Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7088—Compounds having three or more nucleosides or nucleotides
  • A61K31/711—Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7088—Compounds having three or more nucleosides or nucleotides
  • A61K31/712—Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
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  • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
  • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
  • C12N15/09—Recombinant DNA-technology
  • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
  • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
  • C12N15/1131—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
  • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/66—Phosphorus compounds
  • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
  • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
  • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/20—Antivirals for DNA viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
  • C12N2310/00—Structure or type of the nucleic acid
  • C12N2310/10—Type of nucleic acid
  • C12N2310/11—Antisense

Definitions

• 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, wherein the subject has a HBsAg baseline level of not greater than a threshold level.
• Hepatitis B virus is a strict hepatotropic, partially double-stranded DNA virus. Although DNA is the genetic material, the replication cycle involves a reverse transcription step to copy a pregenomic RNA into DNA.
• Primary infection with HBV causes an acute hepatitis with symptoms of organ inflammation, fever, jaundice, and increased liver transaminases in blood. Those patients that are not able to overcome the acute virus infection suffer a chronic disease progression over many years with increased risk of developing cirrhotic liver or liver cancer.
• HBV infection results in the production of two different particles: 1) the HBV virus itself (or Dane particle) which includes a viral capsid assembled from the HBV core antigen protein (HBcAg) and is covered by the hepatitis B surface antigen (HBsAg) and is capable of reinfecting cells and 2) subviral particles (or SVPs) which are high density lipoprotein-like particles comprised of lipids, cholesterol, cholesterol esters and the small and medium forms of the hepatitis B surface antigen (HBsAg) which are non-infectious.
• SVPs subviral particles
• HBV infected cells also secrete a soluble proteolytic product of the pre-core protein called the HBV e-antigen (HBeAg).
• HBeAg HBV e-antigen
• the presence of HBeAg in the serum of patients can serve as a marker of active replication in chronic hepatitis.
• nucleoside and nucleotide therapies entecavir and tenofovir have been successful at reducing viral load (HBV DNA), but the rates of HBeAg seroconversion and HBsAg loss are even lower than those obtained using IFNa therapy.
• Other similar therapies including lamivudine (3TC), telbivudine (LdT), and adefovir are also used, but for nucleoside/nucleotide therapies in general, the emergence of resistance limits therapeutic efficacy.
• CHB chronic hepatitis B
• the present disclosure provides a method for treating a hepatitis B virus (HBV) infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of bepirovirsen, wherein the subject has a HBsAg baseline level of not greater than a threshold level.
• HBV hepatitis B virus
• the present disclosure provides a method for treating chronic hepatitis B (CHB) in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of bepirovirsen, wherein the human has a HBsAg baseline level of not greater than a threshold level.
• CHB chronic hepatitis B
• the present disclosure provides a method for treating chronic hepatitis B in a human in need thereof, the method comprising:
• the present disclosure provides a method for treating chronic hepatitis B in a human in need thereof, the method comprising:
• the present disclosure provides a method for determining an increased likelihood of pharmacological effectiveness of treatment by bepirovirsen in a human with chronic hepatitis B, the method comprising:
• the present disclosure provides a method for increasing response rate for treating chronic hepatitis B by bepirovirsen in a human in need thereof, the method comprising:
• the present disclosure provides bepirovirsen for use in a method of treating chronic hepatitis B in a human in need thereof, wherein the human has a HBsAg baseline level of not greater than a threshold level.
• the present disclosure provides bepirovirsen for use in a method of treating chronic hepatitis B in a human in need thereof, the method comprising:
• FIG. 1 depicts the study design of a Phase 2b clinical trial to assess efficacy and safety of treatment with bepirovirsen in patients with chronic hepatitis B (CHB).
• CHB chronic hepatitis B
• FIG. 2 depicts the percentage of ON-NUC subjects with HBsAg ⁇ LLOQ, > LLOQ - ⁇ 100 lU/mL, and > 100 lU/mL over time by treatment arm.
• FIG. 3 depicts the percentage of NOT ON-NUC subjects with HBsAg ⁇ LLOQ, > LLOQ - ⁇ 100 lU/mL, and > 100 lU/mL over time by treatment arm.
• FIG. 4 depicts the proportion of ON-NUC subjects with virologic response in the end of treatment analysis window by subgroup based on HBeAg baseline levels by treatment arm.
• FIG. 5 depicts the proportion of ON-NUC subjects with virologic response in the end of treatment analysis window by subgroup based on HBsAg baseline levels by treatment arm.
• FIG. 6 depicts the proportion of NOT ON-NUC subjects with virologic response in the end of treatment analysis window by subgroup based on HBeAg baseline levels by treatment arm.
• FIG. 7 depicts the proportion of NOT ON-NUC subjects with virologic response in the end of treatment analysis window by subgroup based on HBsAg baseline levels by treatment arm.
• FIG. 8 depicts the proportion of NOT ON-NUC subjects with virologic response in the end of treatment analysis window by subgroup based on HBV DNA baseline levels by treatment arm.
• FIGs. 9A and 9B depict observed and model-predicted individual subject PK, HBsAg, and ALT profiles of one subject whose HBsAg level increased after the end of bepirovirsen treatment.
• FIGs. 10A and 10B depict observed and model-predicted individual subject PK, HBsAg, and ALT profiles of one subject whose HBsAg level remained low after the end of bepirovirsen treatment.
• FIGs. 11A-11C depict the predicted percentages of subjects who achieved HBsAg ⁇ LLOQ at 12 weeks, at 24 weeks, and at 48 weeks (during the off-treatment period).
• FIG. 12 depicts proportion of ON-NUC subjects achieving HBsAg ⁇ LLOQ and HBV DNA ⁇ LLOQ over time by treatment arm.
• FIG. 13 depicts proportion of NOT ON-NUC subjects achieving HBsAg ⁇ LLOQ and HBV DNA ⁇ LLOQ over time by treatment arm.
• FIG. 14 depicts the study design of a Phase 3 clinical trial to assess efficacy and safety of treatment with bepirovirsen in patients with chronic hepatitis B (CHB).
• CHB chronic hepatitis B
• Antisense oligonucleotide refers to a single-stranded oligonucleotide having a nucleobase sequence that permits hybridization to a corresponding region or segment of a target nucleic acid.
• Baseline values of certain substances are measured in the blood samples taken from patients before the first dose of treatment.
• Bepirovirsen is an ASO currently in clinical evaluation for treating HBV infections. It is compound ISIS No. 505358 as disclosed in WO2012/145697. Bepirovirsen has 20 linked nucleosides and has a nucleobase sequence of 5'-GCAGAGGTGAAGCGAAGTGC-3' (SEQ ID NO: 1), and it includes: a gap segment consisting of ten linked deoxynucleosides, a 5' wing segment consisting of 5 linked nucleosides, and a 3' wing segment consisting of 5 linked nucleosides, wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment, wherein each nucleoside of each wing segment includes a 2'-O-methoxyethyl sugar, wherein each internucleoside linkage is a phosphorothioate linkage, and wherein each cytosine is a 5-methylcytosine.
• the CAS Registry Number of bepirovirsen
• Chronic hepatitis B (CHB) infection occurs when a person initially suffers from an acute infection but is then unable to fight off the infection. About 90% of infants infected at birth will progress to chronic disease. However, as a person ages, the risk of chronic infection decreases such that between 20%-50% of people infected as children and less than 10% of people infected as adults will progress from acute to chronic infection.
• the terms “chronic hepatitis B infection”, “chronic hepatitis B”, “chronic HBV infection”, and “CHB” are used interchangeably herein.
• Dose refers to a specified quantity of an active pharmaceutical agent provided in a single administration, or in a specified time period.
• a dose may be administered in two or more boluses, tablets, or injections.
• the desired dose requires a volume not easily accommodated by a single injection.
• two or more injections may be used to achieve the desired dose.
• a dose may be administered in two or more injections to minimize injection site reaction in an individual.
• Dosing regimen is a combination of doses designed to achieve one or more desired effects.
• Duration refers to the period of time during which an activity or event continues. In certain embodiments, the duration of treatment is the period of time during which doses of a pharmaceutical agent are administered.
• “Functional cure” refers to sustained suppression (24 weeks or longer) of HB V DNA ( ⁇ LLOQ) off all HBV treatment with HBsAg loss ( ⁇ 0.05 lU/mL) with or without HBsAb after a finite duration of therapy.
• HBV refers to mammalian hepatitis B virus, including human hepatitis B virus.
• the term encompasses geographical genotypes of hepatitis B virus, particularly human hepatitis B virus, as well as variant strains of geographical genotypes of hepatitis B virus.
• Human geographical genotypes of HBV include genotypes: A (Northwest Europe, North America, Central America); B (Indonesia, China, Vietnam); C (East Asia, Korea, China, Japan, Polynesia, Vietnam); D (Mediterranean area, Middle East, India); E (Africa); F (Native Americans, Polynesia); G (United States, France); and H (Central America).
• HBV antigen refers to any hepatitis B virus antigen or protein, including core proteins such as “hepatitis B core antigen” or “HBcAg,” “hepatitis B E antigen” or “HBeAg,” and envelope proteins such as “HBV surface antigen” or “HBsAg.”
• Hepatitis B E antigen or “HBeAg” is a secreted, non-particulate form of HBV core protein.
• HBV antigens HBeAg and HBeAg share primary amino acid sequences, so show cross-reactivity at the T cell level.
• HBeAg is not required for viral assembly or replication, although studies suggest they may be required for establishment of chronic infection.
• HBV surface antigen is the envelope protein of infectious HBV viral particles (Dane Particles), but is also secreted as a non-infectious particle (subviral particle, SVP) with serum levels 1000-fold higher than HBV viral particles.
• SVP non-infectious particle
• the serum levels of HBsAg in an infected person or animal can be as high as 1000 pg/mL (Kann and Gehrlich (1998) Topley & Wilson’s Microbiology and Microbial Infections, 9th ed. 745).
• HBV-related condition refers to any disease, biological condition, medical condition, or event which is exacerbated, caused by, related to, associated with, or traceable to a hepatitis B virus infection, exposure, or illness.
• the term hepatitis B-related condition includes chronic HBV infection, inflammation, fibrosis, cirrhosis, liver cancer, serum hepatitisjaundice, liver inflammation, liver fibrosis, liver cirrhosis, liver failure, diffuse hepatocellular inflammatory disease, hemophagocytic syndrome, HBV viremia, liver disease related to transplantation, and conditions having symptoms which may include any or all of the following: flu-like illness, weakness, aches, headache, fever, loss of appetite, diarrhea, nausea and vomiting, pain over the liver area of the body, clay- or grey-colored stool, itching all over, and dark-colored urine, when coupled with a positive test for presence of a hepatitis B virus, a hepatitis B viral antigen, or a positive test for the
• “Induce,” “inhibit,” “potentiate,” “elevate,” “increase,” “decrease” or the like generally denote quantitative differences between two states. Such terms may refer to a statistically significant difference between the two states.
• an amount effective to inhibit the activity or expression of HBV refers to the level of activity or expression of HBV in a treated cell and this will quantitatively differ, and may be statistically significant, from the level of HBV activity or expression in untreated cells. Such terms are applied to, for example, levels of expression and levels of activity.
• Nucleobase refers to a heterocyclic moiety capable of pairing with a base of another nucleic acid.
• Nucleobase sequence refers to the order of contiguous nucleobases independent of any sugar, linkage, and/or nucleobase modification.
• “Pharmaceutically acceptable salts” refer to physiologically acceptable salts of compounds, i.e., salts that retain the desired biological activity of the parent active ingredients and do not impart undesired toxicological effects thereto.
• Phosphorothioate linkage refers to a linkage between nucleotides where the phosphodiester bond is modified by replacing one of the non-bridging oxygen atoms with a sulfur atom.
• a phosphorothioate linkage is a modified intemucleoside linkage.
• Regular is defined as a portion of, for example, a nucleic acid having at least one identifiable structure, function, or characteristic.
• “Stable nucleoside or nucleotide analogue (NA) therapy” is defined as no changes to the nucleoside or nucleotide analogue regimen for at least 6 months prior to the treatment and with no planned changes to the regimen for the duration of the treatment. “Segments” may refer to smaller, or sub-portions of, regions within, for example, a nucleic acid.
• “Seroclearance” refers to the clearance or removal of an antigen (like HBsAg and/or HBV DNA levels) from the blood (or a measurement below the lower limit of quantification (i.e. ⁇ LLOQ) by the lab) in a CHB patient following treatment.
• an antigen like HBsAg and/or HBV DNA levels
• ⁇ LLOQ the lower limit of quantification
• Subject refers to a human or non-human animal selected for treatment or therapy. In one embodiment, the subject is a human.
• “Therapeutically effective amount” refers to the administration of a pharmaceutical agent to a subject, either alone or as part of a pharmaceutical composition and either in a single dose or as part of a series of doses, in an amount capable of having any detectable, positive effect on any symptom, aspect, or characteristic of a disease or condition when administered to the subject.
• Treatment refers to administering a pharmaceutical agent to a subject to affect an alteration or improvement of the disease or condition.
• treating as used herein in relation to chronic hepatitis B infection refers to the administration of suitable compositions with the intention of reducing the symptoms of CHB, preventing the progression of CHB or reducing the level of one or more detectable markers of CHB.
• the present disclosure provides a method for treating a hepatitis B virus (HBV) infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of bepirovirsen, wherein the subject has a HBsAg baseline level of not greater than a threshold level.
• HBV infection is chronic hepatitis B (CHB).
• the present disclosure provides a method for treating chronic hepatitis B in a human in need thereof, the method comprising:
• the HBsAg baseline level in the blood of a CHB patient is measured by methods known in the art before the start of treatment.
• the step “determining” can be achieved by measuring the HBsAg baseline level of the patient and comparing the baseline level with a predetermined threshold level.
• the step “determining” can also be achieved by receiving the HBsAg baseline level information from the patient or a testing facility and comparing the HBsAg baseline level with a predetermined threshold level.
• the present disclosure provides a method for treating chronic hepatitis B in a human in need thereof, the method comprising:
• the present disclosure provides a method for determining an increased likelihood of pharmacological effectiveness of treatment by bepirovirsen in a human with chronic hepatitis B, the method comprising:
• the step “obtaining” can be achieved by measuring the HBsAg baseline level of the patient directly or receiving the HBsAg baseline level information from the patient or a testing facility.
• the present disclosure provides a method for increasing response rate for treating chronic hepatitis B by bepirovirsen in a human in need thereof, the method comprising:
• HBsAg baseline level 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-a2a and adefovir,” Antivir. Ther. 2013;18(7):895-904.
• HBsAg baseline level below 400 lU/mL was identified as a good predictor for treating HBeAg-negative patients with PEG-IFN and adefovir.
• a low HBsAg baseline level could not predict HBsAg loss in HBeAg-positive patients in the same study.
• bepirovirsen can be administered as a free acid, a pharmaceutically acceptable salt thereof (e.g., a sodium salt), or a combination thereof.
• bepirovirsen is administered as a free acid.
• bepirovirsen is administered as a pharmaceutically acceptable salt thereof (e.g., a sodium salt).
• bepirovirsen is administered as a combination of a free acid and a sodium salt.
• bepirovirsen is administered by subcutaneous injection.
• the “therapeutically effective amount of bepirovirsen” refers to the amount of bepirovirsen free acid. In some embodiments, the therapeutically effective amount of bepirovirsen is about 150 mg to 450 mg once weekly. In some embodiments, the therapeutically effective amount of bepirovirsen is about 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 450 mg once weekly, or in a range between any two preceding values. In some embodiments, the therapeutically effective amount of bepirovirsen is about 150 mg once weekly. In some embodiments, the therapeutically effective amount of bepirovirsen is about 300 mg once weekly.
• bepirovirsen is administered weekly with additional loading doses in the first two weeks on Day 4 and Day 11 following the first dose. In some embodiments, bepirovirsen is administered at a dose of about 300 mg once weekly with additional loading doses in the first two weeks on Day 4 and Day 11 following the first dose. In a particular embodiment, the loading dose is 300 mg.
• bepirovirsen is administered for about 12 to 48 weeks. In some embodiments, bepirovirsen 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 for a range between any two preceding periods. In one embodiment, bepirovirsen is administered for 12 weeks. In one embodiment, bepirovirsen is administered for 24 weeks. In one embodiment, bepirovirsen is administered for 36 weeks. In one embodiment, bepirovirsen is administered for 48 weeks. In one embodiment, bepirovirsen and is administered for 12 weeks or 24 weeks, with additional loading doses on Day 4 and Day 11 following the first dose.
• bepirovirsen is administered at a dose of about 300 mg once weekly for 24 weeks. In some embodiments, bepirovirsen is administered at a dose of about 300 mg once weekly for 12 weeks. In some embodiments, bepirovirsen is administered at a dose of about 300 mg once weekly for 12 weeks, and then at a dose of about 150 mg once weekly for 12 weeks.
• bepirovirsen is administered at a dose of about 300 mg once weekly for 24 weeks, with additional loading doses each of 300 mg, on Day 4 and Day 11 following the first dose. In some embodiments, bepirovirsen is administered at a dose of about 300 mg once weekly for 12 weeks, with additional loading doses each of 300 mg on Day 4 and Day 11 following the first dose.
• the present disclosure provides a method for treating CHB in a human in need thereof comprising administering to the human a therapeutically effective amount of bepirovirsen, wherein the subject has a HBsAg baseline level of not greater than a threshold level.
• the threshold level of the HBsAg baseline is in the range of about 500 lU/mL to 10,000 lU/mL, i.e., about 2.7 loglO lU/mL to 4.0 loglO lU/mL.
• the threshold level of the HBsAg baseline 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 lU/mL, or in a range between any two of the preceding numbers.
• the threshold level of the HBsAg baseline is about 1000, 2000, or 3000 lU/mL.
• the threshold level of the HBsAg baseline is about 1000 lU/mL.
• the threshold level of the HBsAg baseline is about 3000 lU/mL.
• the threshold level of the HBsAg baseline 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 loglO lU/mL, or in a range between any two of the preceding numbers.
• the threshold level of the HBsAg baseline is about 3.0 to 4.0 loglO lU/mL.
• the threshold level of the HBsAg baseline is about 3.0 to 3.5 loglO lU/mL.
• the threshold level of the HBsAg baseline is about 3.0 loglO lU/mL.
• the threshold level of the HBsAg baseline is about 3.5 loglO lU/mL.
• the present disclosure provides a method for treating CHB in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of bepirovirsen, wherein the human has a HBsAg baseline level of not greater than about 1000 lU/mL. In one embodiment, the present disclosure provides a method for treating CHB in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of bepirovirsen, wherein the human has a HBsAg baseline level of not greater than about 3000 lU/mL.
• the present disclosure provides a method for treating CHB in a human in need thereof, the method comprising administering bepirovirsen to the human at a dose of 300 mg once weekly for 24 weeks, wherein the human has a HBsAg baseline level of not greater than about 1000 lU/mL. In one embodiment, the present disclosure provides a method for treating CHB in a human in need thereof, the method comprising administering bepirovirsen to the human at a dose of 300 mg once weekly for 24 weeks, wherein the human has a HBsAg baseline level of not greater than about 3000 lU/mL.
• the present disclosure provides a method for treating CHB in a human in need thereof, the method comprising administering bepirovirsen to the human at a dose of 300 mg once weekly for 24 weeks, wherein the human has a HBsAg baseline level of not greater than about 1000 lU/mL and is HBeAg negative.
• the present disclosure provides a method for treating CHB in a human in need thereof, the method comprising administering bepirovirsen to the human at a dose of 300 mg once weekly for 24 weeks, wherein the human has a HBsAg baseline level of not greater than about 3000 lU/mL and is HBeAg negative.
• the present disclosure provides a method for treating CHB in a human in need thereof, the method comprising administering bepirovirsen to the human at a dose of 300 mg once weekly for 24 weeks, wherein the human has a HBsAg baseline level of not greater than about 1000 lU/mL and is HBeAg negative, and wherein the human is on stable nucleoside or nucleotide analogue (NA) therapy.
• a method for treating CHB in a human in need thereof comprising administering bepirovirsen to the human at a dose of 300 mg once weekly for 24 weeks, wherein the human has a HBsAg baseline level of not greater than about 1000 lU/mL and is HBeAg negative, and wherein the human is on stable nucleoside or nucleotide analogue (NA) therapy.
• NA nucleoside or nucleotide analogue
• the present disclosure provides a method for treating CHB in a human in need thereof, the method comprising administering bepirovirsen to the human at a dose of 300 mg once weekly for 24 weeks, wherein the human has a HBsAg baseline level of not greater than about 3000 lU/mL and is HBeAg negative, and wherein the human is on stable nucleoside or nucleotide analogue (NA) therapy.
• a method for treating CHB in a human in need thereof comprising administering bepirovirsen to the human at a dose of 300 mg once weekly for 24 weeks, wherein the human has a HBsAg baseline level of not greater than about 3000 lU/mL and is HBeAg negative, and wherein the human is on stable nucleoside or nucleotide analogue (NA) therapy.
• NA nucleoside or nucleotide analogue
• the human is not treated with another HBsAg reducing agent or immunomodulating agent. That is, bepirovirsen is used as monotherapy for treating CHB.
• a HBsAg reducing agent can be a small/short interfering RNA (siRNA), an antisense oligonucleotide (ASO), a nucleic acid polymer (NAP), an HBV RNA destabilizer, an HBV specific neutralizing mAb, or a combination thereof.
• An immunomodulating agent can be IFN- a, PEG-IFN-a, a therapeutic vaccine, aPD-l/PD-Ll inhibitor, a TLR7 agonist, a TLR8 agonist, a TLR9 agonist, or a combination thereof.
• the human is on stable nucleoside or nucleotide analogue (NA) therapy (e.g., tenofovir disoproxil, tenofovir alafenamide, or entecavir).
• NA therapy e.g., tenofovir disoproxil, tenofovir alafenamide, or entecavir.
• the NA therapy is lamivudine, adefovir, adefovir dipivoxil, telbivudine, entecavir, tenofovir, tenofovir disoproxil fumarate (TDF), or tenofovir alafenamide (TAF), or a pharmaceutically acceptable salt thereof.
• 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.
• the subject is not on NA therapy. In some embodiments, the subject is treatment-naive.
• the human has a higher chance of achieving HBsAg below LLOQ at the end of the bepirovirsen treatment as compared to those with a HBsAg baseline level of greater than the threshold level. In some embodiments, the human has at least 5%, 10%, 15%, 20%, 25%, or 30% higher chance of achieving HBsAg below LLOQ at the end of the bepirovirsen treatment. In some embodiment, the human has at least 5%, 10%, 15%, 20%, 25%, or 30% higher chance of achieving HBsAg below LLOQ 24 weeks after the end of the bepirovirsen treatment.
• the human has a higher chance of achieving HBV DNA below LLOQ at the end of the bepirovirsen treatment as compared to those with a HBsAg baseline level of greater than the threshold level. In some embodiments, the human has at least 5%, 10%, 15%, 20%, 25%, or 30% higher chance of achieving HBV DNA below LLOQ at the end of the bepirovirsen treatment. In some embodiment, the human has at least 5%, 10%, 15%, 20%, 25%, or 30% higher chance of achieving HBV DNA below LLOQ 24 weeks after the end of the bepirovirsen treatment.
• the human with a HBsAg baseline level of not greater than a threshold level has a higher chance of achieving HBsAg and HBV DNA below LLOQ at the end of the bepirovirsen treatment as compared to those with a HBsAg baseline level of greater than the threshold level.
• the human with a HBsAg baseline level of not greater than a threshold level has at least 5%, 10%, 15%, 20%, 25%, or 30% higher chance of achieving HBsAg and HBV DNA below LLOQ at the end of the bepirovirsen treatment.
• the human with a HBsAg baseline level of not greater than a threshold level has at least 5%, 10%, 15%, 20%, 25%, or 30% higher chance of achieving HBsAg and HBV DNA below LLOQ 24 weeks after the end of the bepirovirsen treatment.
• the hepatitis B virus infection is caused by any of the human geographical genotypes: A (Northwest Europe, North America, Central America); B (Indonesia, China, Vietnam); C (East Asia, Korea, China, Japan, Polynesia, Vietnam); D (Mediterranean area, Middle East, India); E (Africa); F (Native Americans, Polynesia); G (United States, France); or H (Central America).
• the subject has chronic hepatitis B (CHB).
• 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.
• the present disclosure provides bepirovirsen for use in a method of treating chronic hepatitis B in a human in need thereof, wherein the human has a HBsAg baseline level of not greater than a threshold level.
• the present disclosure provides bepirovirsen for use in a method of treating chronic hepatitis B in a human in need thereof, the method comprising:
• the present disclosure provides a composition comprising bepirovirsen for treating a hepatitis B virus (HBV) infection in a subject in need thereof, the method of treatment comprising administering to the subject a therapeutically effective amount of bepirovirsen, wherein the subject has a HBsAg baseline level of not greater than a threshold level.
• the HBV infection is chronic hepatitis B (CHB).
• the present disclosure also provides bepirovirsen for treating a hepatitis B virus (HBV) infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of bepirovirsen, wherein the subject has a HBsAg baseline level of not greater than a threshold level.
• HBV infection is chronic hepatitis B (CHB).
• the present invention also provides a composition comprising bepirovirsen, or bepirovirsen, for use in a method of treating chronic hepatitis B in a human in need thereof, wherein the method comprises: (a) determining that the human has a HBsAg baseline level of not greater than a threshold level; and (b) administering to the human a therapeutically effective amount of bepirovirsen.
• the method of administering the composition or bepirovirsen can be according to any of the methods detailed above.
• the threshold level of the HBsAg baseline 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 lU/mL, or in a range between any two of the preceding numbers.
• the threshold level of the HBsAg baseline is about 1000, 2000, or 3000 lU/mL.
• the threshold level of the HBsAg baseline is about 1000 lU/mL. In some embodiments, the threshold level of the HBsAg baseline is about 3000 lU/mL. In some embodiments, the threshold level of the HBsAg baseline 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 loglO lU/mL, or in a range between any two of the preceding numbers. In some embodiments, the threshold level of the HBsAg baseline is about 3.0 to 4.0 loglO lU/mL.
• the threshold level of the HBsAg baseline is about 3.0 to 3.5 loglO lU/mL. In some embodiments, the threshold level of the HBsAg baseline is about 3.0 loglO lU/mL. In some embodiments, the threshold level of the HBsAg baseline is about 3.5 loglO lU/mL.
• the present disclosure provides bepirovirsen for use in a method of treating CHB in a human in need thereof, wherein the method comprises administering to the human a therapeutically effective amount of bepirovirsen, wherein the human has a HBsAg baseline level of not greater than about 1000 lU/mL. In one embodiment, the present disclosure provides bepirovirsen 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 bepirovirsen, wherein the human has a HBsAg baseline level of not greater than about 3000 lU/mL.
• the present disclosure provides bepirovirsen for use in a method of treating CHB in a human in need thereof, wherein the method comprises administering bepirovirsen to the human at a dose of 300 mg once weekly for 24 weeks, wherein the human has a HBsAg baseline level of not greater than about 1000 lU/mL.
• the present disclosure provides bepirovirsen for use in a method of treating CHB in a human in need thereof, the method comprising administering bepirovirsen to the human at a dose of 300 mg once weekly for 24 weeks, wherein the human has a HBsAg baseline level of not greater than about 3000 lU/mL.
• the present disclosure provides bepirovirsen for use in a method of treating CHB in a human in need thereof, wherein the method comprises administering bepirovirsen to the human at a dose of 300 mg once weekly for 12 weeks, wherein the human has a HBsAg baseline level of not greater than about 1000 lU/mL.
• the present disclosure provides bepirovirsen for use in a method of treating CHB in a human in need thereof, the method comprising administering bepirovirsen to the human at a dose of 300 mg once weekly for 12 weeks, wherein the human has a HBsAg baseline level of not greater than about 3000 lU/mL.
• a method for treating chronic hepatitis B in a human in need thereof comprising administering to the human a therapeutically effective amount of bepirovirsen, wherein the human has a HBsAg baseline level of not greater than a threshold level.
• a method for treating chronic hepatitis B in a human in need thereof comprising:
• a method for treating chronic hepatitis B in a human in need thereof comprising:
• a method for determining an increased likelihood of pharmacological effectiveness of treatment by bepirovirsen in a human with chronic hepatitis B comprising
• a method for increasing response rate for treating chronic hepatitis B by bepirovirsen in a human in need thereof comprising:
• the HBsAg reducing agent is an siRNA, an antisense oligonucleotide, a nucleic acid polymer (NAP), an HBV RNA destabilizer, an HBV specific neutralizing mAb, or a combination thereof.
• the immunomodulating agent is IFN-a, PEG-IFN- a, a therapeutic vaccine, a PD-l/PD-Ll inhibitor, a TLR7 agonist, a TLR8 agonist, a TLR9 agonist, or a combination thereof.
• Embodiment 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 pharmaceutically acceptable salt thereof.
• Embodiment 30 The method of Embodiment 29, wherein the human is HBeAg negative prior to treatment.
• Embodiment 33 The method of Embodiment 32, wherein the human has at least 5%, 10%, 15%, 20%, 25%, or 30% higher chance of achieving HBsAg below LLOQ at the end of the bepirovirsen treatment.
• Embodiment 34 wherein the human has at least 5%, 10%, 15%, 20%, 25%, or 30% higher chance of achieving HBV DNA below LLOQ at the end of the bepirovirsen treatment.
• 36 The method of any one of Embodiments 1 to 31, wherein the human has a higher chance of achieving HBsAg below LLOQ 24 weeks after the end of the bepirovirsen treatment as compared to those with a HBsAg baseline level of greater than the threshold level.
• Embodiment 37 The method of Embodiment 36, wherein the human has at least 5%, 10%, 15%, 20%, 25%, or 30% higher chance of achieving HBsAg below LLOQ 24 weeks after the end of the bepirovirsen treatment.
• Embodiment 38 The method of Embodiment 27, wherein the human has a higher chance of achieving HBsAg below LLOQ 24 weeks after the NA therapy discontinuation as compared to those with a HBsAg baseline level of greater than the threshold level.
• Embodiment 39 The method of Embodiment 38, wherein the human has at least 5%, 10%, 15%, 20%, 25%, or 30% higher chance of achieving HBsAg below LLOQ 24 weeks after the NA therapy discontinuation.
• Bepirovirsen for use in a method of any of the preceding embodiments.
• Bepirovirsen for use in a method of treating chronic hepatitis B in a human in need thereof, wherein the human has a HBsAg baseline level of not greater than a threshold level.
• Bepirovirsen for use in a method of treating chronic hepatitis B in a human in need thereof, the method comprising:
• Example 1 While aspects of the disclosure presented herein have been described more particularly in accordance with some embodiments, the following examples, which highlight certain features and properties of the exemplary embodiments of the disclosure described herein, serve only to illustrate the disclosure described herein and are not intended to limit the same.
• Example 1
• Primary estimands supporting the primary objective are defined as:
• the primary estimands for each sub-population is the proportion of participants in each treatment arm 1, 2, and 3 who achieve SVR for 24 weeks after the planned end of bepirovirsen treatment in the absence of rescue medication regardless of completing IP, interruptions in IP or adherence to IP had they not been affected by wide disruptive events.
• a supplementary estimand is defined to support the primary objective:
• the supplementary estimand is defined in the same way as the main estimand, except the assessment time frame for participants achieving SVR is 24 weeks after the actual end of treatment. Therefore, the strategy for intercurrent events of treatment discontinuation is while- on-treatment.
• This supplementary estimand supporting the primary objective in participants with CHB on stable nucloes(t)ide therapy and participants with CHB not currently on nucleos(t)ide therapy is the proportion of participants in each treatment arm 1, 2, and 3 who achieve SVR for 24 weeks after the actual end of bepirovirsen treatment in the absence of rescue medication, regardless of completing IP, interruptions in IP or adherence to IP, had they not been affected by wide disruptive events.
• PK Pharmacokinetics
• PK-PD relationships To evaluate PK-efficacy relationship and PK-safety relationship.
• virology biomarkers including but not limited to HBsAg, and immunological biomarkers.
• Patient Reported Outcomes To assess changes from baseline in patient reported outcomes following 12 weeks, 12 weeks + 12 weeks step-down, and 24 weeks of treatment with bepirovirsen.
• nucleos(t)ide analogue therapy population defined as participants who never received HBV treatment (treatment naive) OR must have ended nucleos(t)ide therapy at least 6 months prior to the screening visit; b. OR Currently receiving stable nucleos(t)ide analogue therapy population defined as no changes to their nucleos(t)ide regimen from at least 6 months prior to screening and with no planned changes to the stable regimen over the duration of the study.
• Plasma or serum HBV DNA concentration a. Participants not currently on nucleos(t)ide analogue therapy, plasma or serum HBV DNA >2000 lU/mL; b. Participants who are receiving stable nucleos(t)ide analogue therapy must be adequately suppressed, defined as plasma or serum HBV DNA ⁇ 90 lU/mL.
• ALT Alanine Transaminase
• the ALT inclusion criteria may be expanded to include participants with ALT ⁇ 5 X ULN. b. ALT ⁇ 2 X ULN for participants who are receiving stable nucleos(t)ide analogue therapy
• HCV Hepatitis C virus
• HAV Human immunodeficiency virus
• HDV Hepatitis D virus
• liver cirrhosis and/or evidence of cirrhosis as determined by a. both Aspartate aminotransferase (AST)-Platelet Index (APRI) >2 and FibroSure/FibroTest result >0.7. i. If only one parameter (APRI or FibroSure/FibroTest) result is positive, a discussion with the Medical Monitor is required before inclusion in study is permitted. b. Regardless of APRI of Fibrosure/FibroTest score, if the participant meets one of the following historical criteria, they will be excluded from the study. i. Liver biopsy (i.e., Metavir Score F4). ii. Liver stiffness >12 kPa .
• vasculitis or presence of symptoms and signs of potential vasculitis [e.g., vasculitic rash, skin ulceration, repeated blood detected in urine without identified cause] or history/presence of other diseases that may be associated with vasculitis condition (e.g., systemic lupus erythematosus, rheumatoid arthritis, relapsing polychondritis, mononeuritis multiplex). History of extrahepatic disorders possibly related to HBV immune conditions (e.g., nephrotic syndrome, any type of glomerulonephritis, polyarteritis nodosa, cryoglobulinaemia, uncontrolled hypertension). Positive (or borderline positive) ANCA at screening: a.
• History of alcohol or drug abuse/dependence a. Current alcohol use as judged by investigator to potentially interfere with participant compliance; b. History of or current drug abuse/dependence as judged by the investigator to potentially interfere with participant compliance i. Refers to illicit drugs and substances with abuse potential. Medications that are used by the participant as directed, whether over-the-counter or through prescription, are acceptable and would not meet the exclusion criteria.
• any immunosuppressing drugs e.g., prednisone
• a short course of therapy ⁇ 2 weeks
• topical/inhaled steroid use e.g., topical/inhaled steroid use.
• the participant has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 5 half-lives (if known) or twice the duration (if known) of the biological effect of the study treatment (whichever is longer) or 90 days (if half-life or duration is unknown).
• Fridericia s QT correction formula (QTcF) >450 msec (if single electrocardiogram [ECG] at screening shows QTcF >450 msec, a mean of triplicate measurements should be used to confirm that participant meets exclusion criterion).
• Laboratory results as follows a. Serum albumin ⁇ 3.5 g/dL b. Glomerular filtration rate (GFR) ⁇ 60 mL/min /1.73m 2 as calculated by the CKD-EPI formula (for Japan, JSN-CKDI equation). c. INR >1.25 d. Platelet count ⁇ 140 X 10 9 /L e. Total bilirubin >1.25 x ULN i.
• Urine albumin to creatinine ratio >0.03 mg/mg (or >30 mg/g).
• eligibility may be confirmed by a second measurement i.
• the investigator should confirm that the participant does not have a history of diabetes, hypertension or other risk factors that may affect renal function and discuss with the Medical Monitor, or designee.
• the primary objective measurements for efficacy include HBsAg and HBV DNA.
• the primary efficacy endpoint is sustained virologic response (SVR), which is a composite endpoint defined as HBsAg ⁇ LLOQ and HBV DNA ⁇ LLOQ at the end of bepirovirsen treatment which is sustained for 24 weeks post-bepirovirsen treatment.
• SVR sustained virologic response
• Seroclearance refers to participants with HBsAg and HBV DNA ⁇ LLOQ (with or without the formation of HBs- antibody).
• Seroconversion refers to participants with HBsAg and HBV DNA ⁇ LLOQ plus formation of HBs-antibody. Both terms are used to evaluate efficacy.
• sustained response is defined as a continuous 24 weeks from end of bepirovirsen treatment during which levels of HBsAg in serum remain less than LLOQ and HBV DNA less than LLOQ. Any HBsAg greater than LLOQ or HBV DNA greater than LLOQ after achieving HBsAg seroclearance and HBV DNA suppression needs to be confirmed by re-test within 1 week of receiving the test result. The re-test result will be used if the first test is not confirmed.
• Safety assessments are conducted at planned time points during the course of the study, and additional time points for safety tests may be added based on newly available data to ensure appropriate safety monitoring.
• Safety assessments include physical examinations, injection site reactions, vital signs, electrocardiograms, and clinical safety laboratory assessment.
• Adverse events and serious adverse events (SAEs) are detected, documents, and reported.
• An adverse event is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention.
• An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
• a serious adverse event is defined as any untoward medical occurrence that, at any dose: results in death or is life-threatening.
• Time to event virologic response, nadir of HBsAg and HBV DNA, seroclearance (HBsAg), HBV DNA level below LLOQ, seroconversion (HBsAb and HBeAb); peak of ALT flares.
• Safety assessments including but not limited to vital signs, electrocardiograms, laboratory measurements and adverse events.
• Table 1 Demographic characteristics of participants in four arms for ON-NUC cohorts.
• ON-NUC cohorts are shown in Tables 3 and 4, respectively.
• ON-NUC and NOT ON-NUC cohorts are shown in Tables 5 and 6, respectively.
• Virologic response at the end of treatment is defined as achieving HBsAg ⁇ LLOQ and HBV DNA ⁇ LLOQ in the absence of rescue medication in the end of treatment visit window.
• SVR success is defined as HBsAg ⁇ LLOQ and HBV DNA ⁇ LLOQ for 24 weeks after the planned end of bepirovirsen treatment in the absence of rescue medication.
• Virologic response at the end of treatment by subgroup - baseline HBeAg status was analyzed as a secondary endpoint.
• ON-NUC cohorts no apparent difference in virologic response in the end of treatment analysis window in patients with HBeAg status positive and negative. See FIG. 4.
• the dashed line represents the overall virologic response rate at the end of treatment across all treatment arms.
• patients with negative HBeAg status appear to have a slightly higher chance of achieving virologic response at the end of the treatment. See FIG. 6.
• Two SVR responders were both HBeAg negative at baseline.
• Virologic response at the end of treatment by subgroup - baseline HBsAg status was also analyzed as a secondary endpoint.
• proportion of subjects with virologic response at the end of treatment is higher for patients with a low HBsAg baseline level ( ⁇ 3 Log 10 lU/mL) as compared to those with a high HBsAg baseline level (> 3 LoglO lU/mL). See FIG. 5.
• Six out of eight SVR responders had a low HBsAg baseline level ( ⁇ 3 LoglO lU/mL).
• Receiver Operating Charateristic (ROC) tables were used to compare different cuts of the data for increasing values of baseline HBsAg.
• the ROC tables can be used to assess each “cut” in terms of the inclusion of subjects who are responders, against the exclusion of subjects who are non-responders. See Tables 7 and 8 for example.
• Table 7 Summary of ROC Analysis for Baseline HBsAg (loglO lU/mL) as a Predictor of Virologic Response at the End of Treatment (ON-NUC, arm 1).
• Table 8 Summary of ROC Analysis for Baseline HBsAg (loglO lU/mL) as a Predictor of Virologic Response at the End of Treatment (NOT ON-NUC, arm 1).
• PK Pharmacokinetics
• PD Pharmacodynamics
• Bepirovirsen was administrated subcutaneously for up to 4 weeks in the Phase 1 and 2a studies and 12 or 24 weeks in the Phase 2b study.
• HBsAg levels below the lower limit of quantification were estimated using a likelihood-based approach in order to predict a complete HBsAg profile during on- and off-treatment periods.
• a threshold for continued viral suppression was implemented to reflect an increased probability of participants achieving and maintaining HBsAg levels below LLOQ (BLQ) at end of study if their predicted HBsAg levels fall below the threshold.
• Direct and indirect drug effects on ALT were explored to describe ALT increases. The indirect effect was driven through reduction of HBsAg, resulting in immune-mediate hepatocyte senescence and subsequent ALT release.
• LD bepirovirsen loading dose
• baseline patient characteristics e.g. demographics, HBsAg, HBeAg, genotype
• FIGs. 9A, 9B, 10A, and 10B Examples of observed and model- predicted individual subject PK, HBsAg, and ALT profiles are shown in FIGs. 9A, 9B, 10A, and 10B (Dots represent observed data, dashed and solid lines represent 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, at 24 weeks, and at 48 weeks (during the off-treatment period) (FIGs. 11 A, 1 IB and 11C).
• the developed PK/PD model provides a useful tool for informing key decisions regarding Phase 3 design, such as dose selection, treatment duration, and patient population.
• patients with low baseline HBsAg levels were predicted to be more likely to achieve HBsAg ⁇ LLOQ following administration of bepirovirsen (BPV) compared with the overall population (HBsAg ⁇ 3000 lU/mL range: 30.1%-40.0% and 12.9%— 16.5% at EOT and EOS, respectively; overall population range: 20.1%-26.1% and 9.2%-10.7% at EOT and EOS, respectively) across different BPV dose regimens (Table 9). Similar response rates were predicted with and without loading doses.
• BPV bepirovirsen
• LLOQ -1.3 logw lU/mL (0.05 lU/mL).
• the arms will be stratified based on HBsAg level (HBsAg >100 lU/mL to ⁇ 1000 lU/mL or >1000 lU/mL to ⁇ 3000 lU/mL) at screening.
• the primary endpoint is: To assess the treatment effect of 24 weeks bepirovirsen with loading doses to achieve functional cure in HBeAg negative participants with chronic HBV infection on NA treatment with baseline HBsAg ⁇ 1000 lU/mL.
• the key secondary endpoints are:
• the safety objective To assess the safety and tolerability of bepirovirsen when dosed for 24 weeks duration with loading doses in HBeAg-negative participants with chronic HBV infection on NA treatment.
• the inclusion criteria are:
• Plasma or serum HBV DNA concentration must be adequately suppressed, defined as plasma or serum HBV DNA ⁇ 90 lU/mL.
• the exclusion criteria are:
• vasculitis e.g., vasculitic rash, skin ulceration, repeated blood detected in urine without identified cause
• vasculitis condition e.g., systemic lupus erythematosus, rheumatoid arthritis, relapsing polychondritis, mononeuritis multiplex
• HBV immune conditions e.g., nephrotic syndrome, any type of glomerulonephritis, polyarteritis nodosa, cryoglobulinemia, uncontrolled hypertension
• Prior/Concomitant Therapy 9 Currently taking, or took within 3 months of screening, any immunosuppressing drugs (e.g., prednisone), other than a short course of therapy ( ⁇ 2 weeks) or topical/inhaled steroid use.
• immunosuppressing drugs e.g., prednisone
• the participant has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 5 half-lives (if known) or twice the duration (if known) of the biological effect of the study treatment (whichever is longer) or 90 days (if half-life or duration is unknown).
• Fridericia s QT correction formula (QTcF) >450 msec (if single ECG at screening shows QTcF >450 msec, a mean of triplicate measurements should be used to confirm that participant meets exclusion criterion).
• Urine albumin to creatinine ratio >0.3 mg/mg (or >300 mg/g). In the event of an uACR above this threshold, eligibility may be confirmed by a second measurement
• the primary efficacy endpoint is functional cure, as defined herein.
• the primary objective measurements for efficacy include HBsAg and HBV DNA.
• Safety assessments are conducted at planned time points during the course of the study, and additional time points for safety tests may be added based on newly available data to ensure appropriate safety monitoring.
• Safety assessments include physical examinations, injection site reactions, vital signs, electrocardiograms, and clinical safety laboratory assessment.
• Adverse events and serious adverse events (SAEs) are detected, documented, and reported.
• Adverse Events of special interest include: ALT increase (flares), vascular inflammation and complement activation, thrombocytopenia, and renal injury. Blood samples are collected for measurement of plasma concentrations of bepirovirsen. Pharmacodynamic parameters will include but are not limited to:
• HBsAg virologic response
• HBV DNA ⁇ LLOQ HBV DNA ⁇ LLOQ
• HBsAb seroconversion
• Safety assessments including, but not limited to, vital signs, laboratory measurements and AEs.
• the amendment was made to include participants with HBeAg positive chronic HBV infection, to increase the frequency of monitoring post NA cessation, and to switch the primary and secondary endpoints.
• the planned minimum sample size of 750 provides 99% power for the primary endpoint of functional cure in the baseline HBsAg ⁇ 3000 lU/mL population and 98% power for the key secondary endpoint of functional cure in the baseline HBsAg ⁇ 1000 lU/mL populations.
• the primary endpoint is: To assess the treatment effect of 24 weeks bepirovirsen with loading doses to achieve functional cure in participants with chronic HBV infection on NA treatment with baseline HBsAg ⁇ 3000 lU/mL.
• the key secondary endpoints are:
• the safety objective To assess the safety and tolerability of bepirovirsen when dosed for 24 weeks duration with loading doses in participants with chronic HBV infection on NA treatment.

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