WO2024223797A1 - Use of cyp3a4 inhibitors for the treatment of hepatitis d virus (hdv) infections - Google Patents

Use of cyp3a4 inhibitors for the treatment of hepatitis d virus (hdv) infections Download PDF

Info

Publication number
WO2024223797A1
WO2024223797A1 PCT/EP2024/061493 EP2024061493W WO2024223797A1 WO 2024223797 A1 WO2024223797 A1 WO 2024223797A1 EP 2024061493 W EP2024061493 W EP 2024061493W WO 2024223797 A1 WO2024223797 A1 WO 2024223797A1
Authority
WO
WIPO (PCT)
Prior art keywords
hdv
ifn
inhibitor
patient
treatment
Prior art date
Application number
PCT/EP2024/061493
Other languages
French (fr)
Inventor
Pierre-Olivier Vidalain
David Durantel
Florentin PASTOR
Vincent Lotteau
Walid EL ORCH
Yves Louis Janin
Clémence JACQUEMIN
Original Assignee
Institut National de la Santé et de la Recherche Médicale
Centre National De La Recherche Scientifique
Ecole Normale Supérieure de Lyon
Université Claude Bernard - Lyon 1
Muséum National D'histoire Naturelle
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 Institut National de la Santé et de la Recherche Médicale, Centre National De La Recherche Scientifique, Ecole Normale Supérieure de Lyon, Université Claude Bernard - Lyon 1, Muséum National D'histoire Naturelle filed Critical Institut National de la Santé et de la Recherche Médicale
Publication of WO2024223797A1 publication Critical patent/WO2024223797A1/en

Links

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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/66—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
    • 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

Definitions

  • the present invention is in the field of medicine, in particular virology.
  • Hepatitis D virus (HDV) infection is the most severe form of chronic viral hepatitis due to rapid progression towards liver-related death and hepatocellular carcinoma.
  • the World Health Organization (WHO) estimates that 15-20 million persons are infected by HDV. The most recent meta-analysis of HDV burden suggests an underestimation of hepatitis D prevalence.
  • hepatitis B virus (HBV) infection of the same cell is necessary.
  • HDV hijacks HBV surface antigens for its own use and the secretion of infectious HDV virions that can spread or maintain the infection.
  • HBV and HDV virions thus contain the same envelope proteins and are undistinguishable from a humoral-response perspective.
  • HDAg-S is mainly involved in the replication step
  • HDAg- L is essential for virion budding.
  • the 19-20 amino acids additional domain in HDAg-L contains a CXXX-box motif, a substrate for cellular farnesyltransferase, which adds a famesyl group to the cysteine of this CXXX-box. This farnesylation process was shown to be essential for virion assembly (Glenn J et al. Science.
  • the present invention is defined by the claims.
  • the present invention relates to the use of CYP3A4 inhibitors for the treatment of hepatitis D virus (HDV) infections.
  • HDV hepatitis D virus
  • the present invention relates to a method of treating a hepatitis D virus (HDV) infection in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a CYP3 A4 inhibitor.
  • HDV hepatitis D virus
  • the term "subject” or “patient” and “subject in need thereof' or “patient in need thereof”, is intended for a human or non-human mammal infected or likely to be infected with a hepatitis D virus.
  • the patient is simultaneously infected with HBV and HDV.
  • the patient suffers from a chronic HDV infection.
  • Hepatitis D virus or “HDV” refers to the well-known noncytopathic, liver-tropic DNA virus belonging to the Hepadnaviridae family. See, e.g., Ciancio and Rizzetto, Nat. Rev. 11 :68-71, 2014; Le Gal et al., Emerg. Infect. Dis. 12: 1447- 1450, 2006; and Abbas and afzal, World J. Hep., 5:666-675, 2013, all of which are incorporated by reference. Unless otherwise indicated, HDV refers to all clades and variants of HDV. HDV produces one protein, namely HDAg.
  • a 27 kDa large-HDAg also referred to herein as 1HD, L-HDAg, and large HDV antigen
  • a small-HDAg of 24 kDa also referred to herein as sHD, S-HDAg, and small HDV antigen.
  • the N-terminals of the two forms are identical, they differ by 19 amino acids in the C-terminal of the large HDAg.
  • Both isoforms are produced from the same reading frame which contains an UAG stop codon at codon 196, which normally produces only the small-HDAg.
  • editing by cellular enzyme adenosine deaminase- 1 changes the stop codon to UCG, allowing the large-HDAg to be produced.
  • HDAg-S is produced in the early stages of an infection and enters the nucleus and supports viral replication.
  • HDAg-L in contrast, is produced during the later stages of an infection, acts as an inhibitor of viral replication, and is required for assembly of viral particles.
  • treatment refers to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a patient having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a patient beyond that expected in the absence of such treatment.
  • therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the phrase “induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
  • the general goal of an induction regimen is to provide a high level of drug to a patient during the initial period of a treatment regimen.
  • An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
  • maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a patient during treatment of an illness, e.g., to keep the patient in remission for long periods of time (months or years).
  • a maintenance regimen may employ continuous therapy (e.g., administering a drug at regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., disease manifestation, etc.]).
  • the efficacy of the treatment may be monitored using standard protocols. Indeed, treatment may be followed by determinations of HDV levels in serum (viral load) and measurement of serum alanine aminotransferase (ALT) levels. For example, the patients may be assessed for the presence of HDV RNA in their serum.
  • HDV RNA (lU/mL) can be measured at regular intervals during the treatment, e.g., at Day 1 (pre-dose and 4, 8, and 12 hours post-dose) and pre-dose at Day 2, Day 3, Day 8, Day 15, Day 29, and at Week 12, Week 24, Week 36, Week 48, Week 72 (when applicable), and at follow up.
  • the efficacy of treatment can be monitored using internationally accepted parameters: a) Serum HDV RNA levels are monitored using sensitive quantitative RT-PCR-based assays to assess the effect on viral replication b) Serum levels of ALT and/or aspartate aminotransferase (AST) are monitored to assess impact on liver inflammation and liver cell death.
  • a) Serum HDV RNA levels are monitored using sensitive quantitative RT-PCR-based assays to assess the effect on viral replication
  • Serum levels of ALT and/or aspartate aminotransferase (AST) are monitored to assess impact on liver inflammation and liver cell death.
  • the treatment may correspond to a single-agent treatment where only one CYP3 A4 inhibitor is administered, or to a combination therapy with another therapeutic agent such as another CYP3 A4 inhibitor or antiviral agents.
  • the treatment can be administered to patients who have been diagnosed with an HDV infection. Any of the above treatment regimens can be administered to patients who have failed previous treatment for HDV infection (treatment failure patients).
  • treatment failure patients refers to patient who have failed previous treatment for HDV infection. More specifically, although there is no effective treatment against HDV, or any FDA-approved drug for the treatment of chronic HDV, the pegylated immune system modulator interferon alpha (PEG-IFN-a) is currently used in clinical practice and thus considered as a standard-of-care for HDV infection.
  • PEG-IFN-a pegylated immune system modulator interferon alpha
  • treatment failure patients generally refers to HDV-infected patients who failed to respond to the PEG-IFN-a treatment (referred to as “non-responders”) or who initially responded to PEG-IFN-a treatment, but in whom the therapeutic response was not maintained (referred to as “relapsers").
  • CYP3A4 has its general meaning in the art and refers to the cytochrome P450 3A4 (EC 1.14.13.97) that is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from the body.
  • CYP3A4 inhibitor is intended to encompass a compound that interacts with CYP3A4 to substantially reduce or eliminate its catalytic activity, thereby increasing the concentrations of its substrate(s).
  • Assays for determining the level of CYP3 A4 inhibition of an agent are well known in the art (e.g. Lin T, Pan K, Mordenti J, Pan L. In vitro assessment of cytochrome P450 inhibition: strategies for increasing LC/MS-based assay throughput using a one-point IC(50) method and multiplexing high-performance liquid chromatography. J Pharm Sci. 2007 Sep;96(9): 2485-93).
  • a CYP3A4 inhibitor can be a molecule of any type that interferes with the activity of CYP3A4 for example, either by decreasing transcription or translation of CYP3A4-encoding nucleic acid, or by inhibiting or blocking CYP3A4 activity, or both.
  • CYP3A4 inhibitors include, but are not limited to, antisense polynucleotides, interfering RNAs, catalytic RNAs, RNA-DNA chimeras, CYP3A4-specific aptamers, anti-CYP3A4 antibodies, CYP3A4-binding fragments of anti- CYP3A4 antibodies, CYP3A4-binding small molecules, CYP3A4-binding peptides, and other polypeptides that specifically bind CYP3A4 (including, but not limited to, CYP3A4-binding fragments of one or more CYP3A4 ligands, optionally fused to one or more additional domains), such that the interaction between the CYP3A4 inhibitor and CYP3A4 results in a reduction or cessation of CYP3 A4 activity or expression.
  • the CYP3 A4 inhibitor is selected from the compounds disclosed in one or more of the following patents and patent applications assigned to Bioavailability Systems, LLC, the disclosure of each of which is incorporated herein by reference: US 2004058982, U.S. Pat. No. 6,248,776, U.S. Pat. No. 6,063,809, U.S. Pat. No. 6,054,477, U.S. Pat. No. 6,162,479, WO 2000054768, U.S. Pat. No. 6,309,687, U.S. Pat. No. 6,476,066, U.S. Pat. No. 6,660,766, WO 2004037827, U.S. Pat. No. 6,124,477, U.S. Pat. No. 5,820,915, U.S. Pat. No. 5,993,887, U.S. Pat. No. 5,990,154, U.S. Pat. No. 6,255,337.
  • the CYP3 A4 inhibitor is selected from the group of CYP3 A4 inhibitors referred to in the following documents (which are incorporated by reference herein): US20040052865A1, US20030150004A1, US20060099667A1, US20030096251A1,
  • W02006024414A2 W02004060370A1, WO9948915A1, W02006054755A1,
  • Non-limiting examples of suitable CYP3A4 inhibitors include ketoconazole (NizoralTM, commercially available from Janssen Pharmaceutica), itraconazole (Sporanox®, commercially available from Janssen-Cilag), ritonavir (Norvir® commercially available from Abbott), nelfinavir (Viracept® commercially available from Pfizer), cobicistat (TYBOST®), indinavir (Crixivan® commercially available from Merck & Co., Inc), erythromycin (Akne-Mycin®, A/T/S®, Emgel®, Erycette®, EryDerm®, Erygel®, Erymax®, Ery-Sol®, Erythra-Derm®, ETS®, Staticin®, Theramycin Z®, T-Stat®), ERYC®, Ery-Tab®, Erythromycin Base Filmtab®, PCE® Dispertab®), clarithromycin (
  • the CYP3A4 inhibitor of the invention is administered to the subject with a therapeutically effective amount.
  • a therapeutically effective amount of the CYP3A4 inhibitor as above described is meant a sufficient amount of the CYP3A4 inhibitor to treat a hepatitis D virus infection at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination with the specific agonist employed; and like factors well known in the medical arts.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day.
  • the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from 1 mg to about 100 mg of the active ingredient.
  • An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
  • the CYP3 A4 inhibitor according to the invention may be administered to the patient in combination with at least one other therapeutic agent, preferably in combination with at least one other antiviral agent, more preferably in combination with at least one other antiviral agent selected from the group consisting of immune system modulators, anti-HDV agents, anti-HBV agents, anti-HDV/HBV agents and any combination thereof.
  • immune system modulator refers to a signalling protein of the interferon type (IFN), preferably to interferon alpha (IFN-a) or interferon lambda (IFN-1), more preferably to pegylated interferon alpha (PEG-IFN-a) or pegylated interferon lambda (PEG- IFN-1).
  • IFN interferon type
  • IFN-1 interferon lambda
  • PEG-IFN-a pegylated interferon alpha
  • PEG- IFN-1 pegylated interferon lambda
  • IFN is selected from the group consisting of consensus IFN-a (e.g., INFERGEN®, Locteron®), IFN-a2a (Roferon-A®, MOR-22, Inter 2A, Inmutag, Inferon), a pegylated IFN-a2a (e.g, PEGASYS®, YPEG-IFNa-2a, PEG-INTRON®, Pegaferon), IFN-a2b (e.g, INTRON A®, Alfarona, Bioferon, Inter 2B, citpheron, Zavinex, Ganapar, etc...), a pegylated IFN-a2b (e.g.
  • consensus IFN-a e.g., INFERGEN®, Locteron®
  • IFN-a2a Roferon-A®, MOR-22, Inter 2A, Inmutag, Inferon
  • a pegylated IFN-a2a e.g, PEGASYS®,
  • IFN can be administered daily, weekly or 2, 3, 4, 5, or 6 times weekly.
  • the treatment period is generally long, for instance from 2 weeks to several months. For instance, the period is from 3-4 months up to 24 months.
  • the dosage can vary from 1 million units to 20 million units, for instance 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 million units.
  • IFN can be administered by subcutaneous, intramuscular, intravenous, transdermal, or intratumoral administration, preferably for subcutaneous or intramuscular administration.
  • anti-HDV agent refers to any compound that treats HDV infection thereby inhibiting HDV replication, HDV virion assembly, or inhibiting HDV virion entry into infectable cells.
  • Some anti-HDV agents are known by the person skilled in the art (see Deterding et al. 2019, AIDS Rev, 21, 126-134; Gilman et al. 2019), World J Gastroenterol, 25, 4580-4597).
  • the anti-HDV agent is selected from the group consisting of ribavirin, lonafarnib and EBP 21.
  • the inhibition of HDV replication corresponds to a reduction of about 10, 20, 30, 40, 50, 60, 70, 80, 90% or 100 % of the number of HDV RNA copies of replicated in infected cells.
  • Techniques for measuring the number of copies, particularly those based on Polymerase Chain Reaction (PCR), are well known to the person skilled in the art.
  • the anti-HDV agent that inhibits HDV replication is a nucleoside analog.
  • the inhibition of HDV virion assembly corresponds to a reduction of about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 % of the amount of HDV virion assembled in infected cells.
  • the anti-HDV agent that inhibits HDV virion assembly is a famesyl transferase inhibitor.
  • the inhibition of HDV virion entry into infectable cells correspond to a reduction of about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 % of the amount of HDV virion entry in infectable cells.
  • anti-HBV agent refers to compounds that treat HBV infection thereby inhibiting HBV replication, inhibiting HBV virion assembly, or inhibiting HBV virion entry into infectable cells.
  • Anti-HBV agent are known by the person skilled in the art, for example such as conventional interferon, pegylated interferon, nucleoside and nucleotide analogues.
  • the anti-HBV agent that inhibits HBV replication is a nucleoside analog, more preferably a nucleoside analog reverse-transcriptase inhibitor, and even more preferably, the anti-HBV agent is selected from the group consisting of lamivudine, adefovir, telbivudine, entecavir, tenofovir and emtricitabine.
  • the inhibition of HBV replication corresponds to a reduction of about 10, 20, 30, 40, 50, 60, 70, 80, 90% or 100 % of the amount of HBV DNA replicated in infected cells.
  • a lower level of replication of HBV DNA helps to reduce the level of HBV virion assembly which in turns induces a lower level of infection of other target cells. Therefore, it occurs a lower probability of providing HBV antigens for the assembly of HDV visions.
  • the inhibition of HBV virion assembly corresponds to a reduction of about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 % of the amount of HBV virion assembled in infected cells.
  • a lower level of HBV virions assembly of HBV virions induces a lower level of infection of other target cells and therefore a lower probability of providing HBV antigens for the assembly of HDV visions.
  • the inhibition of HBV virion entry into infectable cells correspond to a reduction of about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 % of the amount of HBV virion entry in infectable cells.
  • infectious cells refer to cells accessible to virions that express the NTCP receptor required for the HDV virion or HBV virion entry into the cell.
  • a cell, particularly a host cell is considered accessible when there is no biological or physical barrier to prevent its contact with the circulating virion. Since HBV and HDV virions share the same entry receptor, i. e. NTCP, the docking-mediated blockage of NTCPs by anti-HBV agents effectively inhibiting cell entry of HBV virions, also inhibits cell entry of HDV virions.
  • anti-HBV/HDV agent refers to compounds that treat HDV and/or HBV infection thereby inhibiting HBV and HDV virion assembly, or inhibiting HBV and HDV virion entry into infectable cell.
  • the anti-HBV agent is selected from the group consisting of ezetimibe, myrcludexB, nucleic acid polymer REP 2139 and nucleic acid polymer REP 2165 or any combination thereof.
  • the inhibition of HBV and HDV virion assembly respectively correspond to a reduction of about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 % of the amount of HBV virion or HDV virion assembled in infected cells.
  • the anti-HBV/HDV agent that inhibits HBV or HDV virion assembly is a nucleic acid polymer, more preferably a nucleic acid polymer that blocks the HBAgs secretion.
  • the inhibition of HBV virion and HDV virion entry into infectable cells correspond to a reduction of about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 % of the amount of HBV virion or HDV virion entry in infectable cells.
  • the anti-HBV/HDV agent that inhibits HBV or HDV entry in infectable cells is a NTCP inhibitor, more preferably an NTCP-docking inhibitor.
  • the CYP3 A4 inhibitor according to the invention may be administered to the patient in combination with at least one other antiviral agent selected from the group consisting of immune system modulators, anti-HDV agents, anti-HBV agents, anti-HDV/HBV agents as defined above and any combination thereof.
  • said other antiviral agent is selected from the group consisting of immune system modulators of the interferon type, nucleoside analogues, nucleotide analogues, nucleic acid polymers, farnesyl transferase inhibitors, protease inhibitors, NTCP inhibitor and any combination thereof.
  • the CYP3 A4 inhibitor according to the invention may be administered to the patient in combination with PEG-IFN-a2a, PEG-IFN-a2b or PEG-IFN-Ala, ribavirin, lonafarnib and EBP 921, lamivudine, adefovir, telbivudine, entecavir, tenofovir and emtricitabine, ezetimibe, myrcludex B, nucleic acid polymer REP 2139 and nucleic acid polymer REP 2165 and any combination thereof.
  • the CYP3 A4 inhibitor according to the invention may be administered to the patient in combination with PEG-IFN-a2a.
  • the CYP3A4 inhibitor according to the invention may be administered to the patient in combination with myrcludex B.
  • the CYP3A4 inhibitor according to the invention may be administered to the patient in combination with lonafarnib.
  • the CYP3A4 inhibitor according to the invention may be administered to the patient in combination with adefovir.
  • the CYP3A4 inhibitor according to the invention may be administered to the patient in combination with PEG-IFN-a2a and another agent, preferably with PEG-IFN-a2a and myrcludex B.
  • the CYP3A4 inhibitor according to the invention may be administered to the patient in combination with PEG-IFN-a2a and lonafarnib.
  • the CYP3A4 inhibitor according to the invention may be administered to the patient in combination with PEG-IFN-a2a and adefovir.
  • the administration of the combination therapy is simultaneous, so that the CYP3A4 inhibitor and at least one other agent are simultaneously administered to the patient.
  • the administration of the combination therapy is sequential, so that the CYP3 A4 inhibitor and at least one other agent are sequentially administered to the patient with a determined time delay, preferably about 1 to 10 days, more preferably about 1 to 24 hours, even more preferably of about 1 to 12 hours.
  • the CYP3A4 inhibitor is not used in combination with lonafarnib.
  • the scope of the present invention does not encompass the administration of ritonavir in combination with lonafarnib.
  • FIGURES are a diagrammatic representation of FIGURES.
  • FIG. 1 Secretion and antigenic properties of the HBV antigen HBs are altered by Ritonavir.
  • Huh7 cells were transduced to stably express the shortest form of the envelop glycoprotein of HBV (HBs) which was tagged with the NanoLuc peptide (HiBit) at the C- terminus.
  • HBs envelop glycoprotein of HBV
  • HiBit NanoLuc peptide
  • Cells were treated with Ritonavir at 0, 5, 10 or 20 microM and after 2 days, supernatants were collected to quantify the secretion of HBs by two different methods: an immunoassay (CLIA; Autobio Diagnostics) and the biochemical detection of the HiBit Tag (Nano-Gio® HiBiT Lytic Detection System; Promega).
  • CLIA immunoassay
  • HiBit Tag Nano-Gio® HiBiT Lytic Detection System
  • FIG. 1 Secretion and antigenic properties of the HBV antigen HBs are altered by Saquinavir and Ketoconazole.
  • Figure 1 shows that Ritonavir was not toxic. However, this molecule had a significant impact on the secretion of HBs at the highest concentration tested as assessed by the reduced level of HiBit detected in culture supernatants ( Figure 1). Ritonavir effect was even more pronounced on the immunogenic properties of HBs as supported by a lower detection signal obtained by CLIA ( Figure 1). At lowest concentrations where no or limited effects on viability were detected, Saquinavir and Ketoconazole had an impact on the secretion of HBs as assessed by reduced levels of HiBit in culture supernatants ( Figures 2A and 2B). More pronounced effects were found on the immunogenic properties of HBs as supported by a lower detection signal obtained by CLIA ( Figures 2A and 2B).
  • Figure 3 shows that Ritonavir has a limited effect on the replication of HBV and HDV in coinfected cells, but dramatically reduced the number of infectious particles in culture supernatants.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Virology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Hepatitis D virus (HDV) infection is the most severe form of chronic viral hepatitis due to rapid progression towards liver-related death and hepatocellular carcinoma. Now the inventors have demonstrated that CYP3A4 inhibitors can be useful for the treatment of HDV infections. In particular, the inventors showed that ritonavir a very potent CYP3A4 inhibitor had a significant impact on the secretion of HBs. The effects were confirmed with Saquinavir and Ketoconazole on the secretion of HBs. Finally, the inventors showed that ritonavir has a limited effect on the replication of HBV and HDV in coinfected cells, but dramatically reduced the number of infectious particles in culture supernatants. Accordingly, the present invention relates to the use of CYP3A4 inhibitors for the treatment of hepatitis D virus (HDV) infections.

Description

USE OF CYP3A4 INHIBITORS FOR THE TREATMENT OF HEPATITIS D VIRUS (HDV) INFECTIONS
FIELD OF THE INVENTION:
The present invention is in the field of medicine, in particular virology.
BACKGROUND OF THE INVENTION:
Hepatitis D virus (HDV) infection is the most severe form of chronic viral hepatitis due to rapid progression towards liver-related death and hepatocellular carcinoma. The World Health Organization (WHO) estimates that 15-20 million persons are infected by HDV. The most recent meta-analysis of HDV burden suggests an underestimation of hepatitis D prevalence. For a productive HDV viral cycle, hepatitis B virus (HBV) infection of the same cell is necessary. In particular, HDV hijacks HBV surface antigens for its own use and the secretion of infectious HDV virions that can spread or maintain the infection. HBV and HDV virions thus contain the same envelope proteins and are undistinguishable from a humoral-response perspective. In the absence of specific anti-HDV therapy, current guidelines generally recommend subcutaneous injection of Pegylated-interferon-alpha-2a (PEG-IFN-oc2a), which is a non-specific immune-stimulator, rather toxic and poorly supported by patients. It is often used in addition to a nucleoside analogue, which controls HBV viremia. The overall rate of sustained virological response is low. Indeed, a response rate on treatment of about 25% has been reported and a high level of relapse after cessation of treatment. Accordingly, there is an unmet need of new therapeutic agents and strategies for the treatment of infection by HDV. However, there are several difficulties in the development of therapeutic agents for these patients.
HDV genome is a single-stranded RNA (= 1700 nucleotides) of negative polarity containing a single open reading frame encoding two viral proteins: the small and the large delta antigens (HDAg-S and HDAg-L). Whereas HDAg-S is mainly involved in the replication step, HDAg- L is essential for virion budding. The 19-20 amino acids additional domain in HDAg-L contains a CXXX-box motif, a substrate for cellular farnesyltransferase, which adds a famesyl group to the cysteine of this CXXX-box. This farnesylation process was shown to be essential for virion assembly (Glenn J et al. Science. 1992 May 29;256(5061): 1331-3) and prompts the development of lonafarnib, an inhibitor of the enzyme farnesyl transferase so as to repress HDV replication independently of HBV (application US20110129549A1; Mentha N, Clnts.google.com/patAlfaiate D. J. Adv. Res. 2019;17:3-17). However, its low efficacy prevents its broad use in anti-HDV therapy and the combination with ritonavir so as to increase lonafarnib levels by inhibition of cytochrome P450 3A4 (i.e. the predominant mediator of lonafarnib metabolism) is now currently investigated (Yurdaydin, Cihan, et al. "A phase 2 dose -finding study of lonafarnib and ritonavir with or without interferon alpha for chronic delta hepatitis." Hepatology 75.6 (2022): 1551-1565). Several other antiviral molecules targeting the HDV interaction with the HBV HBsAg are currently under development: Myrcludex B, which blocks HDV entry into hepatocytes by inhibiting HBsAg binding to NTCP, siRNA silencing HBV mRNA, including HBsAg mRNA, and REP 2139, which is thought to inhibit HBsAg release from hepatocytes and interact with hepatitis delta antigen (YeXet al. ACS Infect. Dis. 2019;5:738-5:7; Mentha N et al. J. Adv. Res. 2019;17:3-17). However, there is still a need for identifying new targets for the treatment of HDV infections.
SUMMARY OF THE INVENTION:
The present invention is defined by the claims. In particular, the present invention relates to the use of CYP3A4 inhibitors for the treatment of hepatitis D virus (HDV) infections.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to a method of treating a hepatitis D virus (HDV) infection in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a CYP3 A4 inhibitor.
As used herein, the term "subject" or "patient" and "subject in need thereof' or "patient in need thereof", is intended for a human or non-human mammal infected or likely to be infected with a hepatitis D virus. In particular, the patient is simultaneously infected with HBV and HDV. In some embodiments, the patient suffers from a chronic HDV infection.
As used herein, the term “Hepatitis D virus” or “HDV” refers to the well-known noncytopathic, liver-tropic DNA virus belonging to the Hepadnaviridae family. See, e.g., Ciancio and Rizzetto, Nat. Rev. 11 :68-71, 2014; Le Gal et al., Emerg. Infect. Dis. 12: 1447- 1450, 2006; and Abbas and afzal, World J. Hep., 5:666-675, 2013, all of which are incorporated by reference. Unless otherwise indicated, HDV refers to all clades and variants of HDV. HDV produces one protein, namely HDAg. It comes in two forms; a 27 kDa large-HDAg (also referred to herein as 1HD, L-HDAg, and large HDV antigen), and a small-HDAg of 24 kDa (also referred to herein as sHD, S-HDAg, and small HDV antigen). The N-terminals of the two forms are identical, they differ by 19 amino acids in the C-terminal of the large HDAg. Both isoforms are produced from the same reading frame which contains an UAG stop codon at codon 196, which normally produces only the small-HDAg. However, editing by cellular enzyme adenosine deaminase- 1 changes the stop codon to UCG, allowing the large-HDAg to be produced. Despite having 90% identical sequences, these two proteins play diverging roles during the course of an infection. HDAg-S is produced in the early stages of an infection and enters the nucleus and supports viral replication. HDAg-L, in contrast, is produced during the later stages of an infection, acts as an inhibitor of viral replication, and is required for assembly of viral particles.
As used herein, the term "treatment" or "treat" refer to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse. The treatment may be administered to a patient having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a patient beyond that expected in the absence of such treatment. By "therapeutic regimen" is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy. A therapeutic regimen may include an induction regimen and a maintenance regimen. The phrase "induction regimen" or "induction period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease. The general goal of an induction regimen is to provide a high level of drug to a patient during the initial period of a treatment regimen. An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both. The phrase "maintenance regimen" or "maintenance period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a patient during treatment of an illness, e.g., to keep the patient in remission for long periods of time (months or years). A maintenance regimen may employ continuous therapy (e.g., administering a drug at regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., disease manifestation, etc.]).
The efficacy of the treatment may be monitored using standard protocols. Indeed, treatment may be followed by determinations of HDV levels in serum (viral load) and measurement of serum alanine aminotransferase (ALT) levels. For example, the patients may be assessed for the presence of HDV RNA in their serum. HDV RNA (lU/mL) can be measured at regular intervals during the treatment, e.g., at Day 1 (pre-dose and 4, 8, and 12 hours post-dose) and pre-dose at Day 2, Day 3, Day 8, Day 15, Day 29, and at Week 12, Week 24, Week 36, Week 48, Week 72 (when applicable), and at follow up. Accordingly, the efficacy of treatment can be monitored using internationally accepted parameters: a) Serum HDV RNA levels are monitored using sensitive quantitative RT-PCR-based assays to assess the effect on viral replication b) Serum levels of ALT and/or aspartate aminotransferase (AST) are monitored to assess impact on liver inflammation and liver cell death.
The treatment may correspond to a single-agent treatment where only one CYP3 A4 inhibitor is administered, or to a combination therapy with another therapeutic agent such as another CYP3 A4 inhibitor or antiviral agents.
The treatment can be administered to patients who have been diagnosed with an HDV infection. Any of the above treatment regimens can be administered to patients who have failed previous treatment for HDV infection (treatment failure patients). As used herein, the terms "treatment failure patients" refers to patient who have failed previous treatment for HDV infection. More specifically, although there is no effective treatment against HDV, or any FDA-approved drug for the treatment of chronic HDV, the pegylated immune system modulator interferon alpha (PEG-IFN-a) is currently used in clinical practice and thus considered as a standard-of-care for HDV infection. Consequently, “treatment failure patients" generally refers to HDV-infected patients who failed to respond to the PEG-IFN-a treatment (referred to as "non-responders") or who initially responded to PEG-IFN-a treatment, but in whom the therapeutic response was not maintained (referred to as "relapsers").
As used herein, the term “CYP3A4” has its general meaning in the art and refers to the cytochrome P450 3A4 (EC 1.14.13.97) that is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from the body.
As used herein, the term “CYP3A4 inhibitor” is intended to encompass a compound that interacts with CYP3A4 to substantially reduce or eliminate its catalytic activity, thereby increasing the concentrations of its substrate(s). Assays for determining the level of CYP3 A4 inhibition of an agent are well known in the art (e.g. Lin T, Pan K, Mordenti J, Pan L. In vitro assessment of cytochrome P450 inhibition: strategies for increasing LC/MS-based assay throughput using a one-point IC(50) method and multiplexing high-performance liquid chromatography. J Pharm Sci. 2007 Sep;96(9): 2485-93). A CYP3A4 inhibitor can be a molecule of any type that interferes with the activity of CYP3A4 for example, either by decreasing transcription or translation of CYP3A4-encoding nucleic acid, or by inhibiting or blocking CYP3A4 activity, or both. Examples of CYP3A4 inhibitors include, but are not limited to, antisense polynucleotides, interfering RNAs, catalytic RNAs, RNA-DNA chimeras, CYP3A4-specific aptamers, anti-CYP3A4 antibodies, CYP3A4-binding fragments of anti- CYP3A4 antibodies, CYP3A4-binding small molecules, CYP3A4-binding peptides, and other polypeptides that specifically bind CYP3A4 (including, but not limited to, CYP3A4-binding fragments of one or more CYP3A4 ligands, optionally fused to one or more additional domains), such that the interaction between the CYP3A4 inhibitor and CYP3A4 results in a reduction or cessation of CYP3 A4 activity or expression.
In some embodiments, the CYP3 A4 inhibitor is selected from the compounds disclosed in one or more of the following patents and patent applications assigned to Bioavailability Systems, LLC, the disclosure of each of which is incorporated herein by reference: US 2004058982, U.S. Pat. No. 6,248,776, U.S. Pat. No. 6,063,809, U.S. Pat. No. 6,054,477, U.S. Pat. No. 6,162,479, WO 2000054768, U.S. Pat. No. 6,309,687, U.S. Pat. No. 6,476,066, U.S. Pat. No. 6,660,766, WO 2004037827, U.S. Pat. No. 6,124,477, U.S. Pat. No. 5,820,915, U.S. Pat. No. 5,993,887, U.S. Pat. No. 5,990,154, U.S. Pat. No. 6,255,337.
In some embodiments, the CYP3 A4 inhibitor is selected from the group of CYP3 A4 inhibitors referred to in the following documents (which are incorporated by reference herein): US20040052865A1, US20030150004A1, US20060099667A1, US20030096251A1,
US20060073099A1, US20050272045A1, US20020061836A1, US20020016681A1,
US20010041706A1, US20060009645A1, US20050222270A1, US20050031713A1, US20040254156A1, US20040214848A1, WO0173113A2, W02005068611A1,
US20050171037A1, W02003089657A1, W02003089656A1, W02003042898A2,
US20040243319A1, W00045817A1, W02006037993A2, W02004021972A2,
W02006024414A2, W02004060370A1, WO9948915A1, W02006054755A1,
W02006037617A1, JP2006111597A, W00111035A1, WO9844939A1, W02003026573A2,
W02003047594A1, WO0245704A2, W02005020962A1, W02006021456A1,
US20040047920A1, W02003035074A1, W02005007631A1, W02005034963A1,
W02006061714A2, WO0158455A1, W02003040121A1, W02002094865A1,
W00044933A1, U.S. Pat. No. 6,673,778B1, W02005098025A2, US20040106216A1,
W00017366A2, WO9905299A1, WO9719112A1, EP1158045A1, W00034506A2, U.S. Pat.
No. 5,886,157A, WO9841648A2, U.S. Pat. No. 6,200,754Bl, U.S. Pat. No. 6,514,687B1, W02005042020A2, WO9908676A1, WO9817667A1, W00204660A2, W02003046583A2, W02003052123A1, W02003046559A2, US20040101477A1, US20040084867A1,
JP10204091A, WO9635415A2 WO9909976, WO98053658, US2004058982, U.S. Pat. No. 6,248,776, U.S. Pat. No. 6,063,809, U.S. Pat. No. 6,054,477, U.S. Pat. No. 6,162,479, W02000054768, U.S. Pat. No. 6,309,687, U.S. Pat. No. 6,476,066, U.S. Pat. No. 6,660,766, WO 2004037827, U.S. Pat. No. 6,124,477, U.S. Pat. No. 5,820,915, U.S. Pat. No. 5,993,887, U.S. Pat. No. 5,990,154, U.S. Pat. No. 6,255,337, Fukuda et al., “Specific CYP3A4 inhibitors in grapefruit juice: furocoumarin dimers as components of drug interaction,” Pharmacogenetics, 7(5):391-396 (1997), Matsuda et al., “Taurine modulates induction of cytochrome P450 3A4 mRNA by rifampicin in the HepG2 cell line,” Biochim Biophys Acta, 1593(l):98-98 (2002); Tassaneeyakul et al., “Inhibition selectively of grapefruit juice components on human cytochromes P450,” Arch Biochem Biophys, 378(2):356-363 (2000); Widmer and Haun, “Variation in furanocoumarin content and new furanocoumarin dimmers in commercial grapefruit (Citrus paradise Macf.) juices,” Journal of Food Science, 70(4):C307- C312 (2005).
Non-limiting examples of suitable CYP3A4 inhibitors include ketoconazole (Nizoral™, commercially available from Janssen Pharmaceutica), itraconazole (Sporanox®, commercially available from Janssen-Cilag), ritonavir (Norvir® commercially available from Abbott), nelfinavir (Viracept® commercially available from Pfizer), cobicistat (TYBOST®), indinavir (Crixivan® commercially available from Merck & Co., Inc), erythromycin (Akne-Mycin®, A/T/S®, Emgel®, Erycette®, EryDerm®, Erygel®, Erymax®, Ery-Sol®, Erythra-Derm®, ETS®, Staticin®, Theramycin Z®, T-Stat®), ERYC®, Ery-Tab®, Erythromycin Base Filmtab®, PCE® Dispertab®), clarithromycin (Biaxin®), troleandomycin (Tao®), saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine (Prozac®) commercially available from Eli Lilly and Company, Zoloft® commercially available from Pfizer Pharmaceuticals, Anafranil® commercially available from Mallinckrodt Inc.), fluvoxamine (Luvox®), Zyflo (Zileuton® commercially available from Abbott Laboratories), clotrimazole (Fungoid® Solution, Gyne-Lotrimin®, GyneLotrimin® 3, Gyne-Lotrimin® 3 Combination Pack, Gyne- Lotrimin®-3, Lotrim® AF Jock Itch Cream, Lotrimin®, Lotrimin® AF, My cel ex® Troche, Mycelex®-7), midazolam (available from Apotex Corp.), naringenin, bergamottin, BAS 100 (available from Bioavailability Systems). In some embodiments, the CYP3A4 inhibitor is ketoconazole (Nizora™) or clarithromycin (Biaxin®). In some embodiments, the CYP3A4 inhibitor is BAS 100 (available from Bioavailability Systems).
Typically, the CYP3A4 inhibitor of the invention is administered to the subject with a therapeutically effective amount. By a "therapeutically effective amount" of the CYP3A4 inhibitor as above described is meant a sufficient amount of the CYP3A4 inhibitor to treat a hepatitis D virus infection at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination with the specific agonist employed; and like factors well known in the medical arts. For example, it is well known within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. However, the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day. Preferably, the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from 1 mg to about 100 mg of the active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
According to an aspect of the invention, the CYP3 A4 inhibitor according to the invention may be administered to the patient in combination with at least one other therapeutic agent, preferably in combination with at least one other antiviral agent, more preferably in combination with at least one other antiviral agent selected from the group consisting of immune system modulators, anti-HDV agents, anti-HBV agents, anti-HDV/HBV agents and any combination thereof.
As used herein, the term "immune system modulator" refers to a signalling protein of the interferon type (IFN), preferably to interferon alpha (IFN-a) or interferon lambda (IFN-1), more preferably to pegylated interferon alpha (PEG-IFN-a) or pegylated interferon lambda (PEG- IFN-1). In some embodiments, IFN is selected from the group consisting of consensus IFN-a (e.g., INFERGEN®, Locteron®), IFN-a2a (Roferon-A®, MOR-22, Inter 2A, Inmutag, Inferon), a pegylated IFN-a2a (e.g, PEGASYS®, YPEG-IFNa-2a, PEG-INTRON®, Pegaferon), IFN-a2b (e.g, INTRON A®, Alfarona, Bioferon, Inter 2B, citpheron, Zavinex, Ganapar, etc...), a pegylated IFN-a2b (e.g. Pegintron ®, Albuferon, AOP2014/P1101, Algeron, Pai Ge Bin), IFN-a2c (e.g. Berofor Alpha), and IFN-like protein (e.g, Novaferon, FISA-IFN- a2a fusion protein, FISA-IFN-a2b fusion protein). IFN can be administered daily, weekly or 2, 3, 4, 5, or 6 times weekly. The treatment period is generally long, for instance from 2 weeks to several months. For instance, the period is from 3-4 months up to 24 months. The dosage can vary from 1 million units to 20 million units, for instance 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19 million units. IFN can be administered by subcutaneous, intramuscular, intravenous, transdermal, or intratumoral administration, preferably for subcutaneous or intramuscular administration.
As used herein, the term "anti-HDV agent" refers to any compound that treats HDV infection thereby inhibiting HDV replication, HDV virion assembly, or inhibiting HDV virion entry into infectable cells. Some anti-HDV agents are known by the person skilled in the art (see Deterding et al. 2019, AIDS Rev, 21, 126-134; Gilman et al. 2019), World J Gastroenterol, 25, 4580-4597). Preferably, the anti-HDV agent is selected from the group consisting of ribavirin, lonafarnib and EBP 21. In particular, the inhibition of HDV replication, corresponds to a reduction of about 10, 20, 30, 40, 50, 60, 70, 80, 90% or 100 % of the number of HDV RNA copies of replicated in infected cells. Techniques for measuring the number of copies, particularly those based on Polymerase Chain Reaction (PCR), are well known to the person skilled in the art. Preferably, the anti-HDV agent that inhibits HDV replication is a nucleoside analog. In particular, the inhibition of HDV virion assembly corresponds to a reduction of about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 % of the amount of HDV virion assembled in infected cells. Techniques for quantifying the amount of virion, particularly those based on Enzyme- Linked Immunosorbent Assay (ELISA), are well known to the person skilled in the art. Preferably, the anti-HDV agent that inhibits HDV virion assembly is a famesyl transferase inhibitor. In particular, the inhibition of HDV virion entry into infectable cells correspond to a reduction of about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 % of the amount of HDV virion entry in infectable cells.
As used herein, the term "anti-HBV agent" refers to compounds that treat HBV infection thereby inhibiting HBV replication, inhibiting HBV virion assembly, or inhibiting HBV virion entry into infectable cells. Anti-HBV agent are known by the person skilled in the art, for example such as conventional interferon, pegylated interferon, nucleoside and nucleotide analogues. Preferably, the anti-HBV agent that inhibits HBV replication is a nucleoside analog, more preferably a nucleoside analog reverse-transcriptase inhibitor, and even more preferably, the anti-HBV agent is selected from the group consisting of lamivudine, adefovir, telbivudine, entecavir, tenofovir and emtricitabine. In particular, the inhibition of HBV replication corresponds to a reduction of about 10, 20, 30, 40, 50, 60, 70, 80, 90% or 100 % of the amount of HBV DNA replicated in infected cells. A lower level of replication of HBV DNA helps to reduce the level of HBV virion assembly which in turns induces a lower level of infection of other target cells. Therefore, it occurs a lower probability of providing HBV antigens for the assembly of HDV visions. In particular, the inhibition of HBV virion assembly corresponds to a reduction of about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 % of the amount of HBV virion assembled in infected cells. A lower level of HBV virions assembly of HBV virions induces a lower level of infection of other target cells and therefore a lower probability of providing HBV antigens for the assembly of HDV visions. In particular, the inhibition of HBV virion entry into infectable cells correspond to a reduction of about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 % of the amount of HBV virion entry in infectable cells. The term "infectable cells" refer to cells accessible to virions that express the NTCP receptor required for the HDV virion or HBV virion entry into the cell. A cell, particularly a host cell, is considered accessible when there is no biological or physical barrier to prevent its contact with the circulating virion. Since HBV and HDV virions share the same entry receptor, i. e. NTCP, the docking-mediated blockage of NTCPs by anti-HBV agents effectively inhibiting cell entry of HBV virions, also inhibits cell entry of HDV virions.
As used herein, the term "anti-HBV/HDV agent" refers to compounds that treat HDV and/or HBV infection thereby inhibiting HBV and HDV virion assembly, or inhibiting HBV and HDV virion entry into infectable cell. Preferably, the anti-HBV agent is selected from the group consisting of ezetimibe, myrcludexB, nucleic acid polymer REP 2139 and nucleic acid polymer REP 2165 or any combination thereof. In particular, the inhibition of HBV and HDV virion assembly respectively correspond to a reduction of about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 % of the amount of HBV virion or HDV virion assembled in infected cells. Preferably, the anti-HBV/HDV agent that inhibits HBV or HDV virion assembly is a nucleic acid polymer, more preferably a nucleic acid polymer that blocks the HBAgs secretion. In particular, the inhibition of HBV virion and HDV virion entry into infectable cells correspond to a reduction of about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 % of the amount of HBV virion or HDV virion entry in infectable cells. Preferably, the anti-HBV/HDV agent that inhibits HBV or HDV entry in infectable cells is a NTCP inhibitor, more preferably an NTCP-docking inhibitor.
In some embodiments, the CYP3 A4 inhibitor according to the invention may be administered to the patient in combination with at least one other antiviral agent selected from the group consisting of immune system modulators, anti-HDV agents, anti-HBV agents, anti-HDV/HBV agents as defined above and any combination thereof. Preferably said other antiviral agent is selected from the group consisting of immune system modulators of the interferon type, nucleoside analogues, nucleotide analogues, nucleic acid polymers, farnesyl transferase inhibitors, protease inhibitors, NTCP inhibitor and any combination thereof.
More preferably, the CYP3 A4 inhibitor according to the invention may be administered to the patient in combination with PEG-IFN-a2a, PEG-IFN-a2b or PEG-IFN-Ala, ribavirin, lonafarnib and EBP 921, lamivudine, adefovir, telbivudine, entecavir, tenofovir and emtricitabine, ezetimibe, myrcludex B, nucleic acid polymer REP 2139 and nucleic acid polymer REP 2165 and any combination thereof.
In some embodiments, the CYP3 A4 inhibitor according to the invention may be administered to the patient in combination with PEG-IFN-a2a. Alternatively, the CYP3A4 inhibitor according to the invention may be administered to the patient in combination with myrcludex B.
Alternatively, the CYP3A4 inhibitor according to the invention may be administered to the patient in combination with lonafarnib.
Alternatively, the CYP3A4 inhibitor according to the invention may be administered to the patient in combination with adefovir.
Alternatively, the CYP3A4 inhibitor according to the invention may be administered to the patient in combination with PEG-IFN-a2a and another agent, preferably with PEG-IFN-a2a and myrcludex B.
Alternatively, the CYP3A4 inhibitor according to the invention may be administered to the patient in combination with PEG-IFN-a2a and lonafarnib.
Alternatively, the CYP3A4 inhibitor according to the invention may be administered to the patient in combination with PEG-IFN-a2a and adefovir.
In some embodiments of the invention, the administration of the combination therapy is simultaneous, so that the CYP3A4 inhibitor and at least one other agent are simultaneously administered to the patient.
In some embodiments, the administration of the combination therapy is sequential, so that the CYP3 A4 inhibitor and at least one other agent are sequentially administered to the patient with a determined time delay, preferably about 1 to 10 days, more preferably about 1 to 24 hours, even more preferably of about 1 to 12 hours.
In some embodiments, the CYP3A4 inhibitor is not used in combination with lonafarnib. In some embodiments, the scope of the present invention does not encompass the administration of ritonavir in combination with lonafarnib. The invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted in any way as limiting the scope of the present invention.
FIGURES:
Figure 1. Secretion and antigenic properties of the HBV antigen HBs are altered by Ritonavir. Huh7 cells were transduced to stably express the shortest form of the envelop glycoprotein of HBV (HBs) which was tagged with the NanoLuc peptide (HiBit) at the C- terminus. Cells were treated with Ritonavir at 0, 5, 10 or 20 microM and after 2 days, supernatants were collected to quantify the secretion of HBs by two different methods: an immunoassay (CLIA; Autobio Diagnostics) and the biochemical detection of the HiBit Tag (Nano-Gio® HiBiT Lytic Detection System; Promega). The overall viability of the cellular layer was determined by quantification of ATP in culture wells using the CellTiter-Glo reagent (Promega). ATP in culture wells reflects the number of metabolically active cells. Date shown means +/- SEM (n=4).
Figure 2. Secretion and antigenic properties of the HBV antigen HBs are altered by Saquinavir and Ketoconazole. A and B. Huh7-HBs-HiBit cells were treated with Saquinavir or Ketoconazole and after 2 days, cultures were analyzed as in Figure 1. Date shown means +/- SEM (n=2).
Figure 3. Specific infectivity of HDV particles produced by HBV/HDV coinfected cells treated with ritonavir is decreased. Differentiated HepaRG cells were infected by HBV and HDV. The viral inoculum was washed at day 1 post-infection, and cells were treated with Ritonavir at day 6. Three days later, cellular layers were collected to quantify HBV and HDV RNA levels as a measure of viral replication. Cell culture supernatants were also collected and the concentration of HDV particles was determined by RT-qPCR. To measure the specific infectivity of produced HDV particles, equivalent amounts of HDV particles were used to infect freshly differentiated HepaRG cells. At day 6, these cells were lysed and intracellular levels of HDV were quantified by RT-qPCR. Results show that Ritonavir has a limited effect on the replication of HBV and HDV in coinfected cells, but dramatically reduces the specific infectivity of HDV particles in culture supernatants. EXAMPLE:
Figure 1 shows that Ritonavir was not toxic. However, this molecule had a significant impact on the secretion of HBs at the highest concentration tested as assessed by the reduced level of HiBit detected in culture supernatants (Figure 1). Ritonavir effect was even more pronounced on the immunogenic properties of HBs as supported by a lower detection signal obtained by CLIA (Figure 1). At lowest concentrations where no or limited effects on viability were detected, Saquinavir and Ketoconazole had an impact on the secretion of HBs as assessed by reduced levels of HiBit in culture supernatants (Figures 2A and 2B). More pronounced effects were found on the immunogenic properties of HBs as supported by a lower detection signal obtained by CLIA (Figures 2A and 2B). Figure 3 shows that Ritonavir has a limited effect on the replication of HBV and HDV in coinfected cells, but dramatically reduced the number of infectious particles in culture supernatants. These results collectively demonstrate that CYP3 A4 inhibitors are useful for the treatment of HDV infections.
REFERENCES:
Throughout this application, various references describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference into the present disclosure.

Claims

CLAIMS:
1. A method of treating a hepatitis D virus (HDV) infection in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a CYP3 A4 inhibitor.
2. The method of claim 1 wherein the CYP3A4 inhibitor is selected from the group consisting of ketoconazole, itraconazole, ritonavir, nelfinavir, cobicistat, indinavir, erythromycin, clarithromycin, troleandomycin, saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine clotrimazole, midazolam, naringenin, bergamottin, BAS 100.
3. The method of claim 1 or 2 wherein the CYP3 A4 inhibitor is administered to the patient in combination with an interferon alpha (IFN-a), an interferon lambda or a pegylated form thereof, preferably selected from the group consisting of IFN-ala, IFN-alb, IFN- a2a, IFN-a2b, and IFN-Ala or a pegylated form thereof, more preferably PEG-IFN-a2a (e.g., Pegasys), PEG-IFN-a2b (e.g., ViraferonPeg or Introna) or PEG-IFN-Ala.
4. The method of claim 1 or 2 wherein the CYP3 A4 inhibitor is administered to the patient in combination with an anti-HDV agent, preferably a nucleoside analog or a farnesyl transferase inhibitor provided that the CYP3A4 inhibitor and the farnesyl transferase inhibitor is not lonafarnib.
5. The method of claim 1 or 2 wherein the CYP3 A4 inhibitor is administered to the patient in combination with an anti-HBV agent, preferably a nucleoside analog such as lamivudine, adefovir, telbivudine, entecavir, tenofovir or emtricitabine.
6. The method of claim 1 or 2 wherein the CYP3 A4 inhibitor is administered to the patient in combination with an anti-HB V/HDV agent, preferably a nucleoside analog, a nucleic acid polymer or a NTCP inhibitor.
7. The method of claim 6 wherein the anti-HB V/HDV agent is selected from the group consisting of ezetimibe, myrcludex B, nucleic acid polymer REP 2139 and nucleic acid polymer REP 2165.
8. The method according to any one of claims 1 to 7 wherein the patient has failed to respond to a previous treatment for HDV infection.
9. The method of claim 8 wherein the previous treatment is a treatment with PEG-IFNa.
PCT/EP2024/061493 2023-04-28 2024-04-26 Use of cyp3a4 inhibitors for the treatment of hepatitis d virus (hdv) infections WO2024223797A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP23315130 2023-04-28
EP23315130.7 2023-04-28

Publications (1)

Publication Number Publication Date
WO2024223797A1 true WO2024223797A1 (en) 2024-10-31

Family

ID=86776411

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2024/061493 WO2024223797A1 (en) 2023-04-28 2024-04-26 Use of cyp3a4 inhibitors for the treatment of hepatitis d virus (hdv) infections

Country Status (1)

Country Link
WO (1) WO2024223797A1 (en)

Citations (81)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996035415A2 (en) 1995-05-09 1996-11-14 Zylepsis Limited Use of sesquiterpenes for inhibiting oxidative enzymes
WO1997019112A1 (en) 1995-11-17 1997-05-29 United States Of America, Represented By The Secretary, Department Of Health And Human Services Inhibitory and non-inhibitory antigen binding polypeptides against human p450 enzymes
WO1998017667A1 (en) 1996-10-18 1998-04-30 Wayne State University 6',7'-dihydroxybergamottin, a cytochrome p450 ihnibitor in grapefruit juice
JPH10204091A (en) 1996-11-22 1998-08-04 Yasushi Yamazoe Cytochrome P450 3A4 inhibitor
WO1998041648A2 (en) 1997-03-20 1998-09-24 Variagenics, Inc. Target genes for allele-specific drugs
US5820915A (en) 1996-06-27 1998-10-13 Bioavailability Systems, L.L.C. Method for the preparation of a first-pass effective citrus-derived substance and product thereof
WO1998044939A1 (en) 1997-04-10 1998-10-15 Merck & Co., Inc. Anti-peptide antibody against human cytochrome p450 3a4
WO1998053658A2 (en) 1997-05-30 1998-12-03 Bioavailability Systems, L.L.C. Anti-first-pass effect compounds and citrus extract
WO1999005299A1 (en) 1997-07-24 1999-02-04 Trustees Of Boston University Methods of using cytochrome p450 reductase for the enhancement of p450-based anti-cancer gene therapy
WO1999008676A1 (en) 1997-08-19 1999-02-25 Warner-Lambert Company Compositions containing bergamottin for increasing the oral bioavailability of pharmaceutical agents
WO1999009976A1 (en) 1997-08-26 1999-03-04 Bioavailability Systems, L.L.C. Anti-first-pass effect compounds
US5886157A (en) 1994-02-10 1999-03-23 Vanderbilt University Expression and purification of human cytochrome P450
WO1999048915A1 (en) 1998-03-27 1999-09-30 Glaxo Group Limited Orphan nuclear receptor
US5993887A (en) 1998-06-29 1999-11-30 Bioavailability Systems, L.L.C. Safe citrus juice and process for preparation
WO2000017366A2 (en) 1998-09-21 2000-03-30 Transgene S.A. Pharmaceutical composition for the pre-treatment of a patient in need of drug or pro-drug
US6054477A (en) 1997-08-26 2000-04-25 Bioavailability Systems, Llc Anti-first-pass effect compounds
WO2000034506A2 (en) 1998-12-04 2000-06-15 University Of North Carolina At Chapel Hill Method of screening candidate compounds for susceptibility to oxidative metabolism
WO2000044933A1 (en) 1999-01-29 2000-08-03 Smithkline Beecham P.L.C. Resorufin derivatives as substrates for cyp3a4
WO2000045817A1 (en) 1999-02-06 2000-08-10 Astrazeneca Ab Drug combinations comprising (e) -7 - [4 -(4 -fluorophenyl) -6 - isopropyl -2 - [methyl (methylsulfonyl) amino] pyrimidin -5 -yl] (3r,5s) -3,5 - dihydroxyhept -6 - enoic acid and an inhibitor, inducer or substrate of p450 isoenzyme 3a4
WO2000054768A1 (en) 1999-02-17 2000-09-21 Bioavailability Systems, L.L.C. Anti-first-pass effect compounds
US6124477A (en) 1996-06-27 2000-09-26 Bioavailability Systems, Llc Anti-first-pass effect compounds
WO2001011035A1 (en) 1999-08-05 2001-02-15 Merck & Co., Inc. Monoclonal antibodies for human cytochrome p450 3a4 and human cytochrome p450 2c9
US6200754B1 (en) 1998-03-19 2001-03-13 Variagenics, Inc. Inhibitors of alternative alleles of genes encoding products that mediate cell response to environmental changes
WO2001058455A1 (en) 2000-02-11 2001-08-16 Pharmacia Italia S.P.A. Method to potentiate the therapeutic efficacy of taxane and derivatives thereof
WO2001073113A2 (en) 2000-03-29 2001-10-04 Aclara Biosciences, Inc. Monooxygenase assays
US20010041706A1 (en) 2000-03-24 2001-11-15 Synold Timothy W. Blockade of taxane metabolism
EP1158045A1 (en) 2000-05-17 2001-11-28 Universite Catholique De Louvain Culture conditions allowing to modulate the expression of CYP3A4 in CaCo2 cells
WO2002004660A2 (en) 2000-07-12 2002-01-17 Wyeth Method for testing for inhibition of drug-metabolizing cytochrome p450 isozymes
US20020016681A1 (en) 2000-03-31 2002-02-07 Sean Ekins Single point interaction screen to predict IC50
US20020061836A1 (en) 2000-03-24 2002-05-23 Barry Forman Methods for altering SXR activation using peptide mimetic HIV protease inhibitor SXR ligands
WO2002045704A2 (en) 2000-12-04 2002-06-13 Molecular Skincare Limited Prevention and treatment of tachyphylactic response
WO2002094865A1 (en) 2001-05-24 2002-11-28 Smithkline Beecham Corporation Nonhuman pregnane x receptor sequences for use in comparative pharmacology
US6514687B1 (en) 1998-12-14 2003-02-04 Vertex Pharmaceuticals (San Diego), Llc Optical molecular sensors for cytochrome P450 activity
WO2003026573A2 (en) 2001-09-24 2003-04-03 Merck & Co., Inc. Screening and selection methods for statin drug combinations
WO2003035074A1 (en) 2001-10-23 2003-05-01 Ono Pharmaceutical Co., Ltd. Drugs comprising combination of triazaspiro[5,5]undecane derivative with cytochrome p450 isozyme 3a4 inhibitor and/or p-glycoprotein inhibitor
WO2003040121A1 (en) 2001-11-08 2003-05-15 Sepracor, Inc. Methods for treating depression and other cns disorders using enantiomerically enriched desmethyl- and didesmethyl-metabolites of citalopram
WO2003042898A2 (en) 2001-11-13 2003-05-22 Arqule, Inc. Compound prioritization for drug discovery
US20030096251A1 (en) 1998-08-31 2003-05-22 Marco Guida Methods for evaluating the ability to metabolize pharmaceuticals and compositions therefor
WO2003046559A2 (en) 2001-11-28 2003-06-05 Xanthus Life Sciences, Inc. Individualization of therapy with antiviral agents
WO2003046583A2 (en) 2001-11-28 2003-06-05 Xanthus Life Sciences Inc. Individualization of therapy with anesthetics
WO2003047594A1 (en) 2001-11-29 2003-06-12 Molecular Skincare Limited Disease treatment using two related compounds wherein at least one of the compound induces a tachyphylactic response which not affect the other compound
WO2003052123A1 (en) 2001-12-19 2003-06-26 Xanthus Life Sciences, Inc. Individualization of therapy with antihistamines
US20030150004A1 (en) 2000-09-21 2003-08-07 Moore David D. Screening systems and methods for identifying modulators of xenobiotic metabolism
WO2003089656A1 (en) 2002-04-19 2003-10-30 Amersham Health As Methods and compound mixtures for determining protein activity using nmr spectroscopy
WO2003089657A1 (en) 2002-04-19 2003-10-30 Amersham Health As Method for phenotyping using nmr spectroscopy
US6673778B1 (en) 1996-02-23 2004-01-06 The Board Of Regents Of The University Of Nebraska Enzyme inhibitors for metabolic redirection
US20040047920A1 (en) 2002-09-06 2004-03-11 Novemed Group Limited Inhibition of CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 in cryopreserved human hepatocytes by a Tripterygium Wilfordii Hook.F. extract
US20040052865A1 (en) 2002-09-13 2004-03-18 Gower Laurie B. Materials and methods for drug delivery and uptake
WO2004021972A2 (en) 2002-09-03 2004-03-18 Biovail Laboratories, Inc. Pharmaceuticals formulations and methods for modified release of statin drugs
US20040058982A1 (en) 1999-02-17 2004-03-25 Bioavailability System, Llc Pharmaceutical compositions
US20040084867A1 (en) 2002-06-28 2004-05-06 Xanthus Life Sciences, Inc. Individualization of therapy with anticoagulants
WO2004037827A1 (en) 2000-10-20 2004-05-06 Bioavailability Systems, Llc Synthesis of spiro ortho esters, spiro ortho carbonates, and intermediates
US20040101477A1 (en) 2002-11-27 2004-05-27 Xanthus Life Sciences, Inc. Individualization of therapy with anesthetics
US20040106216A1 (en) 2002-07-02 2004-06-03 Toyo Boseki Kabushiki Kaisha Method of measuring drug-metabolizing enzyme activity, method of evaluating inhibition of drug-metabolizing enzyme activity, and composition for these methods
WO2004060370A1 (en) 2002-12-16 2004-07-22 Boehringer Ingelheim Pharmaceuticals, Inc. Treatment of hiv infection through combined administration of tipranavir and capravirine
US20040214848A1 (en) 2001-10-30 2004-10-28 Schoenhard Grant L. Inhibitors of ABC drug transporters in microbial cells
US20040243319A1 (en) 2001-04-02 2004-12-02 Astex Technology Ltd. Crystal structure of cytochrome P450
US20040254156A1 (en) 2003-06-10 2004-12-16 Bertrand Le Bourdonnec Sulfonylamino phenylacetamide derivatives and methods of their use
WO2005007631A1 (en) 2003-07-10 2005-01-27 Osi Pharmaceuticals, Inc. Naphthylene derivatives as cytochrome p450 inhibitors
US20050031713A1 (en) 2003-08-06 2005-02-10 Elliot Ehrich Methods for administering active agents to CYP3A4 sensitive patients
WO2005020962A1 (en) 2003-08-29 2005-03-10 Novagali Pharma Sa Self-nanoemulsifying oily formulation for the administration of poorly water-soluble drugs
WO2005034963A1 (en) 2003-10-15 2005-04-21 Panagin Pharmaceuticals Inc. USE OF GINSENOSIDES Rh2 & Rg3, AND AGLYCON GINSENOSIDES FOR THE PREVENTION OF CANCER
WO2005042020A2 (en) 2003-10-27 2005-05-12 Vertex Pharmaceuticals Incorporated Combinations for hcv treatment
WO2005068611A1 (en) 2004-01-19 2005-07-28 Advanced In Vitro Cell Technologies, S.L. Method for obtaining a singular cell model capable of reproducing in vitro the metabolic idiosyncrasy of humans
US20050171037A1 (en) 2004-01-30 2005-08-04 Agouron Pharmaceuticals, Inc. Therapeutic combinations
US20050222270A1 (en) 2004-02-26 2005-10-06 Olney John W Prolonged administration of NMDA antagonist drug and safener drug to create improved stable neural homeostasis
WO2005098025A2 (en) 2004-04-05 2005-10-20 The University Of North Carolina At Chapel Hill High throughput reactive oxygen species-based cytochrome p450 inhibition assay
US20050272045A1 (en) 2004-06-04 2005-12-08 Rolf Joseph Craven Hpr6 mutants and uses thereof
US20060009645A1 (en) 2004-07-12 2006-01-12 Vanessa Smith Naphthylene derivatives as cytochrome P450 inhibitors
WO2006021456A1 (en) 2004-08-27 2006-03-02 Novartis Ag Combination comprising a staurosporine and a cyp3a4 inhibitor
WO2006024414A2 (en) 2004-08-28 2006-03-09 Boehringer Ingelheim International Gmbh Method for producing a ginger fraction and the use thereof for inhibiting human cyp enzymes
US20060073099A1 (en) 2004-10-01 2006-04-06 Frincke James M Treatment screening methods
WO2006037617A1 (en) 2004-10-07 2006-04-13 Istituto Di Ricerche Di Biologia Molecolare P Angeletti Spa Assay for cytochrome p450 isoforms 3a4 and 3a5
WO2006037993A2 (en) 2004-10-02 2006-04-13 Auvation Limited Cancer markers
JP2006111597A (en) 2004-10-18 2006-04-27 Kanazawa Univ Drug-metabolizing enzyme inhibitor derived from strawberry and method for producing the same
US20060099667A1 (en) 2002-10-28 2006-05-11 Francois Andre Method for performing restrained dynamics docking of one or multiple substrates on multi-specific enzymes
WO2006054755A1 (en) 2004-11-16 2006-05-26 Hiroshima Industrial Promotion Organization Method of screening candidate for drug
WO2006061714A2 (en) 2004-12-09 2006-06-15 Pfizer Inc. Anticoronaviral compounds and compositions, their pharmaceutical uses and materials for their synthesis
US20110129549A1 (en) 2008-04-17 2011-06-02 Liu Julie F Tricyclic benzo[5,6]cyclohepta[1,2-b]pyridine derivatives and uses thereof
EP3620163A1 (en) * 2014-05-01 2020-03-11 Eiger Biopharmaceuticals, Inc. Treatment of hepatitis delta virus infection
US20220023287A1 (en) * 2014-12-04 2022-01-27 Eiger Biopharmaceuticals, Inc. Treatment of hepatitis delta virus infection

Patent Citations (89)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5886157A (en) 1994-02-10 1999-03-23 Vanderbilt University Expression and purification of human cytochrome P450
WO1996035415A2 (en) 1995-05-09 1996-11-14 Zylepsis Limited Use of sesquiterpenes for inhibiting oxidative enzymes
WO1997019112A1 (en) 1995-11-17 1997-05-29 United States Of America, Represented By The Secretary, Department Of Health And Human Services Inhibitory and non-inhibitory antigen binding polypeptides against human p450 enzymes
US6673778B1 (en) 1996-02-23 2004-01-06 The Board Of Regents Of The University Of Nebraska Enzyme inhibitors for metabolic redirection
US6124477A (en) 1996-06-27 2000-09-26 Bioavailability Systems, Llc Anti-first-pass effect compounds
US5820915A (en) 1996-06-27 1998-10-13 Bioavailability Systems, L.L.C. Method for the preparation of a first-pass effective citrus-derived substance and product thereof
WO1998017667A1 (en) 1996-10-18 1998-04-30 Wayne State University 6',7'-dihydroxybergamottin, a cytochrome p450 ihnibitor in grapefruit juice
JPH10204091A (en) 1996-11-22 1998-08-04 Yasushi Yamazoe Cytochrome P450 3A4 inhibitor
WO1998041648A2 (en) 1997-03-20 1998-09-24 Variagenics, Inc. Target genes for allele-specific drugs
WO1998044939A1 (en) 1997-04-10 1998-10-15 Merck & Co., Inc. Anti-peptide antibody against human cytochrome p450 3a4
WO1998053658A2 (en) 1997-05-30 1998-12-03 Bioavailability Systems, L.L.C. Anti-first-pass effect compounds and citrus extract
US5990154A (en) 1997-05-30 1999-11-23 Bioavailability Systems, L.L.C. Anti-first-pass effect compounds and citrus extract
US6255337B1 (en) 1997-05-30 2001-07-03 Bioavailability Systems, L.L.C. Anti-first-pass effect compounds and citrus extract
WO1999005299A1 (en) 1997-07-24 1999-02-04 Trustees Of Boston University Methods of using cytochrome p450 reductase for the enhancement of p450-based anti-cancer gene therapy
WO1999008676A1 (en) 1997-08-19 1999-02-25 Warner-Lambert Company Compositions containing bergamottin for increasing the oral bioavailability of pharmaceutical agents
WO1999009976A1 (en) 1997-08-26 1999-03-04 Bioavailability Systems, L.L.C. Anti-first-pass effect compounds
US6054477A (en) 1997-08-26 2000-04-25 Bioavailability Systems, Llc Anti-first-pass effect compounds
US6063809A (en) 1997-08-26 2000-05-16 Bioavailability Systems, Llc Anti-first-pass effect compounds
US6309687B1 (en) 1997-08-26 2001-10-30 Bioavailability Sys Llc Anti-first-pass effect compounds
US6476066B1 (en) 1997-08-26 2002-11-05 Bioavailability Systems, L.L.C. Anti-first-pass effect compounds
US6248776B1 (en) 1997-08-26 2001-06-19 Bioavailability Systems, L.L.C. Anti-first-pass effect compounds
US6660766B2 (en) 1997-08-26 2003-12-09 Bioavailability Systems, Llc Anti-first-pass effect compounds
US6162479A (en) 1997-08-26 2000-12-19 Bioavailability Systems, Llc Anti-first-pass effect compounds
US6200754B1 (en) 1998-03-19 2001-03-13 Variagenics, Inc. Inhibitors of alternative alleles of genes encoding products that mediate cell response to environmental changes
WO1999048915A1 (en) 1998-03-27 1999-09-30 Glaxo Group Limited Orphan nuclear receptor
US5993887A (en) 1998-06-29 1999-11-30 Bioavailability Systems, L.L.C. Safe citrus juice and process for preparation
US20030096251A1 (en) 1998-08-31 2003-05-22 Marco Guida Methods for evaluating the ability to metabolize pharmaceuticals and compositions therefor
WO2000017366A2 (en) 1998-09-21 2000-03-30 Transgene S.A. Pharmaceutical composition for the pre-treatment of a patient in need of drug or pro-drug
WO2000034506A2 (en) 1998-12-04 2000-06-15 University Of North Carolina At Chapel Hill Method of screening candidate compounds for susceptibility to oxidative metabolism
US6514687B1 (en) 1998-12-14 2003-02-04 Vertex Pharmaceuticals (San Diego), Llc Optical molecular sensors for cytochrome P450 activity
WO2000044933A1 (en) 1999-01-29 2000-08-03 Smithkline Beecham P.L.C. Resorufin derivatives as substrates for cyp3a4
WO2000045817A1 (en) 1999-02-06 2000-08-10 Astrazeneca Ab Drug combinations comprising (e) -7 - [4 -(4 -fluorophenyl) -6 - isopropyl -2 - [methyl (methylsulfonyl) amino] pyrimidin -5 -yl] (3r,5s) -3,5 - dihydroxyhept -6 - enoic acid and an inhibitor, inducer or substrate of p450 isoenzyme 3a4
US20040058982A1 (en) 1999-02-17 2004-03-25 Bioavailability System, Llc Pharmaceutical compositions
WO2000054768A1 (en) 1999-02-17 2000-09-21 Bioavailability Systems, L.L.C. Anti-first-pass effect compounds
WO2001011035A1 (en) 1999-08-05 2001-02-15 Merck & Co., Inc. Monoclonal antibodies for human cytochrome p450 3a4 and human cytochrome p450 2c9
WO2001058455A1 (en) 2000-02-11 2001-08-16 Pharmacia Italia S.P.A. Method to potentiate the therapeutic efficacy of taxane and derivatives thereof
US20010041706A1 (en) 2000-03-24 2001-11-15 Synold Timothy W. Blockade of taxane metabolism
US20020061836A1 (en) 2000-03-24 2002-05-23 Barry Forman Methods for altering SXR activation using peptide mimetic HIV protease inhibitor SXR ligands
WO2001073113A2 (en) 2000-03-29 2001-10-04 Aclara Biosciences, Inc. Monooxygenase assays
US20020016681A1 (en) 2000-03-31 2002-02-07 Sean Ekins Single point interaction screen to predict IC50
EP1158045A1 (en) 2000-05-17 2001-11-28 Universite Catholique De Louvain Culture conditions allowing to modulate the expression of CYP3A4 in CaCo2 cells
WO2002004660A2 (en) 2000-07-12 2002-01-17 Wyeth Method for testing for inhibition of drug-metabolizing cytochrome p450 isozymes
US20030150004A1 (en) 2000-09-21 2003-08-07 Moore David D. Screening systems and methods for identifying modulators of xenobiotic metabolism
WO2004037827A1 (en) 2000-10-20 2004-05-06 Bioavailability Systems, Llc Synthesis of spiro ortho esters, spiro ortho carbonates, and intermediates
WO2002045704A2 (en) 2000-12-04 2002-06-13 Molecular Skincare Limited Prevention and treatment of tachyphylactic response
US20040243319A1 (en) 2001-04-02 2004-12-02 Astex Technology Ltd. Crystal structure of cytochrome P450
WO2002094865A1 (en) 2001-05-24 2002-11-28 Smithkline Beecham Corporation Nonhuman pregnane x receptor sequences for use in comparative pharmacology
WO2003026573A2 (en) 2001-09-24 2003-04-03 Merck & Co., Inc. Screening and selection methods for statin drug combinations
WO2003035074A1 (en) 2001-10-23 2003-05-01 Ono Pharmaceutical Co., Ltd. Drugs comprising combination of triazaspiro[5,5]undecane derivative with cytochrome p450 isozyme 3a4 inhibitor and/or p-glycoprotein inhibitor
US20040214848A1 (en) 2001-10-30 2004-10-28 Schoenhard Grant L. Inhibitors of ABC drug transporters in microbial cells
WO2003040121A1 (en) 2001-11-08 2003-05-15 Sepracor, Inc. Methods for treating depression and other cns disorders using enantiomerically enriched desmethyl- and didesmethyl-metabolites of citalopram
WO2003042898A2 (en) 2001-11-13 2003-05-22 Arqule, Inc. Compound prioritization for drug discovery
WO2003046559A2 (en) 2001-11-28 2003-06-05 Xanthus Life Sciences, Inc. Individualization of therapy with antiviral agents
WO2003046583A2 (en) 2001-11-28 2003-06-05 Xanthus Life Sciences Inc. Individualization of therapy with anesthetics
WO2003047594A1 (en) 2001-11-29 2003-06-12 Molecular Skincare Limited Disease treatment using two related compounds wherein at least one of the compound induces a tachyphylactic response which not affect the other compound
WO2003052123A1 (en) 2001-12-19 2003-06-26 Xanthus Life Sciences, Inc. Individualization of therapy with antihistamines
WO2003089656A1 (en) 2002-04-19 2003-10-30 Amersham Health As Methods and compound mixtures for determining protein activity using nmr spectroscopy
WO2003089657A1 (en) 2002-04-19 2003-10-30 Amersham Health As Method for phenotyping using nmr spectroscopy
US20040084867A1 (en) 2002-06-28 2004-05-06 Xanthus Life Sciences, Inc. Individualization of therapy with anticoagulants
US20040106216A1 (en) 2002-07-02 2004-06-03 Toyo Boseki Kabushiki Kaisha Method of measuring drug-metabolizing enzyme activity, method of evaluating inhibition of drug-metabolizing enzyme activity, and composition for these methods
WO2004021972A2 (en) 2002-09-03 2004-03-18 Biovail Laboratories, Inc. Pharmaceuticals formulations and methods for modified release of statin drugs
US20040047920A1 (en) 2002-09-06 2004-03-11 Novemed Group Limited Inhibition of CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 in cryopreserved human hepatocytes by a Tripterygium Wilfordii Hook.F. extract
US20040052865A1 (en) 2002-09-13 2004-03-18 Gower Laurie B. Materials and methods for drug delivery and uptake
US20060099667A1 (en) 2002-10-28 2006-05-11 Francois Andre Method for performing restrained dynamics docking of one or multiple substrates on multi-specific enzymes
US20040101477A1 (en) 2002-11-27 2004-05-27 Xanthus Life Sciences, Inc. Individualization of therapy with anesthetics
WO2004060370A1 (en) 2002-12-16 2004-07-22 Boehringer Ingelheim Pharmaceuticals, Inc. Treatment of hiv infection through combined administration of tipranavir and capravirine
US20040254156A1 (en) 2003-06-10 2004-12-16 Bertrand Le Bourdonnec Sulfonylamino phenylacetamide derivatives and methods of their use
WO2005007631A1 (en) 2003-07-10 2005-01-27 Osi Pharmaceuticals, Inc. Naphthylene derivatives as cytochrome p450 inhibitors
US20050031713A1 (en) 2003-08-06 2005-02-10 Elliot Ehrich Methods for administering active agents to CYP3A4 sensitive patients
WO2005020962A1 (en) 2003-08-29 2005-03-10 Novagali Pharma Sa Self-nanoemulsifying oily formulation for the administration of poorly water-soluble drugs
WO2005034963A1 (en) 2003-10-15 2005-04-21 Panagin Pharmaceuticals Inc. USE OF GINSENOSIDES Rh2 & Rg3, AND AGLYCON GINSENOSIDES FOR THE PREVENTION OF CANCER
WO2005042020A2 (en) 2003-10-27 2005-05-12 Vertex Pharmaceuticals Incorporated Combinations for hcv treatment
WO2005068611A1 (en) 2004-01-19 2005-07-28 Advanced In Vitro Cell Technologies, S.L. Method for obtaining a singular cell model capable of reproducing in vitro the metabolic idiosyncrasy of humans
US20050171037A1 (en) 2004-01-30 2005-08-04 Agouron Pharmaceuticals, Inc. Therapeutic combinations
US20050222270A1 (en) 2004-02-26 2005-10-06 Olney John W Prolonged administration of NMDA antagonist drug and safener drug to create improved stable neural homeostasis
WO2005098025A2 (en) 2004-04-05 2005-10-20 The University Of North Carolina At Chapel Hill High throughput reactive oxygen species-based cytochrome p450 inhibition assay
US20050272045A1 (en) 2004-06-04 2005-12-08 Rolf Joseph Craven Hpr6 mutants and uses thereof
US20060009645A1 (en) 2004-07-12 2006-01-12 Vanessa Smith Naphthylene derivatives as cytochrome P450 inhibitors
WO2006021456A1 (en) 2004-08-27 2006-03-02 Novartis Ag Combination comprising a staurosporine and a cyp3a4 inhibitor
WO2006024414A2 (en) 2004-08-28 2006-03-09 Boehringer Ingelheim International Gmbh Method for producing a ginger fraction and the use thereof for inhibiting human cyp enzymes
US20060073099A1 (en) 2004-10-01 2006-04-06 Frincke James M Treatment screening methods
WO2006037993A2 (en) 2004-10-02 2006-04-13 Auvation Limited Cancer markers
WO2006037617A1 (en) 2004-10-07 2006-04-13 Istituto Di Ricerche Di Biologia Molecolare P Angeletti Spa Assay for cytochrome p450 isoforms 3a4 and 3a5
JP2006111597A (en) 2004-10-18 2006-04-27 Kanazawa Univ Drug-metabolizing enzyme inhibitor derived from strawberry and method for producing the same
WO2006054755A1 (en) 2004-11-16 2006-05-26 Hiroshima Industrial Promotion Organization Method of screening candidate for drug
WO2006061714A2 (en) 2004-12-09 2006-06-15 Pfizer Inc. Anticoronaviral compounds and compositions, their pharmaceutical uses and materials for their synthesis
US20110129549A1 (en) 2008-04-17 2011-06-02 Liu Julie F Tricyclic benzo[5,6]cyclohepta[1,2-b]pyridine derivatives and uses thereof
EP3620163A1 (en) * 2014-05-01 2020-03-11 Eiger Biopharmaceuticals, Inc. Treatment of hepatitis delta virus infection
US20220023287A1 (en) * 2014-12-04 2022-01-27 Eiger Biopharmaceuticals, Inc. Treatment of hepatitis delta virus infection

Non-Patent Citations (20)

* Cited by examiner, † Cited by third party
Title
ABBASAFZAL, WORLD J. HEP., vol. 5, 2013, pages 666 - 675
CIANCIORIZZETTO, NAT. REV., vol. 11, 2014, pages 68 - 71
DETERDING ET AL., AIDS REV., vol. 21, 2019, pages 126 - 134
FERENCI PETER ET AL: "Treatment of Chronic Hepatitis D with Bulevirtide-A Fight against Two Foes-An Update", CELLS, vol. 11, no. 22, 8 November 2022 (2022-11-08), pages 3531, XP093082679, DOI: 10.3390/cells11223531 *
FUKUDA ET AL.: "Specific CYP3A4 inhibitors in grapefruit juice: furocoumarin dimers as components of drug interaction", PHARMACOGENETICS, vol. 7, no. 5, 1997, pages 391 - 396
GILMAN ET AL., WORLD J GASTROENTEROL., vol. 25, 2019, pages 4580 - 4597
GLENN J ET AL., SCIENCE, vol. 256, no. 5061, 29 May 1992 (1992-05-29), pages 1331 - 3
LE GAL ET AL., EMERG. INFECT. DIS., vol. 12, 2006, pages 1447 - 1450
LIN TPAN KMORDENTI JPAN L.: "In vitro assessment of cytochrome P450 inhibition: strategies for increasing LCIMS-based assay throughput using a one-point IC(50) method and multiplexing high-performance liquid chromatography", J PHARM SCI., vol. 96, no. 9, September 2007 (2007-09-01), pages 2485 - 93
LUCIFORA JULIE ET AL: "Inhibiting cell-to-cell transmission to reach HDV cure: The importance of IFN-[alpha]", JOURNAL OF HEPATOLOGY, ELSEVIER, AMSTERDAM, NL, vol. 77, no. 4, 8 August 2022 (2022-08-08), pages 903 - 905, XP087180475, ISSN: 0168-8278, [retrieved on 20220808], DOI: 10.1016/J.JHEP.2022.07.015 *
MATSUDA ET AL.: "Taurine modulates induction of cytochrome P450 3A4 mRNA by rifampicin in the HepG2 cell line", BIOCHIM BIOPHYS ACTA, vol. 1593, no. 1, 2002, pages 98 - 98, XP004392669, DOI: 10.1016/S0167-4889(02)00345-2
MENTHA N ET AL., J. ADV. RES., vol. 17, 2019, pages 3 - 17
MENTHA N, D. J. ADV. RES., vol. 17, 2019, pages 3 - 17, Retrieved from the Internet <URL:Clnts.google.com/patAlfaiate>
TASSANEEYAKUL ET AL.: "Inhibition selectively of grapefruit juice components on human cytochromes P450", ARCH BIOCHEM BIOPHYS, vol. 378, no. 2, 2000, pages 356 - 363
WIDMERHAUN: "Variation in furanocoumarin content and new furanocoumarin dimmers in commercial grapefruit (Citrus paradise Macf.) juices", JOURNAL OF FOOD SCIENCE, vol. 70, no. 4, 2005, pages C307 - C312
YE XIN ET AL: "Hepatitis B Virus Therapeutic Agent ARB-1740 Has Inhibitory Effect on Hepatitis Delta Virus in a New Dually-Infected Humanized Mouse Model", vol. 5, no. 5, 10 May 2019 (2019-05-10), US, pages 738 - 749, XP055862206, ISSN: 2373-8227, Retrieved from the Internet <URL:https://pubs.acs.org/doi/pdf/10.1021/acsinfecdis.8b00192> DOI: 10.1021/acsinfecdis.8b00192 *
YEXET, ACS INFECT. DIS., vol. 5, no. 7, 2019, pages 738 - 5
YURDAYDIN CIHAN ET AL: "A phase 2 dose-finding study of lonafarnib and ritonavir with or without interferon alpha for chronic delta hepatitis", vol. 75, no. 6, 23 December 2021 (2021-12-23), US, pages 1551 - 1565, XP093082593, ISSN: 0270-9139, Retrieved from the Internet <URL:https://onlinelibrary.wiley.com/doi/full-xml/10.1002/hep.32259> DOI: 10.1002/hep.32259 *
YURDAYDIN, CIHAN ET AL.: "A phase 2 dose -finding study of lonafarnib and ritonavir with or without interferon alpha for chronic delta hepatitis", HEPATOLOGY, vol. 75, no. 6, 2022, pages 1551 - 1565
ZHIMIN GUO ET AL: "Therapeutic Strategies and New Intervention Points in Chronic Hepatitis Delta Virus Infection", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 16, no. 8, 18 August 2015 (2015-08-18), pages 19537 - 19552, XP055245823, DOI: 10.3390/ijms160819537 *

Similar Documents

Publication Publication Date Title
Koh et al. HBV/HDV Coinfection: Emerging therapeutic options for a challenging disease
Au et al. Novel therapeutic approaches for hepatitis C
Cordek et al. Targeting the NS5A protein of HCV: an emerging option
Gentile et al. Daclatasvir: the first of a new class of drugs targeted against hepatitis C virus NS5A
WO2006050250A2 (en) Dose forms comprising vx-950 and their dosage regimen
DK2694087T3 (en) The treatment of infection with Hepatitis B virus alone or in combination with hepatitis delta virus, and in connection with liver diseases
Gentile et al. ABT-450: a novel protease inhibitor for the treatment of hepatitis C virus infection
JP2024156840A (en) Treatment of hepatitis delta virus infection with interferon lambda.
KR20110116136A (en) Cyclosporine Derivatives for Use in the Treatment of HCV and HIV Infections
US20130109647A1 (en) Methods and compositions for treating hepatitis c virus
Schinazi et al. From HCV to HBV cure
JP2023509869A (en) Methods of treating viral infections with TLR7 agonists
Jorns et al. Rapid and simple detection of IFN‐neutralizing antibodies in chronic hepatitis C non‐responsive to IFN‐α
CA2853495A1 (en) Methods and compositions for treating hepatitis c virus
Sakamoto et al. New therapeutic approaches to hepatitis C virus
Cholongitas et al. Novel therapeutic options for chronic hepatitis C
Bhopale et al. Emerging drugs for chronic hepatitis C
Nagra et al. Therapeutic Advances in Viral Hepatitis A–E
WO2024223797A1 (en) Use of cyp3a4 inhibitors for the treatment of hepatitis d virus (hdv) infections
Martin et al. New therapies and management options for hepatitis D
Quer et al. New strategies for the treatment of hepatitis C virus infection and implications of resistance to new direct-acting antiviral agents
Pintelon New therapies for the treatment of hepatitis D virus infection
Tuychiyev et al. A Modern View of The Pathogenesis and Treatment of HDV Infection
Grebely et al. Interferon Alpha
Caviglia et al. The definitive version is available at

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24722237

Country of ref document: EP

Kind code of ref document: A1