How to Treat Chronic Hepatitis B

Abstract

The present disclosure relates to methods for treating chronic hepatitis B. These methods comprise administering to a subject in need thereof a therapeutically effective amount of bepirovirsen, where the subject has a baseline level of HBsAg that does not exceed a threshold level.

Description

[Technical field]

[0001] Field The present disclosure relates to methods for treating chronic hepatitis B. These methods comprise administering to a subject in need thereof a therapeutically effective amount of bepirovirsen, where the subject has a baseline level of HBsAg that does not exceed a threshold level.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted in XML format and is hereby incorporated by reference in its entirety. The XML copy has the filename 70153WO01_Seq_List.xml, is approximately 1,913 bytes in size, and was created on March 24, 2023. [Background technology]

[0003] background Hepatitis B virus (HBV) is a strictly hepatotropic, partially double-stranded DNA virus. DNA is the genetic material, but the replication cycle includes a reverse transcription step that copies pregenomic RNA into DNA. Primary infection with HBV causes acute hepatitis with symptoms of inflammation of the organs, fever, jaundice, and increased hepatic transaminases in the blood. Patients who do not overcome the acute viral infection develop chronic hepatitis over the years and are at high risk of developing cirrhosis or liver cancer.

[0004] Infection with HBV results in the production of two distinct particles: 1) the HBV virus itself (or Dane particle), which contains a viral capsid assembled from HBV core antigen proteins (HBcAg) and covered by hepatitis B surface antigen (HBsAg) and is capable of reinfecting cells, and 2) non-infectious subviral particles (or SVPs), which are high-density lipoprotein-like particles composed of lipids, cholesterol, cholesterol esters, and small and medium-sized hepatitis B surface antigens (HBsAg). With each Dane particle produced, 1,000-10,000 SVPs are released into the blood. Thus, SVPs (and the HBsAg protein they carry) make up the overwhelming majority of viral proteins in the blood. HBV-infected cells also secrete a soluble proteolytic product of the pre-core protein called HBVe antigen (HBeAg). The presence of HBeAg in a patient's serum can serve as a marker of active replication in chronic hepatitis.

[0005] Currently, the therapies recommended by the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) for chronic HBV infection include interferon alpha (IFN-α), pegylated interferon alpha-2a (Peg-IFN2α), entecavir, and tenofovir. However, typical interferon therapy lasts for 48 weeks, has tolerability issues due to side effects, and the HBeAg seroconversion rate 24 weeks after cessation of therapy is 27-36%. The HBsAg seroconversion rate is even lower, at approximately 3% immediately after cessation of treatment, increasing to more than 12% after 5 years.

[0006] The nucleoside and nucleotide therapies entecavir and tenofovir have been successful in reducing viral load (HBV DNA), but the HBeAg seroconversion and HBsAg clearance rates are lower than those seen with IFNα therapy. Other similar therapies, including lamivudine (3TC), telbivudine (LdT), and adefovir, are also in use, but the emergence of resistance generally limits the efficacy of nucleoside / nucleotide therapies. Summary of the Invention

[0007] Therefore, there is a need to discover and develop new anti-HBV therapies, more specifically, therapies that can achieve functional cure in chronic hepatitis B (CHB) patients.

[0008] overview In one aspect, the disclosure provides a method for treating Hepatitis B virus (HBV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of bepivirsen, if the subject has a baseline HBsAg level that does not exceed a threshold level.

[0009] In one embodiment, the disclosure provides a method for treating chronic hepatitis B (CHB) in a human in need thereof, comprising administering to the human a therapeutically effective amount of bepirovirsen, if the human has a baseline level of HBsAg that does not exceed a threshold level.

[0010] In another aspect, the present disclosure provides a method for treating chronic hepatitis B in a human in need thereof, comprising: (a) determining that the human has a baseline level of HBsAg that does not exceed a threshold level; (b) administering to the human a therapeutically effective amount of bepilovirsen. The present invention provides a method comprising the steps of:

[0011] In another aspect, the present disclosure provides a method for treating chronic hepatitis B in a human in need thereof, comprising: (a) determining a baseline level of HBsAg in said human; (b) comparing said HBsAg baseline level to a threshold level; and (c) administering to the human a therapeutically effective amount of bepilovirsen if the baseline HBsAg level does not exceed a threshold level. The present invention provides a method comprising the steps of:

[0012] In another aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: 1. A method for determining the likely increased pharmacological efficacy of bepirovirsen treatment in a human with chronic hepatitis B, comprising: (a) obtaining a baseline level of HBsAg in said human; and (b) comparing said baseline HBsAg level with a threshold level; comprising If said baseline HBsAg level does not exceed said threshold level, this indicates an increased likelihood of pharmacological effectiveness of said treatment.

[0013] In another aspect, the present disclosure provides a method for increasing the success rate of chronic hepatitis B treatment with bepilovirsen in a human in need thereof, comprising: (a) obtaining a baseline level of HBsAg in said human; (c) comparing the HBsAg baseline level to a threshold level; and (b) administering to the human a therapeutically effective amount of bepilovirsen if the baseline HBsAg level does not exceed a threshold level. The present invention provides a method comprising the steps of:

[0014] In another aspect, the disclosure provides bepirovirsen for use in a method of treating chronic hepatitis B in a human in need thereof, wherein the human has a baseline level of HBsAg that does not exceed a threshold level.

[0015] In another aspect, the present disclosure provides a method for administering to a human in need thereof: (a) determining that the human has a baseline level of HBsAg that does not exceed a threshold level; (b) administering to the human a therapeutically effective amount of bepilovirsen. The present invention provides bepivirsen for use in a method for treating chronic hepatitis B comprising the steps of: [Brief description of the drawings]

[0016] [Figure 1]Figure 1 shows the study design of a Phase 2b clinical trial to evaluate the efficacy and safety of bepirovirsen treatment in patients with chronic hepatitis B (CHB). [Diagram 2] Figure 2 shows the percentages of ON-NUC subjects with HBsAg <LLOQ, ≥LLOQ to <100 IU / mL, and ≥100 IU / mL over time by treatment group. [Diagram 3] Figure 3 shows the percentages of NOT ON-NUC subjects with HBsAg <LLOQ, ≥LLOQ to <100 IU / mL, and ≥100 IU / mL over time by treatment group. [Figure 4] Figure 4 shows the percentages of ON-NUC subjects who demonstrated virological response in the end-of-treatment analysis window by treatment group and subgroup based on HBeAg baseline level. [Diagram 5] Figure 5 shows the percentages of ON-NUC subjects who demonstrated virological response in the end-of-treatment analysis window by treatment group and subgroup based on HBsAg baseline level. [Figure 6] Figure 6 shows the percentages of NOT ON-NUC subjects who demonstrated virological response in the end-of-treatment analysis window by treatment group and subgroup based on HBeAg baseline level. [Figure 7] Figure 7 shows the percentages of NOT ON-NUC subjects who demonstrated virological response in the end-of-treatment analysis window by treatment group and subgroup based on HBsAg baseline level. [Figure 8] Figure 8 shows the percentages of NOT ON-NUC subjects who demonstrated virological response in the end-of-treatment analysis window by treatment group and subgroup based on HBV DNA baseline level. [Figure 9A] Figures 9A and 9B show the observed and model-predicted individual PK, HBsAg, and ALT profiles of one subject whose HBsAg level increased after completion of bepirovirsen treatment. [Figure 9B]Figures 9A and 9B show the observed and model-predicted individual PK, HBsAg, and ALT profiles of one subject with an increase in HBsAg level after the end of bepirovirsen treatment. [Figure 10A] Figures 10A and 10B show the observed and model-predicted individual PK, HBsAg, and ALT profiles of one subject with a maintained low HBsAg level after the end of bepirovirsen treatment. [Figure 10B] Figures 10A and 10B show the observed and model-predicted individual PK, HBsAg, and ALT profiles of one subject with a maintained low HBsAg level after the end of bepirovirsen treatment. [Figure 11A] Figures 11A - 11C show the predicted percentages of subjects who achieved HBsAg < LLOQ at 12 weeks, 24 weeks, and 48 weeks (during the non-treatment period). [Figure 11B] Figures 11A - 11C show the predicted percentages of subjects who achieved HBsAg < LLOQ at 12 weeks, 24 weeks, and 48 weeks (during the non-treatment period). [Figure 11C] Figures 11A - 11C show the predicted percentages of subjects who achieved HBsAg < LLOQ at 12 weeks, 24 weeks, and 48 weeks (during the non-treatment period). [Figure 12] Figure 12 shows the percentages of ON-NUC subjects achieving HBsAg < LLOQ and HBV DNA < LLOQ over time by treatment group. [Figure 13] Figure 13 shows the percentages of NOT ON-NUC subjects achieving HBsAg < LLOQ and HBV DNA < LLOQ over time by treatment group. [Figure 14] Figure 14 shows the study design of a Phase 3 clinical trial to evaluate the efficacy and safety of bepirovirsen treatment in patients with chronic hepatitis B (CHB).

Mode for Carrying Out the Invention

[0017] Detailed Description definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. For example, certain terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)," Leuenberger, HGW, Nagel, B. and Klbl, H. (eds.) (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).

[0018] Throughout this specification and the claims that follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" are understood to imply the inclusion of stated elements, integers, or steps, or groups of elements, integers, or steps, but not the exclusion of other elements, integers, or steps, or groups of elements, integers, or steps.

[0019] Unless otherwise stated, the following terms have the following meanings.

[0020] "About," as used herein, is intended to qualify the numerical value it modifies, indicating that such value varies within a range of error. When no specific error is stated, such as a standard deviation for the average value given in a graph or table of data, the term "about" should be understood to mean and include a range encompassing ±10% of the stated value.

[0021] "Antisense oligonucleotide (ASO)" refers to a single-stranded oligonucleotide having a nucleobase sequence capable of hybridizing to a corresponding region or segment of a target nucleic acid.

[0022] "Baseline" levels of certain substances (e.g., HBsAg, HBeAg, HBsAb, HBeAb, HBV DNA, ALT) are measured in a blood sample taken from the patient before the first dose.

[0023] Bepilovirsen is an ASO currently undergoing clinical evaluation for the treatment of HBV infection. Bepilovirsen is a compound disclosed in WO 2012 / 145697, ISIS number 505358. Bepilovirsen has 20 linked nucleosides and has the nucleobase sequence 5'-GCAGAGGTGAAGCGAAGTGC-3' (SEQ ID NO: 1), a gap segment consisting of 10 linked deoxynucleosides; a 5' wing segment consisting of five linked nucleosides; A 3' wing segment consisting of five linked nucleosides wherein the gap segment is located between the 5' wing segment and the 3' wing segment, each nucleoside of each wing segment comprises a 2'-O-methoxyethyl sugar, each internucleoside linkage is a phosphorothioate linkage, and each cytosine is a 5-methylcytosine. The CAS Registry Number for bepirovirsen is 1403787-62-1.

[0024] "Chronic hepatitis B (CHB) infection" occurs when an individual initially suffers from acute infection but is subsequently unable to fight off the infection. Approximately 90% of infants infected at birth progress to chronic disease. However, with increasing age, the risk of chronic infection decreases, with only 20-50% of infected children and less than 10% of infected adults progressing from acute to chronic infection. Herein, the terms "chronic hepatitis B infection," "chronic hepatitis B," "chronic HBV infection," and "CHB" are used interchangeably.

[0025] "Dosage" refers to the specified amount of an active pharmaceutical agent provided in a single administration or within a specified period. In certain embodiments, the dosage can be administered in two or more boluses, tablets, or injections. For example, in certain embodiments, where subcutaneous administration is desired, the desired dosage requires a volume that cannot be easily accommodated in a single injection. In such embodiments, two or more injections can be used to achieve the desired dosage. In certain embodiments, the dosage can be administered in two or more injections to minimize injection site reactions in an individual.

[0026] "Dosing regimen" is a combination of dosages designed to achieve one or more desired effects.

[0027] "Duration" refers to the period during which an activity or event continues. In certain embodiments, the treatment duration is the period during which the pharmaceutical agent is administered.

[0028] "Functional cure" refers to the sustained (for 24 weeks or more) suppression (<LLOQ) of HBV DNA, accompanied by the disappearance of HBsAg (<0.05 IU / mL), regardless of the presence or absence of HBsAb, after a certain treatment duration from all HBV treatments.

[0029] "HBV" refers to mammalian hepatitis B virus, including human hepatitis B virus. This term encompasses the geographical genotypes of hepatitis B virus, particularly human hepatitis B virus, as well as variants of the geographical genotypes of hepatitis B virus. Geographical human genotypes of HBV include genotype: A (northwestern Europe, North America, Central America), B (Indonesia, China, Vietnam), C (East Asia, Korea, China, Japan, Polynesia, Vietnam), D (Mediterranean region, Middle East, India), E (Africa), F (Native Americans, Polynesia), G (United States, France), and H (Central America).

[0030] "HBV antigen" refers to any Hepatitis B virus antigen or protein, including the core protein, such as "Hepatitis B core antigen" or "HBcAg," "Hepatitis B E antigen" or "HBeAg," and the envelope protein, such as "HBV surface antigen" or "HBsAg."

[0031] "Hepatitis B E antigen" or "HBeAg" is the secreted, non-particulate form of the HBV core protein. The HBV antigens HBeAg and HBcAg share a primary amino acid sequence and therefore exhibit cross-reactivity at the T cell level. Studies suggest that HBeAg is not required for viral assembly or replication, but may be required for the establishment of chronic infection.

[0032] "HBV surface antigen", "HBsAg", or "HBs" is an envelope protein of the infectious HBV virion (Dane particle), but is also secreted as a non-infectious particle (subviral particle, SVP), whose serum levels are 1000 times higher than those of the HBV virion. Serum levels of HBsAg in infected individuals or animals can reach 1000 μg / mL (Kann and Gehrlich (1998) Topley & Wilson's Microbiology and Microbial Infections, 9th ed. 745).

[0033] "HBV-related condition" refers to any disease, biological state, medical condition, or event that leads to, is caused by, is associated with, is associated with, or can be attributed to hepatitis B virus infection, exposure, or disease. The term hepatitis B-related condition includes chronic HBV infection, inflammation, fibrosis, cirrhosis, liver cancer, serum hepatitis, jaundice, liver inflammation, liver fibrosis, cirrhosis, liver failure, diffuse hepatocellular inflammatory disease, hemophagocytic syndrome, HBV viremia, transplant-associated liver disease, and conditions with symptoms that may include any and all of the following: flu-like illness, weakness, pain, headache, fever, loss of appetite, diarrhea, nausea and vomiting, pain in the liver area, clay-colored or gray stools, generalized itching, and dark urine when combined with a positive test for the presence of hepatitis B virus, hepatitis B virus antigen, or a positive test for the presence of antibodies specific for hepatitis B virus antigen.

[0034] "Induce," "inhibit," "enhance," "elevate," "increase," "reduce," and the like generally refer to a quantitative difference between two states. Such terms may refer to a statistically significant difference between two states. For example, "an amount effective to inhibit HBV activity or expression" refers to a level of HBV activity or expression in treated cells that is quantitatively different from, and may be statistically significant, from, the level of HBV activity or expression in untreated cells. Such terms apply, for example, to expression levels and activity levels.

[0035] "Nucleobase" refers to a heterocyclic moiety capable of pairing with a base of another nucleic acid.

[0036] "Nucleobase sequence" refers to the order of contiguous nucleobases without regard to sugar, linkage, and / or nucleobase modifications.

[0037] "Pharmaceutically acceptable salt" refers to a physiologically acceptable salt of a compound, ie, a salt that retains the desired biological activity of the parent active ingredient and does not impart undesired toxicological effects.

[0038] "Phosphorothioate bond" refers to a bond between nucleotides in which the phosphodiester bond has been modified by replacing one of the non-bridging oxygen atoms with a sulfur atom. A phosphorothioate bond is a modified internucleoside bond.

[0039] A "region" is defined, for example, as a portion of a nucleic acid having at least one distinguishable structure, function, or characteristic.

[0040] "Stable nucleoside or nucleotide analog (NA) therapy" is defined as no changes in the nucleoside or nucleotide analog dosing regimen for at least 6 months prior to treatment and no changes in the regimen are planned during the treatment period.

[0041] A "segment" can refer to, for example, a smaller region within a nucleic acid, or a small portion of a region.

[0042] "Serum clearance" refers to the clearance or elimination of antigens (e.g., HBsAg and / or HBV DNA levels) in blood (or laboratory measurements below the lower limit of quantification (i.e., LLOQ)) in CHB patients after treatment. When serum HBsAg levels are measured by sandwich immunoassay using the COBAS HBsAg quant II (Roche), the LLOQ is 0.05 IU / mL. When serum HBV DNA levels are measured by COBAS Ampliprep / COBAS Taqman HBV test v.2.0 (Roche), the LLOQ is 20 IU / mL.

[0043] "Subject" refers to a human or non-human animal selected for treatment or therapy. In one embodiment, the subject is a human.

[0044] A "therapeutically effective amount" refers to the administration of a pharmaceutical agent to a subject, either alone or as part of a pharmaceutical composition, in a single dose or as part of a series, in an amount that, when administered to a subject, can have a detectable positive effect on a symptom, aspect, or characteristic of a disease or condition.

[0045] "Treatment" refers to the administration of a pharmaceutical agent to a subject to affect an alteration or amelioration of a disease or condition. The term "treat," as used herein in reference to chronic hepatitis B infection, refers to the administration of a suitable composition with the intent of alleviating the symptoms of CHB, preventing the progression of CHB, or reducing the levels of one or more detectable markers of CHB.

[0046] method The present disclosure provides methods for treating Hepatitis B virus (HBV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of bepilovirsen, if the subject has a baseline HBsAg level that does not exceed a threshold level. In some embodiments, the HBV infection is chronic hepatitis B (CHB).

[0047] In another aspect, the present disclosure provides a method for treating chronic hepatitis B in a human in need thereof, comprising: (a) determining that the human has a baseline level of HBsAg that does not exceed a threshold level; (b) administering to the human a therapeutically effective amount of bepilovirsen. The present invention provides a method comprising the steps of:

[0048] The baseline level of HBsAg in the blood of a CHB patient is measured by methods known in the art before the start of treatment. As used herein, the "determining" step can be accomplished by measuring the patient's baseline level of HBsAg and comparing the baseline level to a predetermined threshold level. The "determining" step can also be accomplished by receiving information on the HBsAg baseline level from the patient or testing facility and comparing the HBsAg baseline level to a predetermined threshold level.

[0049] In another aspect, the present disclosure provides a method for treating chronic hepatitis B in a human in need thereof, comprising: (a) determining a baseline level of HBsAg in said human; (b) comparing said HBsAg baseline level to a threshold level; and (c) administering to the human a therapeutically effective amount of bepilovirsen if the baseline HBsAg level does not exceed a threshold level. The present invention provides a method comprising the steps of:

[0050] In another aspect, the disclosure provides a method for determining the likely increased pharmacological efficacy of bepilovirsen treatment in a human with chronic hepatitis B, comprising: (a) obtaining a baseline level of HBsAg in said human; and (b) comparing said baseline HBsAg level with a threshold level; comprising If said baseline HBsAg level does not exceed said threshold level, this indicates an increased likelihood of pharmacological effectiveness of said treatment.

[0051] As used herein, the step of "obtaining" can be accomplished by directly measuring the patient's baseline HBsAg level or by receiving baseline HBsAg level information from the patient or a testing facility.

[0052] In another aspect, the present disclosure provides a method for increasing the success rate of chronic hepatitis B treatment with bepilovirsen in a human in need thereof, comprising: (a) obtaining a baseline level of HBsAg in said human; (c) comparing the HBsAg baseline level to a threshold level; and (b) administering to the human a therapeutically effective amount of bepilovirsen if the baseline HBsAg level does not exceed a threshold level. The present invention provides a method comprising the steps of:

[0053] It has been reported that low HBsAg baseline levels can be used as a predictor of HBsAg loss in HBeAg-negative patients treated with PEG-IFN and adefovir. See Takkenberg, et al., “Baseline hepatitis B surface antigen (HBsAg) as predictor of sustained HBsAg loss in chronic hepatitis B patients treated with pegylated interferon-α2a and adefovir,” Antivir. Ther. 2013;18(7):895-904. In particular, a baseline HBsAg level of less than 400 IU / mL was identified as a good predictor for treating HBeAg-negative patients with PEG-IFN and adefovir. However, low HBsAg baseline levels could not predict HBsAg loss in HBeAg-positive patients in the same study.

[0054] In the methods disclosed herein, bepilovirsen can be administered as a free acid, a pharma- ceutically acceptable salt thereof (e.g., the sodium salt), or a combination thereof. In some embodiments, bepilovirsen is administered as a free acid. In some embodiments, bepilovirsen is administered as a pharma- ceutically acceptable salt thereof (e.g., the sodium salt). In some embodiments, bepilovirsen is administered as a combination of the free acid and the sodium salt. In some embodiments, bepilovirsen is administered by subcutaneous injection.

[0055] As used herein, "therapeutically effective amount of bepilovirsen" refers to the amount of bepilovirsen free acid. In some embodiments, the therapeutically effective amount of bepilovirsen is about 150 mg to 450 mg once a week. In some embodiments, the therapeutically effective amount of bepilovirsen is about 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 450 mg once a week, or a range between any two of the above values. In some embodiments, the therapeutically effective amount of bepilovirsen is about 150 mg once a week. In some embodiments, the therapeutically effective amount of bepilovirsen is about 300 mg once a week. In some embodiments, bepilovirsen is administered weekly with additional loading doses on days 4 and 11 after the initial dose for the first two weeks. In some embodiments, bepilovirsen is administered at a dose of about 300 mg once a week with additional loading doses on days 4 and 11 after the initial dose for the first two weeks. In a particular embodiment, the loading dose is 300 mg.

[0056] In some embodiments, bepilovirsen is administered for about 12 to 48 weeks. In some embodiments, bepilovirsen is administered for 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks, 34 weeks, 36 weeks, 38 weeks, 40 weeks, 42 weeks, 44 weeks, 46 weeks, or 48 weeks, or a range between any two of the above periods. In one embodiment, bepilovirsen is administered for 12 weeks. In one embodiment, bepilovirsen is administered for 24 weeks. In one embodiment, bepilovirsen is administered for 36 weeks. In one embodiment, bepilovirsen is administered for 48 weeks. In one embodiment, bepilovirsen is administered for 12 or 24 weeks, with additional loading doses administered on days 4 and 11 after the first dose.

[0057] In some embodiments, bepirovirsen is administered at a dose of about 300 mg once a week for 24 weeks. In some embodiments, bepirovirsen is administered at a dose of about 300 mg once a week for 12 weeks. In some embodiments, bepirovirsen is administered at a dose of about 300 mg once a week for 12 weeks, followed by a dose of about 150 mg once a week for 12 weeks.

[0058] In some embodiments, bepilovirsen is administered at a dose of about 300 mg once weekly for 24 weeks, with additional loading doses of 300 mg each given on days 4 and 11 after the initial dose. In some embodiments, bepilovirsen is administered at a dose of about 300 mg once weekly for 12 weeks, with additional loading doses of 300 mg each given on days 4 and 11 after the initial dose.

[0059] In some embodiments, the disclosure provides a method for treating CHB in a human in need thereof, comprising administering to the human a therapeutically effective amount of bepirovirsen when the subject has a baseline HBsAg level that does not exceed a threshold level. In some embodiments, the baseline HBsAg threshold level is in the range of about 500 IU / mL to 10,000 IU / mL, i.e., about 2.7 log10 IU / mL to 4.0 log10 IU / mL.

[0060] In some embodiments, the HBsAg baseline threshold level is about 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, or 10,000 IU / mL, or a range between any two of the above numbers. In some embodiments, the HBsAg baseline threshold level is about 1000, 2000, or 3000 IU / mL. In some embodiments, the HBsAg baseline threshold level is about 1000 IU / mL. In some embodiments, the HBsAg baseline threshold level is about 3000 IU / mL. In some embodiments, the HBsAg baseline threshold level is about 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 log10 IU / mL, or a range between any two of the above values. In some embodiments, the HBsAg baseline threshold level is about 3.0-4.0 log10 IU / mL. In some embodiments, the HBsAg baseline threshold level is about 3.0-3.5 log10 IU / mL. In some embodiments, the HBsAg baseline threshold level is about 3.0 log10 IU / mL. In some embodiments, the HBsAg baseline threshold level is about 3.5 log10 IU / mL.

[0061] In one embodiment, the disclosure provides a method for treating CHB in a human in need thereof, comprising administering to the human a therapeutically effective amount of bepilovirsen when the human has a baseline HBsAg level not exceeding about 1000 IU / mL.In one embodiment, the disclosure provides a method for treating CHB in a human in need thereof, comprising administering to the human a therapeutically effective amount of bepilovirsen when the human has a baseline HBsAg level not exceeding about 3000 IU / mL.

[0062] In one embodiment, the disclosure provides a method for treating CHB in a human in need thereof, comprising administering bepilovirsen to the human at a dose of 300 mg once per week for 24 weeks when the human has a baseline HBsAg level not exceeding about 1000 IU / mL.In one embodiment, the disclosure provides a method for treating CHB in a human in need thereof, comprising administering bepilovirsen to the human at a dose of 300 mg once per week for 24 weeks when the human has a baseline HBsAg level not exceeding about 3000 IU / mL.

[0063] In one embodiment, the disclosure provides a method for treating CHB in a human in need thereof, comprising administering bepilovirsen to the human at a dose of 300 mg once per week for 24 weeks, if the human has a baseline HBsAg level not exceeding about 1000 IU / mL and is HBeAg negative.In one embodiment, the disclosure provides a method for treating CHB in a human in need thereof, comprising administering bepilovirsen to the human at a dose of 300 mg once per week for 24 weeks, if the human has a baseline HBsAg level not exceeding about 3000 IU / mL and is HBeAg negative.

[0064] In one embodiment, the disclosure provides a method for treating CHB in a human in need thereof, comprising administering bepilovirsen to the human at a dose of 300 mg once per week for 24 weeks, when the human has a baseline HBsAg level not exceeding about 1000 IU / mL and is HBeAg negative, and the human is on stable nucleoside or nucleotide analog (NA) therapy.In one embodiment, the disclosure provides a method for treating CHB in a human in need thereof, comprising administering bepilovirsen to the human at a dose of 300 mg once per week for 24 weeks, when the human has a baseline HBsAg level not exceeding about 3000 IU / mL and is HBeAg negative, and the human is on stable nucleoside or nucleotide analog (NA) therapy.

[0065] In some embodiments, the human is not receiving treatment with another HBsAg-reducing agent or immunomodulator. That is, bepivirsen is used as a monotherapy to treat CHB. The HBsAg-reducing agent can be a small / short interfering RNA (siRNA), an antisense oligonucleotide (ASO), a nucleic acid polymer (NAP), an HBV RNA destabilizing agent, an HBV-specific neutralizing mAb, or a combination thereof. The immunomodulator can be IFN-α, PEG-IFN-α, a therapeutic vaccine, a PD-1 / PD-L1 inhibitor, a TLR7 agonist, a TLR8 agonist, a TLR9 agonist, or a combination thereof.

[0066] In one embodiment, the human is under stable nucleoside or nucleotide analog (NA) therapy (e.g., tenofovir disoproxil, tenofovir alafenamide, or entecavir). In some embodiments, the NA therapy is lamivudine, adefovir, adefovir dipivoxil, telbivudine, entecavir, tenofovir, tenofovir disoproxil fumarate (TDF), or tenofovir alafenamide (TAF), or a pharma- ceutically acceptable salt thereof. In some embodiments, the NA therapy is entecavir, tenofovir, tenofovir disoproxil fumarate, or tenofovir alafenamide. In some embodiments, the NA therapy is entecavir. In some embodiments, the NA therapy is tenofovir. In some embodiments, the NA therapy is tenofovir disoproxil fumarate. In some embodiments, the NA therapy is tenofovir alafenamide.

[0067] In another embodiment, the subject is not under NA therapy. In some embodiments, the subject is treatment naive.

[0068] In some embodiments, the human has a higher likelihood of achieving HBsAg below the LLOQ at the end of bepivirsen treatment compared to a human with a baseline level of HBsAg above the threshold level. In some embodiments, the human has at least a 5%, 10%, 15%, 20%, 25%, or 30% higher likelihood of achieving HBsAg below the LLOQ at the end of bepivirsen treatment. In some embodiments, the human has at least a 5%, 10%, 15%, 20%, 25%, or 30% higher likelihood of achieving HBsAg below the LLOQ 24 weeks after the end of bepivirsen treatment.

[0069] In some embodiments, the human has a higher probability of achieving HBV DNA below the LLOQ at the end of bepivirsen treatment compared to a human with a baseline level of HBsAg above the threshold level. In some embodiments, the human has at least a 5%, 10%, 15%, 20%, 25%, or 30% higher probability of achieving HBV DNA below the LLOQ at the end of bepivirsen treatment. In some embodiments, the human has at least a 5%, 10%, 15%, 20%, 25%, or 30% higher probability of achieving HBV DNA below the LLOQ 24 weeks after the end of bepivirsen treatment.

[0070] In some embodiments, the person with a baseline HBsAg level that does not exceed the threshold level has a higher probability of achieving HBsAg and HBV DNA below the LLOQ at the end of bepivirsen treatment than a person with a baseline HBsAg level that exceeds the threshold level. In some embodiments, the person with a baseline HBsAg level that does not exceed the threshold level has at least a 5%, 10%, 15%, 20%, 25%, or 30% higher probability of achieving HBsAg and HBV DNA below the LLOQ at the end of bepivirsen treatment. In some embodiments, the person with a baseline HBsAg level that does not exceed the threshold level has at least a 5%, 10%, 15%, 20%, 25%, or 30% higher probability of achieving HBsAg and HBV DNA below the LLOQ 24 weeks after the end of bepivirsen treatment.

[0071] In some embodiments, the Hepatitis B virus infection is caused by any of the following human geographic genotypes: A (Northwest Europe, North America, Central America); B (Indonesia, China, Vietnam); C (East Asia, Korea, China, Japan, Polynesia, Vietnam); D (Mediterranean region, Middle East, India); E (Africa); F (Native American, Polynesia); G (United States, France); or H (Central America). In some embodiments, the subject has chronic hepatitis B (CHB).

[0072] In some embodiments, the subject is HBeAg negative or HBeAg positive prior to treatment. In some embodiments, the subject is HBeAg negative prior to treatment. In some embodiments, the subject is HBeAg positive prior to treatment.

[0073] In another aspect, the disclosure provides bepirovirsen for use in a method of treating chronic hepatitis B in a human in need thereof, wherein the human has a baseline level of HBsAg that does not exceed a threshold level.

[0074] In another aspect, the present disclosure provides a method for administering to a human in need thereof: (a) determining that the human has a baseline level of HBsAg that does not exceed a threshold level; (b) administering to the human a therapeutically effective amount of bepilovirsen. The present invention provides bepivirsen for use in a method for treating chronic hepatitis B comprising the steps of:

[0075] composition The present disclosure provides a composition comprising bepilovirsen for treating Hepatitis B virus (HBV) infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of bepilovirsen, when the subject has a baseline HBsAg level that does not exceed a threshold level. In some embodiments, the HBV infection is chronic hepatitis B (CHB).

[0076] The present disclosure also provides bepilovirsen for treating Hepatitis B virus (HBV) infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of bepilovirsen, when the subject has a baseline HBsAg level that does not exceed a threshold level. In some embodiments, the HBV infection is chronic hepatitis B (CHB).

[0077] The present invention also provides a composition comprising bepilovirsen, or bepilovirsen, for use in a method of treating chronic hepatitis B in a human in need thereof, the method comprising: (a) determining that the human has a baseline level of HBsAg that does not exceed a threshold level; and (b) administering to the human a therapeutically effective amount of bepilovirsen.

[0078] In other embodiments of the composition or bepilovirsen, the method of administering the composition or bepilovirsen may follow any of the methods detailed above.

[0079] For example, in some embodiments, the HBsAg baseline threshold level is about 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, or 10,000 IU / mL, or a range between any two of the above numbers. In some embodiments, the HBsAg baseline threshold level is about 1000, 2000, or 3000 IU / mL. In some embodiments, the HBsAg baseline threshold level is about 1000 IU / mL. In some embodiments, the HBsAg baseline threshold level is about 3000 IU / mL. In some embodiments, the HBsAg baseline threshold level is about 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 log10 IU / mL, or a range between any two of the above values. In some embodiments, the HBsAg baseline threshold level is about 3.0-4.0 log10 IU / mL. In some embodiments, the HBsAg baseline threshold level is about 3.0-3.5 log10 IU / mL. In some embodiments, the HBsAg baseline threshold level is about 3.0 log10 IU / mL. In some embodiments, the HBsAg baseline threshold level is about 3.5 log10 IU / mL.

[0080] In one embodiment, the disclosure provides bepilovirsen for use in a method of treating CHB in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of bepilovirsen when the human has a baseline HBsAg level not exceeding about 1000 IU / mL.In one embodiment, the disclosure provides bepilovirsen for use in a method of treating CHB in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of bepilovirsen when the human has a baseline HBsAg level not exceeding about 3000 IU / mL.

[0081] In another embodiment, the disclosure provides bepilovirsen for use in a method of treating CHB in a human in need thereof, the method comprising administering bepilovirsen to the human at a dose of 300 mg once per week for 24 weeks when the human has a baseline HBsAg level not exceeding about 1000 IU / mL.In one embodiment, the disclosure provides bepilovirsen for use in a method of treating CHB in a human in need thereof, the method comprising administering bepilovirsen to the human at a dose of 300 mg once per week for 24 weeks when the human has a baseline HBsAg level not exceeding about 3000 IU / mL.

[0082] In another embodiment, the disclosure provides bepilovirsen for use in a method of treating CHB in a human in need thereof, the method comprising administering bepilovirsen to the human at a dose of 300 mg once per week for 12 weeks, when the human has a baseline HBsAg level not exceeding about 1000 IU / mL.In one embodiment, the disclosure provides bepilovirsen for use in a method of treating CHB in a human in need thereof, the method comprising administering bepilovirsen to the human at a dose of 300 mg once per week for 12 weeks, when the human has a baseline HBsAg level not exceeding about 3000 IU / mL.

[0083] Embodiment The present disclosure is also illustrated by the following embodiments.

[0084] 1. A method for treating chronic hepatitis B in a human in need thereof, comprising administering to said human a therapeutically effective amount of bepirovirsen, if said human has a baseline level of HBsAg that does not exceed a threshold level.

[0085] 2. A method for treating chronic hepatitis B in a human in need thereof, comprising: (a) determining that the human has a baseline level of HBsAg that does not exceed a threshold level; (b) administering to the human a therapeutically effective amount of bepilovirsen. The method comprising:

[0086] 3. A method for treating chronic hepatitis B in a human in need thereof, comprising: (a) determining a baseline level of HBsAg in said human; (b) comparing said HBsAg baseline level to a threshold level; and (c) administering to the human a therapeutically effective amount of bepilovirsen if the baseline HBsAg level does not exceed a threshold level. The method comprising:

[0087] 4. A method for determining the likely increased pharmacological efficacy of bepirovirsen treatment in a human with chronic hepatitis B, comprising: (a) obtaining a baseline level of HBsAg in said human; and (b) comparing said baseline HBsAg level with a threshold level; comprising A method wherein if said baseline HBsAg level does not exceed said threshold level, this indicates an increased likelihood of pharmacological effectiveness of said treatment.

[0088] 5. A method for increasing the success rate of chronic hepatitis B treatment with bepirovirsen in a human in need thereof, comprising: (a) obtaining a baseline level of HBsAg in said human; (b) comparing said HBsAg baseline level to a threshold level; and (c) administering to the human a therapeutically effective amount of bepilovirsen if the baseline HBsAg level does not exceed a threshold level. The method comprising:

[0089] 6. The method of any one of the preceding embodiments, wherein the threshold level is within the range of about 500 IU / mL to 4000 IU / mL.

[0090] 7. The method of any one of embodiments 1 to 5, wherein said threshold level is about 1000 IU / mL.

[0091] 8. The method of any one of embodiments 1 to 5, wherein said threshold level is about 3000 IU / mL.

[0092] 9. The method of any one of embodiments 1-8, wherein said human has not undergone treatment with another HBsAg-reducing or immunomodulatory agent.

[0093] 10. The method of embodiment 9, wherein said HBsAg lowering agent is an siRNA, an antisense oligonucleotide, a nucleic acid polymer (NAP), an HBV RNA destabilizing agent, an HBV-specific neutralizing mAb, or a combination thereof.

[0094] 11. The method of embodiment 9, wherein said immunomodulatory agent is IFN-α, PEG-IFN-α, a therapeutic vaccine, a PD-1 / PD-L1 inhibitor, a TLR7 agonist, a TLR8 agonist, a TLR9 agonist, or a combination thereof.

[0095] 12. The method of any one of embodiments 1-11, wherein bepirovirsen is administered by subcutaneous injection.

[0096] 13. The method of any one of embodiments 1-12, wherein bepirovirsen is administered once weekly at a dose of about 150 mg to 450 mg.

[0097] 14. The method of any one of embodiments 1-12, wherein bepirovirsen is administered once a week at a dose of about 150 mg or 300 mg.

[0098] 15. The method of any one of embodiments 1-12, wherein bepirovirsen is administered once a week at a dose of about 300 mg.

[0099] 16. The method of any one of embodiments 1-15, wherein bepirovirsen is administered for 12 weeks to 48 weeks.

[0100] 17. The method according to any one of embodiments 1-15, wherein bepirovirsen is administered for 12 weeks or 24 weeks.

[0101] 18. The method of any one of embodiments 1-15, wherein bepirovirsen is administered for 12 weeks.

[0102] 19. The method of any one of embodiments 1-15, wherein bepirovirsen is administered for 24 weeks.

[0103] 20. The method of any one of embodiments 1-12, wherein bepirovirsen is administered at a dose of about 300 mg once a week for 24 weeks.

[0104] 21. The method of any one of embodiments 1-12, wherein bepirovirsen is administered at a dose of about 300 mg once a week for 12 weeks.

[0105] 22. The method according to any one of embodiments 1-12, wherein bepirovirsen is administered at a dose of about 300 mg once a week for 12 weeks, followed by a dose of about 150 mg once a week for 12 weeks.

[0106] 23. The method of any one of embodiments 13-22, wherein bepirovirsen is administered weekly with additional loading doses administered on days 4 and 11 after the first dose during the first two weeks.

[0107] 24. The method of embodiment 23, wherein the loading dose is 300 mg.

[0108] 25. The method of any one of embodiments 1-24, wherein said human is under stable nucleoside or nucleotide analogue (NA) therapy.

[0109] 26. The method of embodiment 25, wherein the NA therapy is lamivudine, adefovir, adefovir dipivoxil, telbivudine, entecavir, tenofovir, tenofovir disoproxil fumarate, or tenofovir alafenamide, or a pharma- ceutically acceptable salt thereof.

[0110] 27. The method according to embodiment 25 or 26, wherein the human's NA therapy is discontinued 24 weeks after the end of bepirovirsen treatment.

[0111] 28. The method of any one of embodiments 1 to 24, wherein the human has not undergone treatment with a nucleoside or nucleotide analogue (NA).

[0112] 29. The method of any one of embodiments 1-28, wherein said human is HBeAg negative or HBeAg positive prior to treatment.

[0113] 30. The method of embodiment 29, wherein said human is HBeAg negative prior to treatment.

[0114] 31. The method of embodiment 29, wherein said human is HBeAg positive prior to treatment.

[0115] 32. The method of any one of embodiments 1 to 31, wherein the human has a higher probability of achieving an HBsAg level below the LLOQ at the end of bepirovirsen treatment compared to a human having a baseline level of HBsAg above the threshold level.

[0116] 33. The method of embodiment 32, wherein the human has at least a 5%, 10%, 15%, 20%, 25%, or 30% greater probability of achieving an HBsAg below the LLOQ upon completion of bepirovirsen treatment.

[0117] 34. The method of any one of embodiments 1 to 33, wherein the human has a higher probability of achieving HBV DNA below the LLOQ at the end of bepirovirsen treatment compared to a human having a baseline level of HBsAg above the threshold level.

[0118] 35. The method of embodiment 34, wherein the human has at least a 5%, 10%, 15%, 20%, 25%, or 30% higher probability of achieving HBV DNA below the LLOQ at the end of bepirovirsen treatment.

[0119] 36. The method of any one of embodiments 1 to 31, wherein the human has a higher probability of achieving an HBsAg level below the LLOQ 24 weeks after the end of bepirovirsen treatment compared to a human having a baseline level of HBsAg above the threshold level.

[0120] 37. The method of embodiment 36, wherein the human is at least 5%, 10%, 15%, 20%, 25%, or 30% more likely to achieve an HBsAg below the LLOQ 24 weeks after the end of bepirovirsen treatment.

[0121] 38. The method of embodiment 27, wherein the human has a higher probability of achieving HBsAg below the LLOQ 24 weeks after cessation of NA therapy compared to a human with a baseline HBsAg level above the threshold level.

[0122] 39. The method of embodiment 38, wherein the human has at least a 5%, 10%, 15%, 20%, 25%, or 30% higher probability of achieving HBsAg below the LLOQ 24 weeks after cessation of NA therapy.

[0123] 40. Bepirovirsen for use in the method according to any one of the above embodiments.

[0124] 41. Bepirovirsen for use in a method for treating chronic hepatitis B in a human in need thereof, wherein the human has a baseline level of HBsAg that does not exceed a threshold level.

[0125] 42. In humans in need thereof: (a) determining that the human has a baseline level of HBsAg that does not exceed a threshold level; (b) administering to the human a therapeutically effective amount of bepilovirsen. 2. Bepirovirsen for use in a method for treating chronic hepatitis B comprising the steps of:

[0126] 43. Use of bepirovirsen in the manufacture of a medicament for the treatment of chronic hepatitis B in a human in need thereof, where the human to be treated has a baseline level of HBsAg that does not exceed a threshold level. EXAMPLES

[0127] Aspects of the disclosure presented herein have been more particularly described in accordance with several embodiments, and the following examples, which highlight certain features and characteristics of exemplary embodiments of the disclosure described herein, are intended to be merely illustrative of the disclosure described herein and are not intended to be limiting thereof.

[0128] Example 1 Evaluation of the efficacy and safety of bepirovirsen treatment in patients with chronic hepatitis B A. Test Plan This is a Phase 2b, multicenter, randomized, partially blinded (sponsor and participant blinded) study to evaluate the efficacy and safety of bepirovirsen treatment in two populations of chronic hepatitis B (CHB) patients: (1) patients on stable nucleoside(t) therapy (ON-NUC) and (2) patients not currently receiving nucleoside(t) therapy (NOT ON-NUC).

[0129] Both populations of CHB patients were randomized into one of four parallel arms (see Figure 1): 1. 300 mg bepirovirsen once a week for 24 weeks (add a loading dose of 300 mg bepirovirsen on days 4 and 11); 2. 300 mg bepirovirsen once / week for 12 weeks (with an additional loading dose of 300 mg bepirovirsen on days 4 and 11), then reduced to a dose of 150 mg bepirovirsen (with matching placebo to maintain participant blinding), once / week for 12 weeks; 3. 300 mg bepirovirsen once / week for 12 weeks (plus a loading dose of 300 mg bepirovirsen on days 4 and 11), then placebo once / week for 12 weeks; 4. Placebo 1x / week for 12 weeks, then 300 mg bepirovirsen 1x / week for 12 weeks (plus matching placebo loading doses on days 4 and 11, no loading dose for bepirovirsen treatment).

[0130] Patients were treated with bepirovirsen or placebo for 24 weeks, followed by a 24-week post-treatment follow-up period.

[0131] The population was stratified based on HBsAg levels (HBsAg ≤ 3 log10 IU / mL and > 3 log10 IU / mL) and whether participants were HBeAg positive or negative.

[0132] B. Objectives and Endpoints The primary objectives of this study were: Efficacy: To evaluate the efficacy of three dosing regimens of bepirovirsen in patients with CHB

[0133] The key estimands that support the key objectives are defined as follows: - population :Individually assessed for: CHB patients on stable nucleoside therapy CHB patients not currently receiving nucleoside therapy - variable: Participants who achieved sustained virological response (SVR) without using rescue medications 24 weeks after the scheduled end date of bepirovirsen treatment. Sustained virological response is defined as observing HBsAg <LLOQ and HBV DNA <LLOQ during the 24 weeks after the end of bepirovirsen treatment. - treatment : Groups 1, 2, and 3. Evaluation of within-group efficacy. - Intermediate events : Use of rescue medications and discontinuation / interruption / compliance of investigational product (IP). Use of rescue medications was incorporated into the definition of variables (composite strategy). Discontinuation, interruption, and compliance of IP were ignored (treatment policy). Large-scale disruptive events (such as the COVID-19 pandemic) leading to discontinuation, interruption, and non-compliance of bepirovirsen were treated as not having occurred (hypothetical strategy) - Group Overview : The proportion of participants who achieved SVR in each treatment group

[0134] The primary estimator for each subgroup is the proportion of participants in each treatment group 1, 2, 3 who achieved SVR without rescue medication administration 24 weeks after the scheduled end date of bepirovirsen treatment, regardless of completion, interruption, or compliance of IP, and not affected by extensive disruptive events.

[0135] Supplementary estimators are defined to support the primary objective: - The supplementary estimator is defined in the same way as the primary estimator, except that the evaluation period frame for participants who achieved SVR is 24 weeks after the actual end of treatment. Therefore, the strategy for concurrent events of treatment discontinuation is during treatment. This supplementary estimator, which supports the primary objective in CHB patients under stable nucleos(t)ide therapy and participants not currently receiving nucleos(t)ide therapy, is the proportion of participants in each treatment group 1, 2, and 3 who achieved SVR without rescue medication administration 24 weeks after the actual end of bepirovirsen treatment, regardless of completion, interruption, or compliance of IP, and not affected by extensive disruptive events.

[0136] The secondary objectives of this study are: 1. Efficacy: Evaluation of the efficacy of bepirovirsen on biomarkers and virus-specific antibody responses 2. Efficacy: Comparison of efficacy between 12 weeks, 12 weeks + weight loss, 12 weeks and 24 weeks of bepirovirsen treatment; 3. Pharmacokinetics (PK): To characterize the PK of bepirovirsen and nucleoside(t)ides in participants with CHB.

[0137] The safety objectives of this study are: To evaluate the safety and tolerability of bepirovirsen when administered for 12 weeks, 12 weeks plus 12 weeks of dose reduction, and 24 weeks.

[0138] The exploratory objectives of this study were to: 1. Relationship between PK and PD: Evaluation of the relationship between PK and efficacy and the relationship between PK and safety 2. Efficacy: Comparison of the efficacy of 12 weeks of bepirovirsen treatment with or without a loading dose 3. Efficacy: Evaluation of the pharmacodynamic effects of bepirovirsen on exploratory viral biomarkers 4. Virology: assessing the impact of genotype / phenotype and the presence or absence of baseline polymorphisms within the bepirovirsen binding site on treatment response; Assessment of the emergence of mutations within the GSK binding site and within the Hepatitis B genome during and after treatment 5. Immunology: Assessment of the effects of 12 weeks, 12 weeks + reduced dose 12 weeks, or 24 weeks of bepirovirsen treatment on immunological biomarkers; Delineating the relationships between virological and immunological biomarkers, including but not limited to HBsAg 6. Patient-reported outcomes: Assessment of change from baseline in patient-reported outcomes after 12 weeks, 12 weeks + dose reduction, and 24 weeks of bepirovirsen treatment.

[0139] C. Study Population: Inclusion and Exclusion Criteria Inclusion criteria for this study included: 1. Be at least 18 years old at the time of informed consent signature 2. Participants with a record of chronic HBV infection more than 6 months before screening and meeting the following conditions a. Not currently in the nucleoside(nucleotide) analogue therapy group. This is defined as participants who have never received HBV treatment (untreated) or have discontinued nucleoside(nucleotide) therapy at least 6 months before the screening visit b. Or currently in a group receiving stable nucleoside(nucleotide) analogue therapy. This is defined as no change in the nucleoside(nucleotide) dosing schedule since at least 6 months before screening and no planned change in the stable dosing schedule during the study period 3. Plasma or serum HBsAg concentration > 100 IU / mL 4. Plasma or serum HBV DNA concentration a. For participants not currently receiving nucleoside(nucleotide) analogue therapy, plasma or serum HBV DNA > 2000 IU / mL; b. For participants receiving stable nucleoside(nucleotide) analogue therapy, be adequately suppressed (defined as plasma or serum HBV DNA < 90 IU / mL) 5. Alanine transaminase (ALT) a. ALT of untreated participants and participants not currently receiving treatment i. Initially include ALT < 3 times the upper limit of normal (ULN) 1. If the IDMC agrees after verification of safety data, the selection criteria for ALT can be expanded to include participants with ALT < 5 times ULN b. For participants receiving stable nucleoside(nucleotide) analogue therapy, ALT ≤ 2 times ULN

[0140] The exclusion criteria for this study include the following: 1. Medical history (e.g., moderate to severe liver disease other than chronic HBV, acute coronary syndrome within 6 months of screening, major surgery within 3 months of screening, significant / unstable cardiac disease, uncontrolled diabetes, bleeding disorder or coagulation disorder) or clinically significant abnormalities on physical exam other than chronic HBV infection 2. Co-infection with: a. Current or past history of Hepatitis C virus (HCV) b. Human immunodeficiency virus (HIV) CD Hepatitis D virus (HDV) 3. History or suspicion of cirrhosis and / or evidence of cirrhosis as determined by: a. Aspartate aminotransferase (AST)-platelet index (APRI) > 2 and FibroSure / FibroTest result > 0.7 i. Positive results in only one parameter (APRI or FibroSure / FibroTest) require consultation with the medical monitor before admission into the study b. Regardless of APRI or Fibrosure / FibroTest score, participants will be excluded from the study if they meet one of the following history criteria: i. Liver biopsy (i.e., Metavir score F4) ii.Liver stiffness >12kPa 4. Diagnosis or suspicion of hepatocellular carcinoma evidenced by: a. α-protein concentration ≥ 200ng / mL; b. If screening alpha-fetoprotein concentration is ≥ 50ng / mL < 200ng / mL, there must be no liver mass documented by imaging within 6 months prior to randomization 5. History of malignancy within the past 5 years, except for certain cancers that are curable by surgical resection (e.g., skin cancer). Participants undergoing evaluation for possible malignancy will be excluded. 6. History of vasculitis or presence of symptoms and signs that may be vasculitis (e.g., vasculitic skin rash, skin ulcers, repeated detection of blood in the urine without identified cause) or history / presence of other diseases that may be associated with vasculitic pathology (e.g., systemic lupus erythematosus, rheumatoid arthritis, relapsing polychondritis, mononeuritis multiplex) 7. History of extrahepatic disorders that may be related to HBV immunopathology (e.g., nephrotic syndrome, any type of glomerulonephritis, polyarteritis nodosa, cryoglobulinemia, uncontrolled hypertension) 8. Positive (or borderline positive) ANCA at screening: a. Participants who meet this criterion may be considered for inclusion in the study after: i. Analysis of MPO-ANCA [pANCA] and PR3-ANCA [cANCA], and ii. Consultation with the medical monitor to review the participant's complete medical history and ensure that they have no history or current symptoms of vasculitic / inflammatory / autoimmune diseases 9. Low C3 at screening and evidence of a history or current symptoms of a vasculitic / inflammatory / autoimmune condition: All participants with low C3 at screening must discuss their medical history with the medical monitor prior to enrollment 10. History of alcohol or drug abuse / dependence: Current alcohol use that the investigator believes may interfere with participant compliance b. History or current substance abuse / dependence that the investigator believes may interfere with the participant's compliance i. Illegal drugs and substances with the potential for abuse. Medications, whether over-the-counter or prescription, that participants use as directed are acceptable and do not meet the exclusion criteria. 11.Currently taking, or within 3 months of screening, any immunosuppressant other than short-term therapy (≤ 2 weeks) or topical / inhaled steroids (e.g., prednisone) 12. Participants for whom immunosuppressive therapy, including therapeutic doses of steroids, is not recommended will be excluded. 13.Currently receiving interferon-containing therapy or have received it within 12 months of screening 14. Participants requiring anticoagulant therapy (e.g., warfarin, factor Xa inhibitors, or antiplatelet agents such as clopidogrel) 15. Participant has participated in a clinical trial and received an investigational drug within the following period prior to the first dose date of this study: 5 half-lives (if known) or 2 times the duration of the biological effect of the investigational drug (if known), whichever is longer, or 90 days (if half-life or duration is unknown). 16. Prior treatment with oligonucleotides or small interfering RNA (siRNA) within 12 months prior to the first dose 17. Fridericia's QTcF ≥ 450 msec (if a single electrocardiogram [ECG] at screening shows a QTcF ≥ 450 msec, the average of three measurements should be used to determine whether the participant meets the exclusion criteria) 18. The following laboratory test results: Serum albumin < 3.5 g / dL b. Glomerular filtration rate (GFR) < 60 mL / min / 1.73 m as calculated by the CKD-EPI formula (JSN-CKDI formula in Japan) 2 c.INR>1.25 d. Platelet count <140×10 9 / L e. Total bilirubin > 1.25 × ULN i. Participants with unconjugated hyperbilirubinemia (total bilirubin >1.25×ULN) should consult with the medical monitor before enrolling in this study. f. Urinary albumin / creatinine ratio (ACR) ≥ 0.03 mg / mg (or ≥ 30 mg / g). If the ACR exceeds this threshold, eligibility can be confirmed by a second measurement. i. If the calculated urinary ACR value ≥ 0.03 mg / mg (or ≥ 30 mg / g) due to low urinary albumin and low urinary creatinine levels in the participant, the principal investigator of the clinical trial shall confirm that the participant has no history of diabetes, hypertension, or other risk factors that may affect renal function, and consult with the medical monitor or their designee. 19. History of previous exposure / hypersensitivity to bepirovirsen or its components, or history of previous exposure to drugs or other allergies that the principal investigator or medical monitor determines to be contraindications to participation

[0141] D. Examination Assessment and Procedures Measurements related to the efficacy of the primary objective include HBsAg and HBV DNA. The primary efficacy endpoint is sustained virological response (SVR), which is defined as HBsAg < LLOQ and HBV DNA < LLOQ at the end of bepirovirsen treatment, and is a composite endpoint that persists for 24 weeks after bepirovirsen treatment. Serum clearance refers to participants with HBsAg and HBV DNA < LLOQ (regardless of the presence or absence of HBs antibody formation). Seroconversion refers to participants with HBsAg and HBV DNA < LLOQ and the presence of HBs antibody. Both terms are used to evaluate efficacy.

[0142] For the purposes of this trial, sustained response is defined as the levels of HBsAg in serum being less than the LLOQ and the levels of HBV DNA being less than the LLOQ continuously for 24 weeks from the end of bepirovirsen treatment.

[0143] If HBsAg above the LLOQ or HBV DNA above the LLOQ occurs after serum clearance of HBsAg and suppression of HBV DNA have been achieved, it is necessary to confirm by retesting within 1 week after receiving the test results. If it cannot be confirmed by the first test, the results of the retest shall be used.

[0144] Safety evaluations will be conducted at scheduled times during the study, and additional safety study timepoints may be added based on newly available data to ensure appropriate safety monitoring. Safety evaluations will include physical examinations, injection site reactions, vital signs, electrocardiograms, and clinical safety laboratory evaluations.

[0145] Adverse events (AEs) and serious adverse events (SAEs) will be detected, recorded, and reported. An adverse event is any untoward medical occurrence temporarily related to the use of a study intervention in a clinical trial participant, whether or not considered related to the study intervention. Thus, an AE can be any untoward and unintended sign (including abnormal laboratory findings), symptom, or disease (new or worsening) temporarily related to the use of the study intervention. A serious adverse event is defined as an untoward medical occurrence resulting in death or being life-threatening, regardless of dose.

[0146] Blood samples will be taken to measure plasma concentrations of bepirovirsen and / or nucleoside(t)ide. Pharmacodynamic parameters to be examined in this study include, but are not limited to: · Change from baseline: HBsAg, HBV DNA, HBeAg, and HBsAb levels. Time to events: virologic response, HBsAg and HBV DNA nadir, seroclearance (HBsAg), HBV DNA levels below the LLOQ, seroconversion (HBsAb and HBeAb); peak ALT flare Safety assessments, including but not limited to vital signs, electrocardiograms, laboratory measurements and adverse events

[0147] Sample collection for other biomarker studies is also part of the study. These exploratory biomarker samples were collected to evaluate the etiology of CHB, the absorption, distribution, metabolism, or excretion of bepirovirsen, or the participant's response to bepirovirsen. Additionally, continued studies may identify other proteins, transcripts, or biomarkers associated with bepirovirsen treatment, response to bepirovirsen, or the etiology of CHB, which will also be evaluated in these samples.

[0148] Example 2 Interim analysis results from Phase 2b clinical trial At the time of filing the first priority patent (US63 / 324662), a phase 2b clinical trial was ongoing, and the results of the interim analysis (IA) are shown below. The demographic characteristics of participants in the four groups for both the ON-NUC and NOT ON-NUC cohorts are shown in Tables 1 and 2, respectively.

[0149] [Table 1]

[0150] [Table 2]

[0151] The disease characteristics of participants in the four groups for both the ON-NUC and NOT ON-NUC cohorts are shown in Tables 3 and 4 , respectively.

[0152] [Table 3]

[0153] [Table 4]

[0154] Table 5 and Table 6 respectively show the trends of participants in the four groups (treatment-intention population) for both the ON-NUC and NOT-ON-NUC cohorts.

[0155]

Table 5

[0156]

Table 6

[0157] In the ON-NUC cohort, 227 patients (73% male, 52% Asian, 69% HBeAg-negative, 28% HBsAg ≤ 3 log10 IU / mL) were included in the treatment-intention population (68, 68, 68, and 23 patients in groups 1 - 4 respectively), and 12 patients (5%) discontinued treatment. At the end of treatment, the patients with HBsAg < LLOQ and HBV DNA < LLOQ were 28%, 17%, 9%, and 14% in groups 1 - 4 respectively. The HBsAg response data are shown in Figure 2.

[0158] In the NOT-NUC cohort, 230 patients (54% male, 57% Asian, 74% HBeAg-negative, 19% HBsAg ≤ 3 log10 IU / mL) were included in the treatment-intention population (70, 68, 68, and 24 patients in groups 1 - 4 respectively), and 21 patients (9%) discontinued treatment. At the end of treatment, the patients with HBsAg < LLOQ and HBV DNA < LLOQ were 29%, 13%, 7%, and 0% in groups 1 - 4 respectively. The HBsAg response data are shown in Figure 3.

[0159] The efficacy of bepirovirsen treatment was evaluated based on interim data. Virological response at the end of treatment is defined as achieving HBsAg < LLOQ and HBV DNA < LLOQ without using rescue medications during the clinic window at the end of treatment. Success of SVR is defined as achieving HBsAg < LLOQ and HBV DNA < LLOQ without using rescue medications 24 weeks after the scheduled end date of bepirovirsen treatment.

[0160] End-of-treatment virologic response by subgroups - baseline HBeAg status was analyzed as a secondary endpoint. In the ON-NUC cohort, there was no clear difference in virologic response in the end-of-treatment analysis window between patients with positive and negative HBeAg status. See Figure 4. The dashed line indicates the overall end-of-treatment virologic response rate across all treatment groups. In the NOT ON-NUC cohort, patients with negative HBeAg status appear to be slightly more likely to achieve virologic response at end-of-treatment. See Figure 6. Both SVR responders were HBeAg negative at baseline.

[0161] EOT virologic response by subgroup - baseline HBsAg status was also analyzed as a secondary endpoint. In the ON-NUC cohort, the proportion of subjects with EOT virologic response was higher in patients with low baseline HBsAg levels (≤3Log10IU / mL) compared to patients with high baseline HBsAg levels (>3Log10IU / mL). See Figure 5. Six of eight SVR responders had low baseline HBsAg levels (≤3Log10IU / mL). In the NOT ON-NUC cohort, the proportion of subjects with EOT virologic response was also higher in patients with low baseline HBsAg levels (≤3Log10IU / mL). See Figure 7. Both of the two SVR responders had low baseline HBsAg levels (≤3Log10IU / mL).

[0162] Additionally, in the NOT ON-NUC cohort, end-of-treatment virologic response by subgroups - baseline HBV DNA status was analyzed as a secondary endpoint. See Figure 8.

[0163] Receiver operating characteristic (ROC) tables were used to compare various cuts of the data as baseline HBsAg values ​​increased. ROC tables can be used to evaluate each "cut" in terms of including subjects who are responders versus excluding subjects who are non-responders. See, for example, Tables 7 and 8.

[0164] [Table 7]

[0165] [Table 8]

[0166] Example 3 Mechanistic pharmacokinetic / pharmacodynamic modeling of the concurrent effects of bepirovirsen on changes in hepatitis B surface antigen (HBsAg) and alanine transaminase (ALT) in patients with chronic hepatitis B (CHB) After bepirovirsen treatment, a decrease in HBsAg was often observed preceding or parallel to a transient increase in alanine transaminase (ALT), suggesting increased immune-mediated clearance of infected hepatocytes and subsequent release of ALT.We developed a mechanistic pharmacokinetic (PK) / pharmacodynamic (PD) model to describe bepirovirsen systemic exposure over time and its effect on changes in HBsAg and ALT, and to identify patient characteristics that may be predictive of exposure and treatment response.

[0167] PK, HBsAg and ALT data were pooled from a phase 1 study (GSK study 213725) in healthy volunteers (n=28, dose range 75-450 mg), a phase 2a study (GSK study 205695) and a phase 2b study (GSK study 209668) in CHB patients (n=31 and 455, dose 150 or 300 mg, respectively). Bepirovirsen was administered subcutaneously for up to 4 weeks in phase 1 and 2a studies and for 12 or 24 weeks in phase 2b. The developed PK / PD model estimated HBsAg levels below the lower limit of quantification (LLOQ, <0.05 IU / mL) using a likelihood-based approach and predicted the complete HBsAg profile during the treatment and non-treatment periods. A threshold was set for continued viral suppression, reflecting an increased probability that participants would achieve and maintain HBsAg levels below the LLOQ (BLQ) at study end if the predicted HBsAg level was below the threshold. To explain ALT elevation, direct and indirect drug effects on ALT were considered. Indirect effects were caused by a decrease in HBsAg, resulting in immune-mediated hepatocyte senescence and subsequent release of ALT. Using the developed PK / PD model, we assessed the effect of bepirovirsen loading dose (LD), as well as baseline patient characteristics (e.g., demographics, HBsAg, HBeAg, genotype) on response to bepirovirsen treatment.

[0168] This model accurately captured the changes in exposure to bepirovirsen over time, as well as the changes in HBsAg and ALT. The increase in ALT was mainly due to HBsAg suppression rather than a direct drug effect, and baseline HBsAg was identified as a significant predictor of treatment success. The results of the model showed that incorporating LD during the first two weeks of treatment provided no significant benefit in efficacy and there was no difference in the exposure-response relationship based on the combination administration of nucleos(t)ides. Examples of the observed and model-predicted PK, HBsAg, and ALT profiles of individual subjects are shown in Figures 9A, 9B, 10A, and 10B (the dots represent the observed data, and the dashed and solid lines represent the population and individual subject predictions based on the PK / PD model). The model predicted the percentage of subjects who achieved HBsAg <LLOQ at 12 weeks, 24 weeks, and 48 weeks (during the non-treatment period) (Figures 11A, 11B, and 11C).

[0169] The developed PK / PD model becomes a useful tool for making important decisions regarding phase 3 planning, such as dose selection, treatment duration, and patient population. In the simulation, patients with low baseline HBsAg levels were predicted to have a higher likelihood of achieving HBsAg <LLOQ after administration of bepirovirsen (BPV) compared to the entire population in various BPV dosing regimens (range of HBsAg <3000 IU / mL: 30.1% - 40.0% and 12.9% - 16.5% at EOT and EOS respectively, range of the entire population: 20.1% - 26.1% and 9.2% - 10.7% at EOT and EOS respectively) (Table 9). Similar response rates were predicted regardless of the presence or absence of a loading dose. In the population with low baseline HBsAg, a higher percentage of patients were predicted to achieve a response with 24-week and 12-week BPV treatment (39.9% vs. 30.1% and 16.3% vs. 12.9% at EOT and EOS respectively) (Table 9).

[0170]

Table 9

[0171] Example 4 Completion of Phase 2b Clinical Trial Results In the ON-NUC cohort, 227 patients (73% male, 52% Asian, 69% HBeAg negative, 28% HBsAg ≤ 3 log10 IU / mL) were included in the intention-to-treat population (68, 68, 68, and 23 in groups 1–4, respectively). Virologic response (VR) by 24 weeks after BPV treatment was achieved in 6 (9%), 6 (9%), 2 (3%), and 0 patients in groups 1–4, respectively. VR data over time are shown in Figure 12. Patients with low baseline HBsAg levels (≤ 3 log10 IU / mL) were more likely to achieve SVR (14%) compared with patients with high baseline HBsAg levels (> 3 log10 IU / mL; 3%). Ten HBeAg negative patients in groups 1–3 sustained VR, whereas four HBeAg positive patients in groups 1–3 sustained VR. The 300 mg BPV × 24 weeks (arm 1) and 300 mg BPV × 12 weeks + 150 mg BPV × 12 weeks (arm 2) had the highest proportion of patients who achieved SVR after 24 weeks of BPV treatment. See Table 10.

[0172] [Table 10]

[0173] In the NOT-NUC cohort, 230 patients (54% male, 57% Asian, 74% HBeAg negative, 19% HBsAg ≤ 3 log10 IU / mL) were included in the intent-to-treat population (70, 68, 68, and 24 in groups 1-4, respectively). VR was achieved by 24 weeks after BPV treatment in 7 (10%), 4 (6%), 1 (1%), and 0 patients in groups 1-4, respectively. VR data over time are shown in Figure 13. Patients with low baseline HBsAg levels (≤ 3 log10 IU / mL) were more likely to have sustained VR (14%) compared with patients with high baseline HBsAg levels (> 3 log10 IU / mL; 3%). Twelve HBeAg negative patients in groups 1-3 sustained VR, but none were HBeAg positive. The 300 mg BPV treatment for 24 weeks (arm 1) had the highest proportion of patients who achieved SVR 24 weeks after BPV treatment. See Table 11.

[0174] [Table 11]

[0175] Example 5 Evaluating the efficacy and safety of bepirovirsen treatment in HBeAg-negative nucleos(t)ide analogue-treated participants with chronic hepatitis B A. Test Plan This study is a phase 3, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of bepirovirsen treatment in HBeAg-negative chronic HBV-infected participants receiving NA treatment (Figure 14). 24 weeks of double-blind treatment 24 weeks of NA treatment Discontinuation of NA and 24-week follow-up or continuation of NA for 24 weeks For participants who discontinued NA treatment at week 48, duration of response and additional 24-week follow-up

[0176] The study groups were stratified based on HBsAg levels at screening (HBsAg ≥ 100 IU / mL to ≤ 1000 IU / mL or > 1000 IU / mL to ≤ 3000 IU / mL).

[0177] B. Objectives and Endpoints The terms used in this study are defined below.

[0178] [Table 12]

[0179] The primary endpoint was to evaluate the efficacy of 24 weeks of bepirovirsen (with a loading dose) treatment to achieve functional cure in NA-treated, HBeAg-negative, chronically HBV-infected participants with baseline HBsAg ≤1000 IU / mL.

[0180] Key secondary endpoints were: ·To evaluate the efficacy of 24 weeks of bepirovirsen (with a loading dose) treatment to achieve functional cure in HBeAg-negative chronic HBV-infected participants with baseline HBsAg ≤ 3000 IU / mL and receiving NA treatment; ·To evaluate the efficacy of 24-week bepirovirsen (with a loading dose) treatment on HBV DNA suppression at the end of treatment after a period of therapy in HBeAg-negative, chronically HBV-infected participants with baseline HBsAg ≤ 1000 IU / mL receiving NA treatment; To evaluate the efficacy of 24 weeks of bepirovirsen (with a loading dose) treatment on HBV DNA suppression after a period of therapy in HBeAg-negative, chronically HBV-infected participants with baseline HBsAg ≤ 3000 IU / mL receiving NA treatment

[0181] Safety Objective: To evaluate the safety and tolerability of bepirovirsen when administered with a loading dose for a period of 24 weeks in HBeAg-negative chronic HBV-infected participants receiving NA treatment.

[0182] Exploratory objectives and endpoints are: [Table 13] JPEG2025511096000014.jpg147170

[0183] C. Study Population: Inclusion and Exclusion Criteria Inclusion criteria for this study included: 1. Be at least 18 years of age at the time of signing informed consent (if country / institution has different age requirements for consent, that country / institution may require stricter [e.g., higher age] restrictions) 2. Participants must be HBeAg negative at screening 3. Participants with documented chronic HBV infection ≥6 months prior to screening Currently receiving stable NA therapy is defined as no changes to the NA dosing regimen for at least 6 months prior to screening, and no planned changes to the stable regimen during the study period. 4. Plasma or serum HBsAg concentration >100 IU / mL but not exceeding 3000 IU / mL 5. Plasma or serum HBV DNA concentrations must be adequately suppressed (defined as plasma or serum HBV DNA < 90 IU / mL) 6. Alanine aminotransferase (ALT) ≦2x ULN 7. Participants willing and able to discontinue NA treatment according to the protocol

[0184] Exclusion criteria were as follows: Medical conditions 1. Medical history (e.g., moderate to severe liver disease other than chronic HBV, acute coronary syndrome within 6 months of screening, major surgery within 3 months of screening, significant / unstable cardiac disease, uncontrolled diabetes, bleeding disorder or coagulation disorder) or clinically significant abnormalities on physical exam other than chronic HBV infection 2. Co-infection with: Participants with a current history of Hepatitis C or who have been cured within 12 months of screening b. Human immunodeficiency virus (HIV) Hepatitis D virus 3. History or suspicion of cirrhosis and / or evidence of cirrhosis as determined by: APRI>2 and FibroSure / FibroTest result>0.7 Positive results in only one parameter (APRI or FibroSure / FibroTest) require consultation with the medical monitor before admission to the study b. Regardless of APRI or Fibrosure / FibroTest scores, participants will be excluded from the study if they meet one of the following criteria documented in their medical history: Liver biopsy (i.e. Metavir score F4) ·Liver stiffness >12kPa 4. Diagnosis or suspicion of hepatocellular carcinoma evidenced by: a. α-protein concentration ≥ 200ng / mL; b. If screening alpha-fetoprotein concentration is ≥ 50ng / mL < 200ng / mL, there must be no liver mass documented by imaging within 6 months prior to randomization 5. History of malignancy within the past 5 years, except for certain cancers that are curable by surgical resection (e.g., skin cancer). Participants undergoing evaluation for possible malignancy will be excluded. 6. History of vasculitis or presence of symptoms and signs that may be vasculitis (e.g., vasculitic skin rash, skin ulcers, repeated detection of blood in the urine without identified cause) or history / presence of other diseases that may be associated with vasculitic pathology (e.g., systemic lupus erythematosus, rheumatoid arthritis, relapsing polychondritis, mononeuritis multiplex) 7. History of extrahepatic disorders that may be related to HBV immunopathology (e.g., nephrotic syndrome, any type of glomerulonephritis, polyarteritis nodosa, cryoglobulinemia, uncontrolled hypertension) 8. History of alcohol or drug abuse / dependence: Current alcohol use that the investigator believes may interfere with participant compliance b. History or current substance abuse / dependence that the investigator believes may interfere with the participant's compliance i. Illegal drugs and substances with the potential for abuse. Medications, whether over-the-counter or prescription, that participants use as directed are acceptable and do not meet the exclusion criteria. Previous Treatment History / Concomitant Therapy 9.Currently taking, or within 3 months of screening, any immunosuppressant other than short-term therapy (≤ 2 weeks) or topical / inhaled steroids (e.g., prednisone) 10. Participants for whom immunosuppressive therapy, including therapeutic doses of steroids, is not recommended should not be considered for inclusion in this study. 11.Currently receiving or have received interferon-containing therapy within 12 months of screening 12. Participant requiring anticoagulant therapy (e.g., warfarin, factor Xa inhibitors) or antiplatelet agents (e.g., clopidogrel or aspirin), unless, in the investigator's discretion, treatment can be safely discontinued for the duration of the study. Occasional use is permitted. 13. Participant has participated in a clinical trial and received an investigational drug within the following period prior to the first dose date of this study: 5 half-lives (if known) or 2 times the duration of the biological effect of the investigational drug (if known), whichever is longer, or 90 days (if half-life or duration is unknown). 14. Prior treatment with oligonucleotides or siRNAs (excluding COVID vaccination) within 12 months prior to the first dose 15. Prior treatment with bepirovirsen Diagnostic evaluation 16. Fridericia QTcF ≥ 450 msec (if the screening ECG shows a QTcF ≥ 450 msec, the average of three measurements should be used to determine whether the participant meets the exclusion criteria) 17. Laboratory test results such as the following: Serum albumin ≦ 3.5g / dL b. Glomerular filtration rate (GFR) ≦ 60mL / min / 1.73m as calculated by the CKD-EPI formula (JSN-CKDI formula in Japan) 2 c.INR>1.25 d. Platelet count <140×10 9 / L e. Total bilirubin > 1.25 × ULN Participants with unconjugated hyperbilirubinemia (total bilirubin >1.25×ULN) should discuss inclusion in this study with the medical monitor. f. Urinary albumin / creatinine ratio (ACR) >0.03mg / mg (or >30mg / g). If the ACR exceeds this threshold, eligibility can be confirmed by a second measurement. · If the calculated value of urinary ACR in the participant is > 0.03 mg / mg (or > 30 mg / g) due to low urinary albumin and low urinary creatinine level in the participant, the principal investigator of the trial shall confirm that the participant has no history of diabetes, hypertension, or other risk factors that may affect renal function, and consult with the medical monitor or his / her designee. Other Exclusions 18. History of prior exposure / hypersensitivity to bepirovirsen or its components, or history of prior exposure to drugs or other allergies that the principal investigator of the trial or the medical monitor determines to be contraindications to participation 19. Participants who do not wish to discontinue NA therapy for chronic HBV infection

[0185] D. Test Assessment and Procedures The primary efficacy endpoint is functional cure as defined herein. Measurements of the primary objectives of efficacy include HBsAg and HBV DNA.

[0186] After achieving HBsAg < 0.05 IU / mL and HBV DNA < LLOQ, any detectable HBsAg or HBV DNA needs to be confirmed by retesting within 1 week (±3 days) after receiving the test results. Retesting is not required at week 96 (end of the study visit).

[0187] Safety assessments are conducted at the scheduled time points during the study period, and the time points of 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 test evaluations.

[0188] Adverse events (AEs) and serious adverse events (SAEs) are detected, recorded, and reported. Particularly notable adverse events include elevated ALT (relapse), vascular inflammation and complement activation, thrombocytopenia, and kidney impairment.

[0189] Blood samples are taken to measure the plasma concentration of bepirovirsen. Pharmacodynamic parameters include, but are not limited to, the following: · Category: virological response, serum clearance (HBsAg), HBV DNA <LLOQ, and seroconversion (HBsAb) · Change from baseline: HBsAg, HBV DNA, and HBsAb levels · Safety assessments including, but not limited to, vital signs, laboratory measurements, and AEs

[0190] Sample collection for other biomarker studies is also part of this study. These exploratory biomarker samples are taken to evaluate the etiology of chronic HBV infection, the absorption, distribution, metabolism, or excretion of bepirovirsen, or the participants' response to bepirovirsen. Additionally, ongoing research may identify other proteins, transcripts, biomarkers, or assays related to bepirovirsen treatment, response to bepirovirsen, or the etiology of chronic HBV infection, and these will also be evaluated in these samples.

[0191] Example 6 Correction for a Phase 3 study of bepirovirsen in participants with chronic hepatitis B receiving nucleos(t)ide analogue therapy This amendment was made to include HBeAg-positive chronic HBV-infected participants, increase the monitoring frequency after NA discontinuation, and switch the primary and secondary endpoints.

[0192] Approximately 750 - 1050 participants will be randomly assigned to 24 weeks of treatment with bepirovirsen or placebo (2:1 ratio). The planned minimum sample size of 750 provides 99% power for functional cure, the primary endpoint in the baseline HBsAg ≤ 3000 IU / mL population, and 98% power for functional cure, an important secondary endpoint in the baseline HBsAg ≤ 1000 IU / mL population.

[0193] The primary endpoint was to evaluate the efficacy of 24 weeks of bepirovirsen (with a loading dose) treatment to achieve functional cure in NA-treated chronically HBV-infected participants with baseline HBsAg ≤1000 IU / mL.

[0194] Key secondary endpoints were: ·To evaluate the efficacy of 24 weeks of bepirovirsen (with a loading dose) treatment to achieve functional cure in chronically HBV-infected participants with baseline HBsAg ≤ 3000 IU / mL and receiving NA treatment; ·To evaluate the effect of 24 weeks of bepirovirsen (with a loading dose) on HBV DNA suppression at the end of treatment after a period of therapy in chronically HBV-infected participants with baseline HBsAg ≤ 1000 IU / mL and receiving NA treatment; To evaluate the efficacy of 24 weeks of bepirovirsen (with a loading dose) on post-treatment HBV DNA suppression after a period of therapy in participants with chronic HBV infection and baseline HBsAg ≤ 3000 IU / mL receiving NA therapy

[0195] Safety Objective: To evaluate the safety and tolerability of bepirovirsen when administered with a loading dose for a 24-week period in participants with chronic HBV infection receiving NA treatment.

[0196] 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 illustrative and are not intended to limit the scope of the invention. Modifications and other uses thereof will be apparent to those skilled in the art which are encompassed within the spirit of the invention as defined by the appended claims.

[0197] All patent applications, patents, and printed publications cited herein are hereby incorporated by reference in their entirety, except for definitions, disclaimers, or disclaimers of subject matter, and except to the extent the incorporated material contradicts the explicit disclosure of this specification, in which case the language of the present disclosure shall control.

Claims

1. A pharmaceutical composition comprising bepirovirsen for the treatment of chronic hepatitis B in a human, wherein the human has an HBsAg baseline level that does not exceed a threshold level.

2. The treatment is (a) Determining that the person has an HBsAg baseline level that does not exceed a threshold level; (b) Administering a therapeutically effective amount of bepirovirsen to the person. The pharmaceutical composition according to claim 1, comprising the following:

3. The treatment is (a) Measuring the baseline level of the human HBsAg; (b) comparing the HBsAg baseline level with a threshold level; and (c) If the HBsAg baseline level does not exceed the threshold level, administer a therapeutically effective amount of bepirovirsen to the person. The pharmaceutical composition according to claim 1, comprising the following:

4. The pharmaceutical composition according to claim 1, wherein the threshold level is in the range of 500 IU / mL to 4000 IU / mL.

5. The pharmaceutical composition according to claim 1, wherein the threshold level is 1000 IU / mL.

6. The pharmaceutical composition according to claim 1, wherein the threshold level is 3000 IU / mL.

7. The pharmaceutical composition according to claim 1, wherein the person has not received treatment with another HBsAg lowering agent or immunomodulator.

8. The pharmaceutical composition according to claim 1, wherein bepirovirsen is administered by subcutaneous injection.

9. The pharmaceutical composition according to claim 1, wherein bepirovirsen is administered once a week in a dose of 150 mg or 300 mg.

10. The pharmaceutical composition according to claim 1, wherein bepirovirsen is administered for 12 to 48 weeks.

11. The pharmaceutical composition according to claim 9, wherein bepirovirsen is administered weekly, and additional loading doses are administered on the 4th and 11th days after the initial dose during the first two weeks.

12. The pharmaceutical composition according to claim 1, wherein the human is under treatment with a stable nucleoside or nucleotide analog (NA).

13. The pharmaceutical composition according to claim 12, wherein the NA therapy is lamivudine, adefovir, adefovir dipivoxil, terbivudine, entecavir, tenofovir, tenofovir disoproxil fumarate, or tenofovir alafenamide, or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical composition according to claim 1, wherein the human being has not been treated with a nucleoside or nucleotide analog (NA).

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the human is HBeAg negative before treatment with bepilovirsen.

16. The pharmaceutical composition according to any one of claims 1 to 14, wherein the human is HBeAg positive before treatment with bepilovirsen.

17. A method for determining the potential increase in the pharmacological efficacy of bepilovirsen treatment in a person with chronic hepatitis B, (a) obtaining the baseline level of the human HBsAg; and (b) Comparing the HBsAg baseline level with the threshold level. It includes, A method that indicates an increased potential for the pharmacological efficacy of the treatment if the HBsAg baseline level does not exceed the threshold level.

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