Combination of TLR8 modulating compounds with anti-HBV siRNA therapeutics

Abstract

The present disclosure provides for the treatment and / or prevention of Hepatitis B virus infection by administering to a subject a combination therapeutic regimen comprising a toll-like receptor 8 (TLR8) modulator, a dsRNA and a PD-1 / PD-L1 inhibitor.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 336,709, filed April 29, 2022, and U.S. Provisional Patent Application No. 63 / 188,339, filed May 13, 2021, each of which is incorporated herein in their entirety for all purposes. [Background technology]

[0002] The Toll-like receptor (TLR) family plays a fundamental role in pathogen recognition and innate immune activation. Toll-like receptor 8 (TLR-8) is primarily expressed by myeloid immune cells, and activation of this receptor stimulates a broad range of immune responses. Agonists of TLR-8 activate myeloid dendritic cells, monocytes, monocyte-derived dendritic cells, and Kupffer cells, resulting in the production of inflammatory cytokines and chemokines, such as interleukin-18 (IL-18), interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α), and interferon gamma (IFN-γ). Such agonists also promote increased expression of costimulatory molecules, such as CD8+ cells, major histocompatibility complex molecules (MAIT, NK cells), and chemokine receptors. TLR8 modulating compounds include those described in U.S. Pat. No. 9,670,205.

[0003] Collectively, activation of these innate and adaptive immune responses induces immune responses and provides therapeutic benefits in a variety of conditions involving autoimmunity, inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD), infectious diseases, cancer, and immune deficiencies. For example, with respect to hepatitis B, activation of TLR8 on professional antigen-presenting cells (pAPCs) and other intrahepatic immune cells is associated with the induction of IL-12 and proinflammatory cytokines, which are expected to enhance HBV-specific T cell responses, activate intrahepatic NK cells, and promote reconstitution of antiviral immunity. See, e.g., Wille-Reece, U. et al. J Exp Med 203, 1249-1258 (2006); Peng, G. et al., Science 309, 1380-1384 (2005); Jo, J. et al., PLoS Pathogens 10, e1004210 (2014) and Watashi, K. et al., J Biol Chem 288, 31715-31727 (2013). There remains a need for new drugs and therapies that can support the activation of latently HBV-infected cells to enhance the activity of antiretroviral therapy and immune responses. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Wille-Reece,U.et al.J Exp Med 203,1249-1258(2006) [Non-Patent Document 2] Peng, G. et al., Science 309, 1380-1384(2005) [Non-Patent Document 3] Jo, J. et al.,PLoS Pathogens 10,e1004210(2014) [Non-Patent Document 4] Watashi, K. et al., J Biol Chem 288, 31715-31727(2013) Summary of the Invention [Means for solving the problem]

[0005] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutical acceptable salt thereof; and double stranded ribonucleic acid (dsRNA) of SEQ ID NO:1 and SEQ ID NO:2, where SEQ ID NO:1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO:2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3'; and a PD-1 / PD-L1 inhibitor or a pharma- ceutical acceptable salt thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0006] I. Overview The present disclosure describes methods comprising treating and / or preventing heptatis B virus infection in a subject in need thereof comprising administering a therapeutically effective amount of a combination of a toll-like receptor 8 (TLR8) modulator, an anti-HBV siRNA or dsRNA, a programmed cell death protein 1 (PD-1) / programmed cell death ligand 1 (PD-L1) inhibitor. The methods of the present disclosure may also include other additional therapeutic agents.

[0007] II. Definition Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In addition, any methods or materials similar or equivalent to those described herein can be used in the practice of this disclosure. For purposes of this disclosure, the following terms are defined:

[0008] As used herein, "a," "an," or "the" includes not only embodiments having one member, but also embodiments having two or more members. As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to a "cell" includes a plurality of such cells, reference to an "agent" includes reference to one or more agents known to those of skill in the art, and so forth.

[0009] Reference herein to "about" a value or parameter includes (and describes) embodiments that relate to the value or parameter itself. In certain embodiments, the term "about" includes the indicated amount plus 10%. In other embodiments, the term "about" includes the indicated amount plus 5%. In certain other embodiments, the term "about" includes the indicated amount plus 1%. Also, for those terms, "about X" includes the description of "X." Additionally, the singular forms "a" and "the" include plural references unless the context clearly indicates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "an assay" includes reference to one or more assays and equivalents thereof known to those of skill in the art.

[0010] As used herein, "treat", "treatment" or "treating" is an approach to obtain a beneficial or desired result. For purposes of this disclosure, a beneficial or desired result includes, but is not limited to, alleviating symptoms and / or reducing the extent of symptoms and / or preventing the worsening of symptoms associated with a disease or condition. In one embodiment, "treatment" or "treating" includes one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms caused by the disease or condition and / or reducing the extent of the disease or condition), b) delaying the onset or inhibiting one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, slowing the worsening or progression of the disease or condition), and c) relieving the disease or condition, e.g., causing regression of clinical symptoms, ameliorating the pathology, slowing the progression of the disease, improving quality of life, and / or prolonging survival.

[0011] As used herein, "prevent", "prevention" or "preventing" refers to a regimen that protects against the onset of a disease or disorder such that clinical symptoms of the disease do not develop. Thus, "prevention" relates to the administration of a treatment (e.g., administration of a therapeutic agent) to a subject before symptoms of the disease become detectable in the subject (e.g., administration of a therapeutic agent to a subject in which there is no detectable infectious agent (e.g., virus) in the subject). The subject may be an individual at risk of developing a disease or disorder, such as an individual with one or more risk factors known to be associated with the onset or onset of a disease or disorder. Thus, in one embodiment, the term "preventing HBV infection" or "preventing Hepatitis B virus infection" refers to administering an anti-HBV therapeutic agent to a subject without detectable HBV infection. It is understood that the subject of the anti-HBV prophylactic therapy may be an individual at risk of contracting the HBV virus.

[0012] As used herein, "hepatitis B virus infection" or HBV refers to a viral infection that affects the liver and is caused by the hepatitis B virus.

[0013] As used herein, "hepatitis D virus infection" or HDV refers to a viral infection that affects the liver and is caused by the hepatitis D virus.

[0014] As used herein, a "subject" refers to an animal, such as a mammal, including, but not limited to, a primate (e.g., a human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, etc. In certain embodiments, the subject is a human.

[0015] As used herein, "administering" refers to oral administration, administration as a suppository, topical contact, parenteral administration, intravenous administration, intraperitoneal administration, intramuscular administration, intralesional administration, intranasal or subcutaneous administration, intrathecal administration, or implantation of a sustained release device, such as, for example, a mini-osmotic pump, to a subject.

[0016] As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount that, when administered to a subject to treat a disease, is effective to induce a desired biological or medical response, such as an amount sufficient to achieve such treatment of the disease. The effective amount varies depending on the compound, the disease and its severity, as well as the age, weight, etc., of the subject to be treated. The effective amount may include a range of amounts. As is understood in the art, an effective amount may be one or more doses, i.e., a single dose or multiple doses may be required to achieve a desired therapeutic endpoint. An effective amount may be considered in relation to the administration of one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount when a desired or beneficial result can be achieved or is achieved in combination with one or more other agents. The suitable dose of any co-administered compound may optionally be reduced due to the combined action (e.g., additive or synergistic effects) of the compounds.

[0017] As used herein, a "combination therapeutic regimen" refers to administering two or more therapeutic agents to a subject in need thereof. In some non-limiting examples, the two or more therapeutic agents are administered at different times. In some examples, the two or more therapeutic agents are administered simultaneously. The combination therapeutic regimen is administered by any method described herein.

[0018] Administration can also include co-administration, where two or more therapeutic agents are delivered together during the course of treatment. In one embodiment, the two or more therapeutic agents may be co-formulated into a unit dosage form or "combined formulation," typically for intravenous administration or oral administration as a monolayer or bilayer tablet or capsule, or may be formulated separately and then combined into a combined formulation.

[0019] Pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other substances that are useful in preparing pharmaceutical compositions suitable for human pharmaceutical use.

[0020] As used herein, "pharmaceutically acceptable salts" include alkali metal (e.g., sodium, potassium), alkaline earth metal (e.g., magnesium), ammonium and NX4 salts. +(wherein X is C1-C4 alkyl). Base addition salts such as sodium or potassium salts are also included. Pharmaceutically acceptable salts are non-toxic salts of the free base form of compounds that possess the desired pharmacological activity of the free base. These salts can be derived from inorganic or organic acids or inorganic or organic bases. For example, compounds containing a basic nitrogen can be prepared as pharma-ceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharma- ceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyrate-1,4-diol, hexaphosphate ... Examples of suitable pharma- ceutically acceptable salts include phenyl-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharma- ceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0021] As used herein, "double-stranded ribonucleic acid (dsRNA)" refers to a complex of ribonucleic acid molecules having a duplex structure comprising two antiparallel and substantially complementary nucleic acid strands, said to have "sense" and "antisense" orientations to a target RNA, i.e., HBV gene. In some embodiments of the present disclosure, the dsRNA induces degradation of the target RNA, e.g., mRNA, via a post-transcriptional gene silencing mechanism, referred to herein as RNA interference or RNAi.

[0022] As used herein, "PD-1 / PD-L1 inhibitor" refers to a checkpoint inhibitor that blocks the activity of the programmed cell death protein 1 (PD-1) / programmed death ligand 1 (PD-L1) immune checkpoint protein. PD-1 / PD-L1 inhibitors can act to inhibit the association of programmed cell death ligand 1 (PD-L1) with its receptor, programmed cell death protein 1 (PD-1).

[0023] As used herein, "fasting" refers to not eating and / or drinking for a specified amount of time. In a non-limiting example, fasting can refer to a subject not consuming food and / or liquids for 8-24 hours since the last meal. In some examples, fasting can refer to a subject not consuming food and / or liquids for 8-12 hours since the last meal. In some examples, a subject is unable to consume food and / or liquids for 6-12 hours since the last meal.

[0024] The term "viral load" refers to the amount of virus in a volume of fluid that can be measured volumetrically. Viral load can be expressed as virus or infectious particles per mL. Viral load can be expressed as international units per milliliter (IU / mL). Higher viral load can correlate with the severity of active viral infection. Tests for determining viral load can include, but are not limited to, reverse transcription polymerase chain reaction (RT-PCR) test, branched DNA (bDNA) test, qualitative transcription-mediated amplification assay, and nucleic acid sequence-based amplification (NASBA) test.

[0025] III. Treatment method The present disclosure describes the combination of a TLR8 modulating compound, an anti-HBV siRNA or dsRNA therapeutic and a PD-1 / PD-L1 inhibitor.

[0026] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutical acceptable salt thereof; and double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3'; and a PD-1 / PD-L1 inhibitor or a pharma- ceutical acceptable salt thereof, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0027] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutically acceptable salt thereof; and a double-stranded ribonucleic acid (dsRNA) comprising SEQ ID NO: 1 and SEQ ID NO: 2, wherein SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', in which each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, each u is 2'-O-methyl uridine-3'-phosphate, and each Af is 2'-fluoro adenosine-3'-phosphate. wherein each Cf is 2'-fluoro cytidine-3'-phosphate, each Gf is 2'-fluoro guanosine-3'-phosphate, Uf is 2'-fluoro uridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate linkage, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol, and a PD-1 / PD-L1 inhibitor or a pharma- ceutically acceptable salt thereof, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0028] In some embodiments, the methods include treating or preventing a Hepatitis B virus infection in a subject in need thereof. In some embodiments, the methods include treating a Hepatitis B virus infection in a subject in need thereof. In some embodiments, the methods include treating a Hepatitis B virus infection in a subject in need thereof, the methods comprising administering to a subject a compound of formula (I): [ka] or a pharma- ceutical acceptable salt thereof; and double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3'; and a PD-1 / PD-L1 inhibitor or a pharma- ceutical acceptable salt thereof, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0029] In some embodiments, there is provided a method of treating a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutically acceptable salt thereof; and a double-stranded ribonucleic acid (dsRNA) comprising SEQ ID NO: 1 and SEQ ID NO: 2, wherein SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', in which each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, each u is 2'-O-methyl uridine-3'-phosphate, and each Af is 2'-fluoro adenosine-3'-phosphate. wherein each Cf is 2'-fluoro cytidine-3'-phosphate, each Gf is 2'-fluoro guanosine-3'-phosphate, Uf is 2'-fluoro uridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate linkage, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol, and a PD-1 / PD-L1 inhibitor or a pharma- ceutically acceptable salt thereof, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0030] In some embodiments, the method includes preventing a Hepatitis B virus infection in a subject in need thereof. In some embodiments, the method includes preventing a Hepatitis B virus infection in a subject in need thereof, the method comprising administering to a subject an antibody of formula (I): [ka] or a pharma- ceutical acceptable salt thereof; and double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3'; and a PD-1 / PD-L1 inhibitor or a pharma- ceutical acceptable salt thereof, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0031] In some embodiments, there is provided a method for preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof; and a double-stranded ribonucleic acid (dsRNA) comprising SEQ ID NO: 1 and SEQ ID NO: 2, wherein SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', in which each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, each u is 2'-O-methyl uridine-3'-phosphate, and each Af is 2'-fluoro adenosine-3'-phosphate. wherein each Cf is 2'-fluoro cytidine-3'-phosphate, each Gf is 2'-fluoro guanosine-3'-phosphate, Uf is 2'-fluoro uridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate linkage, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol, and a PD-1 / PD-L1 inhibitor or a pharma- ceutically acceptable salt thereof, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0032] The combination therapy regimens of the present disclosure may also be used to treat and / or prevent Hepatitis D virus infection in a subject in need thereof. In some embodiments, the combination therapy regimens of the present disclosure may also be used to treat and / or prevent Hepatitis D virus infection in a subject in need thereof, comprising administering to said subject a compound of formula (I): [ka] or a pharma- ceutical acceptable salt thereof; and double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3'; and a PD-1 / PD-L1 inhibitor or a pharma- ceutical acceptable salt thereof, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0033] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis D virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutically acceptable salt thereof; and a double-stranded ribonucleic acid (dsRNA) comprising SEQ ID NO: 1 and SEQ ID NO: 2, wherein SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', in which each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, each u is 2'-O-methyl uridine-3'-phosphate, and each Af is 2'-fluoro adenosine-3'-phosphate. wherein each Cf is 2'-fluoro cytidine-3'-phosphate, each Gf is 2'-fluoro guanosine-3'-phosphate, Uf is 2'-fluoro uridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate linkage, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol, and a PD-1 / PD-L1 inhibitor or a pharma- ceutically acceptable salt thereof, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0034] A. Combination Therapy Regimens The combination therapy regimen of the present disclosure may include various toll-like receptor 8 (TLR8) modulators. In some embodiments, the compound of formula (I) is a toll-like receptor 8 (TLR8) modulator. An example of a TLR-8 modulator is sergantolimod, also known as (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol, which has the following structure: [ka] Examples of suitable GS-9688 include, but are not limited to, GS-9688, which has the formula:

[0035] The compound of formula (I) is described in U.S. Pat. No. 9,670,205 and in WO 2016 / 141092, Example 98. Other forms of the compound of formula (I) are described in WO 2020 / 214663 and WO 2020 / 214652.

[0036] In some embodiments, TLR8 modulators that may be administered include E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, sergantolimod, (GS-9688), HRS-9950, VTX-1463, VTX-763, 3M-051, 3M-052, and the TLR8 modulators described in U.S. Pat. Nos. 9,670,205 (Gilead Sciences), 10,285,990 (Gilead Sciences), U.S. Patent Application Publication No. 2019 / 0282576 (Gilead Sciences), WO 2016 / 141092 (Gilead Sciences), U.S. Patent Application Publication No. 2016 / 0289229 (Gilead Sciences), and the like. Sciences), 2014 / 0045849 (Janssen), 2014 / 0073642 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 2014 / 0350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 2008 / 0234251 (Array Biopharma), U.S. Patent Application Publication No. 2008 / 0306050 (Array Biopharma), U.S. Patent Application Publication No. 2010 / 0029585 (Ventirx Pharma), U.S. Patent Application Publication No. 2011 / 0092485 (Ventirx Pharma), No. 2011 / 0118235 (Ventirx Pharma), No. 2012 / 0082658 (Ventirx Pharma), No. 2012 / 0219615 (Ventirx Pharma), No. 2014 / 0066432 (Ventirx Pharma), No. 2014 / 0088085 (Ventirx Pharma), No. 2014 / 0275167 (Novira Therapeutics), No. 2013 / 0251673 (Novira Therapeutics), US Patent No. 9,670,205 (Gilead Sciences, Inc.), US Patent Application Publication No. 2016 / 0289229 (Gilead Sciences, Inc.).), WO 2017 / 048727 (Gilead Sciences, Inc.), U.S. Patent Application Publication Nos. 2018 / 0065938 (Gilead Sciences, Inc.) and 2018 / 0086755 (Gilead Sciences, Inc.). In some embodiments, the compound of formula (I) is sergantolimod (SLGN).

[0037] In some embodiments, the compound of formula (I) has the following structure: [ka] has.

[0038] The combination therapy regimen of the present disclosure can include various Hepatitis B virus double-stranded RNA (dsRNA) for inhibiting the expression of Hepatitis B virus. Representative dsRNAs useful in the combination therapy regimen of the present disclosure are described in WO2020 / 036862. Other dsRNAs useful for inhibiting the expression of Hepatitis B virus are known to those skilled in the art.

[0039] In some embodiments, the dsRNA is a short interfering RNA (siRNA). In some embodiments, the dsRNA can include, but is not limited to, the dsRNA described in WO2020 / 036862. In some embodiments, the dsRNA is chemically modified to enhance stability or other beneficial properties.

[0040] In some embodiments, the dsRNA further comprises a ligand. The ligand can be conjugated to the 3' end of the sense strand of the dsRNA. The ligand can be an N-acetylgalactosamine (GalNAc) derivative. The ligand can be: [ka] It could be.

[0041] In some embodiments, the dsRNA is conjugated to a ligand as shown in the following schematic diagram: [ka] wherein X is O or S. In some embodiments, X is O.

[0042] In some embodiments, the dsRNA is modified to include one or more adenosine-glycol nucleic acids ("GNA"). The term "GNA" refers to glycol nucleic acids, which are polymers similar to DNA or RNA but differ in the composition of their "backbone" in that they are made up of repeating glycerol units linked by phosphodiester bonds; [ka] Each substituent is independently a nucleobase. A description of adenosine-GNA can be found, for example, in Zhang, et al. (JACS 127(12):4174-75 (2005)).

[0043] In some embodiments, the dsRNA comprises SEQ ID NO:1 and SEQ ID NO:2, wherein SEQ ID NO:1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO:2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', wherein each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, and each u is 2'-O-methyl uridine-3'-phosphate, each Af is 2'-fluoroadenosine-3'-phosphate, each Cf is 2'-fluorocytidine-3'-phosphate, each Gf is 2'-fluoroguanosine-3'-phosphate, Uf is 2'-fluorouridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate bond, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol.

[0044] In some embodiments, the dsRNA comprises an antisense strand and a sense strand. In some embodiments, the antisense strand is SEQ ID NO: 1. The antisense strand of SEQ ID NO: 1 corresponds to SEQ ID NO: 16 of WO 2020 / 036862. In some embodiments, the sense strand is SEQ ID NO: 2. The sense strand of SEQ ID NO: 2 corresponds to SEQ ID NO: 29 of WO 2020 / 036862, which has an N-acetylgalactosamine moiety, N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol (also known as Hyp-(GalNAc-alkyl)3) or L96), covalently attached to the 3' end.

[0045] The combination therapy regimens of the present disclosure may include various programmed cell death protein 1 (PD-1) / programmed cell death ligand 1 (PD-L1) inhibitors.

[0046] In some embodiments, the PD-1 / PD-L1 inhibitor is nivolumab, pembrolizumab, pidilizumab, BGB-108, SHR-1210, PDR-001, PF-06801591, IBI-308, GB-226, STI-1110, or mDX-400, or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is nivolumab or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is nivolumab. Nivolumab (Opdivo) is an IgG4 kappa immunoglobulin with a calculated molecular weight of about 146 kDa that is a programmed death receptor 1 (PD-1) blocking antibody.

[0047] In some embodiments, the PD-1 / PD-L1 inhibitor is pembrolizumab or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is pidilizumab or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is BGB-108 or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is SHR-1210 or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is PDR-001 or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is PF-06801591 or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is IBI-308 or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is GB-226 or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is STI-1110 or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is mDX-400 or a pharma- ceutically acceptable salt thereof.

[0048] In some embodiments, the PD-1 / PD-L1 inhibitor is GS-4224, atezolizumab, avelumab, dimverelimab, AMP-224, MEDI-0680, RG-7446, GX-P2, durvalumab, KY-1003, KD-033, MSB-0010718C, TSR-042, ALN-PDL, STI-A1014, CX-072, or BMS-936559, or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is GS-4224 or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is atezolizumab or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is avelumab or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is dimverelimab or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is AMP-224 or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is MEDI-0680 or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is RG-7446 or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is GX-P2 or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is durvalumab or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is KY-1003 or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is KD-033 or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is MSB-0010718C or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is TSR-042 or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is ALN-PDL or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is STI-A1014 or a pharma- ceutically acceptable salt thereof.In some embodiments, the PD-1 / PD-L1 inhibitor is CX-072 or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 / PD-L1 inhibitor is BMS-936559 or a pharma- ceutically acceptable salt thereof.

[0049] Additional PD-1 / PD-L1 inhibitors include, but are not limited to, compounds described in U.S. Patent Nos. 10,710,986 and 10,774,071. In some embodiments, the PD-1 / PD-L1 inhibitor is [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0050] In some embodiments, the PD-1 / PD-L1 inhibitor is [ka] or a pharma- ceutically acceptable salt thereof.

[0051] In some embodiments, the PD-1 / PD-L1 inhibitor is [ka] or a pharma- ceutically acceptable salt thereof.

[0052] In some embodiments, the PD-1 / PD-L1 inhibitor is [ka] or a pharma- ceutically acceptable salt thereof.

[0053] In some embodiments, the PD-1 / PD-L1 inhibitor is [ka] or a pharma- ceutically acceptable salt thereof.

[0054] In some embodiments, the PD-1 / PD-L1 inhibitor is [ka] or a pharma- ceutically acceptable salt thereof.

[0055] In some embodiments, the PD-1 / PD-L1 inhibitor is [ka] or a pharma- ceutically acceptable salt thereof.

[0056] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutical acceptable salt thereof; double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3'; and nivolumab, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0057] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, and a double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, wherein SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', in which each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, each u is 2'-O-methyl uridine-3'-phosphate, and each Af is 2'-fluoro adenosine-3'-phosphate. Provided herein are methods comprising administering to a subject a therapeutically effective amount of a combination therapy regimen comprising a double-stranded ribonucleic acid, wherein (Agn) is 2'-fluorocytidine-3'-phosphate, each Cf is 2'-fluoroguanosine-3'-phosphate, each Gf is 2'-fluorouridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate linkage, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0058] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutical acceptable salt thereof; double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3'; and pembrolizumab, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0059] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, and a double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, wherein SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', in which each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, each u is 2'-O-methyl uridine-3'-phosphate, and each Af is 2'-fluoro adenosine-3'-phosphate. and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol; and pembrolizumab, thereby treating and / or preventing hepatitis B virus infection in the subject.

[0060] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutical acceptable salt thereof; double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3'; and pidilizumab, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0061] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, and a double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, wherein SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', in which each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, each u is 2'-O-methyl uridine-3'-phosphate, and each Af is 2'-fluoro adenosine-3'-phosphate. Provided herein are methods comprising administering to a subject a therapeutically effective amount of a combination therapy regimen comprising a double-stranded ribonucleic acid, wherein (Agn) is 2'-fluorocytidine-3'-phosphate, each Cf is 2'-fluoroguanosine-3'-phosphate, each Gf is 2'-fluorouridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate linkage, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0062] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutical acceptable salt thereof; double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3'; and atezolizumab, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0063] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, and a double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, wherein SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', in which each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, each u is 2'-O-methyl uridine-3'-phosphate, and each Af is 2'-fluoro adenosine-3'-phosphate. Provided herein are methods comprising administering to a subject a therapeutically effective amount of a combination therapy regimen comprising a double-stranded ribonucleic acid, wherein (Agn) is 2'-fluorocytidine-3'-phosphate, each Cf is 2'-fluoroguanosine-3'-phosphate, each Gf is 2'-fluorouridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate linkage, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0064] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutical acceptable salt thereof; double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3'; and avelumab, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0065] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, and a double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, wherein SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', in which each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, each u is 2'-O-methyl uridine-3'-phosphate, and each Af is 2'-fluoro adenosine-3'-phosphate. Provided herein are methods comprising administering to a subject a therapeutically effective amount of a combination therapy regimen comprising a double-stranded ribonucleic acid, wherein (Agn) is 2'-fluorocytidine-3'-phosphate, each Cf is 2'-fluoroguanosine-3'-phosphate, each Gf is 2'-fluorouridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate linkage, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0066] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutical acceptable salt thereof; double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3'; and dimverelimab, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0067] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, and a double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, wherein SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', in which each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, each u is 2'-O-methyl uridine-3'-phosphate, and each Af is 2'-fluoro adenosine-3'-phosphate. wherein each Cf is 2'-fluorocytidine-3'-phosphate, each Gf is 2'-fluoroguanosine-3'-phosphate, Uf is 2'-fluorouridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate linkage, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol, and dimvelelimab, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0068] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutical acceptable salt thereof; double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3'; and durvalumab, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0069] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, and a double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, wherein SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', in which each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, each u is 2'-O-methyl uridine-3'-phosphate, and each Af is 2'-fluoro adenosine-3'-phosphate. wherein each Cf is 2'-fluorocytidine-3'-phosphate, each Gf is 2'-fluoroguanosine-3'-phosphate, Uf is 2'-fluorouridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate linkage, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0070] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutically acceptable salt thereof; a double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3'; and a compound: [ka] or a pharmaceutically acceptable salt thereof, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0071] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, and a double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, wherein SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', in which each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, and each u is 2'-O-methyl cytidine-3'-phosphate. wherein Af is 2'-fluoro adenosine-3'-phosphate, each Cf is 2'-fluoro cytidine-3'-phosphate, each Gf is 2'-fluoro guanosine-3'-phosphate, Uf is 2'-fluoro uridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate bond, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol; and the compound: [ka] or a pharmaceutically acceptable salt thereof, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0072] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutically acceptable salt thereof; a double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3'; and a compound: [ka] or a pharmaceutically acceptable salt thereof, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0073] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, and a double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, wherein SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', in which each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, and each u is 2'-O-methyl cytidine-3'-phosphate. wherein Af is 2'-fluoro adenosine-3'-phosphate, each Cf is 2'-fluoro cytidine-3'-phosphate, each Gf is 2'-fluoro guanosine-3'-phosphate, Uf is 2'-fluoro uridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate bond, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol; and the compound: [ka] or a pharmaceutically acceptable salt thereof, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0074] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutically acceptable salt thereof; a double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3'; and a compound: [ka] or a pharmaceutically acceptable salt thereof, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0075] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, and a double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, wherein SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', in which each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, and each u is 2'-O-methyl cytidine-3'-phosphate. wherein Af is 2'-fluoro adenosine-3'-phosphate, each Cf is 2'-fluoro cytidine-3'-phosphate, each Gf is 2'-fluoro guanosine-3'-phosphate, Uf is 2'-fluoro uridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate bond, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol; and the compound: [ka] or a pharmaceutically acceptable salt thereof, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0076] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutically acceptable salt thereof; a double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3'; and a compound: [ka] or a pharmaceutically acceptable salt thereof, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0077] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, and a double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, wherein SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', in which each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, and each u is 2'-O-methyl cytidine-3'-phosphate. wherein Af is 2'-fluoro adenosine-3'-phosphate, each Cf is 2'-fluoro cytidine-3'-phosphate, each Gf is 2'-fluoro guanosine-3'-phosphate, Uf is 2'-fluoro uridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate bond, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol; and the compound: [ka] or a pharmaceutically acceptable salt thereof, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0078] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutically acceptable salt thereof; a double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3'; and a compound: [ka] or a pharmaceutically acceptable salt thereof, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0079] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, and a double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, wherein SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', in which each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, and each u is 2'-O-methyl cytidine-3'-phosphate. wherein Af is 2'-fluoro adenosine-3'-phosphate, each Cf is 2'-fluoro cytidine-3'-phosphate, each Gf is 2'-fluoro guanosine-3'-phosphate, Uf is 2'-fluoro uridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate bond, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol; and the compound: [ka] or a pharmaceutically acceptable salt thereof, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0080] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutically acceptable salt thereof; a double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3'; and a compound: [ka] or a pharmaceutically acceptable salt thereof, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0081] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, and a double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, wherein SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', in which each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, and each u is 2'-O-methyl cytidine-3'-phosphate. wherein Af is 2'-fluoro adenosine-3'-phosphate, each Cf is 2'-fluoro cytidine-3'-phosphate, each Gf is 2'-fluoro guanosine-3'-phosphate, Uf is 2'-fluoro uridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate bond, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol; and the compound: [ka] or a pharmaceutically acceptable salt thereof, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0082] 1. Further drugs In certain embodiments, there is provided a pharmaceutical composition comprising an agent of the present disclosure, or a pharma- ceutically acceptable salt thereof, in combination with one or more (e.g., 1, 2, 3, 4, 1 or 2, 1-3, or 1-4) additional therapeutic agents, and a pharma- ceutically acceptable excipient.

[0083] In certain embodiments, kits are provided that include an agent of the present disclosure, or a pharma- ceutically acceptable salt thereof, in combination with one or more (e.g., 1, 2, 3, 4, 1 or 2, 1-3, or 1-4) additional therapeutic agents.

[0084] In some embodiments, an agent of the present disclosure or a pharma- ceutically acceptable salt thereof is combined with one, two, three, four, or more additional therapeutic agents. In some embodiments, an agent of the present disclosure or a pharma- ceutically acceptable salt thereof is combined with two additional therapeutic agents. In some embodiments, an agent of the present disclosure or a pharma- ceutically acceptable salt thereof is combined with three additional therapeutic agents. In some embodiments, an agent of the present disclosure or a pharma- ceutically acceptable salt thereof is combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents and / or may be selected from different classes of therapeutic agents.

[0085] In certain embodiments, when the agents of the present disclosure are combined with one or more additional therapeutic agents described herein, the components of the composition are administered simultaneously or as a sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.

[0086] Co-administration of an agent disclosed herein with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of an agent disclosed herein with one or more additional therapeutic agents such that a therapeutically effective amount of each agent is present in the patient's body.

[0087] Co-administration includes administration of a unit dose of an agent disclosed herein before or after administration of a unit dose of one or more additional therapeutic agents. An agent disclosed herein may be administered within seconds, minutes, or hours of administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of an agent disclosed herein is administered first, followed within seconds or minutes by a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed within seconds or minutes by a unit dose of an agent disclosed herein. In some embodiments, a unit dose of an agent disclosed herein is administered first, followed hours (e.g., 1-12 hours) later by a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed within hours (e.g., 1-12 hours) later by a unit dose of an agent disclosed herein.

[0088] In certain embodiments, agents of the present disclosure are combined with one or more additional therapeutic agents in a combination preparation for simultaneous administration to a patient, for example as a solid dosage form for oral administration.

[0089] In certain embodiments, the agents of the disclosure include HBV combination drugs, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, Toll-like receptor (TLR) modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, Hepatitis B core antigen (HBcAg) inhibitors, Hepatitis B surface antigen (HBsAg) inhibitors, cytotoxic T-lymphocyte associated protein 4 (ipi4) inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors, viral mRNA targeted antisense oligonucleotides, short interfering RNA (siRNA) and ddRNAi, endonuclease modulators, ribonuclease reductase inhibitors, HBV E antigen inhibitors, covalently closed circular DNA (cccDNA) inhibitors, farnesoid X receptor agonists, STING agonists, anti-HBV antibodies, CCR2 chemokine antagonists, caspase 9 stimulators, CD3 modulators, thymosin agonists, cytokines, nucleoprotein modulators, retinoic acid-inducible gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors, indoleamine-2,3-dioxygenase (IDO) inhibitors and / or one, two, three, four or more further therapeutic agents selected from tract inhibitors, ZCCHC14 inhibitors, derivatives of tertiary lymphoid aggregates, nucleic acid polymers (e.g., NAP and STOPS), PD-1 inhibitors, PD-L1 inhibitors, recombinant thymosin alpha-1, Bruton's tyrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replication inhibitors, arginase inhibitors, gene and cell therapy, gene editors, CAR-T cell therapy, TCR-T cell therapy, and other HBV drugs.

[0090] In certain embodiments, the agents described herein may be used or combined with one of the following: chemotherapeutic agents, immunomodulatory agents, immunotherapeutic agents, therapeutic antibodies, therapeutic vaccines, bispecific antibodies, and "antibody-like" therapeutic proteins (e.g., DARPins®, anti-pMHC TCR-like antibodies, DART®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives), antibody-drug conjugates (ADCs), genetic modifying agents or gene editors (e.g., CRISPR Cas9, zinc finger nucleases, homing endonucleases, homing meganucleases (e.g., ARCUS), synthetic nucleases, TALENs), cell therapies such as CAR-T (chimeric antigen receptor T cells) and TCR-T (genetically engineered T cell receptor) agents, or any combination thereof.

[0091] In certain embodiments, the agents described herein include, for example, 3-dioxygenase (IDO) inhibitors, apolipoprotein A1 modulators, arginase inhibitors, B and T lymphocyte attenuation inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, CCR2 chemokine antagonists, CD137 inhibitors, CD160 inhibitors, CD305 inhibitors, CD4 agonists and modulators, compounds targeting Hepatitis B core antigen (HBcAg), core protein allosteric modulators, covalently closed circular DNA (cccDNA) inhibitors, cyclophilin inhibitors, cytotoxic T lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymerase inhibitors, endonuclease modulators, epigenetic modulators, farnesoid X receptor agonists, free fatty acid (Ffa) receptor 2 (Ffar2; PR43) agonists, free fatty acid (Ffa) receptor 3 (Ffar3; GPR441) agonists, HBV DNA polymerase inhibitors, HBV replication inhibitors, HBVRNAse inhibitors, HBV virus entry inhibitors, HBx inhibitors, hepatitis B large envelope protein inhibitors, hepatitis B large envelope protein stimulators, hepatitis B structural protein modulators, hepatitis B surface antigen (HBsAg) inhibitors, hepatitis B surface antigen (HBsAg) secretion or assembly inhibitors, hepatitis B virus E antigen inhibitors, hepatitis B virus replication inhibitors, hepatitis virus structural protein inhibitors, HIV-1 reverse transcriptase inhibitors, hyaluronidase inhibitors, apoptosis protein family protein (IAP) inhibitors, IL-2 agonists, IL-7 agonists, immunomodulators, indolamine 2 inhibitors, ribonucleotide reductase inhibitors, interleukin 2 ligand, IPI4 inhibitors, lysine demethylase inhibitors, histone demethylase inhibitors, KDM1 inhibitors, KDM5 inhibitors, killer cell lectins G-like receptor subfamily member 1 inhibitors, lymphocyte activation gene 3 inhibitors, lymphotoxin beta receptor activators, Axl modulators, B7-H3 modulators, B7-H4 modulators, CD160 modulators, CD161 modulators, CD27 modulators, CD47 modulators, noncanonical RNA polymerase PAPD5 inhibitors, noncanonical RNA polymerase PAPD7 inhibitors, CD70 modulators, GITR modulators, HEVEM modulators, ICOS modulators, Mer modulators, NKG2A modulators, NKG2D modulators, OX40 modulators, SIRPα modulators, TIGIT modulators, Tim-4 modulators, Tyro modulators, Na+-taurocholate cotransporter cotransporting polypeptide, NTCP inhibitors, natural killer cell receptor 2B4 inhibitors, NOD2 gene stimulators, nucleoprotein inhibitors, nucleoprotein modulators, OX-40 receptor agonists, PD-1 inhibitors, PD-L1 inhibitors, peptidyl prolyl isomerase inhibitors, phosphatidylinositol-3 kinase (PI3K) inhibitors, retinoic acid-inducible gene 1 stimulators, reverse transcriptase inhibitors, ribonuclease inhibitors, RNAand / or one, two, three, four or more additional therapeutic agents, such as DNA polymerase inhibitors, SLC10A1 gene inhibitors, SMAC mimetics, Src tyrosine kinase inhibitors, stimulators of interferon genes (STING) agonists, NOD1 stimulators, T cell surface glycoprotein CD28 inhibitors, T cell surface glycoprotein CD8 modulators, thymosin agonists, thymosin alpha 1 ligands, Tim-3 inhibitors, TLR-3 agonists, TLR-7 agonists, TLR-7 modulators, TLR-8 modulators, TLR-9 agonists, TLR9 agonists or gene stimulators, toll-like receptor (TLR) modulators, viral ribonucleotide reductase inhibitors, and combinations thereof.

[0092] HBV combination drugs Examples of combination drugs for the treatment of HBV include, but are not limited to, TRUVADA® (tenofovir disoproxifumarate and emtricitabine) and adefovir.

[0093] Other HBV drugs Examples of other drugs for the treatment of HBV include α-hydroxytropolone, amdoxovir, antroquinonol, β-hydroxycytosine nucleoside, ARB-199, CCC-0975, ccc-R08, elvucitabine, ezetimibe, cyclosporine A, gentiopicrin (gentiopicroside), HH-003, heparatide, JNJ-56136379, nitazoxanide, birinapant, NJK14047, NOV-205 (Mollixan, BAM-205), oligotide, mibotylate, Feron, GST-HG-131, levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-006IA, Hepuyinfen, DasKloster0014-01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, Picroside, DasKloster-0039, Heplantai, IMB-2613, NCO-48 Fumarate, XTYW-001, SFA-001, TCM-800B, Reduced Glutathione, RO-6864018, ENOB-HB-01, RG-7834, QL-007 sovosbuvir, ledipasvir, UB-551, PA-1010, HPN-BV1, STSG-0002 and ZH-2N, and U.S. Patent Application Publication No. 20150210682 (Roche), No. 2016 / 0122344 (Roche), WO 2015173164, WO 2016023 877, U.S. Patent Application Publication No. 2015252057A (Roche), WO 16128335(A1) (Roche), WO 16120186(A1) (Roche), U.S. Patent Application Publication No. 2016237090A (Roche), WO 16107833(A1) (Roche), WO 16107832(A1) (Roche), U.S. Patent Application Publication No. 2016176899A (Roche), WO 16102438(A1) (Roche), WO 16012470(A1) (Roche), U.S. Patent Application Publication No. 2016220586A (Roche) and U.S. Patent Application Publication No. 2015031687A (Roche).

[0094] HBV vaccine HBV vaccines include both prophylactic and therapeutic vaccines. Examples of HBV prophylactic vaccines include Vaxelis, Hexaxim, Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D / T / P / HBV / M (LBVP-0101; LBVW-0101), DTwP-Hepb-Hib-IPV vaccine, Heberpenta L, DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, Hepatitis B vaccine (Advax Super D), Hepatrol-07, GSK-223192A, ENGERIX B®, recombinant hepatitis B vaccine (intramuscular, Kangtai Biological Products), recombinant hepatitis B vaccine (Hansenual polymorpha yeast, intramuscular, Hualan Biological Products), and others. Engineering), recombinant hepatitis B surface antigen vaccine, Bimmugen, CARG-101, Euforavac, Eutravac, anrix-DTaP-IPV-Hep B, HBAI-20, Infanrix-DTaP-IPV-Hep B-Hib, Pentabio Vaksin DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, Infanrix Hep B, Comvax, DTP-Hib-HBV vaccine, DTP-HBV vaccine, Yi Tai, Heberbiovac HB, Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene, SUPERVAX, Comvac5, Shanvac B, Hebusulin, Recombivax HB, Revac B mcf, Revac These include, but are not limited to, B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan5, Shan6, rhHBsAG vaccine, HBI pentavalent vaccine, LBVD, Infanrix HeXa, YS-HBV-001, IR-101H, TVAX-008 and DTaP-rHB-Hib vaccine.

[0095] Examples of HBV therapeutic vaccines include HBsAG-HBIG conjugate, ARB-1598, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay, GX-110E, GS-4774, peptide vaccine (εPA-44), Hepatrol-07, NASVAC (NASTERAP), IMP-321, BEVAC, Revac B mcf, Revac B+, MGN-1333, KW-2, CVI-HBV-002, AltraHepB, VGX-6200, FP-02, FP-02.2 (HepTcell), NU-500, HBVax, im / TriGrid / antigen vaccine, Mega-CD40L adjuvanted vaccine, HepB-v, RG7944 (INO-1800), recombinant VLP-based therapeutic vaccine (HBV infection, VLP Biotech), Hepatitis B therapeutic DNA vaccine, AdTG-17909, AdTG-17910, AdTG-18202, ChronVac-B, TG-1050, VVX-001, GSK-3528869A (ChAd155-hli-HBV+MVA-HBV+Hbc-HBs / AS01B-4), VBI-2601, VTP-300 (ChAdOx1-SIi-HBV-CPmut-TPA-Ssh prime and MVA-SIi-HBV-CPmut-TPA-Ssh boost), MVA-BN, AVA-2100, HBV-ADV311, YS-HBV-002, and Lm HBV. HBV arenavirus vaccines are described, for example, in WO2017076988 and WO2017198726.

[0096] HBV DNA polymerase inhibitors Examples of HBV DNA polymerase inhibitors include adefovir (HEPSERA®), emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157, tenofovir exalidex, bicifovir, entecavir (BARACL®), These include, but are not limited to, tetracycline, tetracycline, tetracycline (TEV), tetracycline (TVE), tetracycline (TEV ...

[0097] Immunomodulators Examples of immunomodulators include lintatolimod, imidol hydrochloride, ingalon, dermaVir, Plaquenil (hydroxychloroquine), proleukin, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF), JNJ-440, WF-10, AB-452, ribavirin, IL-12, INO-9112, polymer polyethyleneimine (polymer polyethyleneimine, PEI), Gepon, VGV-1, MOR-22, CRV-431, JNJ-0535, TG-1050, ABI-H2158, BMS-936559, GS-9688, GS-9688, RO-7011785, RG-7854, RO-6871765, AIC-649 and IR-103.

[0098] Toll-like receptor (TLR) modulators In various embodiments, the agents described herein are combined with agonists of toll-like receptors (TLRs), such as agonists of TLR1 (NCBI Gene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098), TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI Gene ID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9 (NCBI Gene ID: 54106), and / or TLR10 (NCBI Gene ID: 81793), TLR11, TLR12, and TLR13.

[0099] An example of a TLR modulator includes, but is not limited to, AK-0701.

[0100] Examples of TLR3 modulators include, but are not limited to, lintatorimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1.

[0101] Examples of TLR4 agonists include, but are not limited to, G-100 and GSK-1795091.

[0102] Exemplary TLR7 agonists that may be co-administered include AL-034, DSP-0509, GS-9620 (vesatolimod), LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7854, RG-7795, and those disclosed in U.S. Patent Application Publication Nos. 2010 / 0143301 (Gilead Sciences), 2011 / 0098248 (Gilead Sciences), and US Patent Publication Nos. 2009 / 0047249 (Gilead Sciences), 2014 / 0045849 (Janssen), 2014 / 0073642 (Janssen), WO 2014 / 056953 (Janssen), 2014 / 076221 (Janssen), 2014 / 128189 (Janssen), US Patent Publication Nos. 2014 / 0350031 (Janssen), WO 2014 / 023813 (Janssen), US Patent Publication Nos. 2008 / 0234251 (Array Biopharma), 2008 / 0306050 (Array Biopharma), 2010 / 0029585 (Ventirx

[0033] Examples of suitable medicaments include, but are not limited to, compounds disclosed in Ventirx Pharma, No. 2011 / 0092485 (Ventirx Pharma), No. 2011 / 0118235 (Ventirx Pharma), No. 2012 / 0082658 (Ventirx Pharma), No. 2012 / 0219615 (Ventirx Pharma), No. 2014 / 0066432 (Ventirx Pharma), No. 2014 / 0088085 (Ventirx Pharma), No. 2014 / 0275167 (Novira Therapeutics), and No. 2013 / 0251673 (Novira Therapeutics).

[0103] TLR7 / TLR8 agonists that may be co-administered are NKTR-262, telluritolimod, and BDB-001.

[0104] An example of a TLR-8 inhibitor includes, but is not limited to, ZG-170607.

[0105] Exemplary TLR8 agonists that may be co-administered include E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, sergantolimod (GS-9688), HRS-9950, VTX-1463, VTX-763, 3M-051, 3M-052, and those disclosed in U.S. Patent Application Publication No. 2016289229 (Gilead Sciences), U.S. Patent Application Publication No. 20140045849 (Janssen), U.S. Patent Application Publication No. 20140073642 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Biopharma), U.S. Patent Application Publication No. 20080306050 (Array Biopharma), U.S. Patent Application Publication No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (Ventirx Pharma), No. 20110118235 (Ventirx Pharma), No. 20120082658 (Ventirx Pharma), No. 20120219615 (Ventirx Pharma), No. 20140066432 (Ventirx Pharma), No. 20140088085 (Ventirx No. 20140275167 (Novira Therapeutics), No. 20130251673 (Novira Therapeutics), U.S. Patent No. 9670205 (Gilead Sciences, Inc.), U.S. Patent Publication No. 20160289229 (Gilead Sciences, Inc.), International Publication No. 2017 / 048727 (Gilead Examples of compounds that can be used include, but are not limited to, those disclosed in U.S. Patent Application Publication Nos. 20180065938 (Gilead Sciences, Inc.) and 20180086755 (Gilead Sciences, Inc.).

[0106] Exemplary TLR9 agonists that may be co-administered include, but are not limited to, AST-008, cobitolimod, CMP-001, IMO-2055, IMO-2125, S-540956, ritenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, lefitolimod (MGN-1703), CYT-003, CYT-003-QbG10, tilsotolimod, and PUL-042.

[0107] TLR7, TLR8 and びTLR9 are the same as the others, International Publication No. 2017047769 (Teika Seiyaku), Same No. 2015014815 (Janssen), Same No. 2018045150 (Gilead Sciences) Inc), Same No. 2018045144 (Gilead Sciences Inc), Same No. 2015162075 (Roche), Same No. 2017034986 (University of Kansas), Same No. 2018095426 (Jiangsu Hengrui Medicine Co Ltd), same as No. 2016091698 (Roche), same as No. 2016075661 (GlaxoSmithKline Biologicals), No. 2016180743 (Roche), No. 2018089695 (Dynavax Technologies), No. 2016055553 (Roche), No. 2015168279 (Novartis), No. 2016107536 (Medshine Discovery), No. 2018086593 (Livo (Shanghai) Pharmaceutical), No. 2017106607 (Merck), No. 2017061532 (Sumitomo Dainippon Pharma), No. 2016023511 (Chia Tai Tianqing Pharmaceutical), No. 2017076346 (Chia Tai Tianqing Pharmaceutical), same No. 2017046112 (Roche), same No. 2018078149 (Roche), same No. 2017040233 (3M Co), same No. 2016141092 (Gilead Sciences), same No. 2018049089 (BristolMyers Squibb), same No. 2015057655 (Eisai Co Ltd), same No. 2017001307 (Roche), same No. 2018005586 (BristolMyers Squibb), same No. 201704023 (3M Co), same No. 2017163264 (Council of Scientific and Industrial Research (India)), same No. 2018046460 (GlaxoSmithKlineNo. 2018047081 (Novartis), No. 2016142250 (Roche), No. 2015168269 (Novartis), No. 201804163 (Roche), No. 2018038877 (3M Co), No. 2015057659 (Eisai Co) Ltd), No. 2017202704 (Roche), No. 2018026620 (BristolMyers Squibb), No. 2016029077 (Janus Biotherapeutics), No. 201803143 (Merck), No. 2016096778 (Roche), No. 2017190669 (Shanghai De Novo) Pharmatech), U.S. Pat. No. 09884866 (University Of Minnesota), WO 2017219931 (Sichuan KelunBiotech Biopharmaceutical), WO 2018002319 (Janssen Sciences), WO 2017216054 (Roche), WO 2017202703 (Roche), WO 2017184735 (IFM Therapeutics), WO 2017184746 (IFM Therapeutics), WO 2015088045 (Takeda Pharmaceutical), WO 2017038909 (Takeda Pharmaceutical), WO 2015095780 (University of Kansas), and WO 2015023958 (University of Non-limiting examples of the compounds include those disclosed in US Pat. No. 6,399,323, issued to Kansas.

[0108] In certain embodiments, an agent described herein is co-administered with a TLR7, TLR8, or TLR9 agonist.

[0109] Interferon alpha receptor ligand Examples of interferon alpha receptor ligands include interferon alpha-2b (INTRON A®), pegylated interferon alpha-2a (PEGASYS®), pegylated interferon alpha-1b, interferon alpha 1b (HAPGEN®), Veldona, Infradure, Roferon-A, YPEG-interferon alpha-2a (YPEG-rhIFNalpha-2a), P-1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co (recombinant super compound interferon), YPEG interferon alpha-2b ( YPEG-rhIFNalpha-2b), MOR-22, pegylated interferon alpha-2b (PEG-INTRON®), Bioferon, Novaferon, Inmutag (Inferon), MULTIFERON®, interferon alpha-n1 (HUMOFERON®), interferon beta-1a (AVONEX®), Shaferon, interferon alpha-2b (Axxo), Alfaferone, interferon alpha-2b (BioGeneric Pharma), interferon-alpha 2 (CJ), Laferonum, VIPEG, BLAUFERON-A, BLAUFERON-B, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PD Feron-B, interferon alpha-2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b, Kalferon, Pegnano, Feronsure, PegiHep, interferon alpha 2b (Zydus-Cadila), interferon alpha 2a, Optipeg AA), Realfa 2B, Reliferon, interferon α-2b (Amega), interferon α-2b (Virchow), ropeg interferon α-2b, rHSA-IFN α-2a (recombinant human serum albumin interferon α-2a fusion protein), PEG-IFN-α, rHSA-IFN α 2b, recombinant human interferon α-(1b, 2a, 2b), pegylated interferon α-2b (Amega), pegylated interferon α-2a, Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon α-2b (Changchun Institute of Biological Examples of such products include IFNα-2b, SFR-9216, and Interapo (Interapa).

[0110] Hyaluronidase Inhibitors Examples of hyaluronidases include, but are not limited to, astodrimer.

[0111] Hepatitis B surface antigen (HBsAg) inhibitors Examples of HBsAg inhibitors include, but are not limited to, AK-074, HBF-0259, GP-605, PBHBV-001, PBHBV-2-15, PBHBV-2-1, REP-9AC, REP-9C, REP-9, REP-2139, REP-2139-Ca, REP-2055, REP-2163, REP-2165, REP-2053, REP-2031, REP-006 and REP-9AC'.

[0112] Examples of HBsAg secretion inhibitors include, but are not limited to, BM601, GST-HG-131, AB-452, and ALG-010093.

[0113] Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) inhibitors Examples of cytotoxic T-lymphocyte-associated protein 4 (CTLA4) inhibitors include, but are not limited to, AGEN-2041, AGEN-1884, ipilumimab, belatacept, PSI-001, PRS-010, probody mAbs, tremelimumab, and JHL-1155.

[0114] Cyclophilin Inhibitors Examples of cyclophilin inhibitors include, but are not limited to, CPI-431-32, EDP-494, OCB-030, SCY-635, NVP-015, NVP-018, NVP-019, STG-175, and compounds disclosed in U.S. Pat. No. 8,513,184 (Gilead Sciences), U.S. Patent Application Publication No. 20140030221 (Gilead Sciences), U.S. Patent Application Publication No. 20130344030 (Gilead Sciences), and U.S. Patent Application Publication No. 20130344029 (Gilead Sciences).

[0115] HBV virus entry inhibitor Examples of HBV viral entry inhibitors include, but are not limited to, Myrcludex B.

[0116] Hepatitis B large envelope protein inhibitor Examples of Hepatitis B large envelope protein inhibitors include, but are not limited to, GP-605, GST-HG-121, ALG-010093, and ALG-01013.

[0117] Viral mRNA-targeted antisense oligonucleotides Examples of viral mRNA-targeting antisense oligonucleotides include, but are not limited to, ISIS-HBVRx, IONIS-HBVRx, IONIS-HBV-LRx, IONIS-GSK6-LRx, GSK-3389404, BNC-1701, and RG-6004.

[0118] Small interfering RNA (siRNA) and ddRNAi Examples of siRNAs include, but are not limited to, TKM-HBV (TKM-HepB), ALN-HBV, SR-008, HepB-nRNA, ARC-520, ARC-521, ARB-1740, ARB-1467, AB-729, DCR-HBVS, RG-6084 (PD-L1), RG-6217, ALN-HBV-02, JNJ-3989 (ARO-HBV), STSG-0002, ALG-010133, ALG-ASO, LUNAR-HBV, and DCR-HBVS (DCR-S219).

[0119] An example of DNA-guided RNA interference (ddRNAi) is BB-HB-331.

[0120] Endonuclease Modulators An example of an endonuclease modulator includes, but is not limited to, PGN-514.

[0121] Ribonucleotide reductase inhibitors An example of a ribonucleotide reductase inhibitor includes, but is not limited to, Trimidox.

[0122] Non-nucleoside reverse transcriptase inhibitors Examples of Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) include, but are not limited to, compounds disclosed in WO 2018118826 (Merck), WO 2018080903 (Merck), WO 2018119013 (Merck), WO 2017100108 (Idenix), WO 2017027434 (Merck), WO 2017007701 (Merck), and WO 2008005555 (Gilead).

[0123] HBV replication inhibitors Examples of Hepatitis B virus replication inhibitors include, but are not limited to, GP-31502, isothiafluridine, IQP-HBV, RM-5038, and Xingantie.

[0124] HIV-1 reverse transcriptase inhibitors Examples of HIV-1 reverse transcriptase inhibitors include, but are not limited to, 2,5,6-substituted pyrimidone derivatives (HBV).

[0125] Non-canonical RNA polymerase PAPD5 and PAPD7 inhibitors Examples of non-canonical RNA polymerase PAPD5 and PAPD7 inhibitors include, but are not limited to, locked nucleic acid antisense oligonucleotides targeting PAPD5 and PAPD7 (HBV infection).

[0126] Covalently closed circular DNA (cccDNA) inhibitors Examples of cccDNA inhibitors include, but are not limited to, BSBI-25, ccc-R08, and CHR-101.

[0127] Farnesoid X receptor agonists Examples of farnesoid x receptor agonists include, but are not limited to, EYP-001, cilofexor (GS-9674), EDP-305, MET-409, tropifexor, AKN-083, RDX-023, BWD-100, LMB-763, INV-3, NTX-023-1, EP-024297, and GS-8670.

[0128] Caspase-9 stimulator Examples of caspase-9 stimulators include, but are not limited to, ENOB-HB-01.

[0129] CD3 Modulators An example of a CD3 modulator includes, but is not limited to, IMC-I109V.

[0130] Ffar2 and Ffar3 agonists Examples of Ffar2 and Ffar3 agonists include, but are not limited to, SFA-001.

[0131] Additional HBV antibodies Examples of HBV antibodies that target the surface antigen of the Hepatitis B virus include, but are not limited to, lenbervimab (GC-1102), XTL-17, XTL-19, KN-003, IV Hepabulin SN, VIR-3434, and fully human monoclonal antibody therapy (Hepatitis B virus infection, Humabs BioMed).

[0132] Examples of HBV antibodies, including monoclonal and polyclonal antibodies, include, but are not limited to, Zutectra, Shang Sheng Gan Di, Uman Big (Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B, Igantibe, Niuliva, CT-P24, Hepatitis B Immune Globulin (Intravenous, pH4, HBV Infection, Shanghai RAAS Blood Products), and Fovepta (BT-088).

[0133] An example of a fully human monoclonal antibody includes, but is not limited to, HBC-34.

[0134] Antibodies against HBV viral peptide / major histocompatibility complex (MHC) class I (pMHC) complexes are described, for example, in Sastry, et al., J Virol. 2011 Mar;85(5):1935-42 and WO2011062562.

[0135] CCR2 chemokine antagonists An example of a CCR2 chemokine antagonist includes, but is not limited to, propagermanium.

[0136] Thymosin agonists Examples of thymosin agonists include, but are not limited to, thymalfasin and recombinant thymosin alpha 1 (GeneScience).

[0137] Cytokines Examples of cytokines include, but are not limited to, recombinant IL-7, CYT-107, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus), IL-15, IL-21, IL-24, and celluloleukin.

[0138] Interleukin agonists In certain embodiments, the agents described herein include interleukin agonists, such as IL-2, IL-7, IL-15, IL-10, IL-12 agonists; examples of IL-2 agonists, such as Proleukin (aldesleukin, IL-2); pegylated IL-2 (e.g., NKTR-214); modified variants of IL-2 (e.g., THOR-707), bempegaldosulkin, AIC-284, ALKS-4230, CUI Examples of IL-15 agonists include IL-15 agonists such as IL-15-101, Neo-2 / 15; ALT-803, NKTR-255, and hetIL-15, interleukin-15 / Fc fusion protein, AM-0015, NIZ-985, SO-C101, IL-15 symbolin (PEGylated Il-15), P-22339, and IL-15-PD-1 fusion protein N-809; examples of IL-7 include CYT-107.

[0139] Nucleoprotein Modulators The nucleoprotein modulator may be either an HBV core or capsid protein inhibitor. Examples of nucleoprotein modulators include GS-4882, AB-423, AB-836, AT-130, ALG-001075, ALG-001024, ALG-000184, EDP-514, GLS4, NVR-1221, NVR-3778, AL-3778, BAY These include, but are not limited to, 41-4109, morphotiazine mesylate, ARB-168786, ARB-880, ARB-1820, GST-HG-141, JNJ-379, JNJ-632, RG-7907, GST-HG-141, HEC-72702, KL-060332, AB-506, ABI-H0731, ABI-H3733, JNJ-440, AK-0605, HRS-5091, VNRX-9945, ABI-H2158, CB-HBV-001, AK-0605, SOC-10, SOC-11, and DVR-23.

[0140] Examples of capsid inhibitors are described in U.S. Patent Application Publication No. 2018161307 (Gilead Sciences), U.S. Patent Application Publication No. 20140275167 (Novira Therapeutics), U.S. Patent Application Publication No. 20130251673 (NoviraTherapeutics), Same No. 20140343032 (Roche), International Publication No. 2014037480 (Roche), US Patent Application Publication No. 20130267517 (Roche), International Publication No. 2014131847 (Janssen) , Same as No. 2014033176 (Janssen), Same as No. 2014033170 (Janssen), Same as No. 2014033167 (Janssen), Same as No. 2015 / 059212 (Janssen), Same as No. 2015118057 (Jansse) n), same as No. 2015011281 (Janssen), same as No. 2014184365 (Janssen), same as No. 2014184350 (Janssen), same as No. 2014161888 (Janssen), same as No. 2013096744 (Novira), U.S. Patent Application Publication No. 20150225355 (Novira), same as No. 20140178337 (Novira), same as No. 20150315159 (Novira), same as No. 20150197533 (Novira), same as No. 2015027465 No. 2 (Novira), Same No. 20150259324 (Novira), Same No. 20150132258 (Novira), US Patent No. 9181288 (Novira), International Publication No. 2014184350 (Janssen), Same No. 2013144 No. 129 (Roche), Same as No. 2017198744 (Roche), U.S. Patent Publication No. 20170334882 (Novira), Same as No. 20170334898 (Roche), International Publication No. 2017202798 (Roche), Same as No. 201 7214395 (Enanta), 2018001944 (Roche), 2018001952 (Roche), 2018005881 (Novira), 2018005883 (Novira), 2018011100 (Roche), 2018011160 (Roche), 2018011162 (Roche), 2018011163 (Roche), 2018036941 (Roche), 2018043747 (Kyouto Univ), U.S. Patent Application Publication No. 20180065929 (Janssen), International Publication No. 2016168619 (IndianaNo. 2016195982 (The Penn State Foundation), No. 2017001655 (Janssen), No. 2017048950 (Assembly Biosciences), No. 2017048954 (Assembly Biosciences), No. 2017048962 (Assembly Biosciences), U.S. Patent Application Publication No. 20170121328 (Novira), and No. 20170121329 (Novira).

[0141] Examples of transcription inhibitors include those disclosed in International Publication No. 2017013046 (Roche), International Publication No. 2017016960 (Roche), International Publication No. 2017017042 (Roche), International Publication No. 2017017043 (Roche), International Publication No. 2017061466 (Toyoma chemicals), International Publication No. 2016177655 (Roche), International Publication No. 2016161268 (Enanta), International Publication No. 2017001853 (Redex Pharma), International Publication No. 2017211791 (Roche), International Publication No. 2017216685 (Novartis), International Publication No. 2017216686 (Novartis), International Publication No. 2018019297 (Ginkgo US Patent Publication No. 2018022282 (Newave Pharma), US Patent Publication No. 20180030053 (Novartis), and WO 2018045911 (Zhejiang Pharma).

[0142] STING agonists, RIG-I and NOD2 modulators In some embodiments, the agents described herein are combined with a stimulator of interferon genes (STING). In some embodiments, the STING receptor agonist or activator is selected from the group consisting of ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, STINGVAX, GSK-532, SYN-STING, MSA-1, SR-8291, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic di-AMP. In some embodiments, the agents described herein are combined with a RIG-I modulator, such as RGT-100, or a NOD2 modulator, such as SB-9200 and IR-103.

[0143] Examples of STING agonists include those disclosed in WO 2018065360 (Biolog Life Science Institute Forschungslabor und Biochemica-Vertrieb GmbH, Germany), WO 2018009466 (Aduro Biotech), WO 2017186711 (InvivoGen), WO 2017161349 (Immune Sensor), WO 2017106740 (Aduro Biotech), U.S. Patent Application Publication No. 20170158724 (Glaxo Smithkiline), WO 2017075477 (Aduro Biotech), U.S. Patent Application Publication No. 20170044206 (Merck), WO 2014179760 (University of and 2018060323 (Boehringer), and the like.

[0144] Retinoic acid-inducible gene 1 stimulator Examples of stimulators of retinoic acid-inducible gene 1 include, but are not limited to, inarigivirsoproxil (SB-9200), SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198, ORI-7170, and RGT-100.

[0145] NOD2 stimulator Examples of NOD2 stimulators include, but are not limited to, inarigivirsoproxil (SB-9200).

[0146] Phosphatidylinositol 3-kinase (PI3K) inhibitors Examples of PI3K inhibitors include idelalisib, ACP-319, AZD-8186, AZD-8835, bupallisib, CDZ-173, CLR-457, pictilisib, neratinib, rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, IPI-549, UCB-5857, taselisib, XL-765, jedatolicib, ME-401, VS-5584, copanlisib, CAI otrose salt, perifosine, RG-7666, GSK-2636771, DS-7423, These include, but are not limited to, panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-40093, pilaralisib, BAY-1082439, pukitinib mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib, LY-3023414, SAR-260301, TAK-117, HMPL-689, tenalisib, voxtalisib, and CLR-1401.

[0147] Immune Checkpoint Modulators In various embodiments, the agents described herein are combined with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors, and / or one or more stimulators, activators, or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blocking or inhibiting an inhibitory immune checkpoint can ensure regulation of T cell or NK cell activation and prevent immune leakage of infected cells. Activation or stimulation of a stimulatory immune checkpoint can enhance the effect of immune checkpoint inhibitors in infection treatments. In various embodiments, the immune checkpoint protein or receptor regulates T cell responses (e.g., as reviewed in Xu, et al., J Exp Clin Cancer Res. (2018) 37:110). In various embodiments, immune checkpoint proteins or receptors regulate NK cell responses (e.g., Davis, et al., Semin Immunol. (2017) 31:64-75, and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688).

[0148] Examples of immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain-containing T-cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associated 2 (HHLA2, B7H7); inducible T cell costimulatory molecule (ICOS, CD278); inducible T cell costimulatory molecule ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BT LA);TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF);TNFRSF18 (GITR), TNFSF18 (GITRL);MHC class I polypeptide-related sequence A (MICA);MHC class I polypeptide-related sequence B (MICB);CD274 (CD274, PDL1, PD-L1);Programmed cell death 1 (PDCD1, PD1, PD-1);Cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152);CD80 (B7-1), CD28;Nectin cell adhesion molecule 2 (NECTIN2, CD112);CD226 (DNAM-1);Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155);PVR-related immunoglobulin domain-containing (PVRIG, CD112R);T cell immunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin and mucin domain containing 4 (TIMD4; TIM4); Hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); Galectin 9 (LGALS9); Lymphocyte activation 3 (LAG3, CD223); Signaling lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150); Lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family members UL16 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL16 binding protein 3 (ULBP3); retinoic acid early transcript 1E (RAET1E; ULBP4); retinoic acid early transcript 1G (RAET1G; ULBP5); retinoic acid early transcript 1L (RAET1L; ULBP6); lymphocyte activation 3 (CD223); killer cell immunoglobulin-like receptor receptor, three Ig domains, and long cytoplasmic tail 1 (KIR, CD158E1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); killer cell lectin-like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin-like receptor C3 (KLRC3, NKG2E); killer cell lectin-like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin-like receptor, killer cell immunoglobulin-like receptor, 1 Ig domain and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, 2 Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, 3 Ig domains and long cytoplasmic tail 2 (KIR2DL3); killer cell immunoglobulin-like receptor, 3 Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor D1 (KLRD1); and SLAM family member 7 (SLAMF7).

[0149] In various embodiments, the agents described herein are combined with one or more blockers or inhibitors of one or more T cell inhibitory immune checkpoint proteins or receptors. Exemplary T cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing inhibitor of T cell activation 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); PVR-associated immunoglobulin domain-containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); Hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, one Ig domain and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 2 (KIR2DL3); and killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1). In various embodiments, an agent as described herein is combined with one or more agonists or activators of one or more T cell stimulatory immune checkpoint proteins or receptors.Exemplary T cell stimulatory immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T cell costimulatory molecule (ICOS, CD278); inducible T cell costimulatory molecule ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4), poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, e.g., Xu, et al., J Exp Clin Cancer Res. (2018) 37:110.

[0150] In various embodiments, the agents described herein are combined with one or more blockers or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. Exemplary NK cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, one Ig domain and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 2 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); and killer cell lectin-like receptor D1 (KLRD1, CD94). In various embodiments, the agents described herein are combined with one or more agonists or activators of one or more NK cell stimulatory immune checkpoint proteins or receptors. Exemplary NK cell stimulatory immune checkpoint proteins or receptors include, but are not limited to, CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); Killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). See, for example, Davis, et al., Semin Immunol. (2017) 31:64-75; Fang et al., Semin Immunol. (2017) 31:37-54, and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688.

[0151] In some embodiments, the one or more immune checkpoint inhibitors comprise a proteinaceous (e.g., antibody or fragment thereof, or antibody mimetic) inhibitor of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the one or more immune checkpoint inhibitors comprise an organic small molecule inhibitor of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550, and MAX10181. Further examples of small molecule PD-L1 inhibitors include, but are not limited to, those disclosed in U.S. Patent Application Publication Nos. 2018 / 305315 (Gilead Sciences), 2020 / 017471 (Gilead Sciences), and 2019 / 270727 (Gilead Sciences). In some embodiments, the small molecule inhibitor of CTLA4 comprises BPI-002.

[0152] Examples of CTLA4 inhibitors that may be co-administered include ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-1144, PBI -5D3H5, BPI-002, and the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4), and AK-104 (CTLA4 / PD-1).

[0153] Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors that may be co-administered include pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, ALN-PDL, BMS-936559, CK-301, PF-06801591, BGB-108, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), GB-226, AK-105, CS-1003, HLX-10, MGA-012, BI-754091, PDR-001, AGEN-2034, JS-001 (Tripalimbab), JNJ-63723283, Genolimuzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (Camrelizumab), Sym-021, ABBV-181, PD1-PIK, BAT-1306, RO-6084 (PD-L1 antisense oligonucleotide), STI-1110, GX-P2, RG-7446, mDX-400, (MSB0010718C) , CX-072, CBT-502, TSR-042 (dostallimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155), MEDI-0680, embafolimab (KN-035), KD-033, KY-1003, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, MSB-0010718C, GS-4224, GS-4 416, INCB086550, MAX10181, and multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), MGD-019(PD-1 / CTLA4), KN-046(PD-1 / CTLA4), MEDI-5752(CTLA4 / PD-1), RO-7121661(PD-1 / TIM-3), XmAb-20717(PD-1 / CTLA4), AK-104(CTLA4 / PD-1),These include, but are not limited to, M7824 (PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1), GNS-1480 (epidermal growth factor receptor antagonist; programmed cell death ligand 1 inhibitor), M-7824 (PD L1 / TGFβ bifunctional fusion protein), and INBRX-105 (4-1BB / PDL1).

[0154] Example of PD-1 blocking agent, International Publication No. 2017112730 (Incyte Corp), Same No. 2017087777 (Incyte Corp), Same No. 2017017624, Same No. 2014151634 (BristolMyers Squibb Co), same as No. 201317322 (BristolMyers Squibb Co), same as No. 2018119286 (Incyte Corp), same as No. 2018119266 (Incyte Corp), same as No. 2018119263 (Incyte Corp), same as No. 2018119236 (Incyte Corp) Corp), same as No. 2018119221 (Incyte Corp), same as No. 2018118848 (BristolMyers Squibb Co), No. 20161266460 (BristolMyers Squibb Co), No. 2017087678 (BristolMyers Squibb Co), No. 2016149351 (BristolMyers Squibb Co), No. 2015033299 (Aurigene Discovery Technologies Ltd), No. 2015179615 (Eisai Co Ltd; Eisai Research Institute), No. 2017066227 (BristolMyers Squibb Co), No. 2016142886 (Aurigene Discovery Technologies Ltd), No. 2016142852 (Aurigene Discovery Technologies Ltd), No. 2016142835 (Aurigene Discovery Technologies Ltd; Individual), No. 2016142833 (Aurigene Discovery Technologies Ltd), Same No. 2018085750 (BristolMyers Squibb Co), Same No. 2015033303 (Aurigene Discovery Technologies Ltd), Same No. 2017205464 (Incyte Corp), Same No. 2016019232 (3M Co; Individual; Texas A&M University(BristolMyers Squibb Co), No. 2015160641 (BristolMyers Squibb Co), No. 2017079669 (Incyte Corp), No. 2015033301 (Aurigene Discovery Technologies Ltd), No. 2015034820 (BristolMyers Squibb Co), No. 2018073754 (Aurigene Discovery Technologies Ltd), No. 2016077518 (BristolMyers Squibb Co), No. 2016057624 (BristolMyers Squibb Co), No. 2018044783 (Incyte Corp), No. 2016100608 (BristolMyers Squibb Co), No. 2016100285 (BristolMyers Squibb Co), No. 2016039749 (BristolMyers Squibb Co), No. 2015019284 (Cambridge Enterprise Ltd), No. 2016142894 (Aurigene Discovery Technologies Ltd), No. 2015134605 (BristolMyers Squibb Co), No. 2018051255 (Aurigene Discovery Technologies Ltd), No. 2018051254 (Aurigene Discovery Technologies Ltd), No. 2017222976 (Incyte Corp), No. 2017070089 (Incyte Corp), No. 2018044963 (BristolMyers Squibb Co), No. 2013144704 (Aurigene Discovery Technologies Ltd), No. 2018013789 (Incyte Corp), No. 2017176608 (BristolMyers Squibb Co), No. 2018009505 (BristolMyers Squibb Co), No. 2011161699 (Aurigene Discovery Technologies Ltd), No. 2015119944 (Incyte Corp; MerckSharp & Dohme Corp), No. 2017192961 (Incyte Corp), No. 2017106634 (Incyte Corp), No. 2013132317 (Aurigene Discovery Technologies Ltd), No. 2012168944 (Aurigene Discovery Technologies Ltd), No. 2015036927 (Aurigene Discovery Technologies Ltd), No. 2015044900 (Aurigene Discovery Technologies Ltd), No. 2018026971 (Arising International).

[0155] In various embodiments, the agents described herein are combined with anti-TIGIT antibodies, such as BMS-986207, RG-6058, and AGEN-1307.

[0156] Agonists or activators of members of the TNF Receptor Superfamily (TNFRSF) In various embodiments, the agents described herein are agonists of one or more TNF receptor superfamily (TNFRSF) members, such as TNFRSF1A (NCBI Gene ID 7132), TNFRSF1B (NCBI Gene ID 7133), TNFRSF4 (OX40, CD134; NCBI Gene ID 7293), TNFRSF5 (CD40; NCBI Gene ID 958), TNFRSF6 (FAS, NCBI Gene ID 355), TNFRSF7 ( CD27, NCBI gene ID 939), TNFRSF8 (CD30, NCBI gene ID 943), TNFRSF9 (4-1BB, CD137, NCBI gene ID 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI gene ID 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene ID 8795), TNFRSF10C (CD263, TRAILR3, NCBI gene ID 8794), T NFRSF10D (CD264, TRAILR4, NCBI gene ID 8793), TNFRSF11A (CD265, RANK, NCBI gene ID 8792), TNFRSF11B (NCBI gene ID 4982), TNFRSF12A (CD266, NCBI gene ID 51330), TNFRSF13B (CD267, NCBI gene ID 23495), TNFRSF13C (CD268, NCBI gene ID 115650), TNFRSF16 (NG TNFRSF17 (BCMA, CD269, NCBI Gene ID 608), TNFRSF18 (GITR, CD357, NCBI Gene ID 8784), TNFRSF19 (NCBI Gene ID 55504), TNFRSF21 (CD358, DR6, NCBI Gene ID 27242), and TNFRSF25 (DR3, NCBI Gene ID 8718).

[0157] Exemplary anti-TNFRSF4 (OX40) antibodies that may be co-administered include, but are not limited to, MEDI6469, MEDI6383, MEDI0562 (tabolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, IBI-101, and antibodies described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

[0158] Exemplary anti-TNFRSF5 (CD40) antibodies that may be co-administered include, but are not limited to, RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0159] In some embodiments, the anti-TNFRSF7 (CD27) antibody varlilumab (CDX-1127) is co-administered.

[0160] Exemplary anti-TNFRSF9 (4-1BB, CD137) antibodies that may be co-administered include, but are not limited to, urelumab, utomilumab (PF-05082566), AGEN2373, and ADG-106.

[0161] Exemplary anti-TNFRSF18 (GITR) antibodies that may be co-administered include, but are not limited to, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and antibodies described in WO 2017096179, WO 2017096276, WO 2017096189, and WO 2018089628. In some embodiments, antibodies or fragments thereof that simultaneously target TNFRSF4 (OX40) and TNFRSF18 (GITR) are co-administered. Such antibodies are described, for example, in WO 2017 / 096179 and WO 2018 / 089628.

[0162] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors In various embodiments, the agents described herein are further combined with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI gene ID: 3620). Examples of IDO1 inhibitors include BLV-0801, epacadostat, resminostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, LY-3381916, and U.S. Patent Application Publication No. 20100015178 (Incyte), U.S. Patent Application Publication No. 2016137652 (Flexus Biosciences, Inc.), International Publication No. 2014073738 (Flexus No. 2015188085 (Flexus Biosciences, Inc.) and the compounds disclosed in US Pat. No. 2015188085 (Flexus Biosciences, Inc.).

[0163] LAG-3 and TIM-3 inhibitors In some embodiments, the agents described herein are combined with an anti-TIM-3 antibody, such as TSR-022, LY-3321367, MBG-453, and INCAGN-2390.

[0164] In some embodiments, the agents described herein are combined with an anti-LAG-3 (lymphocyte activating) antibody, such as leratolimab (ONO-4482), LAG-525, MK-4280, REGN-3767, and INCAGN2385.

[0165] Examples of additional immune-based therapies that can be combined with the agents of the present disclosure include interferon alpha; interferon alpha-2b; interferon alpha-n3; pegylated interferon alpha; interferon gamma; Flt3 agonist; gepon; nucleoferon, pegylated interferon alpha-2a, pegylated interferon alpha-2b, RPI-MN.

[0166] Inhibitor of apoptosis protein family proteins (IAPs) An example of an IAP inhibitor includes, but is not limited to, APG-1387.

[0167] Recombinant Thymosin α-1 Examples of recombinant thymosin alpha-1 include, but are not limited to, NL-004 and PEGylated thymosin alpha-1.

[0168] Bruton's tyrosine kinase (BTK) inhibitors Examples of BTK inhibitors include ABBV-105, acalabrutinib (ACP-196), ARQ-531, BMS-986142, dasatinib, ibrutinib, GDC-0853, PRN-1008, SNS-062, ONO-4059, BGB-3111, ML-319, MSC-2364447, RDX-022, X-022, AC-058, RG-7845, spebrutinib, TAS-5315, TP-0158, TP-4207, HM-71224, KBP-7536, M-2951, TAK-020, AC-0025, and the compounds described in U.S. Patent Application Publication No. 20140330015 (Ono No. 20130217880 (Ono Pharmaceutical), and the like.

[0169] KDM inhibitors Examples of KDM5 inhibitors include those described in WO 2016057924 (Genentech / Constellation Pharmaceuticals), U.S. Patent Application Publication No. 20140275092 (Genentech / Constellation Pharmaceuticals), Pharmaceuticals), No. 20140371195 (Epitherapeutics), No. 20140371214 (Epitherapeutics), No. 20160102096 (Epitherapeutics), No. 20140194469 (Quanticel), No. 20140171432, No. 20140213591 (Quanticel), No. 20160039808 (Quanticel), No. 20140275084 (Quanticel) and WO 2014164708 (Quanticel).

[0170] Examples of KDM1 inhibitors include, but are not limited to, the compounds disclosed in US Pat. No. 9,186,337 (B2) (Oryzon Genomics), GSK-2879552, RG-6016, and ORY-2001.

[0171] Arginase inhibitors Examples of arginase inhibitors include, but are not limited to, eCB-1158, C-201, and resminostat.

[0172] Bispecific and Trispecific Natural Killer (NK) Cell Engagers In various embodiments, the agents described herein are bi-specific NK-cell engagers (BiKE) or tri-specific NK-cell engagers (TlKE) directed against NK cell activating receptors, such as CD16A, C-type lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), natural cytotoxicity receptors (NKp30, NKp44, and NKp46), killer cell C-type lectin-like receptors (NKp65, NKp80), Fc receptors FcγR (mediating antibody-dependent cellular cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). The anti-CD16 binding bispecific molecule may be combined with an Fc-free antibody (e.g., Fc-free antibody, TriKE) or a bispecific antibody (e.g., Fc-free antibody). Optionally, the anti-CD16 binding bispecific molecule may or may not have an Fc. An exemplary bispecific NK cell inducer that may be co-administered targets CD16 and one or more HBV-associated antigens, as described herein. BiKE and TriKE are described, for example, in Felices, et al., Methods Mol Biol. (2016) 1441:333-346; Fang, et al., Semin Immunol. (2017) 31:37-54.

[0173] long-acting treatment Long-acting entecavir (subcutaneous depot), long-acting tenofovir (TFD and TAF) implant (device) or subcutaneous depot. Examples of long-acting entecavir are described in Exploration of long-acting implant formulations of hepatitis B drug entecavir., Eur J Pharm Sci. 2019 Aug 1; 136: 104958.

[0174] Gene and Cell Therapy In certain embodiments, the agents described herein are combined with gene or cell therapy regimens.Gene therapy and cell therapy include genetic modification to silence genes; genetic approaches to directly kill infected cells; infusion of immune cells designed to replace most of the patient's own immune system to enhance immune response to infected cells, or activate the patient's own immune system to kill infected cells, or find and kill infected cells; genetic approaches to modify cell activity to further alter endogenous immune responsiveness to infection.

[0175] Gene editing agents Genome editing systems include, but are not limited to, CRISPR / Cas9 systems, zinc finger nuclease systems, TALEN systems, homing endonuclease systems, and meganuclease systems (e.g., the ARCUS system); for example, cccDNA elimination by targeted cleavage, and modifying one or more of the Hepatitis B virus (HBV) viral genes. Modifying (e.g., knocking out and / or knocking down) a PreC, C, X, PreSI, PreS2, S, P, or SP gene refers to (1) reducing or eliminating PreC, C, X, PreSI, PreS2, S, P, or SP gene expression; (2) interfering with precore, core, X protein, long surface protein, middle surface protein, S protein (also known as HBs antigen and HBsAg), polymerase protein, and / or Hepatitis B splice protein function (HBe, HBc, HBx, PreS1, PreS2, S, Pol, and / or HBSP); or (3) reducing or eliminating intracellular, serum, and / or parenchymal levels of HBe, HBc, HBx, LHBs, MHBs, SHB, Pol, and / or HBSP proteins. Knocking down one or more of the PreC, C, X, PreSI, PreS2, S, P, and / or SP genes may be used to reduce or eliminate expression of genes in the HBV cccDNA and / or HBV This is done by targeting the gene into which the DNA is integrated. Additional example genome editing systems include, but are not limited to, those disclosed in U.S. Patent Application Publication No. 2019 / 284543 (Gilead Sciences) and U.S. Patent Application Publication No. 2019 / 338263 (Gilead Sciences).

[0176] Examples of gene therapy such as liver-targeted anti-HBV gene therapy (using ARCUS technology), or using CRISPR / Cas9 gene editing technology, or EBT-106 (LNP-delivered CRISPR / CasX nuclease).

[0177] CAR-T cell therapy CAR T cell therapy includes, but is not limited to, a population of immune effector cells genetically engineered to express a chimeric antigen receptor (CAR). The CAR comprises an HBV antigen binding domain. In certain embodiments, the antigen binding domain is a domain disclosed herein. In certain embodiments, the antigen binding domain is other than a domain disclosed herein. In certain embodiments, the antigen is HBsAg (i.e., HbsAg-CART). The immune effector cells are T cells or NK cells. In certain embodiments, the T cells are CD4+ T cells, CD8+ T cells, NK cells, or combinations thereof. The cells can be autologous or allogeneic. An example of a CART directed against HBV is described in Cytotherapy.2018 May;20(5):697-705.doi:10.1016 / j.jcyt.2018.02.

[0178] TCR-T cell therapy TCR T cell therapy includes, but is not limited to, T cells expressing HBV-specific T cell receptors. TCR-T cells are engineered to target HBV-derived peptides presented on the surface of virus-infected cells. An example of a TCR for HBV is described in Wisskirchen, K. et al. T cell receptor grafting allows virological control of hepatitis B virus infection. J Clin Invest. 2019; 129 (7): 2932-2945.

[0179] TCR-T cell therapy includes, but is not limited to, T cells expressing an HBV surface antigen (HBsAg)-specific TCR.

[0180] TCR-T cell therapy includes, but is not limited to, TCR-T therapy directed to the treatment of HBV, such as LTCR-H2-1.

[0181] In another specific embodiment, the compounds disclosed herein, or pharma- ceutically acceptable salts thereof, are used in the manufacture of therapeutic agents, such as HBV DNA polymerase inhibitors, immunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies and bispecific antibodies, including HBV antibodies targeting the surface antigen of the Hepatitis B virus, and "antibody-like" therapeutic proteins (e.g., DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, or TCR-like antibodies), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1, stimulators of RIG-I-like receptors. , PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors, and NOD2 stimulators, as well as one or two additional therapeutic agents selected from the group consisting of HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the Hepatitis B virus surface antigen, siRNAs, miRNA gene therapy agents, sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV core or capsid protein modulators).

[0182] In another specific embodiment, a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is combined with at least a second additional therapeutic agent selected from the group consisting of an HBV DNA polymerase inhibitor, an immunomodulatory agent, a TLR modulator, an HBsAg inhibitor, an HBV therapeutic vaccine, an HBV antibody and a bispecific antibody, including an HBV antibody targeting a surface antigen of the Hepatitis B virus, and an "antibody-like" therapeutic protein (e.g., DART®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, or TCR-like antibodies), a cyclophilin inhibitor, a stimulator of retinoic acid-inducible gene 1, a stimulator of a RIG-I-like receptor, a PD-1 inhibitor, a PD-L1 inhibitor, an arginase inhibitor, a PI3K inhibitor, an IDO inhibitor, and a stimulator of NOD2.

[0183] In another specific embodiment, a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is combined with at least a second additional therapeutic agent selected from the group consisting of HBV DNA polymerase inhibitors, HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigen of the Hepatitis B virus, siRNAs, miRNA gene therapy agents, sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV core or capsid protein inhibitors).

[0184] In certain embodiments, the compounds disclosed herein, or pharma- ceutically acceptable salts thereof, may be prepared using the methods disclosed in U.S. Patent Application Publication No. 2010 / 0143301 (Gilead Sciences), U.S. Patent Application Publication No. 2011 / 0098248 (Gilead Sciences), U.S. Patent Application Publication No. 2009 / 0047249 (Gilead Sciences), U.S. Patent No. 8,722,054 ... Sciences), U.S. Patent Application Publication No. 2014 / 0045849 (Janssen), U.S. Patent Application Publication No. 2014 / 0073642 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 2014 / 0350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 2008 / 0234251 (Array Biopharma), U.S. Patent Application Publication No. 2008 / 0306050 (Array Biopharma), U.S. Patent Application Publication No. 2010 / 0029585 (Ventirx No. 2011 / 0092485 (Ventirx Pharma), US2011 / 0118235 (Ventirx Pharma), US2012 / 0082658 (Ventirx Pharma), US2012 / 0219615 (Ventirx Pharma), US2014 / 0066432 (Ventirx Pharma), US2014 / 0088085 (Ventirx Pharma), US2014 / 0275167 (Novira Therapeutics), US2013 / 0251673 (Novira Therapeutics), US8513184 (Gilead Gilead Sciences), U.S. Patent Application Publication No. 2014 / 0030221 (Gilead Sciences), U.S. Patent Application Publication No. 2013 / 0344030 (Gilead Sciences), U.S. Patent Application Publication No. 2013 / 0344029 (GileadSciences), US20140275167 (Novira Therapeutics), US20130251673 (Novira Therapeutics), U.S. Publication No. 2014 / 0343032 (Roche), WO 2014037480 (Roche), U.S. Patent Application Publication No. 2013 / 0267517 (Roche), WO 2014131847 (Janssen), WO 2014033176 (Janssen), WO 2014033170 (Janssen), WO 20 WO 2015 / 059212 (Janssen), WO 2015118057 (Janssen), WO 2015011281 (Janssen), WO 2014184365 (Janssen), WO 2014184350 (Janssen), WO 2014161888 (Janssen), WO No. 2013096744 (Novira), U.S. Patent Application Publication No. 20150225355 (Novira), U.S. Patent Application Publication No. 20140178337 (Novira), U.S. Patent Application Publication No. 20150315159 (Novira), U.S. Patent Application Publication No. 20150197533 (Novira), U.S. Patent Application Publication No. 20150274652 (Novira), U.S. Patent Application Publication No. No. 0150259324, (Novira), U.S. Patent Application Publication No. 20150132258 (Novira), U.S. Patent No. 9181288 (Novira), WO 2014184350 (Janssen), WO 2013144129 (Roche), U.S. Patent Application Publication No. 20100015178 (Incyte), U.S. Patent Application Publication No. 2016137652 (Flexus Biosciences, Inc.), WO 2014073738 (Flexus Biosciences, Inc.), WO 2015188085 (Flexus Biosciences, Inc.), U.S. Patent Application Publication No. 2014 / 0330015 (Ono Pharmaceutical), U.S. Patent Application Publication No. 2013 / 0079327 (OnoPharmaceutical), U.S. Patent Application Publication No. 2013 / 0217880 (Ono pharmaceutical), WO 2016057924 (Genentech / Constellation Pharmaceuticals), U.S. Patent Application Publication No. 20140275092 (Genentech / Constellation Pharmaceuticals), U.S. Patent Application Publication No. 20140371195 (Epitherapeutics), and U.S. Patent Application Publication No. 20140371214 (Epitherapeutics), U.S. Patent Application Publication No. 20160102096 (Epitherapeutics), U.S. Patent Application Publication No. 20140194469 (Quantecel), U.S. Patent Application Publication No. 20140171432, U.S. Patent Application No. 20140213591 (Quantecel), U.S. Patent Application Publication No. 20160039808 (Quantecel), U.S. Patent Application Publication No. 20140275084 (Quantecel), WO 2014164708 (Quantecel), U.S. Patent No. 9,186,337 (B2) (Oryzon Genomics), and other HBV therapeutics, and combinations thereof.

[0185] In certain embodiments, an agent disclosed herein, or a pharma- ceutically acceptable salt thereof, is combined with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, an agent disclosed herein, or a pharma- ceutically acceptable salt thereof, is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30, or 10-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, an agent disclosed herein, or a pharma- ceutically acceptable salt thereof, is combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, an agent disclosed herein, or a pharma- ceutically acceptable salt thereof, is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. The agents disclosed herein can be combined with any dosage of the compound (e.g., 50 mg to 500 mg of the compound), as if each combination of dosages of the agents provided herein were specifically and individually recited.

[0186] In one embodiment, an agent disclosed herein, or a pharma- ceutically acceptable salt thereof, is combined with 100-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In certain embodiments, a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is combined with 100-150, 100-200, 100-250, 100-300, 100-350, 150-200, 150-250, 150-300, 150-350, 150-400, 200-250, 200-300, 200-350, 200-400, 250-350, 250-400, 350-400, or 300-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In certain embodiments, the agents disclosed herein, or a pharma- ceutically acceptable salt thereof, are combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In certain embodiments, the agents disclosed herein, or a pharma- ceutically acceptable salt thereof, are combined with 250 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In certain embodiments, the agents disclosed herein, or a pharma- ceutically acceptable salt thereof, are combined with 150 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. The agents disclosed herein can be combined with any dose of the compound (e.g., 50 mg to 500 mg of the compound), as if each combination of doses of the agents provided herein were specifically and individually listed.

[0187] B. Pharmaceutically Acceptable Salts Illustrative examples of pharmaceutically acceptable salts are mineral acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (such as acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, and quaternary ammonium (such as methyl iodide, ethyl iodide, etc.) salts. It is understood that pharmaceutically acceptable salts are non-toxic. Additional information regarding suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0188] Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include primary amino, secondary and tertiary amines (e.g., alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, dialkenylamines, trialkenylamines, substituted alkenylamines, di(substituted alkenyl)amines, tri(substituted alkenyl)amines, cycloalkylamines, di(cycloalkyl)amines, tri(cycloalkyl)amines, substituted cycloalkylamines, disubstituted cycloalkylamines, trisubstituted cycloalkylamines, cycloalkenylamines, di(cycloalkenyl)amines, tri(cycloalkenyl)amines, substituted cycloalkenylamines, disubstituted These include, but are not limited to, cycloalkenylamines, trisubstituted cycloalkenylamines, arylamines, diarylamines, triarylamines, heteroarylamines, diheteroarylamines, triheteroarylamines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed diamines and triamines in which at least two of the substituents on the amine are different and selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted alkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and the like. Also included are amines in which two or three of the substituents together with the amino nitrogen form a heterocyclic or heteroaryl group. Amines have the general structure N(R 30 )(R 31 )(R 32 ) and monosubstituted amines have three substituents (R 30 , R 31 and R 32 ) as hydrogen, and disubstituted amines have three substituents (R 30 , R 31 and R 32 ) as hydrogen, whereas trisubstituted amines have three substituents (R 30 , R31 and R 32 ) does not have any of them as hydrogen. 30 , R 31 and R 32 is selected from a variety of substituents such as hydrogen, optionally substituted alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, and the like.

[0189] Specific examples of suitable amines include, by way of example, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purine, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0190] Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.

[0191] C. Administration The combination therapy regimens of the present disclosure can be delivered by any suitable means, including oral, parenteral and topical. Other methods of administration include intravenous and subcutaneous administration.

[0192] "Intravenous administration" is the administration of a substance into a vein or "into a vein." Compared to other routes of administration, the intravenous (IV) route is a faster way to deliver fluids and medications through the body. Infusion pumps can allow precise control over the flow rate and total amount of medication delivered. However, if changes in flow rate do not have serious consequences or a pump is not available, the drip is often left to flow by simply placing the bag above the patient's level and adjusting the rate with a clamp. Alternatively, if the patient requires a high flow rate and the IV access device is of a large enough diameter to accommodate it, a rapid infuser can be used. This is either an inflatable cuff placed around the fluid bag to force the fluid into the patient, or a similar electrical device that can also heat the fluid being infused. If the patient only requires medication at certain times, an intermittent infusion is used, which does not require additional fluid. This can use the same techniques as an intravenous drip (pump or gravity drip), but the tubing is disconnected from the IV access device after the full dose of medication has been given. Some medications are also given by IV push or bolus. That is, a syringe is connected to an IV access device and the drug is injected directly (slowly if it irritates the vein or causes a rapid effect). When a medication is injected into the fluid stream of the IV tubing, there must be some means to ensure that it reaches the patient from the tube. Usually, this is accomplished by allowing the fluid stream to flow normally, thereby carrying the medication into the bloodstream. However, a second fluid injection may be used after the injection as a "flush" to get the medication into the bloodstream more quickly. Thus, in one embodiment, the compound(s) or combination of compounds described herein may be administered by IV administration, alone or in combination with administration of certain components of the treatment regimen by oral or parenteral routes.

[0193] "Oral administration" refers to a route of administration in which a substance is taken through the mouth, including buccal, sub-labial, and sublingual administration, as well as enteral and administration through the airways, unless the drug is in direct contact with any of the oral mucosa, such as through a tube. Typical forms for oral administration of therapeutic agents include the use of tablets or capsules. Thus, in one embodiment, the compound(s) or combination of compounds described herein may be administered by the oral route, either alone or in combination with administration of certain components of the therapeutic regimen by IV or parenteral routes.

[0194] The components of the combination therapy regimen of the present disclosure can be administered at any suitable frequency, interval and duration.For example, each component of the combination therapy regimen of the present disclosure can be administered once or twice an hour, three or more times, once or twice a day, three or more times, or once every 2, 3, 4, 5, 6 or 7 days, so as to provide a preferred dosage level. Each component of the combination therapy regimen of the present disclosure can be administered once a week, or once every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 weeks, so as to provide a preferred dosage level. The components of the combination therapy regimen of the present disclosure may be administered two or more times per day, with representative intervals including 5, 10, 15, 20, 30, 45, and 60 minutes, as well as 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24 hours. Each component of the combination therapy regimen of the present disclosure may be administered once, twice, or more than three times per hour, 1-6 hours, 1-12 hours, 1-24 hours, 6-12 hours, 12-24 hours, 1 day, 1-7 days, 1 week, 1-4 weeks, 1 month, 1-12 months, 1 year or more, or indefinitely.

[0195] The combination therapy regimen may also include other compatible therapeutic agents. The components described herein may be used in combination with each other, with other active agents, or with adjuvant agents that may not be effective alone but may contribute to the effectiveness of the active agents.

[0196] In some embodiments, the compound of formula (I) is administered at any suitable time known to one of skill in the art. Representative periods of administration of the compound of formula (I) include, but are not limited to, about 4 weeks or 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, 100 weeks, or about 104 weeks. In some embodiments, the compound of formula (I) is administered once a week for 12 to 60 weeks. In some embodiments, the compound of formula (I) is administered once a week for 12 to 48 weeks. In some embodiments, the compound of formula (I) is administered once a week for 12 to 24 weeks.

[0197] In some embodiments, the compound of formula (I) is administered once a week for 104 weeks. In some embodiments, the compound of formula (I) is administered once a week for 52 weeks. In some embodiments, the compound of formula (I) is administered once a week for 48 weeks. In some embodiments, the compound of formula (I) is administered once a week for 24 weeks.

[0198] The compound of formula (I) can be administered to the subject by any suitable means, including but not limited to oral administration.In some embodiments, the compound of formula (I) is administered orally.In some embodiments, the compound of formula (I) is administered orally once a week for 24 weeks.

[0199] In some embodiments, dsRNA is administered at any suitable time known to those skilled in the art.For example, dsRNA can be administered once a week, or once every 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks or 26 weeks. Representative periods of administration of dsRNA include, but are not limited to, about 4 weeks or 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, 100 weeks, or about 104 weeks. In some embodiments, the dsRNA is administered once every week, once every 2 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, or once every 12 weeks for any suitable time period known to those of skill in the art. In some embodiments, the dsRNA is administered for 12 weeks to 60 weeks. In some embodiments, the dsRNA is administered for 12 weeks to 48 weeks. In some embodiments, the dsRNA is administered for 12 weeks to 24 weeks.

[0200] In some embodiments, the dsRNA is administered once every 4 weeks for 104 weeks. In some embodiments, the dsRNA is administered once every 12 weeks for 104 weeks. In some embodiments, the dsRNA is administered once every 4 weeks for 52 weeks. In some embodiments, the dsRNA is administered once every 12 weeks for 52 weeks. In some embodiments, the dsRNA is administered once every 4 weeks for 48 weeks. In some embodiments, the dsRNA is administered once every 12 weeks for 48 weeks. In some embodiments, the dsRNA is administered once every 12 weeks for 24 weeks. In some embodiments, the dsRNA is administered once every 4 weeks for 24 weeks.

[0201] The dsRNA can be administered to the subject by any suitable means, including but not limited to intravenous or subcutaneous injection. In some embodiments, the dsRNA is administered by subcutaneous injection. In some embodiments, the dsRNA is administered by subcutaneous injection once every 4 weeks for 24 weeks. In some embodiments, the dsRNA is administered by intravenous injection. In some embodiments, the dsRNA is administered by intravenous injection once every 4 weeks for 24 weeks.

[0202] In some embodiments, the PD-1 / PD-L1 inhibitors described herein can be administered at any suitable time known to one of skill in the art. For example, the PD-1 / PD-L1 inhibitors can be administered once a week, or once every 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, or 26 weeks. In some embodiments, the PD-1 / PD-L1 inhibitors described herein can be administered once a week, once every 2 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, or once every 12 weeks for any suitable time known to one of skill in the art. Representative periods of administration of the PD-1 / PD-L1 inhibitor include, but are not limited to, about 4 weeks or 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, 100 weeks, or about 104 weeks. In some embodiments, the PD-1 / PD-L1 inhibitor is administered for 12 weeks to 60 weeks. In some embodiments, the PD-1 / PD-L1 inhibitor described herein is administered for 12 weeks to 48 weeks. In some embodiments, the PD-1 / PD-L1 inhibitor is administered for 12 weeks to 24 weeks.

[0203] In some embodiments, the PD-1 / PD-L1 inhibitor is nivolumab. In some embodiments, nivolumab can be administered at any suitable time known to those of skill in the art. For example, nivolumab can be administered once a week, or once every 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, or 26 weeks. In some embodiments, nivolumab can be administered once a week, once every 2 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, or once every 12 weeks over any suitable time known to those of skill in the art. Representative durations of administration of nivolumab include, but are not limited to, about 4 weeks or 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, 100 weeks, or about 104 weeks. In some embodiments, nivolumab is administered for 12 weeks to 60 weeks. In some embodiments, nivolumab as described herein is administered for 12 weeks to 48 weeks. In some embodiments, nivolumab is administered for 12 weeks to 24 weeks.

[0204] In some embodiments, nivolumab is administered once every 4 weeks for 104 weeks. In some embodiments, nivolumab is administered once every 12 weeks for 104 weeks. In some embodiments, nivolumab is administered once every 4 weeks for 52 weeks. In some embodiments, nivolumab is administered once every 12 weeks for 52 weeks. In some embodiments, nivolumab is administered once every 4 weeks for 48 weeks. In some embodiments, nivolumab is administered once every 12 weeks for 48 weeks. In some embodiments, nivolumab is administered once every 12 weeks for 24 weeks. In some embodiments, nivolumab is administered once every 4 weeks for 24 weeks.

[0205] The PD-1 / PD-L1 inhibitor may be administered to the subject by any suitable means, including, but not limited to, orally, intravenous injection, or subcutaneous injection. In some embodiments, the PD-1 / PD-L1 inhibitor is administered orally. In some embodiments, the PD-1 / PD-L1 inhibitor is administered by intravenous injection. In some embodiments, the PD-1 / PD-L1 inhibitor is administered by subcutaneous injection. In some embodiments, the nivolumab is administered by intravenous injection once every 4 weeks for 24 weeks. In some embodiments, the nivolumab is administered by subcutaneous injection once every 4 weeks for 24 weeks.

[0206] In some embodiments, the method includes administering a compound of formula (I), a dsRNA, and nivolumab. In some embodiments, the method includes administering a compound of formula (I), a dsRNA, and nivolumab at any suitable time described herein.

[0207] In some embodiments, the dsRNA is administered by subcutaneous injection once every 4 weeks for 36 weeks, starting on day 1. In some embodiments, the dsRNA is administered by subcutaneous injection once every 4 weeks for 24 weeks, starting on day 1.

[0208] In some embodiments, the compound of formula (I) is orally administered while the subject fasts. In some embodiments, the compound of formula (I) is orally administered once a week for 48 weeks, starting on day 1, while the subject fasts. In some embodiments, the compound of formula (I) is orally administered once a week for 36 weeks, starting on day 1, while the subject fasts.

[0209] In some embodiments, nivolumab is administered by intravenous injection once every 4 weeks for 36 weeks starting on day 1. In some embodiments, nivolumab is administered by intravenous injection once every 4 weeks for 24 weeks starting on day 1.

[0210] In some embodiments, the compound of formula (I) is administered orally once weekly for 24 weeks starting on day 1 while the subject fasts, the dsRNA is administered by subcutaneous injection once every 4 weeks for 24 weeks starting on day 1, and nivolumab is administered by intravenous injection once every 4 weeks for 24 weeks starting on day 1.

[0211] In some embodiments, the compound of formula (I) is administered orally once a week for 24 weeks starting at week 12 while the subject fasts. In some embodiments, nivolumab is administered by subcutaneous or intravenous injection once every 4 weeks for 24 weeks starting at week 12. In some embodiments, nivolumab is administered by intravenous injection every 4 weeks for 24 weeks starting at week 12.

[0212] In some embodiments, the compound of formula (I) is administered orally once weekly for 24 weeks starting at week 12 while the subject fasts, the dsRNA is administered by subcutaneous injection once every 4 weeks for 24 weeks starting on day 1, and nivolumab is administered by intravenous injection every 4 weeks for 24 weeks starting at week 12.

[0213] The combination therapy regimen of the present disclosure can exclude nucleotides. In some embodiments, the subject is not administered a nucleotide. In some embodiments, the method of treating and / or preventing Hepatitis B virus infection in a subject in need thereof comprises administering a compound of formula (I): [ka] or a pharma- ceutical acceptable salt thereof; and double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3'; and a PD-1 / PD-L1 inhibitor or a pharma- ceutical acceptable salt thereof, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0214] In some embodiments, the present invention provides a method for treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising administering to said subject an antibody of formula (I): [ka] or a pharma- ceutically acceptable salt thereof; and a double-stranded ribonucleic acid (dsRNA) comprising SEQ ID NO: 1 and SEQ ID NO: 2, wherein SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', in which each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, each u is 2'-O-methyl uridine-3'-phosphate, and each Af is 2'-fluoro adenosine-3'-phosphate. wherein each Cf is 2'-fluoro cytidine-3'-phosphate, each Gf is 2'-fluoro guanosine-3'-phosphate, Uf is 2'-fluoro uridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate linkage, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol, and a PD-1 / PD-L1 inhibitor or a pharma- ceutically acceptable salt thereof, thereby treating and / or preventing Hepatitis B virus infection in the subject.

[0215] In some embodiments, the combination therapy regimen comprises at least one additional agent. In some embodiments, the additional agent comprises tenofovir alafenamide or tenofovir alafenamide fumarate. In some embodiments, the additional agent is tenofovir alafenamide. In some embodiments, the additional agent is tenofovir alafenamide fumarate.

[0216] In some embodiments, the methods of the present disclosure further comprise administering to the subject an additional therapeutic agent.

[0217] In some embodiments, the method comprises the step of reacting a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof to the subject.

[0218] In some embodiments, the compound of formula (II) has the following structure: [ka] has.

[0219] In some embodiments, the compound of formula (II) has the following structure: [ka] has.

[0220] The compound of formula (II) can be administered in any suitable manner and for any suitable time period as described herein. The compound of formula (II) can be administered for any suitable period, including but not limited to, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, 100 weeks, or about 104 weeks. In some embodiments, the compound of formula (II) is administered orally. In some embodiments, the compound of formula (II) is administered once a day starting on day 1 for 84 weeks. In some embodiments, the compound of formula (II) is administered once a day starting on day 1 for 48 weeks. In some embodiments, the compound of formula (II) is administered once a day starting on day 1 for 42 weeks. In some embodiments, the compound of formula (II) is administered once a day for 104 weeks starting on day 1. In some embodiments, the compound of formula (II) is administered once a day for 36-84 weeks starting on day 1. In some embodiments, the compound of formula (II) is administered once a day for 52 weeks starting on day 1. In some embodiments, the compound of formula (II) is administered once a day for at least 36 weeks starting on day 1. In some embodiments, the compound of formula (II) is administered once a day for 36 weeks starting on day 1. In some embodiments, the compound of formula (II) is administered once a day for 24 weeks starting on day 1.

[0221] In some embodiments, administration of the compound of formula (II) is terminated if, after 36 weeks, the subject is characterized by (i) a hepatitis B viral load of less than about 20 international units per milliliter (IU / mL), (ii) hepatitis B e antigen (HBeAg) negative, and (iii) a hepatitis B surface antigen (HBsAg) concentration of less than about 100 international units per milliliter (IU / mL). In some embodiments, administration of the compound of formula (II) is terminated if, after 36 weeks, the subject is characterized by (i) a hepatitis B viral load of less than about 20 international units per milliliter (IU / mL), (ii) hepatitis B e antigen (HBeAg) negative, and (iii) hepatitis B surface antigen (HBsAg) negative.

[0222] In some embodiments, administration of the compound of formula (II) is terminated if, after 36 weeks, the subject is characterized by (i) a hepatitis B viral load below the lower limit of quantification, (ii) negative for hepatitis B e antigen (HBeAg), (iii) an alanine aminotransferase less than about two times the upper limit of normal, and (iv) a hepatitis B surface antigen (HBsAg) concentration of about 100 international units per milliliter (IU / mL). In some embodiments, administration of the compound of formula (II) is terminated if, after 36 weeks, the subject is characterized by (i) a hepatitis B viral load below the lower limit of quantification, (ii) negative for hepatitis B e antigen (HBeAg), (iii) an alanine aminotransferase less than about two times the upper limit of normal, and (iv) negative for hepatitis B surface antigen (HBsAg).

[0223] In some embodiments, the method includes administering a compound of formula (II), a compound of formula (I), a dsRNA, and nivolumab. In some embodiments, the method includes administering a compound of formula (II), a compound of formula (I), a dsRNA, and nivolumab at any suitable time described herein.

[0224] In some embodiments, the compound of formula (II) is administered orally once daily for 48 weeks. In some embodiments, the compound of formula (II) is administered orally once daily for 36 weeks. In some embodiments, the compound of formula (II) is administered orally once daily for 36 weeks starting on day 1. In some embodiments, the compound of formula (II) is administered orally once daily for 24 weeks. In some embodiments, the compound of formula (II) is administered orally once daily for 24 weeks starting on day 1.

[0225] In some embodiments, dsRNA is administered by subcutaneous injection once every 4 weeks for 36 weeks.In some embodiments, dsRNA is administered by subcutaneous injection once every 4 weeks for 24 weeks.In some embodiments, dsRNA is administered by subcutaneous injection once every 4 weeks for 24 weeks, starting on day 1.

[0226] In some embodiments, the compound of formula (I) is orally administered once a week for 36 weeks while the subject fasts. In some embodiments, the compound of formula (I) is orally administered once a week for 24 weeks while the subject fasts. In some embodiments, the compound of formula (I) is orally administered once a week for 24 weeks while the subject fasts, starting at week 12.

[0227] In some embodiments, nivolumab is administered by intravenous injection every 4 weeks for 36 weeks. In some embodiments, nivolumab is administered by intravenous injection every 4 weeks for 24 weeks starting on day 1. In some embodiments, nivolumab is administered by intravenous injection every 4 weeks for 24 weeks starting on week 12.

[0228] In some embodiments, the compound of formula (II) is administered orally once daily for 36 weeks starting on day 1, the dsRNA is administered by subcutaneous injection once every 4 weeks for 24 weeks starting on day 1, the compound of formula (I) is administered orally once weekly for 24 weeks starting on week 12 while the subject fasts, and nivolumab is administered by intravenous injection every 4 weeks for 24 weeks starting on week 12.

[0229] D. Preparation Each component of the combination therapy regimen of the present disclosure, or a pharma- ceutically acceptable salt thereof, may be administered in a pharmaceutical formulation. Each component of the combination therapy regimen of the present disclosure, or a pharma- ceutically acceptable salt thereof, may be administered in a pharmaceutical formulation. The pharmaceutical formulation / composition of the present disclosure includes a combination of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, a double-stranded ribonucleic acid (dsRNA) and a PD-1-PD-L1 inhibitor or a pharma- ceutically acceptable salt thereof, optionally in combination with an additional agent, such as tenofovir alafenamide or a pharma- ceutically acceptable salt thereof.

[0230] Each component of the combination therapy regimen can be administered by injection, including aqueous solutions, oily suspensions, emulsions (using sesame oil, corn oil, cottonseed oil, or peanut oil), as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and / or by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0231] Sterile injectable solutions are prepared by incorporating the required amount of the component compound(s) in a suitable solvent with various other ingredients as enumerated above or as required, followed by filtered sterilization. In general, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred preparation method is vacuum drying and freeze-drying technology, which results in a powder of the active ingredient(s) plus any additional desired ingredients from a previously sterile-filtered solution.

[0232] Some examples of suitable excipients are lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose.The formulations can additionally further include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methyl- and propyl-hydroxybenzoates, sweetening agents, and flavoring agents.

[0233] Certain compositions are preferably formulated in unit dosage form. The term "unit dosage form" or "compound formulation" refers to a physically separate unit suitable for a compound for human subjects and other mammals, each unit containing a predetermined amount of one or more active substances (e.g., compound (I)) in combination with suitable pharmaceutical excipients such as tablets, capsules, injection ampoules or vials, and optionally with additional drugs calculated to produce the desired effect. However, it will be understood that the amount of each active drug actually administered will be determined by the physician in light of the relevant circumstances, including the condition to be treated, the selected route of administration, the actual compounds administered and their relative activity, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0234] To prepare solid compositions such as tablets, the primary active ingredient(s) are mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogenous mixture of the compounds of the present disclosure. When these preformulation compositions are referred to as homogenous, it is meant that the active ingredient(s) is dispersed evenly throughout the composition, such that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0235] Each component of the combination therapy regimen can be preferably provided in a pharmaceutical preparation in unit dosage form.In this form, the preparation is divided into unit doses containing an appropriate amount of the compound of the present disclosure.The unit dosage form can be a packaged preparation.The package contains individual amounts of the preparation, such as packaged tablets, capsules, and powders in vials or ampoules.Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or any of these in the appropriate number of packaged form.

[0236] Each component of the combination therapy regimen of the present disclosure may be present in any suitable amount. Such components may vary depending on a variety of factors, including but not limited to the subject's weight and age, disease state, etc. Suitable dosage ranges for the compounds of the present disclosure include about 0.1 mg to about 10,000 mg, or about 1 mg to about 1000 mg, or about 10 mg to about 750 mg, or about 25 mg to about 500 mg, or about 50 mg to about 250 mg. Suitable dosages for the compounds of the present disclosure include about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg.

[0237] Each component of the combination therapy regimen of the present disclosure and the active agent may be present in the composition of the present disclosure in any suitable weight ratio, such as about 1:100 to about 100:1 (w / w), or about 1:50 to about 50:1, or about 1:25 to about 25:1, or about 1:10 to about 10:1, or about 1:5 to about 5:1 (w / w). The compound of the present disclosure and the other active agent may be present in any suitable weight ratio, such as about 1:100 (w / w), about 1:50, about 1:25, about 1:10, about 1:5, about 1:4, about 1:3, about 1:2, about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 10:1, about 25:1, about 50:1, or about 100:1 (w / w). Other dosage amounts and dosage ratios of the disclosed compounds and active agents are suitable in the disclosed compositions and methods.

[0238] The compound of formula (I) is administered in any suitable amount known to one of skill in the art. In some embodiments, the compound of formula (I) is administered to the subject in an amount of 0.5-20 mg. In some embodiments, the compound of formula (I) is administered to the subject in an amount of 1-10 mg. Other amounts of the compound of formula (I) that may be administered to the subject include, but are not limited to, about 1.0 mg or about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.5 mg, or about 3.0 mg. In some embodiments, the compound of formula (I) is administered to the subject in an amount of about 3 mg.

[0239] The compound of formula (I) can be administered in two equal or unequal amounts. In some embodiments, the compound of formula (I) can be administered in two equal amounts. In some embodiments, the compound of formula (I) is administered to the subject in two doses of 1.5 mg.

[0240] The dsRNA is administered in any suitable amount known to those of skill in the art. In some embodiments, the dsRNA is administered to the subject in an amount of 100-300 mg. In some embodiments, the dsRNA is administered to the subject in an amount of 150-250 mg. Representative amounts of dsRNA administered to the subject include, but are not limited to, about 100 mg or about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, or about 250 mg. In some embodiments, the dsRNA is administered to a subject in an amount of about 200 mg.

[0241] The PD-1 / PD-L1 inhibitors described herein can be administered in any suitable amount known to one of skill in the art. In some embodiments, the PD-1 / PD-L1 inhibitors described herein are administered to a subject in an amount of 0.01-5 mg / kg. In some embodiments, the PD-1 / PD-L1 inhibitors described herein are administered to a subject in an amount of 0.1-1 mg / kg. Representative amounts of PD-1 / PD-L1 inhibitors administered to a subject include, but are not limited to, about 0.1 mg / kg, or about 0.15 mg / kg, about 0.20 mg / kg, about 0.25 mg / kg, about 0.30 mg / kg, about 0.35 mg / kg, about 0.40 mg / kg, about 0.45 mg / kg, about 0.50 mg / kg, about 0.55 mg / kg, about 0.60 mg / kg, about 0.65 mg / kg, about 0.70 mg / kg, about 0.75 mg / kg, about 0.80 mg / kg, about 0.85 mg / kg, about 0.90 mg / kg, about 0.95 mg / kg, or about 1.0 mg / kg. In some embodiments, the PD-1 / PD-L1 inhibitors described herein are administered to a subject in an amount of 0.1-0.5 mg / kg. In some embodiments, the PD-1 / PD-L1 inhibitor described herein is administered to a subject in an amount of about 0.3 mg / kg.

[0242] The PD-1 / PD-L1 inhibitor may be administered in any suitable amount known to one of skill in the art. In some embodiments, the compound of Formula (I) is administered to a subject in an amount of 0.1-1000 mg. Representative amounts of the PD-1 / PD-L1 inhibitor administered to a subject include, but are not limited to, 0.1-500 mg, 1-100 mg, 1-50 mg, or 10-50 mg. Other amounts of a PD-1 / PD-L1 inhibitor administered to a subject include, but are not limited to, about 1 mg or about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, 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, or about 100 mg.

[0243] In some embodiments, the compound of formula (I) is administered to the subject in an amount of 1-10 mg. Other amounts of the compound of formula (I) that may be administered to the subject include, but are not limited to, about 1.0 mg or about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.5 mg, or about 3.0 mg. In some embodiments, the compound of formula (I) is administered to the subject in an amount of about 3 mg.

[0244] Nivolumab may be administered in any suitable amount known to one of skill in the art. In some embodiments, nivolumab is administered to the subject in an amount of 0.1-1 mg / kg. In some embodiments, nivolumab is administered to the subject in an amount of 0.1-0.5 mg / kg. In some embodiments, nivolumab is administered to the subject in an amount of about 0.3 mg / kg.

[0245] The compound of formula (II) may be administered in any suitable amount known to one of skill in the art. In some embodiments, the compound of formula (II) is administered to the subject in an amount of 10-50 mg. In some embodiments, the compound of formula (II) is administered to the subject in an amount of 20-40 mg. In some embodiments, the compound of formula (II) may be administered to the subject in an amount of 20-30 mg. Representative amounts of the compound of formula (II) include, but are not limited to, about 1 mg, or about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, 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, or about 100 mg. In some embodiments, the compound of formula (II) is administered to the subject in an amount of about 25 mg. In some embodiments, the compound of formula (II) is administered to the subject in an amount of about 28 mg.

[0246] In some embodiments, the disclosed method can reduce the subject's viral load after completion of treatment. In some embodiments, the subject has a hepatitis B viral load of less than about 300 international units per milliliter (IU / mL) after completion of treatment. In some embodiments, the subject has a hepatitis B viral load of less than about 200 international units per milliliter (IU / mL) after completion of treatment. In some embodiments, the subject has a hepatitis B viral load of less than about 100 international units per milliliter (IU / mL) after completion of treatment. In some embodiments, the subject has a hepatitis B viral load of less than about 50 international units per milliliter (IU / mL) after completion of treatment. In some embodiments, the subject has a hepatitis B viral load of less than about 20 international units per milliliter (IU / mL) after completion of treatment. In some embodiments, the subject has a hepatitis B viral load of less than about 5 international units per milliliter (IU / mL) after completion of treatment. In some embodiments, the subject has a hepatitis B viral load of less than the lower limit of quantification (LLOQ) after completion of treatment.

[0247] In some embodiments, the disclosed methods can reduce the subject's Hepatitis B surface antigen (HBsAg) concentration after completion of treatment. In some embodiments, the subject has a Hepatitis B surface antigen (HBsAg) concentration of less than about 200 International Units per milliliter (IU / mL) after completion of treatment. In some embodiments, the subject has a Hepatitis B surface antigen (HBsAg) concentration of less than about 100 International Units per milliliter (IU / mL) after completion of treatment. In some embodiments, the subject is negative for Hepatitis B surface antigen (HBsAg) after completion of treatment.

[0248] In some embodiments, the subject is negative for Hepatitis B e antigen (HBeAg) after completing treatment.

[0249] In some embodiments, the disclosed method can reduce the alanine aminotransferase (ALT) concentration of the subject after completion of treatment. In some embodiments, the subject has an alanine aminotransferase (ALT) concentration less than about 2 times the upper limit of normal (ULN). The upper limit of normal can be about 100 international units per liter (IU / L) or about 95, about 90, about 85, about 80, about 75, about 70, about 65, about 60, about 55, about 50, about 45, about 40, about 35, about 30, about 25, about 20, about 15, or about 10 IU / L. In some embodiments, the upper limit of normal for alanine aminotransferase concentration is about 40 IU / L.

[0250] In some embodiments, after treatment has ended, the subject is characterized by at least one of: (i) a hepatitis B viral load of less than about 20 international units per milliliter (IU / mL), (ii) negativity for hepatitis B e antigen (HBeAg), and (iii) a hepatitis B surface antigen (HBsAg) concentration of less than about 100 international units per milliliter (IU / mL). In some embodiments, after treatment has ended, the subject is characterized by at least one of: (i) a hepatitis B viral load of less than about 20 international units per milliliter (IU / mL), (ii) negativity for hepatitis B e antigen (HBeAg), and (iii) negativity for hepatitis B surface antigen (HBsAg).

[0251] In some embodiments, after treatment has ended, the subject is characterized by at least one of: (i) a hepatitis B viral load below the lower limit of quantification, (ii) negative for hepatitis B e antigen (HBeAg), (iii) an alanine aminotransferase less than about two times the upper limit of normal, and (iv) a hepatitis B surface antigen (HBsAg) concentration of about 100 international units per milliliter (IU / mL). In some embodiments, after treatment has ended, the subject is characterized by at least one of: (i) a hepatitis B viral load below the lower limit of quantification, (ii) negative for hepatitis B e antigen (HBeAg), (iii) an alanine aminotransferase less than about two times the upper limit of normal, and (iv) negative for hepatitis B surface antigen (HBsAg).

[0252] In some embodiments, after treatment has ended, the subject is characterized by (i) a hepatitis B viral load of less than about 20 international units per milliliter (IU / mL), (ii) negativity for hepatitis B e antigen (HBeAg), and (iii) a hepatitis B surface antigen (HBsAg) concentration of less than about 100 international units per milliliter (IU / mL). In some embodiments, after treatment has ended, the subject is characterized by (i) a hepatitis B viral load of less than about 20 international units per milliliter (IU / mL), (ii) negativity for hepatitis B e antigen (HBeAg), and (iii) negativity for hepatitis B surface antigen (HBsAg).

[0253] In some embodiments, after treatment has ended, the subject is characterized by (i) a hepatitis B viral load below the lower limit of quantitation, (ii) negative for hepatitis B e antigen (HBeAg), (iii) an alanine aminotransferase less than about two times the upper limit of normal, and (iv) a hepatitis B surface antigen (HBsAg) concentration of about 100 international units per milliliter (IU / mL). In some embodiments, after treatment has ended, the subject is characterized by (i) a hepatitis B viral load below the lower limit of quantitation, (ii) negative for hepatitis B e antigen (HBeAg), (iii) an alanine aminotransferase less than about two times the upper limit of normal, and (iv) negative for hepatitis B surface antigen (HBsAg).

[0254] In some embodiments, after treatment has ended, the subject is characterized by (i) a hepatitis B viral load of less than about 0.05 international units per milliliter (IU / mL), (ii) negativity for hepatitis B e antigen (HBeAg), and (iii) a hepatitis B surface antigen (HBsAg) concentration of less than about 100 international units per milliliter (IU / mL). In some embodiments, after treatment has ended, the subject is characterized by (i) a hepatitis B viral load of less than about 0.05 international units per milliliter (IU / mL), (ii) negativity for hepatitis B e antigen (HBeAg), and (iii) negativity for hepatitis B surface antigen (HBsAg).

[0255] In some embodiments, after treatment has ended, the subject is characterized by (i) a hepatitis B viral load of less than about 0.05 international units per milliliter (IU / mL), (ii) negative for hepatitis B e antigen (HBeAg), (iii) an alanine aminotransferase of less than about two times the upper limit of normal, and (iv) a hepatitis B surface antigen (HBsAg) concentration of about 100 international units per milliliter (IU / mL). In some embodiments, after treatment has ended, the subject is characterized by (i) a hepatitis B viral load of less than about 0.05 international units per milliliter (IU / mL), (ii) negative for hepatitis B e antigen (HBeAg), (iii) an alanine aminotransferase of less than about two times the upper limit of normal, and (iv) negative for hepatitis B surface antigen (HBsAg).

[0256] In some embodiments, there is provided a method of treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising: 3 mg of Formula (I): [ka] or a pharma- ceutically acceptable salt thereof; 200 mg of dsRNA of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 5'-gsusguGfcAfCfUfucgcuucacaL96-3', the dsRNA being administered by subcutaneous injection once every 4 weeks starting on day 1 for 24 weeks; 0.3 mg / kg nivolumab administered by intravenous injection once every 4 weeks for 24 weeks starting on day 1, After completing treatment, subjects: (i) a hepatitis B viral load of less than about 20 international units per milliliter (IU / mL); (ii) negative for hepatitis B e antigen (HBeAg), and (iii) characterized by being negative for hepatitis B surface antigen (HBsAg); Provided herein are methods whereby to treat and / or prevent Hepatitis B virus infection in a subject.

[0257] In some embodiments, there is provided a method of treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising: 3 mg of Formula (I): [ka] or a pharma- ceutically acceptable salt thereof; 200 mg of dsRNA of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 5'-gsusguGfcAfCfUfucgcuucacaL96-3', the dsRNA being administered by subcutaneous injection once every 4 weeks starting on day 1 for 24 weeks; administering to the subject a therapeutically effective amount of a combination therapy regimen comprising: 0.3 mg / kg nivolumab administered by intravenous injection once every 4 weeks for 24 weeks starting on day 1; After completing treatment, subjects: (i) Hepatitis B viral load below the lower limit of quantification; (ii) negative for hepatitis B e antigen (HBeAg); (iii) alanine aminotransferase less than about twice the upper limit of normal; (iv) characterized by being negative for hepatitis B surface antigen (HBsAg); Provided herein are methods whereby to treat and / or prevent Hepatitis B virus infection in a subject.

[0258] In some embodiments, there is provided a method of treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising: 3 mg of Formula (I): [ka] or a pharma- ceutically acceptable salt thereof; 200 mg of dsRNA of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 5'-gsusguGfcAfCfUfucgcuucacaL96-3', in which each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, each u is 2'-O-methyl uridine-3'-phosphate, and each Af is 2'-furan dsDNA, wherein each Cf is 2'-fluorocytidine-3'-phosphate, each Gf is 2'-fluoroguanosine-3'-phosphate, Uf is 2'-fluorouridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate linkage, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol, and the dsRNA is administered by subcutaneous injection every 4 weeks starting on day 1 for 24 weeks; 0.3 mg / kg nivolumab administered by intravenous injection once every 4 weeks for 24 weeks starting on day 1, After completing treatment, subjects: (i) a hepatitis B viral load of less than about 20 international units per milliliter (IU / mL); (ii) negative for hepatitis B e antigen (HBeAg), and (iii) characterized by being negative for hepatitis B surface antigen (HBsAg); Provided herein are methods whereby to treat and / or prevent Hepatitis B virus infection in a subject.

[0259] In some embodiments, there is provided a method of treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising: 3 mg of Formula (I): [ka] or a pharma- ceutically acceptable salt thereof; 200 mg of dsRNA of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 5'-gsusguGfcAfCfUfucgcuucacaL96-3', in which each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, each u is 2'-O-methyl uridine-3'-phosphate, and each Af is 2'-furan dsDNA, wherein each Cf is 2'-fluorocytidine-3'-phosphate, each Gf is 2'-fluoroguanosine-3'-phosphate, Uf is 2'-fluorouridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate linkage, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol, and the dsRNA is administered by subcutaneous injection every 4 weeks starting on day 1 for 24 weeks; 0.3 mg / kg nivolumab administered by intravenous injection once every 4 weeks for 24 weeks starting on day 1, After completing treatment, subjects: (i) Hepatitis B viral load below the lower limit of quantification; (ii) negative for hepatitis B e antigen (HBeAg); (iii) alanine aminotransferase less than about twice the upper limit of normal; (iv) characterized by being negative for hepatitis B surface antigen (HBsAg); Provided herein are methods whereby to treat and / or prevent Hepatitis B virus infection in a subject.

[0260] In some embodiments, there is provided a method of treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising: 3 mg of Formula (I): [ka] or a pharma- ceutically acceptable salt thereof; 200 mg of dsRNA of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 5'-gsusguGfcAfCfUfucgcuucacaL96-3', the dsRNA being administered by subcutaneous injection once every 4 weeks starting on day 1 for 24 weeks; administering to the subject a therapeutically effective amount of a combination therapy regimen comprising: 0.3 mg / kg nivolumab administered by intravenous injection once every 4 weeks for 24 weeks beginning at week 12; After completing treatment, subjects: (i) a hepatitis B viral load of less than about 20 international units per milliliter (IU / mL); (ii) negative for hepatitis B e antigen (HBeAg), and (iii) characterized by being negative for hepatitis B surface antigen (HBsAg); Provided herein are methods whereby to treat and / or prevent Hepatitis B virus infection in a subject.

[0261] In some embodiments, there is provided a method of treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising: 3 mg of Formula (I): [ka] or a pharma- ceutically acceptable salt thereof; 200 mg of dsRNA of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 5'-gsusguGfcAfCfUfucgcuucacaL96-3', the dsRNA being administered by subcutaneous injection once every 4 weeks starting on day 1 for 24 weeks; administering to the subject a therapeutically effective amount of a combination therapy regimen comprising: 0.3 mg / kg nivolumab administered by intravenous injection once every 4 weeks for 24 weeks beginning at week 12; After completing treatment, subjects: (i) Hepatitis B viral load below the lower limit of quantification; (ii) negative for hepatitis B e antigen (HBeAg); (iii) alanine aminotransferase less than about twice the upper limit of normal; (iv) characterized by being negative for hepatitis B surface antigen (HBsAg); Provided herein are methods whereby to treat and / or prevent Hepatitis B virus infection in a subject.

[0262] In some embodiments, there is provided a method of treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising: 3 mg of Formula (I): [ka] or a pharma- ceutically acceptable salt thereof; 200 mg of dsRNA of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 5'-gsusguGfcAfCfUfucgcuucacaL96-3', in which each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, each u is 2'-O-methyl uridine-3'-phosphate, and each Af is 2'-furan dsDNA, wherein each Cf is 2'-fluorocytidine-3'-phosphate, each Gf is 2'-fluoroguanosine-3'-phosphate, Uf is 2'-fluorouridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate linkage, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol, and the dsRNA is administered by subcutaneous injection every 4 weeks starting on day 1 for 24 weeks; administering to the subject a therapeutically effective amount of a combination therapy regimen comprising: 0.3 mg / kg nivolumab administered by intravenous injection once every 4 weeks for 24 weeks beginning at week 12; After completing treatment, subjects: (i) a hepatitis B viral load of less than about 20 international units per milliliter (IU / mL); (ii) negative for hepatitis B e antigen (HBeAg), and (iii) characterized by being negative for hepatitis B surface antigen (HBsAg); Provided herein are methods whereby to treat and / or prevent Hepatitis B virus infection in a subject.

[0263] In some embodiments, there is provided a method of treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising: 3 mg of Formula (I): [ka] or a pharma- ceutically acceptable salt thereof; 200 mg of dsRNA of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 5'-gsusguGfcAfCfUfucgcuucacaL96-3', in which each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, each u is 2'-O-methyl uridine-3'-phosphate, and each Af is 2'-furan dsDNA, wherein each Cf is 2'-fluorocytidine-3'-phosphate, each Gf is 2'-fluoroguanosine-3'-phosphate, Uf is 2'-fluorouridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate linkage, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol, and the dsRNA is administered by subcutaneous injection every 4 weeks starting on day 1 for 24 weeks; administering to the subject a therapeutically effective amount of a combination therapy regimen comprising: 0.3 mg / kg nivolumab administered by intravenous injection once every 4 weeks for 24 weeks beginning at week 12; After completing treatment, subjects: (i) Hepatitis B viral load below the lower limit of quantification; (ii) negative for hepatitis B e antigen (HBeAg); (iii) alanine aminotransferase less than about twice the upper limit of normal; (iv) characterized by being negative for hepatitis B surface antigen (HBsAg); Provided herein are methods whereby to treat and / or prevent Hepatitis B virus infection in a subject.

[0264] In some embodiments, there is provided a method of treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising: 3 mg of Formula (I): [ka] or a pharma- ceutically acceptable salt thereof; 200 mg of dsRNA of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', the dsRNA being administered by subcutaneous injection once every 4 weeks starting on day 1 for 24 weeks; Nivolumab at 0.3 mg / kg administered intravenously once every 4 weeks for 24 weeks starting at week 12; 25 mg of formula (II) orally administered once daily starting on day 1 for 36 weeks [ka] and administering to the subject a therapeutically effective amount of a combination therapy regimen comprising a compound of the formula: After completing treatment, subjects: (i) a hepatitis B viral load of less than about 20 international units per milliliter (IU / mL); (ii) negative for hepatitis B e antigen (HBeAg), and (iii) characterized by being negative for hepatitis B surface antigen (HBsAg); Provided herein are methods whereby to treat and / or prevent Hepatitis B virus infection in a subject.

[0265] In some embodiments, there is provided a method of treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising: 3 mg of Formula (I): [ka] or a pharma- ceutically acceptable salt thereof; 200 mg of dsRNA of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', the dsRNA being administered by subcutaneous injection once every 4 weeks starting on day 1 for 24 weeks; Nivolumab at 0.3 mg / kg administered intravenously once every 4 weeks for 24 weeks starting at week 12; 25 mg of formula (II) orally administered once daily starting on day 1 for 36 weeks [ka] and administering to the subject a therapeutically effective amount of a combination therapy regimen comprising a compound of the formula: After completing treatment, subjects: (i) Hepatitis B viral load below the lower limit of quantification; (ii) negative for hepatitis B e antigen (HBeAg); (iii) alanine aminotransferase less than about twice the upper limit of normal; (iv) characterized by being negative for hepatitis B surface antigen (HBsAg); Provided herein are methods whereby to treat and / or prevent Hepatitis B virus infection in a subject.

[0266] In some embodiments, there is provided a method of treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising: 3 mg of Formula (I): [ka] or a pharma- ceutically acceptable salt thereof; 200 mg of dsRNA of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 5'-gsusguGfcAfCfUfucgcuucacaL96-3', in which each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, each u is 2'-O-methyl uridine-3'-phosphate, and each Af is 2'-furan dsDNA, wherein each Cf is 2'-fluorocytidine-3'-phosphate, each Gf is 2'-fluoroguanosine-3'-phosphate, Uf is 2'-fluorouridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate linkage, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol, and the dsRNA is administered by subcutaneous injection every 4 weeks starting on day 1 for 24 weeks; Nivolumab at 0.3 mg / kg administered intravenously once every 4 weeks for 24 weeks starting at week 12; 25 mg of formula (II) orally administered once daily starting on day 1 for 36 weeks [ka] and administering to the subject a therapeutically effective amount of a combination therapy regimen comprising a compound of the formula: After completing treatment, subjects: (i) a hepatitis B viral load of less than about 20 international units per milliliter (IU / mL); (ii) negative for hepatitis B e antigen (HBeAg), and (iii) characterized by being negative for hepatitis B surface antigen (HBsAg); Provided herein are methods whereby to treat and / or prevent Hepatitis B virus infection in a subject.

[0267] In some embodiments, there is provided a method of treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising: 3 mg of Formula (I): [ka] or a pharma- ceutically acceptable salt thereof; 200 mg of dsRNA of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 5'-gsusguGfcAfCfUfucgcuucacaL96-3', in which each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, each u is 2'-O-methyl uridine-3'-phosphate, and each Af is 2'-furan dsDNA, wherein each Cf is 2'-fluorocytidine-3'-phosphate, each Gf is 2'-fluoroguanosine-3'-phosphate, Uf is 2'-fluorouridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate linkage, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol, and the dsRNA is administered by subcutaneous injection every 4 weeks starting on day 1 for 24 weeks; Nivolumab at 0.3 mg / kg administered intravenously once every 4 weeks for 24 weeks starting at week 12; 25 mg of formula (II) orally administered once daily starting on day 1 for 36 weeks [ka] and administering to the subject a therapeutically effective amount of a combination therapy regimen comprising a compound of the formula: After completing treatment, subjects: (i) Hepatitis B viral load below the lower limit of quantification; (ii) negative for hepatitis B e antigen (HBeAg); (iii) alanine aminotransferase less than about twice the upper limit of normal; (iv) characterized by being negative for hepatitis B surface antigen (HBsAg); Provided herein are methods whereby to treat and / or prevent Hepatitis B virus infection in a subject.

[0268] In some embodiments, there is provided a method of treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising: 3 mg of Formula (I): [ka] or a pharma- ceutically acceptable salt thereof; 200 mg of dsRNA of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', the dsRNA being administered by subcutaneous injection once every 4 weeks starting on day 1 for 24 weeks; Nivolumab at 0.3 mg / kg administered intravenously once every 4 weeks for 24 weeks starting at week 12; 25 mg of formula (II) orally administered once daily starting on day 1 for 36 weeks [ka] and administering to the subject a therapeutically effective amount of a combination therapy regimen comprising a compound of the formula: After completing treatment, subjects: (i) a hepatitis B viral load of less than about 20 international units per milliliter (IU / mL); (ii) negative for hepatitis B e antigen (HBeAg), and (iii) characterized by being negative for hepatitis B surface antigen (HBsAg); Provided herein are methods whereby to treat and / or prevent Hepatitis B virus infection in a subject.

[0269] In some embodiments, there is provided a method of treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising: 3 mg of Formula (I): [ka] or a pharma- ceutically acceptable salt thereof; 200 mg of dsRNA of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', the dsRNA being administered by subcutaneous injection once every 4 weeks starting on day 1 for 24 weeks; Nivolumab at 0.3 mg / kg administered intravenously once every 4 weeks for 24 weeks starting at week 12; 25 mg of formula (II) orally administered once daily starting on day 1 for 36 weeks [ka] and administering to the subject a therapeutically effective amount of a combination therapy regimen comprising a compound of the formula: After completing treatment, subjects: (i) Hepatitis B viral load below the lower limit of quantification; (ii) negative for hepatitis B e antigen (HBeAg); (iii) alanine aminotransferase less than about twice the upper limit of normal; (iv) characterized by being negative for hepatitis B surface antigen (HBsAg); Provided herein are methods whereby to treat and / or prevent Hepatitis B virus infection in a subject.

[0270] In some embodiments, there is provided a method of treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising: 3 mg of Formula (I): [ka] or a pharma- ceutically acceptable salt thereof; 200 mg of dsRNA of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 5'-gsusguGfcAfCfUfucgcuucacaL96-3', in which each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, each u is 2'-O-methyl uridine-3'-phosphate, and each Af is 2'-furan dsDNA, wherein each Cf is 2'-fluorocytidine-3'-phosphate, each Gf is 2'-fluoroguanosine-3'-phosphate, Uf is 2'-fluorouridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate linkage, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol, and the dsRNA is administered by subcutaneous injection every 4 weeks starting on day 1 for 24 weeks; Nivolumab at 0.3 mg / kg administered intravenously once every 4 weeks for 24 weeks starting at week 12; 25 mg of formula (II) orally administered once daily starting on day 1 for 36 weeks [ka] and administering to the subject a therapeutically effective amount of a combination therapy regimen comprising a compound of the formula: After completing treatment, subjects: (i) a hepatitis B viral load of less than about 20 international units per milliliter (IU / mL); (ii) negative for hepatitis B e antigen (HBeAg), and (iii) characterized by being negative for hepatitis B surface antigen (HBsAg); Provided herein are methods whereby to treat and / or prevent Hepatitis B virus infection in a subject.

[0271] In some embodiments, there is provided a method of treating and / or preventing a Hepatitis B virus infection in a subject in need thereof, comprising: 3 mg of Formula (I): [ka] or a pharma- ceutically acceptable salt thereof; 200 mg of dsRNA of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 5'-gsusguGfcAfCfUfucgcuucacaL96-3', in which each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, each g is 2'-O-methyl guanosine-3'-phosphate, each u is 2'-O-methyl uridine-3'-phosphate, and each Af is 2'-furan dsDNA, wherein each Cf is 2'-fluorocytidine-3'-phosphate, each Gf is 2'-fluoroguanosine-3'-phosphate, Uf is 2'-fluorouridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate linkage, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol, and the dsRNA is administered by subcutaneous injection every 4 weeks starting on day 1 for 24 weeks; Nivolumab at 0.3 mg / kg administered intravenously once every 4 weeks for 24 weeks starting at week 12; 25 mg of formula (II) orally administered once daily starting on day 1 for 36 weeks [ka] and administering to the subject a therapeutically effective amount of a combination therapy regimen comprising a compound of the formula: After completing treatment, subjects: (i) Hepatitis B viral load below the lower limit of quantification; (ii) negative for hepatitis B e antigen (HBeAg); (iii) alanine aminotransferase less than about twice the upper limit of normal; (iv) characterized by being negative for hepatitis B surface antigen (HBsAg); Provided herein are methods whereby to treat and / or prevent Hepatitis B virus infection in a subject.

[0272] In some embodiments, the present disclosure provides a method for manufacturing a medicament for treating and / or preventing Hepatitis B virus infection in a subject in need thereof, comprising: Formula (I): [ka] Compound or a pharma- ceutically acceptable salt thereof; A double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3'; The present invention provides a method for treating cancer, comprising administering to a patient a therapeutically effective amount of a combination therapy regimen comprising a PD-1 / PD-L1 inhibitor or a pharma- ceutical acceptable salt thereof.

[0273] In some embodiments, the present disclosure provides a method for manufacturing a medicament for treating and / or preventing Hepatitis B virus infection in a subject in need thereof, comprising: Formula (I): [ka] Compound or a pharma- ceutically acceptable salt thereof; A double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, wherein SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', wherein SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', wherein each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, and each a double-stranded ribonucleic acid, wherein g is 2'-O-methylguanosine-3'-phosphate, each u is 2'-O-methyluridine-3'-phosphate, each Af is 2'-fluoroadenosine-3'-phosphate, each Cf is 2'-fluorocytidine-3'-phosphate, each Gf is 2'-fluoroguanosine-3'-phosphate, Uf is 2'-fluorouridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate linkage, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol; The present invention provides a method for treating cancer, comprising administering to a patient a therapeutically effective amount of a combination therapy regimen comprising a PD-1 / PD-L1 inhibitor or a pharma- ceutical acceptable salt thereof.

[0274] In some embodiments, the present disclosure provides a method for the manufacture of a medicament for the treatment and / or prevention of Hepatitis B virus infection in a subject in need thereof, comprising: Formula (I): [ka] Compound or a pharma- ceutically acceptable salt thereof; A double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3'; The present invention provides a method for treating cancer, comprising administering to a patient a therapeutically effective amount of a combination therapy comprising administering to said patient a PD-1 / PD-L1 inhibitor or a pharma- ceutical acceptable salt thereof.

[0275] In some embodiments, the present disclosure provides a method for the manufacture of a medicament for the treatment and / or prevention of Hepatitis B virus infection in a subject in need thereof, comprising: Formula (I): [ka] Compound or a pharma- ceutically acceptable salt thereof; A double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, wherein SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', wherein SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', wherein each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, and each a double-stranded ribonucleic acid, wherein g is 2'-O-methylguanosine-3'-phosphate, each u is 2'-O-methyluridine-3'-phosphate, each Af is 2'-fluoroadenosine-3'-phosphate, each Cf is 2'-fluorocytidine-3'-phosphate, each Gf is 2'-fluoroguanosine-3'-phosphate, Uf is 2'-fluorouridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate linkage, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol; The present invention provides a method for treating cancer, comprising administering to a patient a therapeutically effective amount of a combination therapy comprising administering to said patient a PD-1 / PD-L1 inhibitor or a pharma- ceutical acceptable salt thereof.

[0276] In some embodiments, the present disclosure provides a method for the treatment and / or prevention of Hepatitis B virus infection in a subject in need thereof, comprising: Formula (I): [ka] Compound or a pharma- ceutically acceptable salt thereof; A double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, where SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3'; and a PD-1 / PD-L1 inhibitor or a pharma- ceutical acceptable salt thereof.

[0277] In some embodiments, the present disclosure provides a method for the treatment and / or prevention of Hepatitis B virus infection in a subject in need thereof, comprising: Formula (I): [ka] Compound or a pharma- ceutically acceptable salt thereof; A double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, wherein SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', wherein SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3', wherein each a is 2'-O-methyl adenosine-3'-phosphate, each c is 2'-O-methyl cytidine-3'-phosphate, and each a double-stranded ribonucleic acid, wherein g is 2'-O-methylguanosine-3'-phosphate, each u is 2'-O-methyluridine-3'-phosphate, each Af is 2'-fluoroadenosine-3'-phosphate, each Cf is 2'-fluorocytidine-3'-phosphate, each Gf is 2'-fluoroguanosine-3'-phosphate, Uf is 2'-fluorouridine-3'-phosphate, (Agn) is adenosine-glycol nucleic acid (GNA), each s is a phosphorothioate linkage, and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol; and a PD-1 / PD-L1 inhibitor or a pharma- ceutical acceptable salt thereof. EXAMPLES

[0278] IV. Working Examples Example 1. Study to Evaluate the Safety and Efficacy of Sergantolimod Combination Therapy for the Treatment of Chronic Hepatitis B (CHB) Test Purpose The main objectives of this study are to: -Evaluating the safety and tolerability of the study treatment To evaluate the efficacy of the study treatment, as measured by the proportion of subjects achieving functional cure, defined as negative qualitative Hepatitis B surface antigen (HBsAg loss) and Hepatitis B virus (HBV) less than 20 IU / mL at 24-week follow-up (FU).

[0279] The secondary objectives of this study are to: To assess the proportion of subjects with HBsAg loss with or without anti-HBsAg seroexchange during the study. To assess the proportion of subjects achieving HBeAg loss with or without anti-HBeAg seroexchange during the study in patients with CHB who are hepatitis B e antigen (HBeAg) positive at baseline. To assess the proportion of subjects remaining on nucleoside (nucleotide, NUC) treatment during FU. To assess the proportion of subjects experiencing HBV viral reactivation during study treatment. The exploratory objectives of this study are to: To assess changes from baseline in quantitative HBV RNA, HBV DNA (including digital PCR [ddPCR], where available), Hepatitis B core-related antigen (HBcrAg), HBeAg, HBsAg, and glycosylated fraction of HBsAg (where applicable) during study treatment and after discontinuation of study treatment. To evaluate the effect of the test treatment on peripheral cytokine activation and immune responses. · To characterize the relationship between immunological changes and circulating HBV viral markers. In subjects who provide separate and specific consent, genetic discovery studies (e.g., pharmacogenomics [PG]) to identify or evaluate host and / or viral genomic markers that may predict the natural progression of disease, response to therapy, and / or tolerability of medical treatment. To characterize the pharmacokinetics (PK) of SLGN in combination with VIR-2218 and nivolumab. To characterize HBV viral variants present at baseline and / or that regress during treatment that may be related to response to study treatment.

[0280] Test Design This is a Phase 2, open-label study to evaluate the safety and efficacy of SLGN-containing combination therapy in subjects with chronic hepatitis B (CHB). The study will consist of three cohorts (Cohort 1, Cohort 2, and Cohort 3). Approximately 40 NUC-suppressed subjects and approximately 80 viremic CHB-infected subjects will be enrolled and assigned to the following cohorts: Each cohort will enroll approximately equal numbers (±10%) of HBeAg-positive and HBeAg-negative subjects, with up to 20% of subjects having HBsAg ≤100 IU / mL.

[0281] NUC suppression cohort. Cohort 1 (n=40): Tenofovir alafenamide (TAF) 25mg tablet was administered orally once daily for 36 weeks. VIR-2218 200 mg was administered as a subcutaneous (SC) injection once every 4 weeks for 24 weeks (6 doses total) At week 12, the following treatments are added and initiated: SLGN 3 mg (2 × 1.5 mg tablets) was administered orally, fasting, once weekly on the same day for 24 weeks (total of 24 doses) Nivolumab 0.3 mg / kg was administered intravenously (IV) once every 4 weeks for 24 weeks (6 doses total)

[0282] Viremic cohorts (cohorts 2 and 3).

[0283] Cohort 2 subjects were randomized to groups A and B in a 2:1 ratio, and 3 log10 HBsAg > 3 IU / mL log10 Separate with HBsAg below IU / mL.

[0284] Group A (n=40): VIR-2218 200mg administered as a SC injection once every 4 weeks for 24 weeks (6 doses total) At week 12, the following treatments are added and initiated: SLGN 3 mg (2 × 1.5 mg tablets) was administered orally, fasting, once weekly on the same day for 24 weeks (total of 24 doses) Nivolumab 0.3 mg / kg was administered IV once every 4 weeks for 24 weeks (6 doses total)

[0285] Group B (n=20): SLGN 3 mg (2 × 1.5 mg tablets) was administered orally, fasting, once weekly on the same day for 24 weeks (total of 24 doses) Nivolumab 0.3 mg / kg was administered IV once every 4 weeks for 24 weeks (6 doses total)

[0286] Cohort 3 (n=20). Cohort 3 will begin at the sponsor's discretion after enrollment of Cohort 2 is complete. VIR-2218 200mg administered as a SC injection once every 4 weeks for 24 weeks (6 doses total) SLGN 3 mg (2 × 1.5 mg tablets) was administered orally, fasting, once weekly on the same day for 24 weeks (total of 24 doses) Nivolumab 0.3 mg / kg was administered IV once every 4 weeks for 24 weeks (6 doses total)

[0287] Follow-up Period At the end of treatment, all subjects enter the FU period. All subjects not receiving TAF treatment at the end of treatment (EOT) will enter a treatment-free follow-up (TFFU) period Subjects receiving TAF and who meet the following criteria at the EOT visit: (1) HBV DNA <20 IU / mL, (2) HBeAg negative, and (3) HBsAg ≤100 IU / mL will stop all treatment by the visit within 1 week of FU and enter the TFFU period. All remaining subjects will continue on TAF or other NUC treatment and enter the FU period.

[0288] Subjects who do not meet the above criteria but choose to discontinue NUC at EOT may discontinue this treatment with approval from the medical monitor.

[0289] Planned number of subjects: Approximately 120 subjects

[0290] Target population: Adult, non-cirrhotic subjects with CHB who are receiving commercially approved HBV NUC therapy and are viremic or virally suppressed

[0291] Treatment duration: Cohort 1 will receive TAF 25 mg tablets orally once daily for up to 84 weeks if indicated. VIR-2218 200 mg SC administered once every 4 weeks for 24 weeks (6 doses) Nivolumab 0.3 mg / kg IV, administered once every 4 weeks for 24 weeks (6 doses) SLGN 3 mg (2 x 1.5 mg tablets) orally, fasting, once weekly on the same day for 24 weeks (total of 24 doses) Male and non-pregnant female subjects aged 18-65 years who have HBV infection without cirrhosis and are viremic or virally suppressed on NUC for at least 6 months are eligible for the study.

[0292] Study Procedures / Frequency: After consent is obtained, screening assessments will be completed within 30 days prior to Baseline / Day 1 treatment. With sponsor approval, the screening window may be extended to 45 days. All subjects will complete study treatment as follows: Subjects who remain on NUC through the FU period are not required to participate in FU at the Week 2 and Week 8 visits.

[0293] Cohort 1: Screening visit Treatment visits: Baseline / Day 1, Week 4, Week 8, Week 12, Week 13, Week 14, Week 16, Week 20, Week 24, Week 28, Week 32, and Week 36 FU visits: 1st, 2nd, 4th, 8th, 12th, 16th (for women of childbearing potential), 24th (main cases), 36th and 48th weeks

[0294] Cohort 2A: Treatment visits: Baseline / Day 1, Week 4, Week 8, Week 12, Week 13, Week 14, Week 16, Week 20, Week 24, Week 28, Week 32, and Week 36 FU visits: 1st, 2nd, 4th, 8th, 12th, 16th (for women of childbearing potential), 24th (main cases), 36th and 48th weeks

[0295] Cohort 2B: Treatment visits: Baseline / Day 1, Week 1, Week 2, Week 4, Week 8, Week 12, Week 14, Week 16, Week 20, and Week 24 FU visits: 1st, 2nd, 4th, 8th, 12th, 16th (for women of childbearing potential), 24th (main cases), 36th and 48th weeks

[0296] Cohort 3 Treatment visits: Baseline / Day 1, Week 1, Week 2, Week 4, Week 8, Week 12, Week 14, Week 16, Week 20, and Week 24 FU visits: 1st, 2nd, 4th, 8th, 12th, 16th (for women of childbearing potential), 24th (main cases), 36th and 48th weeks

[0297] Test Product, Dose and Administration Selgantolimod is supplied as a tablet in a strength of 1.5 mg. SLGN 3 mg (2 x 1.5 mg tablets) is administered once a week on the same day during fasting. Subjects must have fasted (no food or drink except water) for at least 8 hours the previous night and must continue to fast until the morning with no food or drink, including water, from 1 hour before dosing until 2 hours after dosing. Water is provided 2 hours after dosing and subjects are allowed food and drink 4 hours after dosing. Subjects must take other prescribed medications, including NUC therapy, no earlier than 2 hours after SLGN administration or, if the medication is to be administered with food, no earlier than 4 hours after SLGN administration.

[0298] Study endpoints The primary endpoints of the study are: Proportion of subjects achieving functional cure, defined as HBsAg loss and HBV DNA less than 20 IU / mL at 24 weeks FU.

[0299] Secondary endpoints of the study include: · Proportion of subjects with HBsAg loss with or without anti-HBsAg seroexchange during the study. The proportion of subjects with HBeAg loss with or without anti-HBeAg seroexchange during the study in patients with CHB who are HBeAg positive at baseline. · Proportion of subjects remaining on nucleoside treatment during FU. HBV viral relapse during study treatment (after <20 IU / mL or 1 log from nadir) 10 Percentage of subjects experiencing an HBV DNA increase of ≥ 69 IU / mL on two consecutive visits after a confirmed increase of ≥ 69 IU / mL.

[0300] Test Design This is an open-label study to evaluate the safety and efficacy of SLGN-containing combination therapy in subjects with CHB. Approximately 40 NUC-suppressed and 80 viremic CHB-infected subjects can be enrolled and assigned to the following cohorts: Each cohort will enroll approximately equal numbers (±10%) of HBeAg-positive and HBeAg-negative subjects, with up to 20% of subjects having HBsAg ≤100 IU / mL.

[0301] Study treatment NUC suppression cohort. Cohort 1 (n=40): TAF 25mg tablets were administered orally once daily for 36 weeks. VIR-2218 200mg administered by SC injection once every 4 weeks for 24 weeks (6 doses total) At week 12, the following treatments are added and initiated: SLGN 3 mg (2 × 1.5 mg tablets) was administered orally, fasting, once weekly on the same day for 24 weeks (total of 24 doses) Nivolumab 0.3 mg / kg was administered intravenously (IV) once every 4 weeks for 24 weeks (6 doses total)

[0302] Viremic cohorts (cohorts 2 and 3).

[0303] Cohort 2 subjects were randomized to groups A and B in a 2:1 ratio, and 3 log10 HBsAg > 3 IU / mL log10 Separate with HBsAg below IU / mL.

[0304] Group A (n=40): VIR-2218 200mg administered by SC injection once every 4 weeks for 24 weeks (6 doses total) At week 12, the following treatments are added and initiated: SLGN 3 mg (2 × 1.5 mg tablets) was administered orally, fasting, once weekly on the same day for 24 weeks (total of 24 doses) Nivolumab 0.3 mg / kg was administered IV once every 4 weeks for 24 weeks (6 doses total)

[0305] Group B (n=20): SLGN 3 mg (2 × 1.5 mg tablets) was administered orally, fasting, once weekly on the same day for 24 weeks (total of 24 doses) Nivolumab 0.3 mg / kg was administered IV once every 4 weeks for 24 weeks (6 doses total)

[0306] Cohort 3 (n=20). Cohort 3 will begin at the sponsor's discretion after enrollment of Cohort 2 is complete. VIR-2218 200mg administered by SC injection once every 4 weeks for 24 weeks (6 doses total) SLGN 3 mg (2 × 1.5 mg tablets) was administered orally, fasting, once weekly on the same day for 24 weeks (total of 24 doses) Nivolumab 0.3 mg / kg was administered IV once every 4 weeks for 24 weeks (6 doses total)

[0307] Treatment duration: The duration of study treatment was as follows: In cohort 1, patients will receive TAF 25 mg tablets orally once daily for up to 84 weeks if eligible. VIR-2218 200 mg SC administered once every 4 weeks for 24 weeks (6 doses) Nivolumab 0.3 mg / kg IV, administered once every 4 weeks for 24 weeks (6 doses) SLGN 3 mg (2 x 1.5 mg tablets) orally, fasting, once weekly on the same day for 24 weeks (total of 24 doses) After completing study treatment, all subjects will undergo 48 weeks of FU.

[0308] Study follow-up At the end of treatment, all subjects enter the FU period. All subjects not receiving TAF at the end of treatment (EOT) will enter the TFFU period. Subjects receiving TAF and who meet the following criteria at the EOT visit: (1) HBV DNA <20 IU / mL, (2) HBeAg negative, and (3) HBsAg <100 IU / mL will stop all treatments by the visit within 1 week of FU and enter the TFFU period. All remaining subjects will continue TAF or other treatment and enter the FU period.

[0309] Subjects who do not meet the above criteria but choose to discontinue NUC at EOT may discontinue this treatment with approval from the medical monitor.

[0310] Number of subjects and selection of subjects. Cohorts 1-3 will enroll approximately 120 male and non-pregnant female subjects aged 18-65 years who are non-cirrhotic, have CHB infection, and are viremic or virally suppressed on NUC for at least 6 months.

[0311] Cohort 1 subjects must meet the following additional criteria to be eligible to participate in the study: -No change in regimen for 3 months prior to screening and about to start TAF 25mg, and receiving commercially available HBV NUC therapy (i.e. TAF, TDF, entecavir, adefovir, lamivudine, telbivudine, either as single agents or in combination). Have past HBV DNA less than 69 IU / mL, measured at least once in the respective laboratory ≥6 months prior to screening HBV DNA less than 20 IU / mL at the central laboratory at the time of screening

[0312] Subjects in Cohorts 2 and 3 must meet the following additional criteria to be eligible to participate in the study: HBV DNA >2000IU / mL (HBeAg negative) and HBV DNA >20,000IU / mL (HBeAg positive)

[0313] formulation Sergantolimod. Sergantolimod tablets 1.5 mg are formulated with microcrystalline cellulose, mannitol, croscarmellose sodium and magnesium stearate. The tablets are round, flat, film-coated and white in color. The white tablet film coating contains polyvinyl alcohol, titanium dioxide, polyethylene glycol (PEG) 3350 and talc.

[0314] Nivolumab. The commercially available product of nivolumab injection will be used in this study. Further information about the formulation is available in the currently approved nivolumab product labeling.

[0315] Tenofovir alafenamide. Each film-coated tablet contains 25 mg of TAF and an equivalent amount of tenofovir alafenamide fumarate, formulated with croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The tablets are yellow, round, film-coated, and embossed with "GSI" on one side of the tablet and "25" on the other side.

[0316] VIR-2218 is a clear, transparent to pale yellow solution supplied by the sponsor as a sterile solution for SC injection at a free acid concentration of 200 mg / mL.

[0317] Dosage and administration of sergantolimod, tenofovir, VIR-2218, and nivolumab Sergeantolimod. Sergeantolimod is supplied as a tablet in a strength of 1.5 mg. SLGN 3 mg (2 x 1.5 mg tablets) is administered once a week on the same day while fasting. Subjects must have fasted (no food or drink except water) for at least 8 hours the previous night and must continue to fast until the morning, with no food or drink, including water, from 1 hour before dosing until 2 hours after dosing. Water is provided 2 hours after dosing, and subjects are allowed food and drink 4 hours after dosing. Subjects must take other prescribed medications, including NUC therapy, no more than 2 hours after SLGN administration or no more than 4 hours after SLGN administration if the medication must be administered with food.

[0318] Nivolumab. Nivolumab (Opdivo®) solution for injection 40 mg / 4 mL is supplied as a single dose vial. Nivolumab 0.3 mg / kg is administered as an IV infusion over 30 minutes.

[0319] Tenofovir alafenamide. TAF 25 mg tablet taken orally once daily with food.

[0320] VIR-2218 solution for injection, 200 mg / mL, is supplied in 0.5 mL single dose vials. VIR-2218 200 mg (2 x 0.5 mL solution) is administered subcutaneously.

[0321] Randomization Viremia Cohort 2 (groups A and B) only. Subjects were randomized 2:1 to groups A and B in Cohort 2, and 3 log10 HBsAg > 3 IU / mL log10 Separate with HBsAg below IU / mL.

[0322] Treatment schedule Cohort 1: Baseline / Day 1, Week 4 and Week 8 - SC VIR-2218 Weeks 12, 16, and 20 - SC VIR-2218; add IV nivolumab Weeks 24, 28, and 32 - IV nivolumab Daily oral administration of TAF for 36 weeks SLGN given orally weekly for 24 weeks, starting at week 12 and ending at week 35

[0323] Cohort 2, Arm A: Baseline / Day 1, Week 4 and Week 8 - SC VIR-2218 Weeks 12, 16, and 20 - SC VIR-2218, plus IV nivolumab Weeks 24, 28, and 32 - IV nivolumab SLGN given orally weekly for 24 weeks, starting at week 12 and ending at week 35

[0324] Cohort 2, Group B: Baseline / Day 1, Week 4, Week 8, Week 12, Week 16, and Week 20 - Nivolumab IV SLGN given orally weekly starting on day 1 through week 23 for 24 weeks

[0325] Cohort 3: Baseline / Day 1 and Weeks 4, 8, 12, 16, and 20 - SC VIR-2218, IV nivolumab SLGN given orally weekly starting on day 1 through week 23 for 24 weeks

[0326] Example 2. Study to Evaluate the Safety and Efficacy of Sergantolimod Combination Therapy for the Treatment of Chronic Hepatitis B (CHB) Test Purpose The main objectives of this study are to: -Evaluating the safety and tolerability of the study treatment To evaluate the efficacy of the study treatment as measured by the proportion of subjects achieving functional cure, defined as negative qualitative Hepatitis B surface antigen (HBsAg loss) and Hepatitis B virus (HBV) below the lower limit of qualitative recovery at 24-week follow-up (FU).

[0327] The secondary objectives of this study are to: To assess the proportion of subjects with HBsAg loss with or without anti-HBsAg seroexchange during the study. To assess the proportion of subjects achieving HBeAg loss with or without anti-HBeAg seroexchange during the study in patients with CHB who are hepatitis B e antigen (HBeAg) positive at baseline. To assess the proportion of subjects remaining on nucleoside (nucleotide, NUC) treatment during FU. To assess the proportion of subjects experiencing HBV viral reactivation during study treatment. The exploratory objectives of this study are to: To assess changes from baseline in quantitative HBV RNA, HBV DNA (including digital PCR [ddPCR], where available), Hepatitis B core-related antigen (HBcrAg), HBeAg, HBsAg, and glycosylated fraction of HBsAg (where applicable) during study treatment and after discontinuation of study treatment. To evaluate the effect of the test treatment on peripheral cytokine activation and immune responses. · To characterize the relationship between immunological changes and circulating HBV viral markers. In subjects who provide separate and specific consent, genetic discovery studies (e.g., pharmacogenomics [PG]) to identify or evaluate host and / or viral genomic markers that may predict the natural progression of disease, response to therapy, and / or tolerability of medical treatment. To characterize the pharmacokinetics (PK) of SLGN in combination with VIR-2218 and nivolumab. To characterize HBV viral variants present at baseline and / or that regress during treatment that may be related to response to study treatment.

[0328] Test Design This is a Phase 2, open-label study to evaluate the safety and efficacy of SLGN-containing combination therapy in subjects with chronic hepatitis B (CHB). The study will consist of three cohorts (Cohort 1, Cohort 2, and Cohort 3). Approximately 40 NUC-suppressed subjects and approximately 80 viremic CHB-infected subjects will be enrolled and assigned to the following cohorts: Each cohort will enroll a minimum of 20% HBeAg-positive subjects and a maximum of 20% of subjects will have HBsAg ≤100 IU / mL.

[0329] NUC suppression cohort. Cohort 1 (n=40): Tenofovir alafenamide (TAF) 25mg tablet was administered orally once daily for 36 weeks. VIR-2218 200 mg was administered as a subcutaneous (SC) injection once every 4 weeks for 24 weeks (6 doses total) At week 12, the following treatments are added and initiated: SLGN 3 mg (2 × 1.5 mg tablets) was administered orally, fasting, once weekly on the same day for 24 weeks (total of 24 doses) Nivolumab 0.3 mg / kg was administered intravenously (IV) once every 4 weeks for 24 weeks (6 doses total)

[0330] Viremic cohorts (cohorts 2 and 3).

[0331] Cohort 2 subjects were randomized to groups A and B in a 2:1 ratio, and 3 log10 HBsAg > 3 IU / mL log10 Separate with HBsAg below IU / mL.

[0332] Group A (n=40): VIR-2218 200mg administered as a SC injection once every 4 weeks for 24 weeks (6 doses total) At week 12, the following treatments are added and initiated: SLGN 3 mg (2 × 1.5 mg tablets) was administered orally, fasting, once weekly on the same day for 24 weeks (total of 24 doses) Nivolumab 0.3 mg / kg was administered IV once every 4 weeks for 24 weeks (6 doses total)

[0333] Group B (n=20): SLGN 3 mg (2 × 1.5 mg tablets) was administered orally, fasting, once weekly on the same day for 24 weeks (total of 24 doses) Nivolumab 0.3 mg / kg was administered IV once every 4 weeks for 24 weeks (6 doses total)

[0334] Cohort 3 (n=20). Cohort 3 will begin at the sponsor's discretion after enrollment of Cohort 2 is complete. VIR-2218 200mg administered as a SC injection once every 4 weeks for 24 weeks (6 doses total) SLGN 3 mg (2 × 1.5 mg tablets) was administered orally, fasting, once weekly on the same day for 24 weeks (total of 24 doses) Nivolumab 0.3 mg / kg was administered IV once every 4 weeks for 24 weeks (6 doses total)

[0335] Follow-up Period At the end of treatment, all subjects enter the FU period. All subjects not receiving TAF treatment at the end of treatment (EOT) will enter a treatment-free follow-up (TFFU) period Subjects receiving TAF and who meet the following criteria at the EOT visit: (1) HBV DNA <LLOQ, (2) HBeAg negative, and (3) HBsAg ≤100 IU / mL will stop all treatment by the visit within 1 week of FU and enter the TFFU period. All remaining subjects will continue on TAF or other NUC treatment and enter the FU period.

[0336] Subjects who do not meet the above criteria but choose to discontinue NUC at EOT may discontinue this treatment with approval from the medical monitor.

[0337] Planned number of subjects: Approximately 120 subjects

[0338] Target population: Adult, non-cirrhotic subjects with CHB who are receiving commercially approved HBV NUC therapy and are viremic or virally suppressed

[0339] Treatment duration: Cohort 1 will receive TAF 25 mg tablets orally once daily for up to 84 weeks if indicated. VIR-2218 200 mg SC administered once every 4 weeks for 24 weeks (6 doses) Nivolumab 0.3 mg / kg IV, administered once every 4 weeks for 24 weeks (6 doses) SLGN 3 mg (2 x 1.5 mg tablets) orally, fasting, once weekly on the same day for 24 weeks (total of 24 doses) Male and non-pregnant female subjects aged 18-65 years who have HBV infection without cirrhosis and are viremic or virally suppressed on NUC for at least 6 months are eligible for the study.

[0340] Study Procedures / Frequency: After obtaining consent, screening assessments will be completed within 45 days prior to baseline / Day 1 treatment. All subjects will complete study treatment as follows: Subjects who remain on NUC through the FU period will not be required to participate in FU at the Week 2 and Week 8 visits.

[0341] Cohort 1: Screening visit Treatment visits: Baseline / Day 1, Week 4, Week 8, Week 12, Week 13, Week 14, Week 16, Week 20, Week 24, Week 28, Week 32, and Week 36 FU visits: 1st, 2nd, 4th, 8th, 12th, 16th (for women of childbearing potential), 24th (main cases), 36th and 48th weeks

[0342] Cohort 2A: Treatment visits: Baseline / Day 1, Week 4, Week 8, Week 12, Week 13, Week 14, Week 16, Week 20, Week 24, Week 28, Week 32, and Week 36 FU visits: 1st, 2nd, 4th, 8th, 12th, 16th (for women of childbearing potential), 24th (main cases), 36th and 48th weeks

[0343] Cohort 2B: Treatment visits: Baseline / Day 1, Week 1, Week 2, Week 4, Week 8, Week 12, Week 14, Week 16, Week 20, and Week 24 FU visits: 1st, 2nd, 4th, 8th, 12th, 16th (for women of childbearing potential), 24th (main cases), 36th and 48th weeks

[0344] Cohort 3 Treatment visits: Baseline / Day 1, Week 1, Week 2, Week 4, Week 8, Week 12, Week 14, Week 16, Week 20, and Week 24 FU visits: 1st, 2nd, 4th, 8th, 12th, 16th (for women of childbearing potential), 24th (main cases), 36th and 48th weeks

[0345] Test Product, Dose, and Administration. Sergeantolimod is supplied as a tablet in 1.5 mg strength. SLGN 3 mg (2 x 1.5 mg tablets) is administered once a week on the same day during fasting. Subjects must have fasted (no food or drink except water) for at least 8 hours the previous night and must continue fasting until the morning with no food or drink, including water, from 1 hour before dosing until 2 hours after dosing. Water is provided 2 hours after dosing, and subjects are provided with food and drink 4 hours after dosing. Subjects must take other prescribed medications, including NUC therapy, no earlier than 2 hours after SLGN administration or, if the medication must be administered with food, no earlier than 4 hours after SLGN administration.

[0346] Study endpoints The primary endpoints of the study are: Proportion of subjects achieving functional cure, defined as HBsAg loss at FU at week 24 and HBV DNA below the LLOQ.

[0347] Secondary endpoints of the study include: · Proportion of subjects with HBsAg loss with or without anti-HBsAg seroexchange during the study. The proportion of subjects with HBeAg loss with or without anti-HBeAg seroexchange during the study in patients with CHB who are HBeAg positive at baseline. · Proportion of subjects remaining on nucleoside treatment during FU. HBV viral relapse during study treatment (after being below the LLOQ or after 1 log from nadir) 10 Percentage of subjects experiencing an HBV DNA increase of ≥ 69 IU / mL on two consecutive visits after a confirmed increase of ≥ 69 IU / mL.

[0348] Test Design This is an open-label study to evaluate the safety and efficacy of SLGN-containing combination therapy in subjects with CHB. Approximately 40 NUC-suppressed subjects and approximately 80 viremic CHB-infected subjects can be enrolled and assigned to the following cohorts: Each cohort will enroll a minimum of 20% HBeAg-positive subjects and a maximum of 20% of subjects can have HBsAg ≤100 IU / mL.

[0349] Study treatment NUC suppression cohort. Cohort 1 (n=40): TAF 25mg tablets were administered orally once daily for 36 weeks. VIR-2218 200mg administered by SC injection once every 4 weeks for 24 weeks (6 doses total) At week 12, the following treatments are added and initiated: SLGN 3 mg (2 × 1.5 mg tablets) was administered orally, fasting, once weekly on the same day for 24 weeks (total of 24 doses) Nivolumab 0.3 mg / kg was administered intravenously (IV) once every 4 weeks for 24 weeks (6 doses total)

[0350] Viremic cohorts (cohorts 2 and 3).

[0351] Cohort 2 subjects were randomized to groups A and B in a 2:1 ratio, and 3 log10 HBsAg > 3 IU / mL log10 Separate with HBsAg below IU / mL.

[0352] Group A (n=40): VIR-2218 200mg administered by SC injection once every 4 weeks for 24 weeks (6 doses total) At week 12, the following treatments are added and initiated: SLGN 3 mg (2 × 1.5 mg tablets) was administered orally, fasting, once weekly on the same day for 24 weeks (total of 24 doses) Nivolumab 0.3 mg / kg was administered IV once every 4 weeks for 24 weeks (6 doses total)

[0353] Group B (n=20): SLGN 3 mg (2 × 1.5 mg tablets) was administered orally, fasting, once weekly on the same day for 24 weeks (total of 24 doses) Nivolumab 0.3 mg / kg was administered IV once every 4 weeks for 24 weeks (6 doses total)

[0354] Cohort 3 (n=20). Cohort 3 will begin at the sponsor's discretion after enrollment of Cohort 2 is complete. VIR-2218 200mg administered by SC injection once every 4 weeks for 24 weeks (6 doses total) SLGN 3 mg (2 × 1.5 mg tablets) was administered orally, fasting, once weekly on the same day for 24 weeks (total of 24 doses) Nivolumab 0.3 mg / kg was administered IV once every 4 weeks for 24 weeks (6 doses total)

[0355] Duration of treatment The duration of study treatment was as follows: In cohort 1, patients will receive TAF 25 mg tablets orally once daily for up to 84 weeks if eligible. VIR-2218 200 mg SC administered once every 4 weeks for 24 weeks (6 doses) Nivolumab 0.3 mg / kg IV, administered once every 4 weeks for 24 weeks (6 doses) SLGN 3 mg (2 x 1.5 mg tablets) orally, fasting, once weekly on the same day for 24 weeks (total of 24 doses) After completing study treatment, all subjects will undergo 48 weeks of FU.

[0356] Study follow-up At the end of treatment, all subjects enter the FU period. All subjects not receiving TAF at the end of treatment (EOT) will enter the TFFU period. Subjects receiving TAF and who meet the following criteria at the EOT visit: (1) HBV DNA <LLOQ, (2) HBeAg negative, (3) alanine aminotransferase (ALT) <2x upper limit of normal (ULN), and (4) HBsAg <100 IU / mL confirmed by repeat testing will stop all treatments after the FU visit after week 1 and enter the TFFU period. All remaining subjects will continue TAF or other treatment and enter the FU period. HBeAg positive subjects who meet all of the above criteria except for HBeAg status may also discontinue NUC treatment upon agreement between the investigator and the sponsor's medical monitor.

[0357] Subjects who do not meet the above criteria but choose to discontinue NUC treatment at the EOT may discontinue upon agreement between the investigator and the sponsor's medical monitor approval. Subjects who meet the above criteria but the investigator wishes to continue NUC treatment at the EOT may continue upon agreement between the investigator and the sponsor's medical monitor after discussion to assess risks and benefits.

[0358] Number of subjects and selection of subjects. Cohorts 1-3 will enroll approximately 120 male and non-pregnant female subjects aged 18-65 years who are non-cirrhotic, have CHB infection, and are viremic or virally suppressed on NUC for at least 6 months.

[0359] Cohort 1 subjects must meet the following additional criteria to be eligible to participate in the study: -No change in regimen for 3 months prior to screening and about to start TAF 25mg, and receiving commercially available HBV NUC therapy (i.e. TAF, TDF, entecavir, adefovir, lamivudine, telbivudine, either as single agents or in combination). Have past HBV DNA less than 69 IU / mL, measured at least once in the respective laboratory ≥6 months prior to screening HBV DNA below the LLOQ at the central laboratory at the time of screening

[0360] Subjects in Cohorts 2 and 3 must meet the following additional criteria to be eligible to participate in the study: HBV DNA >2000IU / mL (HBeAg negative) and HBV DNA >20,000IU / mL (HBeAg positive)

[0361] formulation Sergantolimod. Sergantolimod tablets 1.5 mg are formulated with microcrystalline cellulose, mannitol, croscarmellose sodium and magnesium stearate. The tablets are round, flat, film-coated and white in color. The white tablet film coating contains polyvinyl alcohol, titanium dioxide, polyethylene glycol (PEG) 3350 and talc.

[0362] Nivolumab. The commercially available product of nivolumab injection will be used in this study. Further information about the formulation is available in the currently approved nivolumab product labeling.

[0363] Tenofovir alafenamide. Each film-coated tablet contains 25 mg of TAF and an equivalent amount of tenofovir alafenamide fumarate, formulated with croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The tablets are yellow, round, film-coated, and embossed with "GSI" on one side of the tablet and "25" on the other side.

[0364] VIR-2218 is a clear, transparent to pale yellow solution supplied by the sponsor as a sterile solution for SC injection at a free acid concentration of 200 mg / mL.

[0365] Dosage and administration of sergantolimod, tenofovir, VIR-2218, and nivolumab Sergeantolimod. Sergeantolimod is supplied as a tablet in a strength of 1.5 mg. SLGN 3 mg (2 x 1.5 mg tablets) is administered once a week on the same day while fasting. Subjects must have fasted (no food or drink except water) for at least 8 hours the previous night and must continue to fast until the morning, with no food or drink, including water, from 1 hour before dosing until 2 hours after dosing. Water is provided 2 hours after dosing, and subjects are allowed food and drink 4 hours after dosing. Subjects must take other prescribed medications, including NUC therapy, no more than 2 hours after SLGN administration or no more than 4 hours after SLGN administration if the medication must be administered with food.

[0366] Nivolumab. Nivolumab (Opdivo®) solution for injection 40 mg / 4 mL is supplied as a single dose vial. Nivolumab 0.3 mg / kg is administered as an IV infusion over 45-60 minutes.

[0367] Tenofovir alafenamide. TAF 25 mg tablet taken orally once daily with food.

[0368] VIR-2218 solution for injection, 200 mg / mL, is supplied in 0.5 mL single dose vials. VIR-2218 200 mg (2 x 0.5 mL solution) is administered subcutaneously.

[0369] Randomization Viremia Cohort 2 (groups A and B) only. Subjects were randomized 2:1 to groups A and B in Cohort 2, and 3 log10 HBsAg > 3 IU / mL log10 Separate with HBsAg below IU / mL.

[0370] Treatment schedule Cohort 1: Baseline / Day 1, Week 4 and Week 8 - SC VIR-2218 Weeks 12, 16, and 20 - SC VIR-2218; add IV nivolumab Weeks 24, 28, and 32 - IV nivolumab Daily oral administration of TAF for 36 weeks SLGN given orally weekly for 24 weeks, starting at week 12 and ending at week 35

[0371] Cohort 2, Arm A: Baseline / Day 1, Week 4 and Week 8 - SC VIR-2218 Weeks 12, 16, and 20 - SC VIR-2218, plus IV nivolumab Weeks 24, 28, and 32 - IV nivolumab SLGN given orally weekly for 24 weeks, starting at week 12 and ending at week 35

[0372] Cohort 2, Group B: Baseline / Day 1, Week 4, Week 8, Week 12, Week 16, and Week 20 - Nivolumab IV SLGN given orally weekly starting on day 1 through week 23 for 24 weeks

[0373] Cohort 3: Baseline / Day 1 and Weeks 4, 8, 12, 16, and 20 - SC VIR-2218, IV nivolumab SLGN given orally weekly starting on day 1 through week 23 for 24 weeks

[0374] Although the above disclosure has been described in some detail by way of illustration and example for clarity of understanding, it will be understood by those skilled in the art that certain changes and modifications may be implemented within the scope of the appended claims.In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference were individually incorporated by reference.In the event of any inconsistency between this application and the references provided herein, this application shall control.

Claims

1. 1. A combination for treating and / or preventing Hepatitis B virus infection in a subject in need thereof, comprising: Formula (I): 【Chemistry 96】 Compound or a pharma- ceutically acceptable salt thereof; A double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, in which SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3'; and a PD-1 / PD-L1 inhibitor or a pharma- ceutical acceptable salt thereof, wherein said combination is administered to said subject as a combination therapeutic regimen.

2. The compound of formula (I) has the structure: 【Chemistry 97】 2. The combination of claim 1, having the formula:

3. 2. The combination of claim 1, wherein the PD-1 / PD-L1 inhibitor is nivolumab.

4. 2. The combination of claim 1, wherein the PD-1 / PD-L1 inhibitor is GS-4224, atezolizumab, avelumab, dimverelimab, AMP-224, MEDI-0680, RG-7446, GX-P2, durvalumab, KY-1003, KD-033, MSB-0010718C, TSR-042, ALN-PDL, STI-A1014, CX-072 or BMS-936559, or a pharma- ceutical acceptable salt thereof.

5. The PD-1 / PD-L1 inhibitor is 【Chemistry 98】 【Chemistry 99】 or a pharma- ceutically acceptable salt thereof.

6. The combination described in claim 1, characterized in that the combination comprising the compound of formula (I), the dsRNA and nivolumab is administered.

7. wherein the compound of formula (I) is orally administered once a week starting on day 1 for 24 weeks while the subject fasts; The dsRNA is administered by subcutaneous injection once every 4 weeks starting on day 1 for 24 weeks; 7. The combination of claim 6, wherein said nivolumab is administered by intravenous injection once every 4 weeks starting on day 1 for 24 weeks.

8. wherein the compound of formula (I) is orally administered once a week starting at week 12 for 24 weeks while the subject fasts; wherein the dsRNA is administered by subcutaneous injection once every 4 weeks starting on day 1 for 24 weeks; 7. The combination of claim 6, wherein said nivolumab is administered by intravenous injection every 4 weeks starting at week 12 for 24 weeks.

9. Formula (II): 【Chemistry 100】 or a pharma- ceutically acceptable salt thereof is further administered to the subject.

10. The compound of formula (II) has the structure: 【Chemistry 101】 10. The combination of claim 9, having the formula:

11. 10. The combination according to claim 9, characterized in that the compound of formula (II) is administered orally.

12. 10. The combination according to claim 9, characterized in that the compound of formula (II) is administered once a day starting on day 1 for 48 weeks.

13. Administration of the compound of formula (II) results in the subject having, after 36 weeks: (i) a hepatitis B viral load of less than about 20 international units per milliliter (IU / mL); (ii) negative for hepatitis B e antigen (HBeAg); and (iii) a hepatitis B surface antigen (HBsAg) concentration of less than about 100 international units per milliliter (IU / mL); The combination of claim 9, which terminates when characterized by:

14. 10. The combination according to claim 9, characterized in that the compound of formula (II) is administered once a day starting on day 1 for 36 weeks.

15. The combination of claim 9, wherein the combination comprising the compound of formula (II), the compound of formula (I), the dsRNA and nivolumab is administered.

16. 10. The combination according to claim 9, characterized in that the compound of formula (II) is administered orally once a day starting on day 1 for 36 weeks.

17. 16. The combination of claim 15, wherein the dsRNA is administered by subcutaneous injection once every 4 weeks starting on day 1 for 24 weeks.

18. 16. The combination according to claim 15, characterized in that the compound of formula (I) is administered orally once a week starting at week 12 for 24 weeks while the subject fasts.

19. 16. The combination of claim 15, wherein said nivolumab is administered by intravenous injection every 4 weeks starting at week 12 for 24 weeks.

20. wherein the compound of formula (II) is orally administered once daily starting on day 1 for 36 weeks; wherein the dsRNA is administered by subcutaneous injection once every 4 weeks starting on day 1 for 24 weeks; wherein the compound of formula (I) is orally administered once a week starting at week 12 for 24 weeks while the subject fasts; 16. The combination of claim 15, wherein said nivolumab is administered by intravenous injection every 4 weeks starting at week 12 for 24 weeks.

21. 2. The combination according to claim 1, characterized in that the compound of formula (I) is administered to the subject in an amount of about 3 mg.

22. 2. The combination according to claim 1, characterized in that the compound of formula (I) is administered to the subject in two doses of 1.5 mg.

23. The combination of claim 1, wherein the dsRNA is administered to the subject in an amount of about 200 mg.

24. 4. The combination of claim 3, wherein the nivolumab is administered to the subject in an amount of about 0.3 mg / kg.

25. 10. The combination according to claim 9, characterized in that the compound of formula (II) is administered to the subject in an amount of about 25 mg.

26. 2. The combination of claim 1, wherein the subject has a hepatitis B viral load of less than about 20 international units per milliliter (IU / mL) after completing treatment.

27. The combination of claim 1, wherein the subject is negative for Hepatitis B surface antigen (HBsAg).

28. 2. The combination of claim 1, wherein the subject is Hepatitis B e antigen (HBeAg) negative after completing treatment.

29. A composition for treating and / or preventing Hepatitis B virus infection in a subject in need thereof, comprising: Formula (I): 【Chemistry 96】 Compound or a pharma- ceutically acceptable salt thereof, The composition, A double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, in which SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3'; PD-1 / PD-L1 inhibitor or pharma- ceutically acceptable salt thereof The composition is administered to the subject as a combination therapy regimen in combination with 30. A composition for treating and / or preventing Hepatitis B virus infection in a subject in need thereof, comprising: A double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, wherein SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3'; The composition, Formula (I): 【Chemistry 96】 Compound or a pharma- ceutically acceptable salt thereof; PD-1 / PD-L1 inhibitor or pharma- ceutically acceptable salt thereof The composition is administered to the subject as a combination therapy regimen in combination with 31. A composition for treating and / or preventing Hepatitis B virus infection in a subject in need thereof, comprising: comprising a PD-1 / PD-L1 inhibitor or a pharma- ceutically acceptable salt thereof; The composition, Formula (I): 【Chemistry 96】 Compound or a pharma- ceutically acceptable salt thereof; A double-stranded ribonucleic acid (dsRNA) of SEQ ID NO: 1 and SEQ ID NO: 2, in which SEQ ID NO: 1 is 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' and SEQ ID NO: 2 is 5'-gsusguGfcAfCfUfucgcuucacaL96-3'. The composition is administered to the subject as a combination therapy regimen in combination with

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