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WO2025240242A1 - Polythérapies avec ribavirine - Google Patents

Polythérapies avec ribavirine

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Publication number
WO2025240242A1
WO2025240242A1 PCT/US2025/028569 US2025028569W WO2025240242A1 WO 2025240242 A1 WO2025240242 A1 WO 2025240242A1 US 2025028569 W US2025028569 W US 2025028569W WO 2025240242 A1 WO2025240242 A1 WO 2025240242A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
acceptable salt
ribavirin
bulevirtide
inhibitors
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/028569
Other languages
English (en)
Inventor
Simon P. Fletcher
Meghan M. Holdorf
Aleksander A. SHORNIKOV
Helen Yu
Mei Yu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gilead Sciences Inc
Original Assignee
Gilead Sciences Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gilead Sciences Inc filed Critical Gilead Sciences Inc
Publication of WO2025240242A1 publication Critical patent/WO2025240242A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • 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
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • 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
    • 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 present application provides combinations of bulevirtide, or a pharmaceutically acceptable salt thereof, and ribavirin, or a pharmaceutically acceptable salt thereof, which are useful for the inhibition of hepatitis B virus (HBV) and/or hepatitis D virus (HDV) infection, prevention of primary HBV and/or HDV infection, as well as treatment of (chronic) hepatitis B and/or D.
  • HBV hepatitis B virus
  • HDV hepatitis D virus
  • Hepatitis B virus is the prototype of a family of small, enveloped DNA viruses of mammals and birds (Seeger et al, Microbiol. Mol. Biol. Rev. 64, 51-68 (2000)).
  • Hepatitis D virus is a negative sense single stranded circular RNA satellite virus of HBV that is encapsulated by envelope proteins encoded by HBV. HDV depends on the HBV envelope for assembly, infection and extracellular viral spread.
  • the HBV envelope consists of three proteins termed L-(large), M-(middle) and S-(small) surface antigen (HBsAg) derived from the same open reading frame with a common C terminal domain.
  • the M- and L-protein carry additional N-terminal extensions of 55 (preS2) and, genotype-dependent, 107 or 118 aa (preSl).
  • preS2 preS2
  • preSl genotype-dependent, 107 or 118 aa
  • NTCP sodium taurocholate co-transporting polypeptide
  • SVPs small non- infectious subviral particles mainly composed of S-HBsAg are also present in the serum of HBV and HDV-infected patients in large abundance.
  • the present application provides, inter alia, a method of treating hepatitis D virus (HDV) infection in a patient, comprising administering to the patient: i) bulevirtide, or a pharmaceutically acceptable salt thereof; and ii) ribavirin, or a pharmaceutically acceptable salt thereof.
  • HDV hepatitis D virus
  • the present application further provides one or more pharmaceutical compositions comprising bulevirtide, or a pharmaceutically acceptable salt thereof; and ribavirin, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • the present application further provides a combination of bulevirtide, or a pharmaceutically acceptable salt thereof; and ribavirin, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.
  • the present application further provides a combination of bulevirtide, or a pharmaceutically acceptable salt thereof; and ribavirin, or a pharmaceutically acceptable salt thereof, for the preparation of one or more medicaments for use in any of the methods described herein.
  • FIG. 1 shows the structure of bulevirtide.
  • FIGs. 2A-2F show that ribavirin (RB V) demonstrated dose-dependent antiviral activity in HDV-infected primary human hepatocytes in a 4-day treatment (FIGs. 2A-2C) and a 13-day treatment (FIGs. 2D-2F).
  • RB V ribavirin
  • FIGs. 3 A-3B show that RBV exhibited additive antiviral activity in presence of bulevirtide (BLV) in HDV-infected primary human hepatocytes in a HDAg dose-response curve (FIG. 3 A) and a nuclei count dose-response curve (FIG. 3B).
  • BLV bulevirtide
  • FIGs. 4A-4B show that lamivudine, telbivudine, entecavir, tenofovir, and adefovir exhibited no antiviral activity in HDV-infected primary human hepatocytes in a HDAg dose-response curve (FIG. 4A) and nuclei count dose-response curve (FIG. 4B).
  • FIG. 4A dose-response curve
  • FIG. 4B nuclei count dose-response curve
  • the present application provides a method of treating hepatitis D virus (HDV) infection in a patient, comprising administering to the patient: i) bulevirtide, or a pharmaceutically acceptable salt thereof; and ii) ribavirin, or a pharmaceutically acceptable salt thereof.
  • HDV hepatitis D virus
  • bulevirtide refers to a coupled myristic acid group (z.e., Ci3H2?C(O)-).
  • bulevirtide may also be referred to as “the compound of Formula I”, “Myr-(SEQ ID N0: l)-NH2”, or “Ci3H2?C(O)-(SEQ ID N0: l)-NH2”. The structure of bulevirtide is shown in FIG. 1.
  • SEQ ID NO: 1 refers to the following sequence:
  • Ribavirin i.e., l-((27?,37?,45,57?)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-lH-l,2,4-triazole-3-carboxamide (structure shown below), is a nucleoside antiviral agent useful, e.g., for the treatment of HCV and viral hemorrhagic fevers.
  • the bulevirtide, or a pharmaceutically acceptable salt thereof, and ribavirin, or a pharmaceutically acceptable salt thereof are administered simultaneously.
  • the bulevirtide, or a pharmaceutically acceptable salt thereof, and ribavirin, or a pharmaceutically acceptable salt thereof are administered sequentially.
  • the bulevirtide, or a pharmaceutically acceptable salt thereof is administered subcutaneously.
  • the bulevirtide, or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dosage of about 1 mg to about 10 mg, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg.
  • the bulevirtide, or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dosage of about 1 mg to about 5 mg. In some embodiments, the bulevirtide, or a pharmaceutically acceptable salt thereof, is administered subcutaneously at a dosage of about 1 mg to about 3 mg. In some embodiments, the bulevirtide, or a pharmaceutically acceptable salt thereof, is administered subcutaneously at a dosage of about 2 mg. [0025] In some embodiments, the bulevirtide is bulevirtide acetate.
  • the bulevirtide acetate is administered subcutaneously at a dosage of about 1 mg to about 10 mg, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg.
  • the bulevirtide acetate is administered subcutaneously at a dosage of about 1 mg to about 5 mg. In some embodiments, the bulevirtide acetate is administered subcutaneously at a dosage of about 1 mg to about 3 mg. In some embodiments, the bulevirtide acetate is administered subcutaneously at a dosage of about 2 mg.
  • the ribavirin, or a pharmaceutically acceptable salt thereof is administered to the patient at a concentration of about 20 mg/mL to about 60 mg/mL, for example, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 55 mg/mL, or about 60 mg/mL.
  • the ribavirin, or a pharmaceutically acceptable salt thereof is administered to the patient at a concentration of about 40 mg/mL to about 60 mg/mL.
  • the ribavirin, or a pharmaceutically acceptable salt thereof is administered at a concentration of about 40 mg/mL.
  • the method provided herein comprises administering about 100 mg to about 800 mg of the ribavirin, or a pharmaceutically acceptable salt thereof, for example, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, or about 800 mg of the ribavirin, or a pharmaceutically acceptable salt thereof.
  • the method provided herein comprises administering about 100 mg to about 300 mg of the ribavirin, or a pharmaceutically acceptable salt thereof, to the patient, for example, about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg of the ribavirin, or a pharmaceutically acceptable salt thereof.
  • the method provided herein comprises administering about 200 mg of the ribavirin, or a pharmaceutically acceptable salt thereof, to the patient. In some embodiments, the method provided herein comprises administering about 400 mg of the ribavirin, or a pharmaceutically acceptable salt thereof, to the patient. In some embodiments, the method provided herein comprises administering about 600 mg of the ribavirin, or a pharmaceutically acceptable salt thereof, to the patient.
  • the ribavirin, or a pharmaceutically acceptable salt thereof is administered orally or nasally. In some embodiments, the ribavirin, or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments, the ribavirin, or a pharmaceutically acceptable salt thereof, is administered nasally.
  • the present disclosure includes all tautomers of compounds detailed herein, even if only one tautomer is expressly represented (e.g., both tautomeric forms are intended and described by the presentation of one tautomeric form where a pair of two tautomers may exist).
  • a compound containing an amide e.g., by structure or chemical name
  • the corresponding imidic acid tautomer is included by this disclosure and described the same as if the amide were expressly recited either alone or together with the imidic acid.
  • the present disclosure includes all such tautomers even if only a single tautomeric form is depicted by chemical name and/or structure.
  • this disclosure also includes any compound disclosed herein (e.g., bulevirtide, or a pharmaceutically acceptable salt thereof, and/or ribavirin, or a pharmaceutically acceptable salt thereof) that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium ( 2 H or D).
  • bulevirtide or a pharmaceutically acceptable salt thereof
  • ribavirin or a pharmaceutically acceptable salt thereof
  • the deuterium atom is a non-radioactive isotope of the hydrogen atom.
  • Such compounds may increase resistance to metabolism, and thus may be useful for increasing the half-life of the compounds when administered to a mammal. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci., 5(12):524-527 (1984).
  • Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.
  • isotopes that can be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, n C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 O, 31 P, 32 P, 35 S, 18 F, 36 C1, 123 I, and 125 I, respectively.
  • isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine such as 2 H, 3 H, n C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 O, 31 P, 32 P, 35 S, 18 F, 36 C1, 123 I, and 125 I, respectively.
  • positron emitting isotopes such as n C, 18 F, 15 O and 13 N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • An isotopically-labeled compound of Formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • isotopically-labeled compounds of Formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • Compounds described herein may have chiral centers and/or geometric isomeric centers (E- and Z- isomers), and it is to be understood that all such optical, enantiomeric, diastereoisomeric and geometric isomers are encompassed.
  • E- and Z- isomers chiral centers and/or geometric isomeric centers
  • all such optical, enantiomeric, diastereoisomeric and geometric isomers are encompassed.
  • compounds are represented in their chiral form, it is understood that the embodiment encompasses, but is not limited to, the specific diastereomerically or enantiomerically enriched form. Where chirality is not specified but is present, it is understood that the embodiment is directed to either the specific diastereomerically or enantiomerically enriched form; or a racemic or scalemic mixture of such compound(s).
  • “scalemic mixture” is a mixture of stereoisomers at a ratio other than 1 : 1.
  • bulevirtide, or a pharmaceutically acceptable salt thereof, and ribavirin, or a pharmaceutically acceptable salt thereof, of the present disclosure may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer.
  • a dosage may be expressed as a number of milligrams of a compound provided herein, or a pharmaceutically acceptable salt thereof, per kilogram of the subject’s body weight (mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate. In some embodiments, about 0.1 and 100 mg/kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg/kg may be appropriate.
  • Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.
  • the dosage may also be described as a total amount of a compound described herein, or a pharmaceutically acceptable salt thereof, administered per dose.
  • the dosage or dosing frequency of the combination of the present disclosure may be adjusted over the course of the treatment, based on the judgment of the administering physician.
  • the combination of the present disclosure may be administered to an individual (e.g., a human) in a therapeutically effective amount.
  • the combination is administered once daily, once weekly, once monthly, once every two months, once every three months, or once every six months.
  • the combination is administered once daily.
  • the combination is administered once weekly.
  • the combination is administered once monthly.
  • the combination is administered once every two months.
  • the combination is administered once every three months.
  • the combination is administered once every six months.
  • a single dose of the combination can be administered hourly, daily, weekly, or monthly. For example, a single dose can be administered once every 1 hour, 2, 3, 4, 6, 8, 12, 16 or once every 24 hours. A single dose can also be administered once every 1 day, 2, 3, 4, 5, 6, or once every 7 days. A single dose can also be administered once every 1 week, 2, 3, or once every 4 weeks.
  • the frequency of dosage of the combination of the present disclosure will be determined by the needs of the individual patient. Administration of the combination continues for as long as necessary to treat the infection, including an HDV infection, or any other indication described herein.
  • Administration can be intermittent, with a period of several or more days during which a patient receives a daily dose of the combination of the present disclosure, followed by a period of several or more days during which a patient does not receive a daily dose of the combination.
  • a patient can receive a dose of the combination, every other day, or three times per week.
  • a patient can receive a dose of the combination each day for a period of from 1 to 14 days, followed by a period of 7 to 21 days during which the patient does not receive a dose of the combination followed by a subsequent period (e.g., from 1 to 14 days) during which the patient again receives a daily dose of the combination.
  • the methods provided herein comprise administering to the patient: i) a pharmaceutical composition comprising bulevirtide, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients; and ii) a pharmaceutical composition comprising ribavirin, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition comprising the bulevirtide, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients; and the pharmaceutical composition comprising the ribavirin, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, are administered simultaneously.
  • the pharmaceutical composition comprising the bulevirtide, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients; and the pharmaceutical composition comprising the ribavirin, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, are administered sequentially.
  • compositions disclosed herein can be prepared by methodologies well known in the pharmaceutical art.
  • a pharmaceutical composition intended to be administered by injection can prepared by combining a compound of the disclosure with sterile, distilled water so as to form a solution.
  • a surfactant is added to facilitate the formation of a homogeneous solution or suspension.
  • Surfactants are compounds that non-covalently interact with the compound of the disclosure so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous delivery system.
  • compositions of the disclosure can be prepared by combining a compound of the disclosure, or a pharmaceutically acceptable salt thereof, with an appropriate pharmaceutically acceptable carrier and, in specific embodiments, are formulated into preparations in solid, semi solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.
  • compositions of the disclosure are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient.
  • Compositions that will be administered to a subject or patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound of the disclosure in aerosol form may hold a plurality of dosage units.
  • compositions to be administered will, in any event, contain a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for treatment of a disease or condition of interest in accordance with the teachings described herein.
  • Pharmaceutical compositions containing an active ingredient may be in any form suitable for the intended method of administration.
  • the compound or salt is prepared according to one or more of the processes described herein.
  • “Pharmaceutically acceptable” refers to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
  • “Pharmaceutically acceptable excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • compositions provided herein may be prepared with conventional carriers (e.g., inactive ingredient or excipient material) which may be selected in accord with ordinary practice.
  • tablets may contain excipients including glidants, fillers, binders and the like.
  • Aqueous compositions may be prepared in sterile form, and when intended for delivery by other than oral administration generally may be isotonic. All compositions may optionally contain excipients such as those set forth in the Rowe et al, Handbook of Pharmaceutical Excipients, 5 th edition, American Pharmacists Association, 1986.
  • a first pharmaceutical composition disclosed herein comprises bulevirtide, or a pharmaceutically acceptabl salt thereof, and one or more pharmaceutically acceptable excipients.
  • a first pharmaceutical composition disclosed herein comprises bulevirtide or an acetic acid salt of bulevirtide (z.e., bulevirtide acetate), and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition comprises about 1 mg to about 5 mg of the bulevirtide, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, or about 5 mg of the bulevirtide, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprises about 2 mg of the bulevirtide, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • the pharmaceuticla compositoin comprises about 2 mg on a free base basis of bulevirtide acetate, and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition comprising the bulevirtide, or a pharmaceutically acceptable salt thereof is an injectable solution. In some embodiments, the pharmaceutical composition comprising the bulevirtide, or a pharmaceutically acceptable salt thereof, is an injectable solution suitable for subcutaneous administration to the patient.
  • the injectable solution comprises about 1 mg to about 5 mg of the bulevirtide, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, or about 5 mg of the bulevirtide, or a pharmaceutically acceptable salt thereof. In some embodiments, the injectable solution comprises about 2 mg of the bulevirtide, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the injectable solution comprises about 2 mg on a free base basis of bulevirtide acetate, and one or more pharmaceutically acceptable excipients.
  • the injectable solution comprises one or more pharmaceutically acceptable excipients selected from sodium carbonate, sodium bicarbonate, and mannitol; or any combination thereof.
  • the injectable solution comprises bulevirtide, or a pharmaceutically acceptable salt thereof, sodium carbonate, sodium bicarbonate, and mannitol.
  • the injectable solution comprises bulevirtide acetate, sodium carbonate, sodium bicarbonate, and mannitol.
  • the injectable solution comprises about 2 mg on a free base basis of bulevirtide acetate, sodium carbonate, sodium bicarbonate, and mannitol.
  • the injectable solution comprises: about 2 mg on a free base basis of bulevirtide acetate; about 0.1 %w/w to about 0.5 %w/w of sodium carbonate; about 3.5 %w/w to about 4.0 %w/w of sodium bicarbonate; and about 90 %w/w to about 95 %w/w of mannitol.
  • the injectable solution comprises: about 2 mg on a free base basis of bulevirtide acetate; about 0.25 %w/w of sodium carbonate; about 3.7 %w/w of sodium bicarbonate; and about 92 %w/w of mannitol.
  • the injectable solution provided herein further comprises one or more buffering agents and a solvent.
  • the one or more buffering agents comprise sodium hydroxide and hydrochloric acid.
  • the solvent comprises water.
  • a second pharmaceutical composition disclosed herein comprises ribavirin, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition comprising the ribavirin, or a pharmaceutically acceptable salt thereof is selected from a capsule, tablet, and a solution.
  • the pharmaceutical composition comprising the ribavirin, or a pharmaceutically acceptable salt thereof is a solution.
  • the solution is suitable for oral or nasal administration.
  • the solution is suitable for oral administration.
  • the solution is suitable for nasal administration.
  • the ribavirin, or a pharmaceutically acceptable salt thereof is administered as an oral solution comprising the ribavirin, or a pharmaceutically acceptable salt thereof.
  • the ribavirin, or a pharmaceutically acceptable salt thereof is administered as a nasal solution comprising the ribavirin, or a pharmaceutically acceptable salt thereof.
  • the ribavirin, or a pharmaceutically acceptable salt thereof is administered as an oral solution comprising the ribavirin, or a pharmaceutically acceptable salt thereof, at a concentration of about 20 mg/mL to about 60 mg/mL, for example, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 55 mg/mL, or about 60 mg/mL.
  • the ribavirin, or a pharmaceutically acceptable salt thereof is administered as an oral solution comprising the ribavirin, or a pharmaceutically acceptable salt thereof, at a concentration of about 40 mg/mL.
  • the pharmaceutical composition comprising the ribavirin, or a pharmaceutically acceptable salt thereof is a capsule.
  • the capsule comprises from about 100 mg to about 300 mg of the ribavirin, or a pharmaceutically acceptable salt thereof, for example, about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg of the ribavirin, or a pharmaceutically acceptable salt thereof. In some embodiments, the capsule comprises about 200 mg of the ribavirin, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprising the ribavirin, or a pharmaceutically acceptable salt thereof is a tablet.
  • the tablet comprises from about 100 mg to about 800 mg of the ribavirin, or a pharmaceutically acceptable salt thereof, for example, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, or about 800 mg of the ribavirin, or a pharmaceutically acceptable salt thereof.
  • the tablet comprises about 200 mg of the ribavirin, or a pharmaceutically acceptable salt thereof.
  • the tablet comprises about 400 mg of the ribavirin, or a pharmaceutically acceptable salt thereof.
  • the tablet comprises about 600 mg of the ribavirin, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprising the ribavirin, or a pharmaceutically acceptable salt thereof is a solution.
  • the solution is suitable for oral administration.
  • the solution comprises about 20 mg/mL to about 60 mg/mL of the ribavirin, or a pharmaceutically acceptable salt thereof, for example, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 55 mg/mL, or about 60 mg/mL.
  • the solution comprises about 40 mg/mL to about 60 mg/mL of the ribavirin, or a pharmaceutically acceptable salt thereof.
  • the present application further provides a method of inhibiting or treating an HBV and/or HDV infection in a patient in need thereof, comprising administering to a patient (e.g., a patient in need thereof), bulevirtide, or a pharmaceutically acceptable salt thereof, and ribavirin, or a pharmaceutically acceptable salt thereof.
  • a patient e.g., a patient in need thereof
  • bulevirtide or a pharmaceutically acceptable salt thereof
  • ribavirin or a pharmaceutically acceptable salt thereof.
  • the present application further provides a method of inhibiting or treating an HDV infection in a patient in need thereof, comprising administering to a patient (e.g., a patient in need thereof), bulevirtide, or a pharmaceutically acceptable salt thereof, and ribavirin, or a pharmaceutically acceptable salt thereof.
  • a patient e.g., a patient in need thereof
  • bulevirtide or a pharmaceutically acceptable salt thereof
  • ribavirin or a pharmaceutically acceptable salt thereof.
  • the patient has been identified as having hepatitis B.
  • the patient has been identified as having compensated liver disease (e.g, compensated cirrhosis).
  • compensated liver disease e.g., compensated cirrhosis
  • the terms “compensated liver disease” or “compensated cirrhosis” refer to asymptomatic liver disease (e.g., asymptomatic cirrhosis).
  • the patient identified as having compensated liver disease does not exhibit one or more symptoms of the liver disease, including, but not limited to, ascites, variceal hemorrhage, hepatic encephalopathy, and jaundice.
  • the patient identified as having compensated liver disease does not exhibit symptoms of the liver disease, including, but not limited to, ascites, variceal hemorrhage, hepatic encephalopathy, and jaundice.
  • the present application further provides a method of preventing a primary HBV and/or HDV infection in a patient in need thereof, comprising administering to the patient bulevirtide, or a pharmaceutically acceptable salt thereof, and ribavirin, or a pharmaceutically acceptable salt thereof.
  • the present application further provides a method of preventing an HDV infection in a patient in need thereof, comprising administering to the patient bulevirtide, or a pharmaceutically acceptable salt thereof, and ribavirin, or a pharmaceutically acceptable salt thereof.
  • the present application further provides methods of treating and/or preventing chronic hepatitis B and/or D in a patient in need thereof, comprising administering to the patient bulevirtide, or a pharmaceutically acceptable salt thereof, and ribavirin, or a pharmaceutically acceptable salt thereof.
  • the present application further provides methods of treating and/or preventing chronic hepatitis D in a patient in need thereof, comprising administering to the patient bulevirtide, or a pharmaceutically acceptable salt thereof, and ribavirin, or a pharmaceutically acceptable salt thereof.
  • the present application further provides bulevirtide, or a pharmaceutically acceptable salt thereof, and ribavirin, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.
  • the present application further provides bulevirtide, or a pharmaceutically acceptable salt thereof, and ribavirin, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein.
  • patient refers to humans, domestic animals (e.g, dogs and cats), farm animals (e.g, cattle, horses, sheep, goats and pigs), laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs, and monkeys), and the like.
  • the patient is a human patient.
  • treatment is an approach for obtaining beneficial or desired results.
  • beneficial or desired results include, but are not limited to, alleviation of a symptom and/or diminishment of the extent of a symptom and/or preventing a worsening of a symptom associated with a disease or condition.
  • treatment includes one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); and/or c) relieving the disease or condition, e.g., causing the regression of clinical symptoms, ameliorating the disease state, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
  • inhibiting the disease or condition e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition
  • slowing or arresting the development of one or more symptoms associated with the disease or condition e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition
  • relieving the disease or condition e.g., causing the
  • prevention refers to a regimen that protects against the onset of the disease or disorder such that the clinical symptoms of the disease do not develop.
  • prevention relates to administration of a therapy (e.g., administration of a therapeutic substance) to a patient before signs of the disease are detectable in the patient (e.g., administration of a therapeutic substance to a patient in the absence of detectable infectious agent (e.g., virus) in the patient).
  • the patient may be an individual at risk of developing the disease or disorder, such as an individual who has one or more risk factors known to be associated with development or onset of the disease or disorder.
  • preventing HBV infection and “preventing HDV infection” refer to administering to a patient who does not have a detectable HBV or HDV infection an anti- HBV or HDV therapeutic substance (e.g., bulevirtide, or a pharmaceutically acceptable salt thereof, and ribavirin, or a pharmaceutically acceptable salt thereof, as described herein).
  • an anti- HBV or HDV therapeutic substance e.g., bulevirtide, or a pharmaceutically acceptable salt thereof, and ribavirin, or a pharmaceutically acceptable salt thereof, as described herein.
  • prevention may not result in complete protection against onset of the disease or disorder.
  • prevention includes reducing the risk of developing the disease or disorder. The reduction of the risk may not result in complete elimination of the risk of developing the disease or disorder.
  • an “at risk” individual is an individual who is at risk of developing a condition to be treated.
  • An individual “at risk” may or may not have detectable disease or condition, and may or may not have displayed detectable disease prior to the treatment of methods described herein.
  • At risk denotes that an individual has one or more so- called risk factors, which are measurable parameters that correlate with development of a disease or condition and are known in the art. An individual having one or more of these risk factors has a higher probability of developing the disease or condition than an individual without these risk factor(s).
  • the term "therapeutically effective amount” or “effective amount” refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a patient for treating a disease, is sufficient to effect such treatment for the disease or to an amount that is effective to protect against the contracting or onset of a disease.
  • the effective amount will vary depending on the compound, the disease, and its severity and the age, weight, etc., of the patient to be treated.
  • the effective amount can include a range of amounts.
  • an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment outcome.
  • An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.
  • Suitable doses of any co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.
  • compositions including an agent(s) of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents, and a pharmaceutically acceptable excipient are provided.
  • kits including an agent(s) of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents are provided.
  • one or more e.g., one, two, three, four, one or two, one to three, or one to four
  • an agent(s) of the present disclosure, or a pharmaceutically acceptable salt thereof is combined with one, two, three, four or more additional therapeutic agents. In some embodiments, an agent(s) of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In some embodiments, an agent(s) of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In some embodiments, an agent(s) of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents.
  • the one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and/or they can be selected from different classes of therapeutic agents.
  • the components of the composition are administered as a simultaneous or sequential regimen.
  • the combination may be administered in two or more administrations.
  • Co-administration of an agent(s) disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of an agent disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of each agent are present in the body of the patient.
  • Co-administration includes administration of unit dosages of the agent(s) disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents.
  • the agent(s) disclosed herein may be administered within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of an agent(s) disclosed herein is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents.
  • a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of an agent(s) disclosed herein within seconds or minutes.
  • a unit dose of an agent(s) disclosed herein is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents.
  • a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of an agent(s) disclosed herein.
  • an agent(s) of the present disclosure is combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous administration to a patient, for example as a solid dosage form for oral administration.
  • an agent(s) of the present disclosure is combined with one, two, three, four or more additional therapeutic agents selected from HDV combination drugs, HBV vaccines, DNA polymerase inhibitors, interferon alpha receptor ligands, hepatitis b surface antigen (HBsAg) inhibitors, HDV/HBV viral entry inhibitors, sodium bile acid cotransporter inhibitors, gene expression inhibitors (eg siRNA), famesoid X receptor agonists, anti -HBV antibodies, anti-PD-1 antibodies, HIV protease inhibitors, nucleoside reverse transcriptase inhibitors and other HBV drugs.
  • additional therapeutic agents selected from HDV combination drugs, HBV vaccines, DNA polymerase inhibitors, interferon alpha receptor ligands, hepatitis b surface antigen (HBsAg) inhibitors, HDV/HBV viral entry inhibitors, sodium bile acid cotransporter inhibitors, gene expression inhibitors (eg siRNA), famesoid X receptor agonists, anti -
  • the additional therapeutic agent is a DNA polymerase inhibitor, such as fosclevudine alafenamide, entecavir.
  • the additional therapeutic agent is an interferon alpha receptor ligand, such as peginterferon alfa-2b, peginterferon alfa-2a, interferon, ropeginterferon- alfa-2b, peginterferon lambda-la (BMS-914143).
  • the additional therapeutic agent is a hepatitis B surface antigen (HBsAg) inhibitor, such as REP-9 (REP 2139-Mg), BJT-778, BM-012.
  • HBsAg hepatitis B surface antigen
  • the additional therapeutic agent is an HDV/HBV viral entry inhibitor, such as hepalatide, HH-003, AB-543, AB-6250, and HH-006.
  • the additional therapeutic agent is a sodium bile acid cotransporter inhibitor such as A-2342 and AB-6250.
  • the additional therapeutic agent is a gene expression inhibitor, such as JNJ-3989, VIR-2218 (ALN-HBV-02), AB-729, RG6346, Bepiprovirsen.
  • the additional therapeutic agent is aHBV antibody, such as VIR-3434.
  • the additional therapeutic agent is an anti-PD-1 antibody, such as nivolumab.
  • the additional therapeutic agent is an HIV protease inhibitor, such as ritonavir.
  • the additional therapeutic agent is a nucleoside reverse transcriptase inhibitor, such as tenofovir disoproxil fumarate.
  • an agent(s) of the present disclosure is combined with one, two, three, four or more additional therapeutic agents selected from HBV combination drugs, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, toll-like receptor (TLR) modulators, interferon alpha receptor ligands, hepatitis b core antigen (HBcAg) inhibitors, hepatitis b surface antigen (HBsAg) inhibitors, hepatitis B virus X interacting protein inhibitor, cytotoxic T-lymphocyte-associated protein 4 (CTLA4) inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors, antisense oligonucleotide targeting viral mRNA, short interfering RNAs (siRNA) and ddRNAi, endonuclease modulators, ribonucelotide reductase inhibitors, HBV E antigen inhibitors, covalently closed circular DNA (cccDNA) inhibitors, farnesoi
  • TLR toll-like receptor
  • an agent(s) as described herein may be used or combined with one or more of a chemotherapeutic agent, an immunomodulator, an immunotherapeutic agent, a therapeutic antibody, a therapeutic vaccine, a bispecific antibody and “antibody -like” therapeutic protein (such as DARPins®, anti-pMHC TCR-like antibodies, DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives), an antibody-drug conjugate (ADC), gene modifiers or gene editors (such as CRISPR Cas9, zinc finger nucleases, homing endonucleases, homing meganucleases (e.g., ARCUS), synthetic nucleases, TALENs), cell therapies such as CAR-T (chimeric antigen receptor T-cell ), and TCR-T (an engineered T cell receptor) agent or any combination thereof.
  • a chemotherapeutic agent such as DARPins®, anti-pMHC
  • an agent(s) as described herein is combined with one, two, three, four or more additional therapeutic agents, e.g., as 3-dioxygenase (IDO) inhibitors, apolipoprotein Al modulator, arginase inhibitors, B- and T-lymphocyte attenuator inhibitors, Bruton’s tyrosine kinase (BTK) inhibitors, CCR2 chemokine antagonist, CD137 inhibitors, CD160 inhibitors, CD305 inhibitors, CD4 agonist and modulator, compounds targeting hepatitis B core antigen (HBcAg), core protein allosteric modulators, covalently closed circular DNA (cccDNA) inhibitors, cyclophilin inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymerase inhibitor, endonuclease modulators, epigenetic modifiers, Farnesoid X receptor agonists, free fatty acid (Ffa)
  • IDO 3-dioxygen
  • Non canonical RNA polymerase PAPD7 inhibitors modulators of CD70, modulators of GITR, modulators of HEVEM, modulators of ICOS, modulators of Mer, modulators of NKG2A, modulators of NKG2D, modulators of 0X40, modulators of SIRPalpha, modulators of TIGIT, modulators of Tim-4, modulators of Tyro, Na+ -taurocholate cotransporting polypeptide (NTCP) inhibitors, natural killer cell receptor 2B4 inhibitors, N0D2 gene stimulator, Nucleoprotein inhibitor, nucleoprotein modulators, OX-40 receptor agonist, PD-1 inhibitors, PD-L1 inhibitors, peptidylprolyl isomerase inhibitor, phosphatidylinositol-3 kinase (PI3K) inhibitors, Retinoic acid-inducible gene 1 stimulator, Reverse transcriptase inhibitor, Ribonuclease inhibitor, RNA DNA polymerase inhibitor, SLC10A1 gene
  • an agent(s) of the present disclosure is combined with one, two, three, or four additional therapeutic agents as disclosed herein.
  • HBV DNA polymerase inhibitors include, but are not limited to, adefovir (HEPSERA®), emtricitabine (EMTRIVA®), emtricitabine+tenofovir disoproxil fumarate (TRUVADA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil , tenofovir dipivoxil fumarate, tenofovir octadecyl oxy ethyl ester, CMX-157, tenofovir exalidex, besifovir, entecavir (BARACLUDE®), entecavir maleate, telbivudine (TYZEKA®), filocil
  • HsAg Hepatitis B Surface Antigen
  • HBsAg inhibitors include, but are not limited to, AK-074, HBF- 0259, GP-605, PBHBV-001, PBHBV-2-15, PBHBV-2-1, REP-9AC, REP-9C, REP-9, REP- 2139, REP-2139-Ca, REP-2165-Mg, REP-2055, REP-2163, REP-2165, REP-2053, REP-2031, REP-006, CB-07, GST-HG121, GST-HG131, BTJ-778, NWP-1080, and REP-9AC'.
  • HBsAg secretion inhibitors include, but are not limited to, BM601, GST-HG-131, AB-452, and ALG-010093.
  • HBV viral entry inhibitors include, but are not limited to, AB-543, HH-003, and HH-006.
  • NTCP Sodium Bile Acid Cotransporter
  • sodium bile acid cotransporter inhibitors include, but are not limited to A2342, L-47, PRX-202, CIM-212930, IPN-60260, AB6250.
  • Hepatitis B large envelope protein inhibitors include, but are not limited to, EDP-721, KW-027, GP-605, GST-HG-121, ALG-010093, ALG-01013, BJT-778, and SAG-282.
  • antisense oligonucleotide targeting viral mRNA examples include, but are not limited to, ISIS-HBVRx, Bepirovirsen, IONIS-HBV-LRX, IONIS-GSK6-LRx, GSK-3389404, BNC-1701, SB-527 and RG-6004.
  • short Interfering RNAs (siRNA)and ddRNAi short Interfering RNAs (siRNA)and ddRNAi
  • siRNA examples include, but are not limited to, TKM-HBV (TKM-HepB), ALN-HBV, SR-008, HepB-nRNA, ARC-520, ARC-521, ARB-1740, ARB-1467, AB-729, RG- 6084 (PD-L1), RG-6217, JNJ-3989 (ARO-HBV), STP-155G, STSG-0002, ALG-010133, ALG- 020755, ALG-125755, ALG-126081, ALG-126101, SR-016 (RBD1016), TQA-3729, Hepbama (BB-103), KW-040, elebsiran (VIR-2218), xalnesiran (RG-6346), ALG-125097, ALG-ASO, LUNAR-HBV, DCR-HBVS (DCR-S219), OLX-703A, Kylo-02, Kylo-04, HT-101, A
  • ddRNAi DNA-directed RNA interference
  • NRTIs non-nucleoside reverse transcriptase inhibitors
  • WO2018118826 Merck
  • WO20 18080903 (Merck), WO2018119013 (Merck), W02017100108 (Idenix), WO2017027434 (Merck), W02017007701 (Merck), W02008005555 (Gilead).
  • hepatitis B virus replication inhibitors include, but are not limited to, ALG-000286, ASN-008, KW-034, GP-31502, isothiafludine, IQP-HBV, RM-5038, and Xingantie.
  • HIV-1 reverse transcriptase inhibitors HIV-1 reverse transcriptase inhibitors
  • HIV-1 reverse transcriptase inhibitors include, but are not limited to, 2,5,6-substituted pyrimidone derivative (HBV).
  • HBV transcript inhibitors include, but are not limited to, BJT-628.
  • Non canonical RNA polymerase PAPD5 and PAPD7 inhibitors include, but are not limited to, BJT-628.
  • PAPD5 and PAPD7 inhibitors include, but are not limited to, PAPD5 and PAPD7 targeting locked nucleic acid antisense oligonucleotides (HBV infection), GSK3965193, GST-HG131, and AB-161.
  • cccDNA inhibitors include, but are not limited to, BSBI-25, ccc-
  • Nucleoprotein modulators may be either HBV core or capsid protein inhibitors.
  • nucleoprotein modulators include, but are not limited to, GS-4882, AB-423, AB- 836, AT-130, ALG-001075, ALG-001024, ALG-000184, EDP-514, GLS4, NVR-1221, NVR- 3778, AL-3778, BAY 41-4109, morphothiadine mesilate, ARB-168786, ARB-880, ARB-1820, GST-HG-141, bersacapavir (JNJ-379), JNJ-632, RG-7907, GST-HG-141, HEC-72702, KL- 060332, AB-506, vebicorvir (ABI-H0731), ABI-H3733, ABI-4334, JNJ-440, AK-0605, HRS- 5091, VNRX-9945, ABI-H2158, canocapavir
  • capsid inhibitors include, but are not limited to, the compounds disclosed in US2018161307 (Gilead Sciences), US20140275167 (Novira Therapeutics), US20130251673 (Novira Therapeutics), US20140343032 (Roche), W02014037480 (Roche), US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), W02014033170 (Janssen), WO2014033167 (Janssen), WO2015/059212 (Janssen), WO2015118057(Janssen), W02015011281 (Janssen), WO2014184365 (Janssen), WO2014184350 (Janssen), WO2014161888 (Janssen), WO2013096744 (Novira), US20150225355 (Novira), US20140178337 (Novira), US20150315159 (Novira), US20150197533 (Novira), US201502
  • transcript inhibitors include, but are not limited to, the compounds disclosed in W02017013046 (Roche), W02017016960 (Roche), W02017017042 (Roche), W02017017043 (Roche), WO2017061466 (Toyoma chemicals), WO2016177655 (Roche), WO2016161268 (Enanta), W02017001853 (Redex Pharma), WO2017211791 (Roche), WO2017216685 (Novartis), WO2017216686 (Novartis), WO2018019297 (Ginkgo Pharma), WO2018022282 (Newave Pharma), US20180030053 (Novartis), and W02018045911 (Zhejiang Pharma).
  • Examples of farnesoid x receptor agonists include, but are not limited to, e.g.,
  • Caspase-9 stimulators include, but are not limited to, ENOB-HB-01.
  • HBV antibodies targeting the surface antigens of the hepatitis B virus include, but are not limited to, lenvervimab (GC-1102), XTL-17, XTL-19, KN-003, IV Hepabulin SN, VIR-3434, 162 (Yangshengtang/Syneos Health), APB-A101, and fully human monoclonal antibody therapy (hepatitis B virus infection, Humabs BioMed).
  • HBV antibodies including monoclonal antibodies and polyclonal antibodies
  • examples of HBV antibodies include, but are not limited to, Zutectra, Shang Sheng Gan Di, Uman Big (Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B, igantibe, Niuliva, CT- P24, EI-001, hepatitis B immunoglobulin (intravenous, pH4, HBV infection, Shanghai RAAS Blood Products), EVT-075, and Fovepta (BT-088).
  • Examples of fully human monoclonal antibodies include, but are not limited to, HBC-34, HT-102.
  • IgG4 monoclonal antibodies examples include burfiralimab.
  • IFN-fused anti-CD40 antibodies include type I IFN/CD40 costimulator (HBV infection). It. Immune Modulators
  • HBV vaccines include both prophylactic and therapeutic vaccines.
  • HBV prophylactic vaccines include, but are not limited to, Vaxelis, Hexaxim, Heplisav, Mosquirix, DTwP-HBV vaccine, PreHevbri (Bio-Hep-B), D/T/P/HBV/M (LB VP-0101; LB VW- 0101), DTwP-Hepb-Hib-IPV vaccine, Heberpenta L, DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, hepatitis B prophylactic vaccine (Advax Super D), Hepatrol-07, GSK-223192A, ENGERIX B®, recombinant hepatitis B vaccine (intramuscular, Kangtai Biological Products), recombinant hepatitis B vaccine (Hansenual polymorpha yeast, intramuscular, Hualan Biological Engineering), recombinant
  • HBV therapeutic vaccines include, but are not limited to, HbsAG- HBIG complex, ARB-1598, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, CP-BNPs, Tetrabhay, GX-110E, GS-4774, peptide vaccine (epsilonPA-44), Hepatrol-07, NASVAC (NASTERAP), IMP-321, BEVAC, Revac B mcf, Revac B+, MGN-1333, KW-2, CVI-HBV- 002, AltraHepB, VGX-6200, FP-02, FP-02.2 (HepTcell), NU-500, HBVax, im/TriGrid/antigen vaccine, Mega-CD40L-adjuvanted vaccine, HepB-v, RG7944 (INO-1800), recombinant VLP- based therapeutic vaccine (HBV infection, VLP Biotech), hepatit
  • telomerase vaccines include, but are not limited to, tertomotide (GV- 1001).
  • TLR Toll-Like Receptor
  • the agent(s) as described herein are combined with an agonist of a toll-like receptor (TLR), e.g., an agonist of TLR1 (NCBI Gene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098), TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI Gene ID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9 (NCBI Gene ID: 54106), and/or TLR10 (NCBI Gene ID: 81793), TLR11, TLR12 and TLR13.
  • TLR toll-like receptor
  • TLR modulators include, but are not limited to, AK-0701.
  • TLR3 modulators include, but are not limited to, rintatolimod, poly- ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475 and ND-1.1.
  • TLR4 agonists include, but are not limited to, G-100, and GSK-
  • Example TLR7 agonists that can be co-administered include without limitation RO-7020531, AL-034 (JNJ-4964), DSP-0509, GS-9620 (vesatolimod), LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI- 9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, ruzotolimod (RG- 7854), RG-7795, APR-003, and the compounds disclosed in US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014/056953 (Janssen),
  • TLR7/TLR8 agonist that can be co-administered is NKTR-262, telratolimod and BDB-001.
  • TLR-8 inhibitors include, but are not limited to, ZG-170607, ZG- 0895.
  • Example TLR8 agonists that can be co-administered include without limitation E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, GSK-5251738, selgantolimod (GS-9688), CB-06, HRS-9950, SBT-8230, VTX-1463, VTX-763, 3M-051, 3M-052, and the compounds disclosed in US2016289229 (Gilead Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189 (Janssen), US20140350031 (Janssen), WO2014/023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US
  • Patent No. 9670205 (Gilead Sciences, Inc.), US20160289229 (Gilead Sciences, Inc.), WO2017/048727 (Gilead Sciences, Inc.), US20180065938 (Gilead Sciences, Inc.), and US20180086755 (Gilead Sciences, Inc.).
  • Example TLR9 agonists that can be co-administered include without limitation AST-008, cobitolimod, vidutolimod (CMP-001), IMO-2055, IMO-2125, S-540956, litenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS- 9054, DV-1079, DV-1179, AZD-1419, lefitolimod (MGN-1703), CYT-003, CYT-003-QbG10, tilsotolimod and PUL-042.
  • TLR7, TLR8 and TLR9 modulators include, but are not limited to, the compounds disclosed in WO2017047769 (Teika Seiyaku), W02015014815 (Janssen), W02018045150(Gilead Sciences Inc), WO2018045144 (Gilead Sciences Inc), WO2015162075 (Roche), WO2017034986 (University of Kansas), WO2018095426 (Jiangsu Hengrui Medicine Co Ltd), WO2016091698(Roche), WO2016075661 (GlaxoSmithKline Biologicals), WO2016180743 (Roche), WO2018089695 (Dynavax Technologies), WO2016055553 (Roche), WO2015168279 (Novartis), WO2016107536 (Medshine Discovery), WO2018086593 (Livo (Shanghai) Pharmaceutical), W02017106607 (Merck), WO2017061532 (Sumitomo
  • an agent(s) as described herein is co-administered with a TLR7, TLR8 or TLR9 agonist.
  • interferon alpha receptor ligands include interferon alpha-2b (INTRON A®), pegylated interferon alpha-2a (PEGASYS®), PEGylated interferon alpha-lb, interferon alpha lb (HAPGEN®), Veldona, Infradure, Roferon-A, YPEG-interferon alfa-2a (YPEG-rhIFNalpha-2a), P-1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co (recombinant super compound interferon), Ypeginterferon alfa-2b (YPEG-rhIFNalpha-2b), MOR-22, peginterferon alfa-2b (PEG-INTRON®), Bioferon, Novaferon, Inmutag (Inferon), MULTIFERON®, interferon alfa-nl(HUMOFERON®), interferon beta-la
  • CD3 modulators include, but are not limited to, IMC-H09V, IMC- M113V, anti-HBVxCD3.
  • Examples of diacylglycerol kinase alpha (DGKa) inhibitors include, but are not limited to, GS-9911, ASP-1570, BAY-2965501. Cyclophilin Inhibitors
  • cyclophilin inhibitors include, but are not limited to, rencofilstat (CPI-431-32), EDP-494, OCB-030, SCY-635, NVP-015, NVP-018, NVP-019, STG-175, and the compounds disclosed in US8513184 (Gilead Sciences), US20140030221 (Gilead Sciences), US20130344030 (Gilead Sciences), and US20130344029 (Gilead Sciences).
  • thymosin agonists include, but are not limited to, Thymalfasin, and recombinant thymosin alpha 1 (GeneScience).
  • the agents described herein are combined with an interleukin agonist, such as IL-2, IL-7, IL-15, IL-10, IL-12 agonists;
  • IL-2 agonists such as proleukin (aldesleukin, IL-2); pegylated IL-2 (eg NKTR-214); modified variants of IL-2 (eg THOR-707), bempegaldesleukin, AIC-284, ALKS-4230, CUI-101, Neo-2/15, AB-359;
  • examples of IL-15 agonists such as ALT-803, NKTR-255, and hetIL-15, interleukin- 15/Fc fusion protein, AM-0015, NIZ-985, SO-C101, IL-15 Synthorin (pegylated 11-15), P-22339, and a IL-15 -PD-1 fusion protein N-809;
  • examples of IL-7 include CYT-107.
  • the agents described herein are combined with a stimulator of interferon genes (STING).
  • STING receptor agonist or activator is selected from the group consisting of ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, STINGVAX, GSK-532, SYN-STING, MSA-1, SR-8291, 5,6- dimethylxanthenone-4-acetic acid (DMXAA), cyclic-GAMP (cGAMP) and cyclic-di-AMP.
  • the agents described herein are combined with a RIG-I modulator such as RGT-100, or NOD2 modulator, such as SB-9200, and IR-103.
  • STING agonists include, but are not limited to, the compounds disclosed in WO 2018065360 (“Biolog Life Science Institute Klaslabor und Biochemica-maschine GmbH, Germany), WO 2018009466 (Aduro Biotech), WO 2017186711 (InvivoGen), WO 2017161349 (Immune Sensor), WO 2017106740 (Aduro Biotech), US 20170158724 (Glaxo Smithkiline), WO 2017075477 (Aduro Biotech), US 20170044206 (Merck), WO 2014179760 (University of California), W02018098203 (JanssnJanssen), WO2018118665 (Merck), WO2018118664 (Merck), W02018100558 (Takeda), WO2018067423 (Merck), and WO20 18060323 (Boehringer).
  • Examples of stimulators of retinoic acid-inducible gene 1 include, but are not limited to, inarigivir soproxil (SB-9200), SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI- 9020, ORI-9198, ORI-7170, and RGT-100.
  • Examples of stimulators of N0D2 include, but are not limited to, inarigivir soproxil (SB-9200).
  • the agent(s) as described herein are combined with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and/or with one or more stimulators, activators, or agonists of one or more stimulatory immune checkpoint proteins or receptors.
  • Blockade or inhibition of inhibitory immune checkpoints can positively regulate T-cell or NK cell activation and prevent immune escape of infected cells.
  • Activation or stimulation of stimulatory immune check points can augment the effect of immune checkpoint inhibitors in infective therapeutics.
  • the immune checkpoint proteins or receptors regulate T cell responses (e.g., reviewed in Xu et al., J Exp Clin Cancer Res. (2016) 37: 110).
  • the immune checkpoint proteins or receptors regulate NK cell responses (e.g., reviewed in Davis et al., Semin Immunol. (2017) 31 :64-75 and Chiossone et al., Nat Rev Immunol. (2016) 18(11):671-688).
  • immune checkpoint proteins or receptors include without limitation
  • the agent(s) described herein are combined with one or more blockers or inhibitors of one or more T-cell inhibitory immune checkpoint proteins or receptors.
  • T-cell inhibitory immune checkpoint proteins or receptors include without limitation CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD- L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD 152); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); PVR related immunoglobulin domain containing (
  • T-cell stimulatory immune checkpoint proteins or receptors include without limitation CD27, CD70; CD40, CD40LG; inducible T cell costimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, 0X40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4), Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD 155). See, e
  • NK-cell inhibitory immune checkpoint proteins or receptors include without limitation killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor Cl (KLRC1, NKG2A, CD159A); and killer cell lectin like receptor DI (KLRD1, CD94).
  • KIR, CD158E1 killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1
  • KIR2DL1 killer cell immunoglobulin like receptor, two Ig domains
  • NK-cell stimulatory immune checkpoint proteins or receptors include without limitation CD 16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin like receptor KI (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). See, e.g., Davis et al., Semin Immunol. (2017) 31 :64-75; Fang et al., Semin Immunol. (2017) 31 :37-54; and Chiossone et al., Nat Rev Immunol. (2016) 18(11):671-688.
  • the one or more immune checkpoint inhibitors comprises a proteinaceous (e.g., antibody or fragment thereof, or antibody mimetic) inhibitor of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4.
  • the one or more immune checkpoint inhibitors comprises a small organic molecule inhibitor of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4.
  • the small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of evixapodlin (GS-4224), GS-4416, INCB086550 and MAX10181.
  • small molecule PD-L1 inhibitors include, but are not limited to, those disclosed in U.S. Publication No. US2018305315 (Gilead Sciences), US2020017471 (Gilead Sciences) and US2019270727 (Gilead Sciences).
  • the small molecule inhibitor of CTLA4 comprises BPI-002.
  • inhibitors of CTLA4 include without limitation ipilimumab, tremelimumab, belatacept, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA- 3071, ONC-392, AGEN-2041, AGEN-1884, JHL-1155, KN-044, CG-0161, ATOR-1144, PBI- 5D3H5, BPI-002, PSI-001, PRS-010 as well as multi-specific inhibitors FPT-155 (CTLA4/PD- L1/CD28), PF-06936308 (PD-1/ CTLA4), MGD-019 (PD-1/CTLA4), KN-046 (PD-1/CTLA4), MEDI-5752 (CTLA4/PD-1), XmAb-20717 (PD-
  • inhibitors of PD-L1 (CD274) or PD-1 (PDCD1) include without limitation pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, AB- 101, ALN-PDL, BMS-936559, CK-301, PF-06801591, BGB-108, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), GB-226, AK-105, CS-1003, serplulimab (HLX-10), MGA-012, BI-754091, PDR-001, AGEN-2034, JS-001 (toripalimab), Cetrelimab (JNJ- 63723283), geno
  • Examples of PD-1 inhibitors include, but are not limited to, the compounds disclosed in WO2017112730 (Incyte Corp), WO2017087777 (Incyte Corp), WO2017017624, WO2014151634 (BristolMyers Squibb Co), WO201317322 (BristolMyers Squibb Co), WO2018119286 (Incyte Corp), WO2018119266 (Incyte Corp), WO2018119263 (Incyte Corp), WO2018119236 (Incyte Corp), WO2018119221(Incyte Corp), WO2018118848 (BristolMyers Squibb Co), WO20161266460(BristolMyers Squibb Co), WO2017087678 (BristolMyers Squibb Co), WO2016149351 (BristolMyers Squibb Co), WO2015033299 (Aurigene Discovery Technologies Ltd), WO2015179615 (Eisai
  • the agents as described herein are combined with anti- TIGIT antibodies, such as BMS-986207, RG-6058, and AGEN-1307.
  • anti- TIGIT antibodies such as BMS-986207, RG-6058, and AGEN-1307.
  • the agents as described herein are combined with an agonist of one or more TNF receptor superfamily (TNFRSF) members, e.g., an agonist of one or more of TNFRSF1A (NCBI Gene ID: 7132), TNFRSF1B (NCBI Gene ID: 7133), TNFRSF4 (0X40, CD134; NCBI Gene ID: 7293), TNFRSF5 (CD40; NCBI Gene ID: 958), TNFRSF6 (FAS, NCBI Gene ID: 355), TNFRSF7 (CD27, NCBI Gene ID: 939), TNFRSF8 (CD30, NCBI Gene ID: 943), TNFRSF9 (4-1BB, CD137, NCBI Gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI Gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI Gene ID: 8795), TNFRSF 10C (CD263,
  • TNFRSF10A CD
  • Example anti-TNFRSF4 (0X40) antibodies that can be co-administered include without limitation, MEDI6469, MEDI6383, MEDI0562 (tavolixizumab), MOXR0916, PF- 04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, IB I- 101 and those described in WO2016179517, WO2017096179, WO2017096182, WO20 17096281, and WO2018089628.
  • Example anti-TNFRSF5 (CD40) antibodies that can be co-administered include without limitation RG7876, SEA-CD40, APX-005M and ABBV-428.
  • the anti-TNFRSF7 (CD27) antibody varlilumab (CDX- 1127) is co-administered.
  • Example anti-TNFRSF9 (4-1BB, CD137) antibodies that can be co-administered include without limitation urelumab, utomilumab (PF-05082566), AGEN2373 and ADG-106.
  • Example anti-TNFRSFl 8 (GITR) antibodies that can be co-administered include without limitation, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in WO2017096179, WO2017096276, WO2017096189, and WO2018089628.
  • an antibody, or fragment thereof, co-targeting TNFRSF4 (0X40) and TNFRSF18 (GITR) is co-administered.
  • Such antibodies are described, e.g., in WO2017096179 and WO2018089628. LAG-3 and TIM-3 inhibitors.
  • the agent(s) as described herein are combined with an anti-TIM-3 antibody, such as TSR-022, LY-3321367, MBG-453, and INCAGN-2390.
  • an anti-TIM-3 antibody such as TSR-022, LY-3321367, MBG-453, and INCAGN-2390.
  • the agent(s) described herein are combined with an anti- LAG-3 (Lymphocyte-activation) antibody, such as relatlimab (ONO-4482), LAG-525, MK- 4280, REGN-3767, and INCAGN2385.
  • an anti- LAG-3 (Lymphocyte-activation) antibody such as relatlimab (ONO-4482), LAG-525, MK- 4280, REGN-3767, and INCAGN2385.
  • an anti- LAG-3 (Lymphocyte-activation) antibody such as relatlimab (ONO-4482), LAG-525, MK- 4280, REGN-3767, and INCAGN2385.
  • IAPS Inhibitor of apoptosis proteins family proteins
  • IAP inhibitors include, but are not limited to, APG-1387. vi. Bi-and Tri-Specific Natural Killer (NK)-Cell Engagers
  • the agents as described herein are combined with a bispecific NK-cell engager (BiKE) or a tri-specific NK-cell engager (TriKE) (e.g., not having an Fc) or bi-specific antibody (e.g., having an Fc) against an NK cell activating receptor, e.g., CD 16 A, C-type lectin receptors (CD94/NKG2C, NKG2D, NKG2E/H and NKG2F), natural cytotoxicity receptors (NKp30, NKp44 and NKp46), killer cell C-type lectin-like receptor (NKp65, NKp80), Fc receptor FcyR (which mediates antibody-dependent cell cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6 and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1 and CD137 (41BB).
  • a bispecific NK-cell engager
  • the anti-CD16 binding bi-specific molecules may or may not have an Fc.
  • Illustrative bi-specific NK- cell engagers that can be co-administered target CD16 and one or more HBV-associated antigens as described herein.
  • BiKEs and TriKEs are described, e.g., in Felices, et al., Methods Mol Biol. (2016) 1441 :333-346; Fang, et al., Semin Immunol. (2017) 31 :37-54. This example is for one, but it explains the platform. vii. Long Acting Treatments
  • Long acting entecavir subcutaneous depot
  • long acting tenofovir TAF
  • devices devices
  • subcutaneous depot An example of long acting entecavir is described in Exploration of long-acting implant formulations of hepatitis B drug entecavir., Eur J Pharm Sci. 2019 Aug 1; 136: 104958.
  • the agents described herein are combined with a gene or cell therapy regimen.
  • Gene therapy and cell therapy include without limitation the genetic modification to silence a gene; genetic approaches to directly kill the infected cells; the infusion of immune cells designed to replace most of the patient’s own immune system to enhance the immune response to infected cells, or activate the patient’s own immune system to kill infected cells, or find and kill the infected cells; genetic approaches to modify cellular activity to further alter endogenous immune responsiveness against the infection.
  • the genome editing system is selected from the group consisting of: a CRISPR/Cas9 system, a zinc finger nuclease system, a TALEN system, a homing endonucleases system, and a meganuclease system (e.g., an ARCUS system); e.g., cccDNA elimination via targeted cleavage, and altering one or more of the hepatitis B virus (HBV) viral genes.
  • a CRISPR/Cas9 system e.g., a zinc finger nuclease system, a TALEN system, a homing endonucleases system, and a meganuclease system (e.g., an ARCUS system); e.g., cccDNA elimination via targeted cleavage, and altering one or more of the hepatitis B virus (HBV) viral genes.
  • HBV hepatitis B virus
  • Altering e.g., knocking out and/or knocking down
  • the PreC, C, X, PreSI, PreS2, S, P or SP gene refers to (1) reducing or eliminating PreC, C, X, PreSI, PreS2, S, P or SP gene expression, (2) interfering with Precore, Core, X protein, Long surface protein, middle surface protein, S protein (also known as HBs antigen and HBsAg), polymerase protein, and/or Hepatitis B spliced protein function (HBe, HBc, HBx, PreSI, PreS2, S, Pol, and/or HBSP or (3) reducing or eliminating the intracellular, serum and/or intraparenchymal levels of HBe, HBc, HBx, LHBs, MHBs, SHBs, Pol, and/or HBSP proteins.
  • Knockdown of one or more of the PreC, C, X, PreSI, PreS2, S, P and/or SP gene(s) is performed by targeting the gene(s) within HBV cccDNA and/or integrated HBV DNA.
  • Additional examples genome editing systems include, but are not limited to, those disclosed in US2019284543 (Gilead Sciences), and US2019338263 (Gilead Sciences).
  • Examples of gene therapy includes, but is not limited to, PBGENE-HBV, or using CRISPR/Cas9 gene editing technology, TG-HBV, EBT-107, CRISPR-Casl2 gene therapy, or EBT-106 (LNP-delivered CRISPR/CasX nuclease).
  • PBGENE-HBV or using CRISPR/Cas9 gene editing technology
  • TG-HBV TG-HBV
  • EBT-107 CRISPR-Casl2 gene therapy
  • EBT-106 LNP-delivered CRISPR/CasX nuclease
  • CAR-T cell therapy includes, but is not limited to, a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR includes an HBV antigen-binding domain.
  • the antigen-binding domain is a domain disclosed herein.
  • the antigen-binding domain is other than a domain disclosed herein.
  • the antigen is HBsAg (i.e., HbsAg- CART).
  • the immune effector cell is a T-cell or an NK cell.
  • the T-cell is a CD4+ T-cell, a CD8+ T-cell, a NK cell or a combination thereof.
  • Cells can be autologous or allogeneic.
  • An example of a CART directed to HBV is described in Cytotherapy. 2018 May;20(5):697-705. doi: 10.1016/j .jcyt.2018.02. xi. TCR-T cell therapy
  • TCR-T cell therapy includes, but is not limited to, T cells expressing HBV- specific T cell receptors. TCR-T cells are engineered to target HBV derived peptides presented on the surface of virus-infected cells. An example of a TCR directed to HBV is described in Wiss Meinn, K. et al. T cell receptor grafting allows virological control of hepatitis B virus infection. J Clin Invest. 2019;129(7):2932-2945. [0188] TCR-T cell therapy includes, but is not limited to, T-Cells expressing HBV surface antigen (HBsAg)-specific TCR, such as YT-HBV-x, Liocyx-M.
  • HBV surface antigen HBsAg
  • TCR-T cell therapy includes, but is not limited to, TCR-T therapy directed to treatment of HBV, such as LTCR-H2-1 (LT-C21), ALVR-107, SQZ-APC-HBV.
  • an agent(s) disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HBV DNA polymerase inhibitor, one or two additional therapeutic agents selected from the group consisting of immunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus and bispecific antibodies and “antibody-like” therapeutic proteins (such as DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, or TCR-like antibodies), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1, stimulators of RIG-I like receptors, PD-1 inhibitors, PD-L1 inhibitors, Arginase inhibitors, PI3K inhibitors, IDO inhibitors, and stimulators of N0D2, and one or two additional therapeutic agents selected from the group consisting of
  • an agent(s) disclosed herein, or a pharmaceutically acceptable salt thereof is combined with at least a second additional therapeutic agent selected from the group consisting of: HBV DNA polymerase inhibitors, immunomodulator, TLR modulators, HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus and bispecific antibodies and “antibody-like” therapeutic proteins (such as DARPins®, anti-pMHC TCR-like antibodies, DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, or TCR-like antibodies), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1, stimulators of RIG-I like receptors, PD-1 inhibitors, PD-L1 inhibitors, Arginase inhibitors, PI3K inhibitors, IDO inhibitors, and stimulators of N0D2.
  • HBV DNA polymerase inhibitors such as DARP
  • an agent(s) disclosed herein, or a pharmaceutically acceptable salt thereof is combined with at least a second additional therapeutic agent selected from the group consisting of: HBV DNA polymerase inhibitors, HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HB V antibodies targeting the surface antigens of the hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV core or capsid protein inhibitors).
  • a second additional therapeutic agent selected from the group consisting of: HBV DNA polymerase inhibitors, HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HB V antibodies targeting the surface antigens of the hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV core or capsid protein inhibitors).
  • an agent(s) disclosed herein, or a pharmaceutically acceptable salt thereof is combined with compounds such as those disclosed in U.S. Publication No. 2010/0143301 (Gilead Sciences), U.S. Publication No. 2011/0098248 (Gilead Sciences), U.S. Publication No. 2009/0047249 (Gilead Sciences), U.S. Patent No. 8722054 (Gilead Sciences), U.S. Publication No. 2014/0045849 (Janssen), U.S. Publication No.
  • an agent(s) disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 5-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide.
  • an agent disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide.
  • an agent disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 10 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, an agent disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide.
  • An agent(s) as disclosed herein may be combined with the agents provided herein in any dosage amount of the compound (e.g., from 50 mg to 500 mg of compound) the same as if each combination of dosages were specifically and individually listed.
  • an agent(s) disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 100-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil.
  • an agent(s) disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 100-150; 100-200, 100- 250; 100-300; 100-350; 150-200; 150-250; 150-300; 150-350; 150-400; 200-250; 200-300; 200- 350; 200-400; 250-350; 250-400; 350-400 or 300-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil.
  • an agent(s) disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In some embodiments, an agent(s) disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 250 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil.
  • an agent(s) disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 150 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil.
  • An agent(s) as disclosed herein may be combined with the agents provided herein in any dosage amount of the compound (e.g., from 50 mg to 500 mg of compound) the same as if each combination of dosages were specifically and individually listed. xii. Other HBV Drugs
  • Examples of other drugs for the treatment of HBV include, but are not limited to, alpha-hydroxytropolones, amdoxovir, antroquinonol, beta-hydroxycytosine nucleosides, ARB- 199, CCC-0975, ccc-R08, CKD-388, DF-006, elvucitabine, ezetimibe, cyclosporin A, gentiopicrin (gentiopicroside), HH-003, hepalatide, ISR-51, JNJ-56136379, M-1428, nitazoxanide, birinapant, NJK14047, NOV-205 (molixan, BAM-205), oligotide, mivotilate, feron, GST-HG-131, levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai), PEG- IIFNm, KW-3, BP-Inter-01
  • Ribavirin (RBV) anti-viral activity was profiled in HDV-infected primary human hepatocytes (PHH).
  • PSH HDV-infected primary human hepatocytes
  • cryopreserved primary human hepatocytes (PHH) thawed and resuspended in hepatocyte cell-plating medium (Life Technologies) were plated at a density of 60,000 cells/well in 96-well collagen-coated plates (Life Technologies) and allowed to attach for 4 hours at 37°C in a humidified 5% CO2 incubator. After attachment, the media changed, and cells incubated overnight in hepatocyte maintenance medium (Life Technologies) supplemented with 1.5% DMSO and 2% fetal bovine serum at 37°C in a humidified 5% CO2 incubator.
  • Intracellular HDV total RNA was quantified by Real-time RT-PCR with HDV-specific primer/probe (HDV-F: GTAGACTCCGGACCTAGGAAGAG (SEQ ID NO:2); HDV-R: CTTCCTTCGTCGGTGATCCT (SEQ ID NO:3); HDV-P: CCTTGTCGGTGAATCC (SEQ ID NO:4)) in TaqMan Fast Virus 1-Step Master Mix (Life Technology) using a QuantStudio 7 Flex Real-Time PCR system (Life Technology). Human GAPDH (Life Technology) mRNA expression was used to normalize HDV RNA levels.
  • RBV demonstrates HDV antiviral activity with either 4 or 13 days of treatment, as shown in FIGs. 2A-2F and Table 1. Table 1. Effect of RBV in anti-HDV Activity
  • a combination of ribavirin (RBV) and bulevirtide (BLV) was profiled in HDV- infected PHH.
  • Cryopreserved primary human hepatocytes (PHH) thawed and plated as described above.
  • PHH primary human hepatocytes
  • One day post cell plating, the cells were pre-treated with serially diluted BLV (from a top concentration of lOOnM, 1 :3 dilution) alone or combined with 2, 5, 10, or 20 pM RBV in presence of 1 mM ABT for 1 hour, followed by inoculation with HDV.
  • HDAg-positive cells were quantified by immunofluorescence as described above. Cytotoxicity was assessed by nuclei staining with Hoechst 33342.
  • the combination effects of RBV and BLV were analyzed using the Prichard and Shipman method within MacSynergy II software. The results of the combination assays were expressed as the mean synergy/antagonism volumes (pM 2 .%) calculated at the 95% confidence level from two independent experiments (Table 3). The combination effects were defined as: Highly synergistic: > 100 pM 2 .%
  • Antagonistic ⁇ -100 pM 2 .% Table 3. Anti-HDV activity of RBV and BLV in Pairwise Combination Studies
  • Nucleos(t)ide compounds targeting HBV polymerase were profiled in HDV- infected PHH. Cryopreserved primary human hepatocytes (PHH) thawed and plated as described above. The cells were pre-treated with serially diluted nucleos(t)ides compounds lamivudine, telbivudine, entecavir, tenofovir, and adefovir (from a top concentration of 50pM, 1 :3 dilution) in presence of ImM ABT for 1 hour, followed by inoculation with HDV as described above.
  • PHH Cryopreserved primary human hepatocytes

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Abstract

La présente invention concerne des combinaisons de bulévirtide, ou d'un sel pharmaceutiquement acceptable de celui-ci, et de ribavirine, ou d'un sel pharmaceutiquement acceptable de celle-ci, utiles pour traiter une infection par le virus de l'hépatite D (VHD).
PCT/US2025/028569 2024-05-13 2025-05-09 Polythérapies avec ribavirine Pending WO2025240242A1 (fr)

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