Method of treating HBV / HIV coinfection

Abstract

The present disclosure is related to methods for treating chronic hepatitis B infection in a human having HBV / HIV coinfection. The methods comprise administering to a human having HBV / HIV coinfection a therapeutically effective amount of an antisense oligonucleotide (ASO), wherein the subject has a HBsAg baseline level of not greater than a threshold level.

Description

[0001] METHOD OF TREATING HBV / HIV COINFECTION

[0002] FIELD

[0003] The present disclosure relates to methods for treating chronic hepatitis B infection in a subject having HBV / HIV coinfection. These methods comprise administering to a subject in need thereof a therapeutically effective amount of an antisense oligonucleotide (e.g. bepirovirsen), wherein the subject has a HBsAg baseline level of not greater than a threshold level.

[0004] BACKGROUND

[0005] Hepatitis B virus (HBV) is a strict hepatotropic, partially double-stranded DNA virus. Although DNA is the genetic material, the replication cycle involves a reverse transcription step to copy a pregenomic RNA into DNA. Primary infection with HBV causes an acute hepatitis with symptoms of organ inflammation, fever, jaundice, and increased liver transaminases in blood. Those patients that are not able to overcome the acute virus infection suffer a chronic disease progression over many years with increased risk of developing cirrhotic liver or liver cancer.

[0006] HBV infection results in the production of two different particles: 1) the HBV virus itself (or Dane particle) which includes a viral capsid assembled from the HBV core antigen protein (HBcAg) and is covered by the hepatitis B surface antigen (HBsAg) and is capable of reinfecting cells and 2) subviral particles (or SVPs) which are high density lipoprotein-like particles comprised of lipids, cholesterol, cholesterol esters and the small and medium forms of the hepatitis B surface antigen (HBsAg) which are non-infectious. For each Dane particle produced, 1,000-10,000 SVPs are released into the blood. As such SVPs (and the HBsAg protein they carry) represent the overwhelming majority of viral protein in the blood. HBV infected cells also secrete a soluble proteolytic product of the pre-core protein called the HBV e-antigen (HBeAg). The presence of HBeAg in the serum of patients can serve as a marker of active replication in chronic hepatitis.

[0007] Currently the recommended therapies for chronic HBV infection by the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASE) include interferon alpha (IFN-a), pegylated interferon alpha-2a, entecavir, and tenofovir. However, typical interferon therapy is 48-weeks and is associated with tolerability issues due to side effects, and HBeAg seroconversion 24 weeks after therapy has ceased ranges from 27-36%. Seroconversion of HBsAg is even lower - approximately 3% observed immediately after treatment ceases, with an increase to upwards of 12% after 5 years.

[0008] The nucleoside and nucleotide therapies entecavir and tenofovir have been successful at reducing viral load (HBV DNA), but the rates of HBeAg seroconversion and HBsAg loss are even lower than those obtained using IFN-a therapy. Tenofovir includes tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF). Other similar therapies, including lamivudine (3TC), telbivudine (LdT), and adefovir are also used, but for nucleoside / nucleotide therapies in general, the emergence of resistance limits therapeutic efficacy. Although treatment of chronic HBV infection has been effective in reducing the long-term complications of chronic HBV infection, and evidence is emerging that HBsAg loss is associated with lower rates of HCC, spontaneous HBsAg loss only occurs in a small percentage of patients and is rarely achieved with standard of care therapies, such as nucleoside or nucleotide analogue (NA) therapy.

[0009] Antisense oligonucleotides (ASOs) include bepirovirsen, an experimental antisense oligonucleotide in development for the treatment of chronic hepatitis B (CHB) infection. Bepirovirsen directly targets all HBV messenger ribonucleic acids (mRNAs) via ribonuclease H (RNase H) mediated degradation, resulting in the reduction of viral proteins including HBsAg.

[0010] A Phase 2b clinical study (B-Clear) was conducted to evaluate the efficacy and safety of treatment with bepirovirsen in participants with chronic hepatitis B. See Yuen et al. “Efficacy and safety of bepirovirsen in chronic hepatitis B infection,” N. Engl. J. Med. 2022; 387: 1957-68. In this study, 9% of participants with chronic HBV infection who were on NA therapy had a sustained virological response, defined as HBV DNA <LLOQ (lower limit of quantification) with HBsAg <LLOD (lower limit of detection) for 24 weeks after the end of weekly injections of bepirovirsen 300 mg (24 weeks) with loading doses in Weeks 1 and 2. The 24-week dosing regimen evaluated in Phase 2 also demonstrated an acceptable safety profile with no signals of concern to preclude further development. Patients with HBV and human immunodeficiency virus (HIV) coinfection were excluded from the bepirovirsen Phase 2b and Phase 3 studies.

[0011] HBV and HIV share modes of transmission. Of 36.7 million persons living with HIV worldwide, an estimated 2.7 million also have chronic HBV infection. Liver diseases are a major cause of morbidity and mortality among those living with HIV and coinfected with viral hepatitis. National and international guidelines recommend starting antiretroviral treatment (ART) for HIV / HBV coinfection as soon as possible after diagnosis to prevent immune dysfunction and reduce disease progression. ART in HIV / HBV coinfection should include TDF or TAF typically in combination with 3TC or emtricitabine (FTC) as part of a fully suppressive regimen treating both viruses. The rate of HBsAg loss after initiation of ART for HBV / HIV coinfection is variable but overall, the rate appears to be higher than observed in chronic HBV infection, possibly because of a positive impact on the immune response to HBV once HIV is controlled. There is a need to develop new therapies for treating patients with HIV / HBV coinfection to reduce the risk of HBV-related complications.

[0012] SUMMARY

[0013] In one aspect, the present disclosure provides a method for treating chronic hepatitis B (CHB) infection in a human having HBV / HIV coinfection, the method comprising administering to the human a therapeutically effective amount of an antisense oligonucleotide (ASO) (e.g. bepirovirsen), wherein the human has a HBsAg baseline level of not greater than a threshold level.

[0014] In another aspect, the present disclosure provides a method for treating CHB infection in a human having HBV / HIV coinfection, the method comprising:

[0015] (a) determining that the human has a HBsAg baseline level of not greater than a threshold level; and

[0016] (b) administering to the human a therapeutically effective amount of an ASO (e.g. bepirovirsen).

[0017] In another aspect, the present disclosure provides a method for treating CHB infection in a human having HBV / HIV coinfection, the method comprising:

[0018] (a) measuring the HBsAg baseline level of the human;

[0019] (b) comparing the HBsAg baseline level with a threshold level; and

[0020] (c) if the HBsAg baseline level is not greater than the threshold level, then administering to the human a therapeutically effective amount of an ASO (e.g. bepirovirsen).

[0021] In another aspect, the present disclosure provides an ASO (e.g. bepirovirsen) for use in a method of treating CHB infection in a human having HBV / HIV coinfection, wherein the human has a HBsAg baseline level of not greater than a threshold level.

[0022] In another aspect, the present disclosure provides an ASO (e.g. bepirovirsen) for use in a method of treating CHB infection in a human having HBV / HIV coinfection, the method comprising: (a) determining that the human has a HBsAg baseline level of not greater than a threshold level; and

[0023] (b) administering to the human a therapeutically effective amount of the ASO (e.g. bepirovirsen).

[0024] In another aspect, the present disclosure provides an ASO (e.g. bepirovirsen) for use in a method of treating CHB infection in a human having HBV / HIV coinfection, the method comprising:

[0025] (a) measuring the HBsAg baseline level of the human;

[0026] (b) comparing the HBsAg baseline level with a threshold level; and

[0027] (c) if the HBsAg baseline level is not greater than the threshold level, then administering to the human a therapeutically effective amount of an ASO (e.g. bepirovirsen).

[0028] In another aspect, the present disclosure provides the use of an antisense oligonucleotide (ASO) in the manufacture of a medicament for the treatment of chronic hepatitis B infection in a human in need thereof according to a method of the present disclosure.

[0029] BRIEF DESCRIPTION OF THE DRAWINGS

[0030] FIG. 1 shows the study design overview for a Ph2b study to assess efficacy and safety of treatment with bepirovirsen in participants living with HIV / HBV coinfection.

[0031] DETAILED DESCRIPTION

[0032] Definitions

[0033] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. For example, certain terms used herein are defined as described in “A multilingual glossary of biotechnological terms: (IUPAC Recommendations),” Leuenberger, H.G.W, Nagel, B. and Klbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).

[0034] Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise,” and variations such as “comprises” and “comprising,” will be understood to imply the inclusion of a stated element, integer, or step, or group of elements, integers, or steps but not the exclusion of any other element, integer, or step, or group of elements, integers, or steps.

[0035] Unless otherwise indicated, the following terms have the following meanings: “About,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass ± 10% of the recited value and the range is included.

[0036] “Antisense oligonucleotide (ASO)” refers to a single-stranded oligonucleotide having a nucleobase sequence that permits hybridization to a corresponding region or segment of a target nucleic acid.

[0037] “Baseline” values of certain substances (e.g., HBsAg, HBeAg, HBsAb, HBeAb, HBV DNA, ALT) are measured in the blood samples taken from patients before the first dose of ASO (e.g. bepirovirsen) treatment.

[0038] Bepirovirsen is an ASO currently in clinical evaluation for treating HBV infections. It is compound ISIS No. 505358 as disclosed in WO2012 / 145697. Bepirovirsen has 20 linked nucleosides and has a nucleobase sequence of 5'-GCAGAGGTGAAGCGAAGTGC-3' (SEQ ID NO: 1), and it includes: a gap segment consisting of 10 linked deoxynucleosides, a 5' wing segment consisting of 5 linked nucleosides, and a 3' wing segment consisting of 5 linked nucleosides, wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment, wherein each nucleoside of each wing segment includes a 2'-O-methoxyethyl sugar, wherein each intemucleoside linkage is a phosphorothioate linkage, and wherein each cytosine is a 5 -methylcytosine. The CAS Registry Number of bepirovirsen is 1403787-62-1.

[0039] AHB-137 is an unconjugated ASO that is believed to have the same nucleobase sequence as bepirovirsen. AHB-137 is developed by Ausper Biopharma Co., Ltd. and is currently investigated in clinical studies for treating HBV infections. See WO2023 / 131098; Qiu, X. et al., “AHB-137, a novel and potent hepatitis B virus antisense oligonucleotide with a favorable preclinical pharmacokinetics and safety profile,” EASL 2023, Abstract No. SAT-178 (concluding that “the novel HBV ASO AHB-137 has demonstrated a favorable preclinical pharmacokinetics and safety profile”); Wu, X. et al., “AHB-137, a novel hepatitis B virus antisense oligonucleotide with substantially enhanced in vitro and in vivo antiviral activity,” EASL 2023, Abstract No. SAT-173 (concluding that “AHB-137 has more potent activity in reducing serum HBsAg than BPV [bepirovirsen] across multiple in vitro and in vivo HBV models, by reducing intrahepatic HBV RNA and HBsAg”); see also Gane, E.J. et al., “Safety and antiviral activity of AHB-137, a novel antisense oligonucleotide, in healthy volunteers and subjects with chronic hepatitis B,” EASL 2024, LBP-019; and Wang, W. et al., “A phase 1, dose-escalation and dose-expansion study evaluating the safety, tolerability, pharmacokinetics and preliminary efficacy of AHB-137 in Chinese healthy volunteers and subjects with chronic hepatitis B,” EASL 2024, LBP-043.

[0040] “Bicyclic sugar” means a ribose ring modified by the bridging of two non-geminal carbon atoms. A bicyclic sugar is a modified sugar. Examples of bicyclic sugars include, without limitation, a ribose sugar comprising a bridge between the 4’ and the 2’ ring atoms, such as 4’-(CH2)-O-2’ (LNA), 4’-(CH2)-S-2’, 4’-(CH2)2-O-2’ (ENA), 4’-CH(CH3)-O-2’ (cEt), and 4’-CH(CH2OCH3)-O-2’.

[0041] “Chronic hepatitis B (CHB) infection” occurs when a person initially suffers from an acute infection but is then unable to fight off the infection. About 90% of infants infected at birth will progress to chronic disease. However, as a person ages, the risk of chronic infection decreases such that between 20%-50% of people infected as children and less than 10% of people infected as adults will progress from acute to chronic infection. The terms “chronic hepatitis B infection”, “chronic hepatitis B”, “chronic HBV infection”, and “CHB” are used interchangeably herein.

[0042] “Dose” refers to a specified quantity of an active pharmaceutical agent provided in a single administration, or in a specified time period. In certain embodiments, a dose may be administered in two or more boluses, tablets, or injections. For example, in certain embodiments, where subcutaneous administration is desired, the desired dose requires a volume not easily accommodated by a single injection. In such embodiments, two or more injections may be used to achieve the desired dose. In certain embodiments, a dose may be administered in two or more injections to minimize injection site reaction in an individual.

[0043] “Dosing regimen” is a combination of doses designed to achieve one or more desired effects.

[0044] “Duration” refers to the period of time during which an activity or event continues. In certain embodiments, the duration of treatment is the period of time during which doses of a pharmaceutical agent are administered.

[0045] “Functional cure” refers to sustained suppression (24 weeks or longer) of HBV DNA (<lower limit of quantification or “LLOQ”) off all HBV treatment with HBsAg loss (<0.05 lU / mL) or HBsAg negative with or without HBsAb after a finite duration of therapy.

[0046] “HBV” refers to mammalian hepatitis B virus, including human hepatitis B virus. The term encompasses geographical genotypes of hepatitis B virus, particularly human hepatitis B virus, as well as variant strains of geographical genotypes of hepatitis B virus. Human geographical genotypes of HBV include genotypes: A (Northwest Europe, North America, Central America); B (Indonesia, China, Vietnam); C (East Asia, Korea, China, Japan, Polynesia, Vietnam); D (Mediterranean area, Middle East, India); E (Africa); F (Native Americans, Polynesia); G (United States, France); and H (Central America).

[0047] “HBV / HIV coinfection” refers to a human living with HIV and chronic HBV infection. It was estimated that globally 8% to 10% of people with HIV have chronic HBV infection.

[0048] “HBV antigen” refers to any hepatitis B virus antigen or protein, including core proteins such as “hepatitis B core antigen” or “HBcAg,” “hepatitis B E antigen” or “HBeAg,” and envelope proteins such as “HBV surface antigen” or “HBsAg.”

[0049] “Hepatitis B E antigen” or “HBeAg” is a secreted, non-particulate form of HBV core protein. HBV antigens HBeAg and HBeAg share primary amino acid sequences, so show cross-reactivity at the T cell level. HBeAg is not required for viral assembly or replication, although studies suggest they may be required for establishment of chronic infection.

[0050] “HBV surface antigen,” “HBsAg,” or “HBs” is the envelope protein of infectious HBV viral particles (Dane Particles), but is also secreted as a non-infectious particle (subviral particle, SVP) with serum levels 1000-fold higher than HBV viral particles. The serum levels of HBsAg in an infected person or animal can be as high as 1000 pg / mL (Kann and Gehrlich (1998) Topley & Wilson’s Microbiology and Microbial Infections, 9th ed. 745).

[0051] “HBV-related condition” refers to any disease, biological condition, medical condition, or event which is exacerbated, caused by, related to, associated with, or traceable to a hepatitis B virus infection, exposure, or illness. The term hepatitis B-related condition includes chronic HBV infection, inflammation, fibrosis, cirrhosis, liver cancer, serum hepatitis jaundice, liver inflammation, liver fibrosis, liver cirrhosis, liver failure, diffuse hepatocellular inflammatory disease, hemophagocytic syndrome, HBV viremia, liver disease related to transplantation, and conditions having symptoms which may include any or all of the following: flu-like illness, weakness, aches, headache, fever, loss of appetite, diarrhea, nausea and vomiting, pain over the liver area of the body, clay- or grey-colored stool, itching all over, and dark-colored urine, when coupled with a positive test for presence of a hepatitis B virus, a hepatitis B viral antigen, or a positive test for the presence of an antibody specific for a hepatitis B viral antigen.

[0052] “Induce,” “inhibit,” “potentiate,” “elevate,” “increase,” “decrease” or the like, generally denote quantitative differences between two states. Such terms may refer to a statistically significant difference between the two states. For example, “an amount effective to inhibit the activity or expression of HBV” refers to the level of activity or expression of HBV in a treated cell and this will quantitatively differ, and may be statistically significant, from the level of HBV activity or expression in untreated cells. Such terms are applied to, for example, levels of expression and levels of activity.

[0053] “Modified intemucleoside linkage” refers to a substitution or any change from a naturally occurring intemucleoside bond (i.e. a phosphodiester intemucleoside bond).

[0054] “Modified nucleobase” means any nucleobase other than adenine, cytosine, guanine, thymidine, or uracil.

[0055] “Modified sugar” means substitution and / or any change from a natural sugar moiety.

[0056] “Nucleobase” refers to a heterocyclic moiety capable of pairing with a base of another nucleic acid.

[0057] “Nucleobase sequence” refers to the order of contiguous nucleobases independent of any sugar, linkage, and / or nucleobase modification.

[0058] “Pharmaceutically acceptable salts” refer to physiologically acceptable salts of compounds, i.e., salts that retain the desired biological activity of the parent active ingredients and do not impart undesired toxicological effects thereto.

[0059] “Phosphorothioate linkage” refers to a linkage between nucleotides where the phosphodiester bond is modified by replacing one of the non-bridging oxygen atoms with a sulfur atom. A phosphorothioate linkage is a modified intemucleoside linkage.

[0060] “Region” is defined as a portion of, for example, a nucleic acid having at least one identifiable stmcture, function, or characteristic.

[0061] “Stable nucleoside or nucleotide analogue (NA) therapy” is defined as no changes to the nucleoside or nucleotide analogue regimen for at least 6 months prior to the treatment and with no planned changes to the regimen for the duration of the treatment.

[0062] “Segments” may refer to smaller, or sub-portions of, regions within, for example, a nucleic acid.

[0063] “Seroclearance” refers to the clearance or removal of an antigen (like HBsAg and / or HBV DNA levels) from the blood (or a measurement below the lower limit of quantification (i.e. < LLOQ) by the lab) in a CHB patient following treatment. In testing human samples, when serum HBsAg level is measured by a sandwich immunoassay with COBAS HBsAg quant II (Roche), the LLOQ is 0.05 lU / mL. In testing human samples, when the semm HBV DNA level is measured with COBAS Ampliprep / COBAS Taqman HBV test v.2.0 (Roche), the LLOQ is 20 lU / mL and when the semm HBV DNA level is measured with cobas HBV (Roche), the LLOQ is 10 lU / mL. When a qualitative assay is used to measure the semm HBsAg level, a binary terminology (positive / detected, negative / undetected) is used. “Subject” refers to a human or non-human animal selected for treatment or therapy. In one embodiment, the subject is a human. A human subject is also referred to as a patient.

[0064] “Therapeutically effective amount” refers to the administration of a pharmaceutical agent to a subject, either alone or as part of a pharmaceutical composition and either in a single dose or as part of a series of doses, in an amount capable of having any detectable, positive effect on any symptom, aspect, or characteristic of a disease or condition when administered to the subject.

[0065] “Treatment” refers to administering a pharmaceutical agent to a subject to affect an alteration or improvement of the disease or condition. The term “treating” as used herein in relation to chronic hepatitis B infection refers to the administration of suitable compositions with the intention of reducing the symptoms of CHB, preventing the progression of CHB or reducing the level of one or more detectable markers of CHB.

[0066] Methods

[0067] As in chronic HBV infection, suppression of HBV DNA in HIV / HBV coinfection is associated with a reduction in HCC risk. A study of patients coinfected with HIV / HBV found that the highest risk of hepatocellular carcinoma (HCC) was associated with detectable HBV viremia, and that sustained HBV suppression with HBV and HIV-active ART for >1 year was associated with a 58% reduction in HCC risk. Kim H. et al. “Risk of HCC with hepatitis B viremia among HIV / HBV-coinfected persons in North America,” Hepatology 2021; 74: 1190- 1202. It is believed that an antisense oligonucleotide (ASO) would be beneficial as a finite HBV treatment option resulting in HBsAg loss and a reduction in risk of HBV-related complications in the HIV / HBV coinfected population.

[0068] The present disclosure provides a method for treating chronic hepatitis B (CHB) infection in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of an ASO (e.g. bepirovirsen), wherein the human has HBV / HIV coinfection and has a HBsAg baseline level of not greater than a threshold level.

[0069] In some embodiments, the ASO comprises 20 linked nucleosides and has a nucleobase sequence of SEQ ID NO: 1. In some embodiments, the ASO consists of 20 linked nucleosides and has a nucleobase sequence of SEQ ID NO: 1. In some embodiments, the ASO comprises at least one modified sugar. In some embodiments, the at least one modified sugar is a bicyclic sugar or comprises a 2'-O-methoxyethyl (2'-M0E) group.

[0070] In some embodiments, the ASO comprises at least one modified intemucleoside linkage. In some embodiments, the at least one modified intemucleoside linkage is a phosphorothioate linkage. In some embodiments, each intemucleoside linkage of the ASO is a phosphorothioate linkage.

[0071] In some embodiments, the ASO comprises at least one modified nucleobase. In some embodiments, the modified nucleobase is 5 -methylcytosine.

[0072] In some embodiments, the ASO comprises: a gap segment consisting of linked deoxynucleosides, a 5’ wing segment consisting of linked nucleosides, and a 3’ wing segment consisting of linked nucleosides, wherein the gap segment is positioned between the 5 ’ wing segment and the 3 ’ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

[0073] In some embodiments, the ASO comprises a separator segment placed in between gap segments as disclosed in WO2023 / 131098, which is incorporated herein by reference in its entirety. In one embodiment, the ASO is selected from Compounds AUS 1233 / AUS 1138, AUS1444, AUS1458, AUS1459, AUS1460, AUS 1427 / AUS 1461, AUS1462, AUS1463, AUS1464, AUS1465, AUS1463, AUS1467, AUS1468, AUS1470, AUS1471, AUS1472, AUS 1473, AUS 1474, AUS 1475, AUS 1476 / AUS 1493, AUS 1478, AUS 1479, AUS 1489, AUS 1490, AUS 1443, and AUS 1322 as disclosed in WO2023 / 131098. In one embodiment, the ASO is selected from Compounds AUS1233 / AUS1138, AUS1463, and AUS 1476 / AUS 1493 as disclosed in WO2023 / 131098. In one embodiment, the ASO is Compound AUS1493 as disclosed in WO2023 / 131098.

[0074] In one embodiment, the ASO is bepirovirsen. In another embodiment, the ASO is AHB- 137.

[0075] In one embodiment, the ASO has the modified nucleotide sequence set out in SEQ ID NO:2. In one embodiment, the ASO has the modified nucleotide sequence set out in SEQ ID NO:3.

[0076] SEQ ID NO:2, 5' moeG-s-moe5MeC-s-moeA-s-moeG-s-moeA-s-dG-s-dG-s-dT-s-dG-s-dA-s- dA-s-dG-s-d5MeC-s-dG-s-dA-s-moeA-s-moeG-s-moe5MeU-s-moeG-s-moe5MeC 3';

[0077] SEQ ID NO:3, 5' moeG-s-moe5MeC-s-moeA-s-moeG-s-dA-s-dG-s-dG-s-dT-s-dG-s-moeA-s- dA-s-dG-s-d5MeC-s-dG-s-dA-s-moeA-s-lnaG-s- moe5MeU-s-lnaG-s-lna5MeC 3'; wherein: moeA = 2'-O-(2 -methoxyethyl) adenosine; moe5MeC = 2'-O-(2-methoxyethyl) 5 -methylcytidine; moeG = 2'-O-(2 -methoxyethyl) guanosine; moe5MeU = 2'-O-(2 -methoxyethyl) 5-methyl uridine; dA = 2'-deoxy adenosine; d5MeC = 2'-deoxy 5 -methylcytidine; dG = 2'-deoxy guanosine; dT = 2'-deoxy thymidine; lna5MeC = LNA 5 -methylcytidine;

[0078] InaG = LNA guanosine;

[0079] -s- = phosphorothioate.

[0080] In another embodiment, the ASO is selected from Compounds PA0088, PA0089, PA0I I4, PA0090, PA0155, PA0091, PA0116, PA0092, PA0093, PA0094 and PA0095 disclosed in WO2025 / 039916, which is incorporated herein by reference in its entirety. In one embodiment, the ASO is Compound PA0088. In another embodiment, the ASO is Compound PA0089.

[0081] PA0088 has the modified nucleotide sequence set out in SEQ ID NO:4.

[0082] SEQ ID NO: 4, 5' moeG-s-moe5MeC-s-moeA-s-moeG-s-dA-s-dG-s-dG-s-dT-s-dG-s- moeA-s-dA-s-dG-s-d5MeC-s-dG-s-dA-s-dA-s-moeG -s- moeT-s-moeG-s-moe5MeC 3'

[0083] PA0089 has the modified nucleotide sequence set out in SEQ ID NO: 5.

[0084] SEQ ID NO: 5, 5' moeG-s-moe5MeC-s-moeA-s-dG-s-dA-s-dG-s-dG-s-dT-s-dG-s- moeA-s-dA-s-dG-s-d5MeC-s-dG-s-dA-s-dA-s-dG -s- moeT-s-moeG-s-moe5MeC 3' wherein: moeA = 2'-O-(2 -methoxyethyl) adenosine; moe5MeC = 2'-O-(2-methoxyethyl) 5 -methylcytidine; moeG = 2'-O-(2 -methoxyethyl) guanosine; moeT = 2'-O-(2 -methoxyethyl) thymidine dA = 2'-deoxy adenosine; d5MeC = 2'-deoxy 5 -methylcytidine; dG = 2'-deoxy guanosine; dT = 2'-deoxy thymidine;

[0085] -s- = phosphorothioate.

[0086] In another aspect, the present disclosure provides a method for treating CHB in a human having HBV / HIV coinfection, the method comprising:

[0087] (a) determining that the human has a HBsAg baseline level of not greater than a threshold level; and (b) administering to the human a therapeutically effective amount of an ASO (e.g. bepirovirsen).

[0088] The HBsAg baseline level in the blood of a CHB patient is measured by methods known in the art before the start of treatment. As used herein, the step “determining” can be achieved by measuring the HBsAg baseline level of the patient and comparing the baseline level with a predetermined threshold level. The step “determining” can also be achieved by receiving the HBsAg baseline level information from the patient or a testing facility and comparing the HBsAg baseline level with a predetermined threshold level.

[0089] In another aspect, the present disclosure provides a method for treating CHB in a human having HBV / HIV coinfection, the method comprising:

[0090] (a) measuring the HBsAg baseline level of the human;

[0091] (b) comparing the HBsAg baseline level with a threshold level; and

[0092] (c) if the HBsAg baseline level is not greater than the threshold level, then administering to the human a therapeutically effective amount of an ASO (e.g. bepirovirsen).

[0093] In certain embodiments, measuring the HBsAg baseline level of the human comprises measuring the HBsAg level in a sample from the human, wherein the sample is taken before the first dose of ASO. In certain embodiments, measuring the HBsAg baseline level of the human comprises measuring the HBsAg level in a blood sample (for example a whole blood, plasma, serum or PBMC sample) from the human wherein the sample is taken before the first dose of ASO.

[0094] In the methods as disclosed herein, the ASO (e.g. bepirovirsen) can be administered as a free acid, a pharmaceutically acceptable salt thereof (e.g., a sodium salt), or a combination thereof. In some embodiments, the ASO (e.g. bepirovirsen) is administered as a free acid. In some embodiments, the ASO (e.g. bepirovirsen) is administered as a pharmaceutically acceptable salt thereof (e.g., a sodium salt). In some embodiments, the ASO (e.g. bepirovirsen) is administered as a combination of a free acid and a sodium salt. In some embodiments, the ASO (e.g. bepirovirsen) is administered by subcutaneous injection.

[0095] As used herein, the “therapeutically effective amount of the ASO (e.g. bepirovirsen)” refers to the amount of the ASO (e.g. bepirovirsen) free acid. In some embodiments, the therapeutically effective amount of the ASO (e.g. bepirovirsen) is about 150 mg to 450 mg once weekly. In some embodiments, the therapeutically effective amount of the ASO (e.g. bepirovirsen) is about 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 450 mg once weekly, or in a range between any two preceding values. In some embodiments, the therapeutically effective amount of the ASO (e.g. bepirovirsen) is about 150 mg once weekly. In some embodiments, the therapeutically effective amount of the ASO (e.g. bepirovirsen) is about 300 mg once weekly. In some embodiments, the ASO (e.g. bepirovirsen) is administered weekly with additional loading doses in the first two weeks on Day 4 and Day 11 following the first dose (also referred to as “2 loading doses”). In some embodiments, the ASO (e.g. bepirovirsen) is administered at a dose of about 300 mg once weekly with additional loading doses in the first two weeks on Day 4 and Day 11 following the first dose. In a particular embodiment, the loading dose is 300 mg.

[0096] In some embodiments, the ASO (e.g. bepirovirsen) is administered for about 12 to 48 weeks. In some embodiments, the ASO (e.g. bepirovirsen) is administered for 12 weeks, 24 weeks, or 48 weeks, or for a range between any two preceding periods. In one embodiment, the ASO (e.g. bepirovirsen) is administered for 12 weeks. In one embodiment, the ASO (e.g. bepirovirsen) is administered for 24 weeks. In one embodiment, the ASO (e.g. bepirovirsen) is administered for 48 weeks. In one embodiment, the ASO (e.g. bepirovirsen) is administered for 12 weeks or 24 weeks, with additional loading doses on Day 4 and Day 11 following the first dose.

[0097] In some embodiments, the ASO (e.g. bepirovirsen) is administered at a dose of about 300 mg once weekly for 24 weeks. In some embodiments, the ASO (e.g. bepirovirsen) is administered at a dose of about 300 mg once weekly for 12 weeks. In some embodiments, the ASO (e.g. bepirovirsen) is administered at a dose of about 300 mg once weekly for 12 weeks, and then at a dose of about 150 mg once weekly for 12 weeks.

[0098] In some embodiments, the ASO (e.g. bepirovirsen) is administered at a dose of about 300 mg once weekly for 24 weeks, with additional loading doses each of 300 mg, on Day 4 and Day 11 following the first dose. In some embodiments, the ASO (e.g. bepirovirsen) is administered at a dose of about 300 mg once weekly for 12 weeks, with additional loading doses each of 300 mg on Day 4 and Day 11 following the first dose.

[0099] In one embodiment, the present disclosure provides a method for treating CHB in a human having HBV / HIV coinfection, the method comprising administering to the human a therapeutically effective amount of an ASO (e.g. bepirovirsen), wherein the human has a HBsAg baseline level of not greater than a threshold level and is on HBV- and HIV-active antiretroviral treatment. In some embodiments, the antiretroviral treatment comprises entecavir, tenofovir, or a tenofovir prodrug. In some embodiments, the antiretroviral treatment comprises tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF), in combination with emtricitabine (FTC) or lamivudine (3TC). In some embodiments, the present disclosure provides a method for treating CHB in a human having HBV / HIV coinfection comprising administering to the human a therapeutically effective amount of an ASO (e.g. bepirovirsen), wherein the human has a HBsAg baseline level of not greater than a threshold level. In some embodiments, the threshold level of the HBsAg baseline is in the range of 1000 lU / mL to 3000 lU / mL.

[0100] In some embodiments, the threshold level of the HBsAg baseline is about 1000, 1500, 2000, 2500, or 3000 lU / mL, or in a range between any two of the preceding numbers. In some embodiments, the threshold level of the HBsAg baseline is about 1000, 2000, or 3000 lU / mL. In some embodiments, the threshold level of the HBsAg baseline is about 1000 lU / mL. In some embodiments, the threshold level of the HBsAg baseline is about 3000 lU / mL.

[0101] In one embodiment, the present disclosure provides a method for treating CHB in a human having HBV / HIV coinfection, the method comprising administering to the human a therapeutically effective amount of an ASO (e.g. bepirovirsen), wherein the human has a HBsAg baseline level of not greater than about 1000 lU / mL. In one embodiment, the present disclosure provides a method for treating CHB in a human having HBV / HIV coinfection, the method comprising administering to the human a therapeutically effective amount of an ASO (e.g. bepirovirsen), wherein the human has a HBsAg baseline level of not greater than about 3000 lU / mL.

[0102] In one embodiment, the present disclosure provides a method for treating CHB in a human having HBV / HIV coinfection, the method comprising administering an ASO (e.g. bepirovirsen) to the human at a dose of 300 mg once weekly for 24 weeks, wherein the human has a HBsAg baseline level of not greater than about 1000 lU / mL. In one embodiment, the present disclosure provides a method for treating CHB in a human having HBV / HIV coinfection, the method comprising administering an ASO (e.g. bepirovirsen) to the human at a dose of 300 mg once weekly for 24 weeks, wherein the human has a HBsAg baseline level of not greater than about 3000 lU / mL.

[0103] In one embodiment, the present disclosure provides a method for treating CHB in a human having HBV / HIV coinfection, the method comprising administering an ASO (e.g. bepirovirsen) to the human at a dose of 300 mg once weekly for 24 weeks, wherein the human has a HBsAg baseline level of not greater than about 1000 lU / mL and is on HBV- and HIV- active antiretroviral treatment. In one embodiment, the present disclosure provides a method for treating CHB in a human having HBV / HIV coinfection, the method comprising administering an ASO (e.g. bepirovirsen) to the human at a dose of 300 mg once weekly for 24 weeks, wherein the human has a HBsAg baseline level of not greater than about 3000 lU / mL and is on HBV- and HIV-active antiretroviral treatment.

[0104] In some embodiments, the hepatitis B virus infection is caused by any of the human geographical genotypes: A (Northwest Europe, North America, Central America); B (Indonesia, China, Vietnam); C (East Asia, Korea, China, Japan, Polynesia, Vietnam); D (Mediterranean area, Middle East, India); E (Africa); F (Native Americans, Polynesia); G (United States, France); or H (Central America). In some embodiments, the subject has chronic hepatitis B (CHB). The term “CHB patient” is used interchangeably with “subject having CHB.”

[0105] In some embodiments, the subject is HBeAg negative or HBeAg positive prior to ASO treatment. In some embodiments, the subject is HBeAg negative prior to ASO treatment. In some embodiments, the subject is HBeAg positive prior to ASO treatment.

[0106] In another aspect, the present disclosure provides an ASO (e.g. bepirovirsen) for use in a method of treating chronic hepatitis B infection in a human having HBV / HIV coinfection, wherein the human has a HBsAg baseline level of not greater than a threshold level.

[0107] In a further aspect, the present disclosure provides an ASO (e.g. bepirovirsen) for use in a method of treating chronic hepatitis B infection in a human having HBV / HIV coinfection according to a method of the present disclosure.

[0108] In another aspect, the present disclosure provides an ASO (e.g. bepirovirsen) for use in a method of treating chronic hepatitis B infection in a human having HBV / HIV coinfection, the method comprising:

[0109] (a) determining that the human has a HBsAg baseline level of not greater than a threshold level; and

[0110] (b) administering to the human a therapeutically effective amount of the ASO (e.g. bepirovirsen).

[0111] In another aspect, the present disclosure provides an ASO (e.g. bepirovirsen) for use in a method of treating chronic hepatitis B infection in a human having HBV / HIV coinfection, the method comprising:

[0112] (a) measuring the HBsAg baseline level of the human;

[0113] (b) comparing the HBsAg baseline level with a threshold level; and

[0114] (c) if the HBsAg baseline level is not greater than the threshold level, then administering to the human a therapeutically effective amount of an ASO (e.g. bepirovirsen). In a further aspect, the present disclosure provides the use of an antisense oligonucleotide (ASO) in the manufacture of a medicament for the treatment of chronic hepatitis B infection in a human in need thereof according to a method of the present disclosure.

[0115] Compositions

[0116] The present disclosure provides a composition comprising an ASO (e.g. bepirovirsen) for treating CHB infection in a human having HBV / HIV coinfection, the method of treatment comprising administering to the human a therapeutically effective amount of the ASO (e.g. bepirovirsen), wherein the human has a HBsAg baseline level of not greater than a threshold level. The present disclosure also provides a composition comprising an ASO (e.g. bepirovirsen) for use in a method of treating chronic hepatitis B infection in a human having HBV / HIV coinfection according to a method of the present disclosure.

[0117] The present disclosure provides a composition comprising an ASO (e.g. bepirovirsen), for use in a method of treating CHB infection in a human having HBV / HIV coinfection, wherein the method comprises: (a) determining that the human has a HBsAg baseline level of not greater than a threshold level; and (b) administering to the human a therapeutically effective amount of the ASO (e.g. bepirovirsen).

[0118] The present disclosure also provides a composition comprising an ASO (e.g. bepirovirsen), for use in a method of treating CHB infection in a human having HBV / HIV coinfection, wherein the method comprises: (a) measuring the HBsAg baseline level of the human; (b) comparing the HBsAg baseline level with a threshold level; and (c) if the HBsAg baseline level is not greater than the threshold level, then administering to the human a therapeutically effective amount of an ASO (e.g. bepirovirsen). In other embodiments of the composition comprising an ASO (e.g. bepirovirsen), the method of administering the composition comprising an ASO can be according to any of the methods detailed herein.

[0119] Such compositions comprise a pharmaceutically acceptable carrier and / or excipient as known and called for by acceptable pharmaceutical practice.

[0120] Pharmaceutical compositions may be administered by injection or continuous infusion (examples include, but are not limited to, intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intraocular, and intraportal). In one embodiment, the composition is suitable for subcutaneous administration. In an embodiment, the composition comprising the ASO (e.g. bepirovirsen) also comprises water for injection and has been adjusted to pH 8.0 with acid or base.

[0121] EXAMPLES

[0122] While aspects of the disclosure presented herein have been described more particularly in accordance with some embodiments, the following examples, which highlight certain features and properties of the exemplary embodiments of the disclosure described herein, serve only to illustrate the disclosure described herein and are not intended to limit the same.

[0123] Example 1

[0124] Study of Bepirovirsen in Participants living with Human Immunodeficiency Virus and Chronic Hepatitis B Virus Infection (B Focus)

[0125] A. Study Design

[0126] This is a Phase 2b, multicenter, randomized, double-blind, placebo-controlled study to assess efficacy and safety of treatment with bepirovirsen in participants living with HIV / HBV coinfection on HBV and HIV-active ART. After a screening period, this study has 2 stages (see FIG. 1):

[0127] • Double-Blind Study Intervention with HBV and HIV-active ART for 24 weeks,

[0128] • HBV and HIV-active ART only for an additional 36 weeks, including a 12-week washout period.

[0129] The randomization will be stratified based on HBsAg level (HBsAg >100 lU / mL to <1000 lU / mL or >1000 lU / mL to <3000 lU / mL) and HBeAg positive or negative at Screening to balance the distribution of these key HBV characteristics between the arms.

[0130] The total duration of the study, including Screening (up to 45 days), the Double-blind Treatment Stage (24 weeks), and the HBV and HIV-active ART Only Stage (36 weeks) is up to approximately 66 weeks for each participant.

[0131] This Phase 2b, multicenter, randomized, double-blind, placebo-controlled study is designed to minimize bias and provide an estimate of any difference in HBV virologic response (defined as HBsAg not detected and HBV DNA <LLOQ) 36 weeks after cessation of bepirovirsen as compared with placebo.

[0132] The placebo arm is required for a valid evaluation of adverse effects (AEs) attributable to bepirovirsen treatment versus those independent of bepirovirsen treatment. Participants randomized to the placebo arm will also serve as controls for the biomarker and efficacy assessments. The functional cure endpoint would require that all HBV active medications be stopped. However, switching ART to remove HBV-active medications to support a functional cure assessment is not feasible given the potential safety risks, limited availability of non-HBV active ART, and potential impact on HIV suppression. Therefore, this study will evaluate the loss of HBsAg 36 weeks after completing bepirovirsen treatment versus placebo with background HBV and HIV-active ART.

[0133] To minimize the risk of HIV-related complications (virologic rebound, HIV-associated conditions) throughout the study period, participants with stably suppressed HIV / HBV coinfection with evidence of satisfactory immune function (CD4 >350 cells / mm3) will be enrolled.

[0134] The inclusion criterion of baseline HBsAg <3000 lU / mL was selected as the B-Clear study identified this as an appropriate threshold for predicting virologic response following bepirovirsen monotherapy for up to 24 weeks.

[0135] B. Objectives and Endpoints The terms used in this study are defined below:

[0136] HBV DNA LLOQ is defined as <10 lU / mL.

[0137] The primary, secondary, safety, and exploratory objective s / endpoints are listed below:

[0138] C. Study Population: Inclusion and Exclusion Criteria

[0139] The main inclusion criteria are:

[0140] 1. At least 18 years of age at the time of signing the informed consent (if country / site age requirements for consent differ, the more stringent [e.g., higher age] restriction will be required forthat country / site).

[0141] 2. Documented chronic HBV infection and documented HIV-1 infection >12 months prior to Screening.

[0142] 3. Must be on uninterrupted ART containing at least TDF or TAF plus 3TC or FTC for >12 months, with no planned changes to the stable regimen over the duration of the study.

[0143] • Switch in ART is permitted >6 months prior to Screening for reasons NOT related to loss of HIV or HBV control (e.g., change in formulary, tolerability, side effects).

[0144] 4. Documented evidence of at least 2 plasma HIV-1 RNA measurements <50 copies / mL are required in the 12 months prior to Screening: 1 within 6 to 12 months prior to screening and 1 within 6 months prior to Screening.

[0145] 5. Plasma or serum HBsAg concentration >100 lU / mL and <3000 lU / mL.

[0146] 6. Plasma or serum HBV DNA concentration must be adequately suppressed, defined as plasma or serum HBV DNA <90 lU / mL.

[0147] 7. Plasma HIV-1 RNA concentration must be undetectable, defined as plasma HIV 1 RNA <50 copies / mL.

[0148] 8. CD4 count >350 cells / mm3.

[0149] 9. ALT <2x ULN.

[0150] The main exclusion criteria are: 1. HIV-1 RNA measurement >200 copies / mL <6 months prior to screening.

[0151] 2. Any evidence of an active CDC Stage 3 HIV disease.

[0152] 3. History of or suspected liver cirrhosis and / or evidence of cirrhosis as determined by: a. Both APRI >2 and FibroSure / FibroTest result >0.7. b. Regardless of APRI or Fibrosure / FibroTest score, if the participant has historic record of either / both liver biopsy or liver stiffness measurements in their medical records and meets 1 of the following criteria, they will be excluded from the study. o Liver biopsy (i.e., Metavir Score F4). o Liver stiffness >12 kPa. (measured with transient elastography).

[0153] 4. Diagnosed or suspected HCC as evidenced by the following: a. Alpha fetoprotein concentration >200 ng / mL. b. If the screening alpha fetoprotein concentration is >50 ng / mL and <200 ng / mL, the absence of liver mass must be documented by imaging within 6 months before randomization or at screening (at the investigator’s discretion). c. Participants who have received potentially curative treatment for HCC will not be eligible for inclusion until 5 years after such treatment without suspected or confirmed recurrence.

[0154] 5. History of extrahepatic disorders possibly related to HBV immune conditions (e.g., nephrotic syndrome, any type of glomerulonephritis, polyarteritis nodosa, cryoglobulinemia, uncontrolled hypertension).

[0155] 6. Coinfection with: a. HCV with positive HCV antibody and detectable HCV RNA at Screening. b. HDV defined as positive or equivocal HDV antibody regardless of HDV RNA level.

[0156] D. Study Assessments and Procedures

[0157] The primary efficacy endpoint is HBV virologic response 36 weeks after scheduled end of study intervention in the absence of rescue medication. The primary objective measurements for efficacy include: HBsAg and HBV DNA.

[0158] Any positive HBsAg or HBV DNA >LLOQ result after achieving HBsAg not detected and HBV DNA <LLOQ needs to be confirmed by re-test within 1 week (±3 days) of receiving the test result. At Week 60 (end of study visit), confirmation of a positive result is required only if the previous visit was a negative result.

[0159] Safety assessments are conducted at planned time points during the course of the study, and additional time points for safety tests may be added based on newly available data to ensure appropriate safety monitoring. Safety assessments include physical examinations, injection site reactions, vital signs, electrocardiograms, and clinical safety laboratory assessment.

[0160] Adverse events (AEs) and serious adverse events (SAEs) are detected, documented, and reported. Adverse Events of special interest include: ALT increase (flares), vascular inflammation and complement activation, thrombocytopenia, renal injury, and injection site reactions.

[0161] Blood samples are collected for measurement of plasma concentrations of bepirovirsen. Pharmacodynamic parameters will include but are not limited to:

[0162] • Categorical: virologic response, seroclearance (HBsAg), HBV DNA <LLOQ, and seroconversion (anti HBs);

[0163] • Change from baseline: HBsAg, HBV DNA, and anti-HBs levels.

[0164] • Safety assessments including, but not limited to, vital signs, laboratory measurements and AEs.

[0165] Blood samples (including whole blood, plasma, serum and PBMCs) are used to evaluate virologic, disease and immune biomarkers and assays related to the pathogenesis of chronic HBV and HIV coinfection; and the participant’s response to bepirovirsen.

[0166] One skilled in the art will readily appreciate that the present disclosure is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The particular embodiments described herein are intended to be representative and exemplary and are not intended as limitations on the scope of the invention. Changes therein and other uses will be apparent to those skilled in the art which are encompassed within the spirit of the invention as defined by the scope of the claims.

[0167] All patent applications, patents, and printed publications cited herein are incorporated herein by reference in the entireties, except for any definitions, subject matter disclaimers or disavowals, and except to the extent that the incorporated material is inconsistent with the express disclosure herein, in which case the language in this disclosure controls.

Claims

THAT WHICH IS CLAIMED:

1. A method for treating chronic hepatitis B infection in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of an antisense oligonucleotide (ASO), wherein the human has HBV / HIV coinfection and has a HBsAg baseline level of not greater than a threshold level.

2. A method for treating chronic hepatitis B infection in a human having HBV / HIV coinfection, the method comprising:(a) determining that the human has a HBsAg baseline level of not greater than a threshold level; and(b) administering to the human a therapeutically effective amount of antisense oligonucleotide (ASO).

3. A method for treating chronic hepatitis B infection in a human having HBV / HIV coinfection, the method comprising:(a) measuring the HBsAg baseline level of the human;(b) comparing the HBsAg baseline level with a threshold level; and(c) if the HBsAg baseline level is not greater than the threshold level, then administering to the human a therapeutically effective amount of antisense oligonucleotide (ASO).

4. The method of any one of claims 1 to 3, wherein the threshold level is about 1000 lU / mL.

5. The method of any one of claims 1 to 3, wherein the threshold level is about 3000 lU / mL.

6. The method of any one of claims 1 to 4, wherein the human is on HBV- and HIV-active antiretroviral treatment.

7. The method of claim 6, wherein the antiretroviral treatment comprises entecavir, tenofovir, or a tenofovir prodrug.

8. The method of claim 6, wherein the antiretroviral treatment comprises tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF), in combination with emtricitabine (FTC) or lamivudine (3TC).

9. The method of any one of claims 1 to 8, wherein the ASO is administered by subcutaneous injection.

10. The method of any one of claims 1 to 9, wherein the ASO is administered at a dose of about 150 mg or 300 mg once weekly.

11. The method of any one of claims 1 to 10, wherein ASO is administered for 12 weeks to 48 weeks.

12. The method of claim 10 or claim 11, wherein ASO is administered weekly with additional loading doses in the first two weeks on Day 4 and Day 11 following the first dose.

13. The method of any one of the preceding claims, wherein the ASO is administered at a dose of 300 mg once weekly for 12 weeks.

14. The method of any one of claims 1 to 12, wherein the ASO is administered at a dose of 300 mg once weekly for 24 weeks.

15. The method of any one of claims 1 to 14, wherein the human is HBeAg negative prior to the ASO treatment.

16. The method of any one of claims 1 to 14, wherein the human is HBeAg positive prior to the ASO treatment.

17. The method of any one of the preceding claims, wherein the ASO comprises 20 linked nucleosides and has a nucleobase sequence of SEQ ID NO: 1.

18. The method of any one of the preceding claims, wherein the ASO consists of 20 linked nucleosides and has a nucleobase sequence of SEQ ID NO: 1.

19. The method of any one of the preceding claims, wherein the ASO comprises: a gap segment consisting of linked deoxynucleosides, a 5’ wing segment consisting of linked nucleosides, and a 3’ wing segment consisting of linked nucleosides, wherein the gap segment is positioned between the 5 ’ wing segment and the 3 ’ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

20. The method of claim 19, wherein the modified sugar comprises a 2'-O- methoxyethyl (2'-M0E) group or is a bicyclic sugar.

21. The method of claim 19 or claim 20, wherein each intemucleoside linkage of the ASO is a phosphorothioate linkage.

22. The method of any one of claims 1 to 21, wherein the ASO is selected from the group consisting of AUS1233 / AUS1138, AUS1444, AUS1458, AUS1459, AUS1460, AUS 1427 / AUS 1461, AUS1462, AUS1463, AUS1464, AUS1465, AUS1463, AUS1467, AUS1468, AUS1470, AUS1471, AUS1472, AUS1473, AUS1474, AUS1475,AUS 1476 / AUS 1493, AUS 1478, AUS 1479, AUS 1489, AUS 1490, AUS 1443, and AUS 1322.

23. The method of any one of claims 1 to 16, wherein the ASO is bepirovirsen.

24. The method of any one of claims 1 to 16, wherein the ASO is AUS 1493.

25. The method of any one of claims 1 to 16, wherein the ASO is AHB-137.

26. An antisense oligonucleotide (ASO) for use in the treatment of chronic hepatitis B infection in a human wherein the human has HBV / HIV coinfection and has a HBsAg baseline level of not greater than a threshold level.

27. An antisense oligonucleotide (ASO) for use in the treatment of chronic hepatitis B infection in a human having HBV / HIV coinfection, the treatment comprising:(a) determining that the human has a HBsAg baseline level of not greater than a threshold level; and(b) administering to the human a therapeutically effective amount of antisense oligonucleotide (ASO).

28. An antisense oligonucleotide (ASO) for use in the treatment of chronic hepatitis B infection in a human having HBV / HIV coinfection, the method comprising:(a) measuring the HBsAg baseline level of the human;(b) comparing the HBsAg baseline level with a threshold level; and(c) if the HBsAg baseline level is not greater than the threshold level, then administering to the human a therapeutically effective amount of antisense oligonucleotide (ASO).

29. An antisense oligonucleotide for use according to any one of claims 26 to 28, wherein the threshold level is about 1000 lU / mL.

30. An antisense oligonucleotide for use according to any one of claims 26 to 28, wherein the threshold level is about 3000 lU / mL.

31. An antisense oligonucleotide for use according to any one of claims 26 to 30, wherein the human is on HBV- and HIV-active antiretroviral treatment.

32. An antisense oligonucleotide for use according to claim 31, wherein the antiretroviral treatment comprises entecavir, tenofovir, or a tenofovir prodrug.

33. An antisense oligonucleotide for use according to claim 31, wherein the antiretroviral treatment comprises tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF), in combination with emtricitabine (FTC) or lamivudine (3TC).

34. An antisense oligonucleotide for use according to any one of claims 26 to 33, wherein the ASO is administered by subcutaneous injection.

35. An antisense oligonucleotide for use according to any one of claims 26 to 34, wherein the ASO is administered at a dose of about 150 mg or 300 mg once weekly.

36. An antisense oligonucleotide for use according to any one of claims 26 to 35, wherein ASO is administered for 12 weeks to 48 weeks.

37. An antisense oligonucleotide for use according to claim 35 or 36, wherein ASO is administered weekly with additional loading doses in the first two weeks on Day 4 and Day 11 following the first dose.

38. An antisense oligonucleotide for use according to any one of claims 26 to 37, wherein the ASO is administered at a dose of 300 mg once weekly for 12 weeks.

39. An antisense oligonucleotide for use according to any one of claims 26 to 37, wherein the ASO is administered at a dose of 300 mg once weekly for 24 weeks.

40. An antisense oligonucleotide for use according to any one of claims 26 to 39, wherein the human is HBeAg negative prior to the ASO treatment.

41. An antisense oligonucleotide for use according to any one of claims 26 to 39, wherein the human is HBeAg positive prior to the ASO treatment.

42. An antisense oligonucleotide for use according to any one of claims 26 to 41, wherein the ASO comprises 20 linked nucleosides and has a nucleobase sequence of SEQ ID NO: 1.

43. An antisense oligonucleotide for use according to any one of claims 26 to 42, wherein the ASO consists of 20 linked nucleosides and has a nucleobase sequence of SEQ ID NO: 1.

44. An antisense oligonucleotide for use according to any one of claims 26 to 43, wherein the ASO comprises: a gap segment consisting of linked deoxynucleosides, a 5’ wing segment consisting of linked nucleosides, and a 3’ wing segment consisting of linked nucleosides, wherein the gap segment is positioned between the 5 ’ wing segment and the 3 ’ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

45. An antisense oligonucleotide for use according to claim 44, wherein the modified sugar comprises a 2'-O-methoxyethyl (2'-M0E) group or is a bicyclic sugar.

46. An antisense oligonucleotide for use according to claim 43 or claim 44, wherein each intemucleoside linkage of the ASO is a phosphorothioate linkage.

47. An antisense oligonucleotide for use according to any one of claims 26 to 46, wherein the ASO is selected from the group consisting of AUS1233 / AUS1138, AUS1444, AUS1458, AUS1459, AUS1460, AUS 1427 / AUS 1461, AUS1462, AUS1463, AUS1464, AUS1465, AUS1463, AUS1467, AUS1468, AUS1470, AUS1471, AUS1472, AUS1473, AUS 1474, AUS 1475, AUS 1476 / AUS 1493, AUS 1478, AUS 1479, AUS 1489, AUS 1490, AUS1443, and AUS1322.

48. An antisense oligonucleotide for use according to any one of claims 26 to 41, wherein the ASO is bepirovirsen.

49. An antisense oligonucleotide for use according to any one of claims 26 to 41, wherein the ASO is AUS 1493.

50. An antisense oligonucleotide for use according to any one of claims 26 to 41, wherein the ASO is AHB-137.

51. Use of an antisense oligonucleotide (ASO) in the manufacture of a medicament for the treatment of chronic hepatitis B infection in a human in need thereof according to the method of any one of claims 1 to 25.

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