methyl modified nucleotides, Af, Cf, Gf and Uf are 2'-fluoro modified nucleotides, s is a phosphorothioate nucleoside internucleoside linkage, (invAb) is an inverted (3'-3' linkage) abasic deoxyribonucleotide, (invAb)s is an inverted (3'-3' linkage) abasic deoxyribonucleotide-5'-phosphorothioate, wherein the molar ratio of the first RNAi agent to the second RNAi agent is about 2:1, the medicament, wherein the subject has been previously determined to have mild renal impairment. The medicament according to claim 1, wherein the first RNAi agent and the second RNAi agent are pharmaceutically acceptable salts. The medicament according to claim 2, wherein the first RNAi agent is a sodium salt having the following structure: [Chemical 2] having, wherein the second RNAi agent is a sodium salt having the following structure: 【Chemical Formula 3】 having,

4. The medicament according to claim 1, wherein the subject has an ALT / AST of less than 2 ULN, a direct bilirubin of less than 1.1 ULN and a lipase level of less than grade 2.

5. The medicament according to claim 1, wherein the subject is a patient with no treatment history.

6. The medicament according to claim 5, wherein the subject is a treatment-naive HBeAg-positive patient.

7. The medicament according to claim 1, wherein the subject is a treatment-experienced patient, and the treatment experienced by the subject consists of administering a nucleoside analog or nucleotide analog and / or IFN.

8. The medicament according to any one of claims 1 to 7, wherein the RNAi component is administered to the subject at a dose of about 40 to 200 mg.

9. The medicament according to claim 8, wherein the first RNAi agent is administered in an amount of about 33 mg and the second RNAi agent is administered in an amount of about 17 mg with respect to a total dose of about 50 mg.

10. The medicament according to claim 8, wherein the first RNAi agent is administered in an amount of about 133 mg and the second RNAi agent is administered in an amount of about 67 mg with respect to a total dose of about 200 mg.

11. The medicament according to claim 8, wherein the RNAi component is administered to the subject once a month (i.e., Q4W).

12. The medicament according to claim 11, wherein the RNAi component is administered to the subject for a period of 12 to 48 weeks.

13. The medicament according to claim 1, wherein the RNAi component is administered by subcutaneous injection.

14. The medicament according to claim 1, further comprising administering an effective amount of at least one additional agent.

15. The medicament according to claim 14, wherein the at least one additional agent is a nucleoside analog or nucleotide analog.

16. The medicament according to claim 15, wherein the nucleotide analog or nucleoside analog is entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide, lamivudine, telbivudine, or a combination thereof.

17. The medicament according to claim 15, wherein the nucleoside analog or nucleotide analog is selected from the group consisting of tenofovir or a pharmaceutically acceptable salt or prodrug thereof, and entecavir or a pharmaceutically acceptable salt thereof.

18. The medicament according to claim 15, wherein the nucleoside analog or nucleotide analog is tenofovir or a prodrug thereof, particularly tenofovir alafenamide or tenofovir disoproxil fumarate.

19. The medicament according to claim 15, wherein the administration of the nucleoside analog or nucleotide analog is optionally continued after the administration of an effective amount of the medicament containing the RNAi component has ended.

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