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
  • A61K31/66—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
  • 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
  • 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
  • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
  • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
• • 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
  • A61K31/7072—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 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/162—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from virus
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/19—Cytokines; Lymphokines; Interferons
  • A61K38/20—Interleukins [IL]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/19—Cytokines; Lymphokines; Interferons
  • A61K38/21—Interferons [IFN]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • 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
  • A61P31/14—Antivirals for RNA viruses
• • 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

Definitions

• the invention relates to a drug and a method for treating chronic hepatitis B with nucleoside (acid) drugs.
• nucleoside (acid) drugs are approved for the treatment of chronic hepatitis B.
• Nucleoside (acid) drugs play a role in inhibiting HBV replication by inhibiting HBV DNA polymerase.
• Nucleoside (acid) drugs currently approved by the FDA for the treatment of hepatitis B include lamivudine, adefovir dipivoxil, entecavir, tenofovir dipivoxil (TDF), telbivudine and tenofovir alafenamide fumarate (TAF).
• TDF tenofovir dipivoxil
• TAF tenofovir alafenamide fumarate
• tenofovir which was developed in the later period, has not only been improved in safety, but also has an inhibition rate of about 70% for viral DNA.
• nucleotide drugs can effectively inhibit virus replication, long-term medication is required, and relapse and rebound often occur after drug withdrawal. Therefore, NAs treatment for hepatitis B is an infinite therapy.
• TAF is an antiviral drug developed by Gilead, which was approved by the FDA in 2016 for the treatment of chronic hepatitis B.
• TAF is a novel nucleotide reverse transcriptase inhibitor. After entering the liver cells, it can be hydrolyzed into tenofovir, and then phosphorylated to block virus replication.
• As an upgraded version of tenofovir disoproxil TDF TAF not only retains TDF's advantages of "highly effective antiviral and low drug resistance", but also overcomes some of TDF's shortcomings of nephrotoxicity and bone density damage. Compared with TDF, under the same curative effect, the dosage of TAF is lower, and the risk of osteoporosis and nephrotoxicity is smaller.
• Interferon is a cytokine with a broad-spectrum antiviral effect. It was originally used in the treatment of HIV and other viruses. In 1992, it was approved by the FDA for the treatment of hepatitis B. Its mechanism of action is mainly through immune regulation and induction of antiviral proteins in liver cells to exert antiviral effects.
• the meta-analysis showed that after 4 to 6 months of treatment of HBeAg-positive patients with common interferon ⁇ (ordinary IFN ⁇ ), the HBV DNA negative rate (hybrid method) in the treatment group and the untreated group were 37% and 17%, the HBeAg negative rate was 33% and 12%, and the HBsAg negative rate was 7.8% and 1.8%, respectively.
• HBeAg-positive chronic hepatitis B (87% Asians) was treated with pegylated interferon ⁇ -2a (PegIFN ⁇ -2a) (40KD) for 48 weeks and followed up for 24 weeks after drug withdrawal, and the HBeAg seroconversion rate was 32%; HBeAg-negative patients (60% Asians) were followed up for 24 weeks after 48 weeks of treatment, and HBV DNA ⁇ 2 ⁇ 104 copies/ml was 4 3%, and 42% at 48 weeks of follow-up.
• PegIFN ⁇ -2a pegylated interferon ⁇ -2a
• influenza-like syndrome manifested as fever, chills, headache, muscle aches, and fatigue
• transient peripheral blood cell reduction mainly manifested as peripheral blood leukocytes (neutrophils) and thrombocytopenia
• mental abnormalities manifested as depression, delusions, severe anxiety and other psychotic symptoms
• Lupus-like syndrome, etc. other rare adverse reactions, including renal damage (interstitial nephritis, nephrotic syndrome, and acute renal failure, etc.), cardiovascular complications (arrhythmia, ischemic heart disease, and cardiomyopathy, etc.), retinopathy, hearing loss, and interstitial pneumonia.
• the current standard course of treatment for interferon therapy is 48 weeks.
• Viral entry inhibitors include peptides derived from the HBV Pre-S1 region and anti-Pre-S1 antibodies or anti-surface antigens Antibody.
• Polypeptides derived from the HBV Pre-S1 region include, but are not limited to, hepalatide and bulevirtide.
• the amino acid sequence of hepalatide is derived from the amino acid sequence of positions 13-59 in the HBVPre-S1 region of genotype C, and its N-terminus is modified with myristic acid.
• NTCP sodium taurocholate cotransporting polypeptide
• the first aspect of the present invention provides the use of an HBV virus entry inhibitor and an optional immunomodulator in the preparation of a drug or kit for limiting or terminating nucleoside (acid) drug treatment of chronic hepatitis B.
• the HBV virus entry inhibitor is selected from the HBV entry inhibitory polypeptide derived from HBV Pre-S1 region or HBV Pre-S1 derived peptide, anti-Pre-S1 antibody, anti-surface antigen antibody or other agents that can inhibit HBV from entering liver cells or infecting liver cells.
• the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region is derived from the pre-S1 region of any one of the surface antigens of HBV genotypes A, B, C, D, E, F, G, H and I.
• the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region is 10-118 amino acid residues in length.
• the immunomodulator includes interferons, toll-like receptor agonists, CPG, CPG ODN, PD-1 inhibitors, PD-L1 inhibitors, interleukins and cytokines.
• the interferon is selected from IFN- ⁇ , IFN- ⁇ and IFN- ⁇ , preferably IFN ⁇ -2a and/or IFN ⁇ -2b, more preferably PEG IFN ⁇ -2a and/or PEG IFN ⁇ -2b.
• the HBV entry-inhibiting polypeptide derived from the HBV Pre-S1 region is derived from the HBV surface antigen pre-S1 region of genotype C; preferably, the HBV entry-inhibiting polypeptide is a fragment of the N-terminal of the HBV surface antigen pre-S1 region of genotype C or a variant thereof, and the fragment contains at least amino acid residues 13-44 of the N-terminus; preferably, the HBV entry-inhibiting polypeptide contains the 2nd- Amino acid residues 119, 2-69, 2-59, 13-119, 13-88, 13-72, 13-67, 13-59, 13-52, or 13-47, or variants thereof.
• the HBV entry-inhibiting polypeptide derived from the HBV Pre-S1 region is a fragment of the N-terminal of the HBV surface antigen pre-S1 region of A, B, F, H or I genotype or a variant thereof, and the fragment contains at least amino acid residues 13-44 of the N-terminus, preferably at least amino acid residues 13-69 of the N-terminus.
• the HBV entry-inhibiting polypeptide derived from the HBV Pre-S1 region is a fragment of the N-terminal of the HBV surface antigen pre-S1 region of genotype D or a variant thereof, and the fragment contains at least amino acid residues 2-33 of the N-terminus, preferably at least amino acid residues 2-48 of the N-terminus.
• the HBV entry-inhibiting polypeptide derived from the HBV Pre-S1 region is a fragment of the N-terminal of the HBV surface antigen pre-S1 region of E and G genotypes or a variant thereof, and the fragment contains at least amino acid residues 12-43 of the N-terminus, preferably at least amino acid residues 12-68 of the N-terminus.
• the variant has 1-30 amino acid deletions, substitutions or insertions compared to the fragment, and the variant retains the biological activity of inhibiting HBV entry or binding to NTCP.
• said variants comprise insertions at the N- and/or C-terminal ends of said fragments of natural flanking amino acid sequences from any of said HBV subtypes.
• the natural flanking amino acid sequence is selected from the amino acid sequence at positions 2-12 of the N-terminus of the pre-S1 region of the HBV surface antigen of A, B, F, H, and I genotypes and the amino acid sequence of positions 2-11 at the N-terminus of the pre-S1 region of the HBV surface antigen of the E and G genotypes.
• the variant is a variant obtained by introducing one or a combination of any two or more of the following amino acid substitutions into the derivative peptide derived from the amino acid sequence at positions 13-59 of the HBV Pre-S1 region of genotype C: N15D, F25L, G35K, N39E, F45L, N46K, N48H or N48Y or N48K, D50A, H51Q or H51N, E54K or E54D, A55S, N56K or N56D, and Q57K, optionally, the N- and/or C-terminus of the variant is inserted into the native flanking amino acid sequence from any of said HBV subtypes.
• the amino acid sequence of the fragment is as shown in any one of SEQ ID NO: 2-32, or has at least 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence shown in any one of SEQ ID NO: 2-32.
• the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region has N-terminal modification and/or C-terminal modification.
• the N-terminal modification is a hydrophobic group modification.
• the hydrophobic group modification is selected from myristic acid, palmitic acid, stearic acid, cholesterol, oleic acid, linoleic acid, polyethylene glycol, and arachidonic acid.
• the C modification is amidation or isoprenylation modification.
• the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region is shown in SEQ ID NO: 33-44.
• the use is HBV viral entry inhibitors, nucleoside (acid) drugs for the treatment of chronic hepatitis B and optional immunomodulators in the preparation of nucleosides for limiting or terminating chronic hepatitis B Use in a medicine or kit for (acid) drug therapy.
• the nucleoside (acid) drug is selected from lamivudine, adefovir dipivoxil, entecavir, tenofovir dipivoxil, telbivudine and tenofovir alafenamide fumarate, preferably tenofovir alafenamide fumarate.
• the kit contains 1 dose or 2 doses of the above drug, so as to meet the daily dose of 2.1-10.5 mg, preferably 4.2-8.4 mg, more preferably 4.2 mg of the HBV viral entry inhibitor.
• the kit also optionally contains 1 dose or 2 doses of the interferon above, and its content meets the dosage of 1-360 micrograms per week, preferably 30-180 micrograms per week, more preferably 60-135 micrograms per week, and more preferably 90 micrograms per week.
• the kit is used for combined administration with the nucleoside (acid) drug for 1-96 weeks, preferably 12-60 weeks, more preferably 24-48 weeks.
• the second aspect of the present invention provides a method for limiting or terminating nucleoside (acid) drug treatment of chronic hepatitis B patients, said method comprising giving chronic hepatitis B patients HBV virus entry inhibitors and optional immunomodulators for combined treatment on the basis of nucleoside (acid) drugs, and terminating nucleoside (acid) drug treatment, HBV virus entry inhibitor treatment and said immunomodulator treatment after a certain course of combined treatment.
• the nucleoside (acid) drug is as described in any embodiment herein; the HBV virus entry inhibitor is as described in any embodiment herein, and the immunomodulator is as described in any embodiment herein.
• the duration of the combination therapy is 1-96 weeks, preferably 12-60 weeks, more preferably 24-48 weeks.
• the patient has received continuous NAs treatment, preferably has received NAs treatment for more than 0 months, more than 3 months, NAs treatment for more than 12 months, and NAs treatment for more than 36 months before performing the combined treatment.
• the daily dose of the HBV viral entry inhibitor is 2.1-10.5 mg, preferably 4.2-8.4 mg, more preferably 4.2 mg.
• the immunomodulator is interferon, and its weekly dose is 1-360 micrograms, preferably 30-180 micrograms, more preferably 60-135 micrograms, more preferably 90 micrograms.
• the nucleoside (acid) drug is tenofovir alafenamide fumarate
• the HBV viral entry inhibitor is hepalatide or bulevirtide
• the treatment cycle of the hepalatide or bulevirtide is from 1 week to 96 weeks.
• the therapeutic dose of hepalatide or bulevirtide is 2.1 mg to 8.4 mg per day.
• the immunomodulator is PEG interferon, and its dosage is preferably 10-170ug per week.
• the nucleoside (acid) drug is tenofovir alafenamide fumarate; combined with hepalatide or bulevirtide for treatment, the treatment cycle is 48 weeks, and the dose is 4.2 mg per day; PEG interferon is given at the same time, the dose is 90ug per week, and the treatment cycle is 48 weeks.
• Figure 1 Flowchart of a randomized double-blind placebo-controlled multicenter phase II clinical trial (finite-new) of TAF combined with PEG interferon and hepalatide for a limited course of treatment of chronic hepatitis B.
• NAs are the main drugs for the treatment of HBV chronic infection, but the treatment is not a limited course of treatment, and HBV rebound and recurrence occur after stopping the drug.
• the invention provides a method capable of limiting NAs treatment, so that chronic hepatitis B patients receiving NAs treatment can safely stop the drug, avoid HBV recurrence, and make NAs a limited course of treatment medicine.
• the limited NAs treatment method provided by the present invention is based on CHB patients continuously receiving NAs treatment, adding an HBV entry inhibitor for combined treatment, and after a certain course of combined treatment, both NAs and HBV entry inhibitor treatment are terminated.
• the present invention finds that, with the method of the present invention, the HBV of CHB patients does not rebound after the treatment is terminated.
• limitation means that the regimen of the present invention can limit the course of NAs treatment, meet the criteria for terminating the withdrawal of NAs treatment, and there will be no rebound or recurrence of HBV after drug withdrawal.
• the continuous NAs treatment drugs received by CHB patients include but not limited to lamivudine, adefovir dipivoxil, entecavir, TDF, telbivudine, TAF and other NAs drugs.
• the NAs treated by CHB patients are entecavir, TDF, telbivudine or TAF.
• the continuous NAs treatment received by the CHB patient is the Nas treatment that has been received for more than 0 months, preferably more than 3 months of NAs treatment, more preferably more than 12 months of NAs treatment, and still more preferably more than 36 months of NAs treatment.
• the HBV entry inhibitors include, but are not limited to, HBV entry inhibitory polypeptides derived from the HBVPre-S1 region or HBVPre-S1 derived peptides, anti-Pre-S1 antibodies, anti-surface antigen antibodies, or other HBV-inhibiting Agents that enter or infect liver cells.
• HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region or "HBV Pre-S1 derived peptide” refers to a polypeptide originating from or derived from the HBV surface antigen Pre-S1 region that can inhibit HBV virus entry into liver cells, including but not limited to natural, recombinant, synthetic or purified polypeptides, including but not limited to full-length natural HBV surface antigen Pre-S1 region or its fragments and variants, full-length non-natural HBV surface antigen Pre-S1 region or fragments thereof and variants thereof, non-full-length natural HBV surface antigen Pre-S1 region or its fragments and variants thereof, non-full-length non-native HBV surface antigen Pre-S1 region or its fragments and variants thereof, and other forms of variants.
• the HBV entry-inhibiting polypeptide derived from the HBV Pre-S1 region may contain the entire surface antigen pre-S1 region starting from the second amino acid G (glycine) of the HBV surface antigen pre-S1 region of any genotype.
• the HBV entry inhibitory polypeptides derived from the HBV Pre-S1 region described herein can be derived from the pre-S1 region of any one of the surface antigens of HBV genotypes A, B, C, D, E, F, G, H, and I. Exemplary genome sequences for these HBV genotypes can be found, eg, at GenBank Accession Nos.
• the HBV Pre-S1 derived peptides used include but are not limited to HBV virus entry inhibitory polypeptides derived from the amino acid sequence of the C genotype HBV surface antigen Pre-S1 region, including but not limited to the exemplary amino acid sequence of the HBV surface antigen Pre-S1 region SEQ ID NO: 1 and variants thereof.
• the HBV entry-inhibiting polypeptide derived from the HBVPre-S1 region at least retains the biological activity of inhibiting HBV virus entry or binding to NTCP.
• the HBV entry-inhibiting polypeptides derived from the HBV Pre-S1 region described herein may consist of 10-118 amino acids in length.
• the polypeptide may be, but is not limited to, 15-100, 15-80, 20-100, 20-80, 20-60, 25-60, 30-60, 35-60, or 40-60 (including all integers between these ranges) amino acids in length.
• the HBV entry-inhibiting polypeptides derived from the HBV Pre-S1 region described herein may be at least 20 amino acids in length, such as at least 25, 30, 35 or 40 amino acids in length.
• the HBV entry-inhibiting polypeptides derived from the HBV Pre-S1 region described herein may be, but are not limited to, 20, 25, 30, 35, 40, 47, 55, or 60 amino acids in length. In some embodiments, the HBV entry-inhibiting polypeptides described herein derived from the HBV Pre-S1 region can be 47 amino acids in length.
• the variants of different lengths derived from HBV entry inhibitory polypeptides in the HBV Pre-S1 region described herein retain one or more biological activities related to the corresponding polypeptides, at least including biological activities that can inhibit HBV virus entry or bind to NTCP.
• the HBV entry inhibitory polypeptides derived from the HBV Pre-S1 region described herein can be derived from the pre-S1 region of the HBV surface antigen of genotype C, including but not limited to positions 2-119, positions 2-119 of the pre-S1 region, 2-69, 2-59, 13-119, 13-88, 13-72, 13-67, 13-59, 13-52, 13-47, 13-42, 13-37, 13-32 amino acids and variants thereof, example sequences thereof include but are not limited to SEQ ID NO: 2-14 and variants thereof.
• the HBV entry-inhibiting polypeptide derived from the HBV Pre-S1 region comprises the amino acid sequence of at least 13-44 amino acid residues at the N-terminal of the HBV surface antigen pre-S1 region of genotype C described herein and variants thereof.
• the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region may be 32-47 amino acid residues in length.
• the exemplary amino acid sequence of the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region is shown in SEQ ID NO: 9; the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region HBV also includes a variant of the amino acid sequence shown in SEQ ID NO: 9.
• the HBV entry-inhibiting polypeptide derived from the HBV Pre-S1 region contains at least amino acid residues 1-32 in the exemplary sequence SEQ ID NO: 16 or variants thereof, preferably the HBV entry-inhibiting polypeptide derived from the HBV Pre-S1 region contains at least positions 1 to 33, 34, 35, 36, 37, 38, 39, 40, 41, 4 in the exemplary sequence SEQ ID NO: 16 Amino acid residue 2, 43, 44, 45 or 46 or variants thereof.
• the HBV entry-inhibiting polypeptide derived from the HBV Pre-S1 region refers to a fragment containing at least 13-44 amino acid residues at the N-terminal of the HBV surface antigen pre-S1 region of A, B, F, H, and I genotypes described herein or a variant thereof, a fragment of at least the 2-33 amino acid residues at the N-terminal of the HBV surface antigen pre-S1 region of D genotype or a variant thereof, or at least the 12th amino acid residue at the N-terminal of the HBV surface antigen pre-S1 region of E and G genotypes. - a fragment of amino acid residue 43 or a variant thereof.
• the HBV entry-inhibiting polypeptide derived from the HBV Pre-S1 region contains a fragment of at least 13-69 amino acid residues at the N-terminal of the HBV surface antigen pre-S1 region of A, B, F, H, I genotype or a variant thereof, a fragment of at least the 2-48 amino acid residues or a variant thereof at the N-terminal of the HBV surface antigen pre-S1 region of D genotype, or at least the 12-6th amino acid residue at the N-terminal of the HBV surface antigen pre-S1 region of E or G genotype Fragments of amino acid residues at position 8 or variants thereof.
• the "variant" related to the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region refers to a difference in amino acid sequence with a given polypeptide, but retains the biological activity of inhibiting HBV entry or binding to NTCP.
• one or a combination of any two or more of the following amino acid substitutions can be introduced into the derived peptide derived from the amino acid sequence at positions 13-59 of the HBVPre-S1 region of genotype C: N15D, F25L, G35K, N39E, F45L, N46K, N48H or N48Y or N48K, D50A, H51Q or H51N, E54K or E54D, A55S , N56K or N56D, and QS7K
• exemplary sequences include but are not limited to the sequences shown in SEQ ID NO: 15-32.
• the term “variant” also includes homologous polypeptide sequences found in different virus species, strains or subtypes of Hepadovirus. Based on the antigenic epitopes on its envelope protein, HBV is divided into four major serotypes (adr, adw, ayr and ayw), according to the variability of the entire nucleotide sequence in the genome, HBV is divided into nine genotypes (A, B, C, D, E, F, G, H and I). Thus, the term “variant” includes any of these homologous polypeptides found in HBV subtypes.
• variants may also include polypeptides with natural flanking amino acid sequences from any of these HBV subtypes added at the N- and/or C-terminus, or variants thereof.
• fragments including but not limited to amino acid residues at least 2-12 at the N-terminal of the pre-S1 region of the HBV surface antigen of genotypes A, B, F, H, and I, or at least 2-11 amino acid residues at the N-terminal of the pre-S1 region of the HBV surface antigen of the E and G genotypes can be used as the natural flanking amino acid sequence to form a fusion polypeptide with a polypeptide derived from the amino acid sequence at positions 13-59 of the surface antigen Pre-S1 region of the C genotype.
• the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region described herein may contain an amino acid sequence selected from, but not limited to, any one of SEQ ID NO: 2-32, and a native amino acid sequence flanked by the N and/or C terminus of a surface antigen derived from any genotype in HBV genotype AI.
• the natural flanking amino acid sequence may be derived from a group including, but not limited to, GenBank accession numbers KC875260 (genotype A), AY220704 (genotype B), AF461363 (genotype C), AY796030 (genotype D), AB205129 (genotype E), DQ823095 (genotype F), HE981176 (genotype G) or AB Amino acid sequence of the HBV surface antigen of 179747 (genotype H).
• the HBV entry-inhibiting polypeptide derived from the HBV Pre-S1 region described herein may contain the amino acid sequence shown in SEQ ID NO: 9, and at its N and/or C-terminus, contain the natural flanking amino acid sequences from the pre-S1 region of HBV genotype C.
• the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region described herein may contain the amino acid sequence shown in SEQ ID NO: 9, and at its N and/or C terminus, contain the natural flanking amino acid sequence from the pre-S1 region of any genotype in HBV genotypes A, B, C, D, E, F, G and H.
• the N and/or C-termini of the HBV entry-inhibiting polypeptides derived from the HBVPre-S1 region described herein may independently contain natural flanking amino acid sequences of 1-10, such as 1-8, 1-5, or 1-3 (including all integers within these ranges) amino acids in length.
• the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region described herein may contain the amino acid sequence shown in SEQ ID NO: 9, and at its N-terminus, contain a natural flanking amino acid sequence of 10 amino acids from the pre-S1 region of HBV genotype C.
• the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region may contain amino acids 2-59 of the pre-S1 region of HBV genotype C (SEQ ID NO: 4).
• the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region described herein may contain the amino acid sequence shown in SEQ ID NO: 9, and at its N-terminus, contain a natural flanking amino acid sequence of 9 amino acids from the E genotype HBV pre-S1 region.
• the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region may contain amino acids 13-59 of the pre-S1 region of HBV genotype C and amino acids 2-11 of the pre-S1 region of HBV genotype E.
• HBV entry inhibitory polypeptide in the HBV Pre-S1 region can have a natural flanking amino acid sequence of any length extending from its N and/or C terminal, and the resulting HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region retains the biological activity of inhibiting HBV entry or binding to NTCP.
• the "variant" related to the HBV entry-inhibiting polypeptide derived from the HBVPre-S1 region may also include one or more amino acid deletions, substitutions or insertions, while retaining the biological activity of inhibiting HBV entry or binding to NTCP.
• the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region preferably retains glycine corresponding to the 13th amino acid in the HBV pre-S1 region of genotype C (ie, the N-terminal glycine of SEQ ID NO: 9).
• the HBV entry inhibiting polypeptides described herein derived from the HBV Pre-S1 region may have one or more naturally occurring mutations in the HBV pre-S1 region.
• the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region described herein may have 1-30, such as 1-20, 1-10, 1-8, 1-5 or 1-3 (including all integers within these ranges) amino acid deletions, substitutions or insertions.
• the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region described herein may have 1-30, such as 1-20, 1-10, 1-8, 1-5 or 1-3 (including all integers within these ranges) amino acid deletions, substitutions or insertions relative to the amino acid sequence selected from any example of SEQ ID NO: 2-32.
• the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region described herein may have 1-30, such as 1-20, 1-10, 1-8, 1-5 or 1-3 (including all integers within these ranges) amino acid deletions, substitutions or insertions relative to the exemplary amino acid sequence of SEQ ID NO: 9. In some embodiments, the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region described herein may have 1-3 amino acid deletions, substitutions or insertions relative to the exemplary amino acid sequence of SEQ ID NO: 9.
• the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region described herein has 1-30, such as 1-20, 1-10, 1-8, 1-5 or 1-3 (including all integers within these ranges) amino acid deletions or insertions at the C-terminus relative to the amino acid sequence selected from any of the examples of SEQ ID NO: 2-32.
• polypeptides included herein are, but are not limited to, said polypeptides, and polypeptides that are at least about 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to any of said polypeptides.
• the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region may comprise an amino acid sequence having at least about 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identity to any of the exemplified sequences of SEQ ID NO: 2-32; preferably, the amino acid sequence having said identity is from any of the HBV described herein , including but not limited to genotype A, B, C, D, E, F, G, H and I genotype HBV, more preferably from genotype C.
• the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region may contain an amino acid sequence
• the amino acid sequence has at least about 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identity with the exemplary sequence of SEQ ID NO: 9; preferably, the amino acid sequence having said identity is from any one of HBV described herein including but not limited to genotype A, B, C, D, E, F, G, H and I genotype HBV, More preferably from genotype C.
• variants having a certain sequence identity with the HBV entry inhibitory polypeptides derived from the HBV Pre-S1 region described herein retain one or more biological activities of the corresponding polypeptides, including the biological activities of inhibiting HBV virus entry or binding to NTCP.
• the N-terminus of the HBV entry-inhibiting polypeptide derived from the HBV Pre-S1 region and variants thereof may be modified with a hydrophobic group, such as but not limited to myristic acid (myr), palmitic acid (plam), stearic acid (stearoyl), cholesterol (cho1), oleic acid, linoleic acid, polyethylene glycol (PEG), arachidonic acid or other hydrophobic groups.
• the hydrophobic group may be selected from myristic acid, palmitic acid, stearic acid, and cholesterol.
• the hydrophobic group is myristic acid.
• the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region described herein may contain an amino acid sequence selected from any of SEQ ID NO: 2-32 or a variant thereof, wherein the N-terminus of the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region may be modified by a hydrophobic group selected from myristic acid, palmitic acid, stearic acid and cholesterol.
• the polypeptide may contain an amino acid sequence selected from any one of SEQ ID NO: 2-32 or a variant thereof, wherein the N-terminus of the HBV entry-inhibiting polypeptide derived from the HBV Pre-S1 region may be myristoylated.
• the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region described herein may contain the amino acid sequence shown in SEQ ID NO: 9 or SEQ ID NO: 32, wherein the N-terminus of the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region may be myristoylated.
• the C-terminus of the HBV entry-inhibiting polypeptide derived from the HBV Pre-S1 region may be modified.
• C-terminal modifications may be selected from, but are not limited to, amidation (amination), prenylation, and other C-terminal modifications, or may be deleted.
• the C-terminal modification may be amidation (NH2).
• the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region may contain the amino acid sequence shown in SEQ ID NO: 9 or SEQ ID NO: 32, and its C-terminus may be amidated.
• the N-terminus of the HBV entry-inhibiting polypeptide derived from the HBV Pre-S1 region may be modified with a hydrophobic group, and/or the C-terminus may be modified by other methods. In some embodiments, the N-terminus of the HBV entry-inhibiting polypeptide derived from the HBV Pre-S1 region may be modified by a hydrophobic group, and/or the C-terminus may be modified by amidation.
• the HBV entry-inhibiting polypeptide derived from the HBV Pre-S1 region may contain an amino acid sequence selected from any of SEQ ID NO: 2-32 and variants thereof, and its N-terminal hydrophobic group modification, and/or C-terminus may be modified by amidation.
• the HBV entry-inhibiting polypeptide derived from the HBVPre-S1 region may contain the amino acid sequence shown in SEQ ID NO: 9 or SEQ ID NO: 32, and its N-terminus is covered with myristic acid (myr), palmitic acid (plam), stearic acid (stearoyl), cholesterol (cho1) hydrophobic group modification, its C-terminus is modified by amidation, such as the polypeptide shown in SEQ ID NO: 33-37.
• the N-terminal of the HBV entry-inhibiting polypeptide derived from the HBV Pre-S1 region may be modified by a myristic acid (myr) hydrophobic group, and/or the C-terminal may be modified by amidation.
• the polypeptide may contain an amino acid sequence selected from any one of SEQ ID NO: 2-32 and variants thereof, and its N-terminus may be modified by myristoylation, and/or its C-terminus may be modified by amidation.
• the HBV entry inhibitory polypeptide derived from the HBV Pre-S1 region may contain the polypeptide shown in SEQ ID NO: 9 or 32, its N-terminus is modified by a myristic acid (myr) hydrophobic group, and its C-terminus is modified by amidation, as shown in any of SEQ ID NOs: 33, 34 and 38-44.
• the loaded HBV entry inhibitors include but are not limited to hepalatide (SEQ ID NO: 33), bulevirtide (SEQ ID NO: 43) and other HBV Pre-S 1 derived peptides.
• hepalatide N-myristoyl-glycyl-L-threonyl-L-asparaginyl-L-leucyl-L-seryl-L-valyl-L-prolyl-L-asparagyl-L-prolyl-L-leucyl-glycyl-L-phenylalanyl-L-phenylalanyl-L-prolyl-L-aspartyl-L-histidyl-L-glutamyl-L-leucyl-L- Aspartyl-L-Prolyl-L-Alanyl-L-Phenylalanyl-Glycyl-L-A
• hepalatide or bulevirtide treatment is loaded on the basis of NAs treatment.
• hepalatide treatment is loaded on the basis of NAs treatment.
• the therapeutic dose of hepalatide is 2.1-10.5 mg per day. In a preferred scheme, the therapeutic dose of hepalatide is 4.2-8.4 mg per day. In a further preferred scheme, the therapeutic dose of hepalatide is 4.2 mg per day.
• the treatment cycle of hepalatide is 1-96 weeks. In a preferred scheme, the treatment cycle of hepalatide is 12-48 weeks. In a further preferred scheme, the treatment cycle of hepalatide is 24-48 weeks. In a more preferred scheme, the treatment cycle of hepalatide is 48 weeks.
• the anti-Pre-S1 antibodies include but are not limited to anti-HBV Pre-S1 monoclonal antibodies, anti-HBV Pre-S1 bifunctional antibodies (diabodies), anti-HBV Pre-S1 polyclonal antibodies (polyclonal antibodies), anti-HBV Pre-S1 serum, and other forms of antibodies and compositions thereof, which can bind to HBV Pre-S1 and inhibit HBV infection.
• the anti-surface antigen antibodies include but are not limited to anti-surface antigen monoclonal antibodies, anti-surface antigen diabodies (diabodies), anti-surface antigen polyclonal antibodies (polyclonal antibodies), anti-surface antigen serum, HBIG and other forms of antibodies and compositions thereof, which can bind to surface antigens to inhibit HBV infection.
• the other agents that can inhibit HBV from entering or infecting liver cells include but are not limited to small molecules, proteins and other molecules, which can act on NTCP, HBV virus or other targets to achieve the technical effect of inhibiting HBV infection.
• the NAs are loaded with an HBV entry inhibitor for a certain period of combination therapy, in one embodiment, 1-96 weeks of combination therapy.
• the combination therapy is for 12-60 weeks.
• the combination therapy is for 24-48 weeks.
• the combination therapy is for 48 weeks.
• the non-rebound of HBV in CHB patients after the termination of treatment refers to the non-rebound of HBV within at least 24 weeks after the patient stops the combination therapy.
• the HBV does not rebound in CHB patients after the termination of treatment means that the HBV does not rebound within at least 48 weeks after the patient stops the combination therapy.
• the non-rebound of HBV in CHB patients after the termination of treatment means that the HBV does not rebound within at least 96 weeks after the patient stops the combination therapy.
• the non-rebound of HBV in CHB patients after the cessation of treatment refers to the success of drug withdrawal after the patient stops the combination therapy, and the patient does not need to receive NAs treatment again (retreatment).
• the HBV in CHB patients does not rebound after terminating the treatment means that the HBV DNA is continuously lower than 2000 IU/ml after the patient stops the combined treatment.
• the CHB patient's HBV does not rebound after the termination of treatment means that the patient's HBV DNA continues to be lower than the lower limit of quantitative detection (below 20 IU/m1).
• the non-rebound of HBV in CHB patients after terminating treatment means that HBV DNA continues to be undetectable (less than 10 IU/m1) after the patient stops the combined treatment.
• the basic NAs are changed to TDF or TAF, and HBV entry inhibitors are added for combined treatment.
• CHB patients change the basic NAs to TAF, and add HBV entry inhibitors for combined treatment.
• HBV entry inhibitors and immunomodulators are loaded for combined therapy, said immunomodulators include but not limited to interferon (IFN), toll-like receptor (Toll-like receptors, TLR) agonist, CPG (Cytidine-phosphatte-guanonine), CPG ODN (CpG oligonucleotide), PD-1 (Programmed Death Receptor-1) inhibitors, PD-L1 (Programmed Death Receptor ligan 1) inhibitors, interleukin (IL), cytokines, and other immunomodulators.
• IFN interferon
• Toll-like receptors TLR
• CPG Cytidine-phosphatte-guanonine
• CPG ODN CpG oligonucleotide
• PD-1 Programmed Death Receptor-1
• PD-L1 Programmed Death Receptor ligan 1
• IL interleukin
• cytokines interleukin
• the TLR agonists include but are not limited to TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11 and other TLR receptor agonists.
• PD-1 inhibitors include but are not limited to anti-PD-1 monoclonal antibodies, anti-PD-1 bispecific antibodies, anti-PD-1 polyclonal antibodies, small molecule drugs that inhibit PD-1 or PD-1 signaling, and other PD-1 inhibitors.
• PD-L1 inhibitors include but are not limited to anti-PD-L1 monoclonal antibodies, anti-PD-L1 bispecific antibodies, anti-PD-L1 polyclonal antibodies, inhibitors of PD-L1, recombinant PD-L1 proteins, recombinant PD-L1 fusion proteins, small molecule drugs that inhibit PD-L1 or PD-L1 signaling, and other PD-L1 inhibitors.
• the loaded HBV entry inhibitors include, but are not limited to, HBV Pre-S1-derived peptides, anti-Pre-S1 antibodies, anti-surface antigen antibodies, or other agents that can inhibit HBV from entering or infecting liver cells.
• the HBV Pre-S1 derived peptides include but not limited to hepalatide (SEQ ID NO: 33), bulevirtide (SEQ ID NO: 34) and other HBV Pre-S1 derived peptides.
• HBVPre-S1 derived peptides include, but are not limited to, the exemplified sequences of SEQ ID NO: 2-44 and other polypeptides derived from the A-I genotype HBVPre-S1 region, which are characterized in that they can bind NTCP and inhibit HBV infection.
• hepalatide or bulevirtide treatment is loaded on top of NAs treatment. In a further preferred scheme, hepalatide treatment is loaded on the basis of NAs treatment.
• the therapeutic dose of hepalatide is 2.1-10.5 mg per day. In a preferred scheme, the therapeutic dose of hepalatide is 4.2-8.4 mg per day. In a further preferred scheme, the therapeutic dose of hepalatide is 4.2 mg per day.
• the treatment cycle of hepalatide is 1-96 weeks. In a preferred scheme, the treatment cycle of hepalatide is 12-48 weeks. In a further preferred scheme, the treatment cycle of hepalatide is 24-48 weeks.
• the treatment cycle of hepalatide is 48 weeks.
• the loaded immunomodulator is interferon (IFN).
• the loaded interferon is IFN- ⁇ , IFN- ⁇ , IFN- gamma.
• the loaded interferon is IFN ⁇ -2a or IFN ⁇ -2b.
• the loaded interferon is common interferon or peginterferon.
• the loaded interferon is polyethylene glycol (PEG) interferon.
• the loaded interferon is PEG IFN ⁇ -2a or PEG IFN ⁇ -2b, and these interferons include but are not limited to Pegasys, Pegabine, PegIntron and other interferons.
• the dose of interferon is lower than the standard dose of clinical treatment.
• the loaded interferon is Pegasys, and its dosage is 1-360ug per week; in one embodiment, its dosage is 30-180ug per week; in one embodiment, its dosage is 60-135ug per week; in one embodiment, its dosage is 90ug per week.
• the NAs are loaded with an HBV entry inhibitor for a certain course of combined treatment with interferon, and in one embodiment, the combined treatment is 1-96 weeks.
• the combination therapy is for 12-60 weeks.
• the combination therapy is for 24-48 weeks.
• the combination therapy is for 48 weeks.
• the method for limiting NAs treatment provided by the present invention its basic NAs treatment includes but not limited to lamivudine, telbivudine, adefovir dipivoxil, tenofovir, entecavir, tenofovir alafenamide fumarate and other NAs drugs; HBV entry blockers include but not limited to hepalatide, bulevirtide and other HBV entry blockers; immune modulators include but not limited to interferon and other immunomodulators.
• the limited NAs treatment method provided by the present invention at least includes loading HBV entry blocker treatment on the basis of NAs treatment, and can also further add immunomodulator treatment.
• the methods for limiting NAs treatment provided by the present invention include but are not limited to the schemes listed in the following table. In some embodiments of the present invention, schemes 6, 13, 27, 34 may be employed, but not limited to.
• the present invention provides the use of an HBV virus entry inhibitor and an optional immunomodulator in the preparation of a medicament or kit for limiting or terminating nucleoside (acid) drug treatment of chronic hepatitis B.
• the HBV virus entry inhibitors, immunomodulators, nucleoside (acid) drugs, medicines and kits are as described in any of the above embodiments.
• the present invention provides the HBV virus entry inhibitor described in any embodiment herein and an optional immunomodulator for limiting or terminating nucleoside (acid) drug treatment of chronic hepatitis B or a drug or kit containing the HBV virus entry inhibitor described in any embodiment herein and an optional immunomodulator.
• the medicament or kit of the present invention is used in the method of limiting or terminating NAs drug treatment of chronic hepatitis B as described in any of the embodiments herein.
• the kit of the present invention further contains one or more doses of nucleoside (acid) drugs described in any embodiment herein.
• the pharmaceutical preparations contained in the kit meet the dosage required for one or more courses of treatment described herein.
• Example 1 TAF combined with PEG interferon and hepalatide for a limited course of treatment of chronic hepatitis B randomized double-blind placebo-controlled multi-center phase II clinical trial protocol (L47-HB-FIN-1)
• Table 1 Test grouping table
• Pegylated interferon treatment contraindications such as severe depression, epilepsy, autoimmune diseases, uncontrolled thyroid dysfunction, etc.
• liver cirrhosis There is clinical evidence of liver cirrhosis: such as abdominal color Doppler ultrasound, CT and other imaging examinations clearly show liver cirrhosis; liver biopsy Metavir fibrosis score is 4 points; the investigator clinically diagnoses liver cirrhosis;
• liver disease (ascites, hepatic encephalopathy, variceal hemorrhage, hepatorenal syndrome, etc.);
• autoimmune diseases Those with autoimmune diseases, immune-related extrahepatic manifestations (vasculitis, purpura, nodular arteritis, peripheral neuropathy, and glomerulonephritis), thyroid disease, malignant tumor, and immunosuppressive therapy;
• Dosage form tablet
• Approval number Import drug registration certificate number H20180060;
• Dosage form powder injection
• Transportation and storage transportation temperature ⁇ 8 °C, 2-8 °C sealed and protected from light;
• Dosage form powder injection
• Transportation and storage transportation temperature ⁇ 8 °C, 2-8 °C sealed and protected from light;
• Hepalatide treatment (4.2mg, s.c.QD) was added to the basic treatment for 48 weeks of continuous treatment.
• the basic treatment was loaded with subcutaneous injection of hepalatide placebo once a day, and the treatment continued for 48 weeks.
• Treatment cycle 48 weeks;
• HBV DNA HBV DNA, HBsAg, HBsAb, HBeAb, ALT, LSM, HBcrAg, HBV pgRNA
• Virological sustained response response at the end of treatment and follow-up for 24 or 48 weeks after drug withdrawal;
• HBV DNA level increased by >1log10IU/mL from the lowest value in the treatment, or turned negative and then turned positive, and confirmed by repeated detection with the same reagent one month later, with or without ALT increase;
• HBsAg negative conversion HBsAg negative conversion
• HBsAg seroconversion HBsAg negative with HBsAb positive
• HBeAg seroconversion HBeAg negative with HBeAb positive.
• Auxiliary examination electrocardiogram, B-ultrasound examination (liver, gallbladder, spleen, pancreas, kidney, ascites), liver CT plain scan;
• Symptomatic adverse events are classified into mild (transient symptoms, which do not affect the subjects' daily activities), moderate (obvious symptoms, which have a certain impact on the subjects' daily activities) and severe (obviously affect the subjects' daily activities, unacceptable) according to the 3-level classification standard. Objective adverse events were graded according to NCI CTCAE v5.0, using Level 5 judgment standard.
• the investigator will decide whether to restart the antiviral treatment after evaluation, or continue the scheduled visit/additional visit, or the patient should be suspended from the study.
• Secondary endpoint analysis The secondary efficacy endpoints were tested by mITT and PPS respectively. The L474.2mg dose group was compared with the placebo group for the secondary endpoint, and the test level was one-sided 0.025.
• Safety analysis A safety set (SS) was used, including all subjects exposed to at least one dose of the trial drug (L47, L47 placebo). Descriptive statistics were mainly used for safety indicators.
• the efficacy endpoint is treatment failure.

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