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WO2025133697A2 - Polythérapie pour l'inhibition de virus ebola - Google Patents

Polythérapie pour l'inhibition de virus ebola Download PDF

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Publication number
WO2025133697A2
WO2025133697A2 PCT/IB2024/000726 IB2024000726W WO2025133697A2 WO 2025133697 A2 WO2025133697 A2 WO 2025133697A2 IB 2024000726 W IB2024000726 W IB 2024000726W WO 2025133697 A2 WO2025133697 A2 WO 2025133697A2
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effective amount
pharmaceutically acceptable
acceptable salt
triisopropylphenylsulfonyl
phenylalanine
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WO2025133697A3 (fr
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Reza Fathi
Dror BEN-ASHER
Guy GOLDBERG
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Redhill Biopharma Ltd
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Redhill Biopharma Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof

Definitions

  • Ebola disease is a rare and often deadly illness, caused by infection by one of a group of four viruses, known as ebolaviruses, that are found primarily in sub-Saharan Africa and are known as: Zaire, Sudan, Tai Forest (formerly Cote d’Irium) and Bundibugyo.
  • Combination therapies for the inhibition of single-stranded RNA virus replication, such as ebolaviruses are disclosed herein.
  • the combination therapy comprises Opaganib and Remdesivir.
  • the combination therapy comprises Upamostat and Remdesivir.
  • the combination therapy comprises Opaganib and Upamostat.
  • Compositions and methods for treating symptomatic and/or asymptomatic infections of ebolaviruses are disclosed herein.
  • aspects of the disclosure relate to a method of treating a human infected with or exposed to an Ebolavirus, the method comprising administering to the human, for a suitable period of time, an effective amount of 3 -(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4- ylmethyl)amide or a pharmaceutically acceptable salt thereof, and an effective amount of remdesivir.
  • the effective amount of 3-(4-chlorophenyl)-adamantane-1- carboxylic acid (pyridin-4- ylmethyl)amide or a pharmaceutically acceptable salt thereof is administered orally.
  • the effective amount of 3-(4-chlorophenyl)- adamantane-1- carboxylic acid (pyridin-4-ylmethyl)amide or a pharmaceutically acceptable salt thereof ranges from about 9.5 mg/kg to about 15.5 mg/kg daily. In some embodiments, the effective amount of3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide or a pharmaceutically acceptable salt thereof ranges from about 10.5 mg/kg to about 14.5 mg/kg daily.
  • the effective amount of 3-(4-chlorophenyl)-adamantane- 1 - carboxylic acid (pyridin-4-ylmethyl)amide or a pharmaceutically acceptable salt thereof ranges from about 11.5 mg/kg to about 13.5 mg/kg daily. In some embodiments, the effective amount of
  • 3-(4-chlorophenyl)-adamantane-1- carboxylic acid (pyridin-4-ylmethyl)amide or a pharmaceutically acceptable salt thereof ranges from about 15.0 mg/kg to about 20.0 mg/kg daily.
  • the method comprises administering orally a solid dosage form comprising the effective amount of the 3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4- ylmethyl)amide or a pharmaceutically acceptable salt thereof.
  • remdesivir is administered intravenously.
  • the human weighs more than 40 kg and the effective amount of remdesivir ranges from 50 mg to 250 mg daily.
  • the effective amount of remdesivir ranges from 150 to 250 mg daily on day 1, and 50 mg to 150 mg daily on following days.
  • the method comprises administering intravenously remdesivir over a period of 5 to 10 days.
  • the human weighs from 3.5 kg to less than 40 kg and the effective amount of remdesivir ranges from 2.5 mg/kg to 5 mg/kg daily.
  • the effective amount of remdesivir ranges is 5 mg/kg daily on day 1, and 2.5 mg/kg daily on following days.
  • the method comprises administering intravenously remdesivir over a period of 5 to 10 days.
  • the method further comprise confirming if the human is infected with an Ebola virus prior to the administering.
  • the confirming is performed via a test that detects viral antigens or RNA in a sample of blood. In some embodiments, the confirming is performed via a test that detects viral antigens or RNA in a sample of bodily fluids other than blood.
  • aspects of the disclosure relate to a method of treating a human infected with or exposed to an Ebola virus, the method comprising administering to the human, for a suitable period of time, an effective amount of N- ⁇ (2,4,6-triisopropylphenylsulfonyl)-3-amidino-phenylalanine-
  • the pharmaceutically acceptable salt of N- ⁇ (2,4,6-triisopropylphenylsulfonyl)-3-amidino- phenylalanine-4-ethoxy-carbonylpiperazide-hydrochloride, N- ⁇ -(2,4,6- triisopropylphenylsulfonyl)-3-hydroxyamidino-phenylalanine-4-ethoxycarbonylpiperazide is a hydrogen sulfate salt.
  • the effective amount of N- ⁇ (2,4,6- triisopropylphenylsulfonyl)-3-amidino-phenylalanine-4-ethoxy-carbonylpiperazide- hydrochloride, N- ⁇ -(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-phenylalanine-4- ethoxycarbonylpiperazide, free base or a pharmaceutically acceptable salt thereof ranges from 200 mg to about 400 mg.
  • the effective amount of N- ⁇ (2,4,6- triisopropylphenylsulfonyl)-3-amidino-phenylalanine-4-ethoxy-carbonylpiperazide- hydrochloride, N- ⁇ -(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-phenylalanine-4- ethoxycarbonylpiperazide, free base or a pharmaceutically acceptable salt thereof is about 231 mg.
  • the effective amount of N- ⁇ (2,4,6-triisopropylphenylsulfonyl)-3-amidino- phenylalanine-4-ethoxy-carbonylpiperazide-hydrochloride, N- ⁇ -(2,4,6- triisopropylphenylsulfonyl)-3-hydroxyamidino-phenylalanine-4-ethoxycarbonylpiperazide, free base or a pharmaceutically acceptable salt thereof ranges from 50 mg to about 200 mg.
  • remdesivir is administered intravenously.
  • the human weighs more than 40 kg and the effective amount of remdesivir ranges from 50 mg to 250 mg daily. In some embodiments, the effective amount of remdesivir ranges from 150 to 250 mg daily on day 1, and 50 mg to 150 mg daily on following days.
  • the method comprises administering intravenously remdesivir over a period of 5 to 10 days. In some embodiments, the human weighs from 3.5 kg to less than 40 kg and the effective amount of remdesivir ranges from 2.5 mg/kg to 5 mg/kg daily.
  • the effective amount of remdesivir ranges is 5 mg/kg daily on day 1, and 2.5 mg/kg daily on following days.
  • the method comprises administering intravenously remdesivir over a period of 5 to 10 days.
  • the method further comprises confirming if the human is infected with an Ebola virus prior to the administering.
  • the confirming is performed via a test that detects viral antigens or RNA in a sample of blood.
  • the confirming is performed via a test that detects viral antigens or RNA in a sample of bodily fluids other than blood.
  • aspects of the disclosure relate to a method of treating a human infected with or exposed to an Ebola virus, the method comprising administering to the human, for a suitable period of time, an effective amount of 3 -(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4- ylmethyl)amide or a pharmaceutically acceptable salt thereof, and an effective amount of N- ⁇ (2,4,6-triisopropylphenylsulfonyl)-3-amidino-phenylalanine-4-ethoxy-carbonylpiperazide- hydrochloride, N- ⁇ -(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-phenylalanine-4- ethoxycarbonylpiperazide, free base or a pharmaceutically acceptable salt thereof.
  • the effective amount of 3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin- 4- ylmethyl)amide or a pharmaceutically acceptable salt thereof is administered orally.
  • the effective amount of 3-(4-chlorophenyl)- adamantane- 1-carboxylic acid (pyridin-4-ylmethyl)amide or a pharmaceutically acceptable salt thereof ranges from about 9.5 mg/kg to about 15.5 mg/kg daily.
  • the effective amount of 3-(4- chlorophenyl)-adamantane-1- carboxylic acid (pyridin-4-ylmethyl)amide or a pharmaceutically acceptable salt thereof ranges from about 10.5 mg/kg to about 14.5 mg/kg daily. In some embodiments, the effective amount of 3-(4-chlorophenyl)-adamantane- 1-carboxylic acid (pyridin-4-ylmethyl)amide or a pharmaceutically acceptable salt thereof ranges from about 11.5 mg/kg to about 13.5 mg/kg daily.
  • the effective amount of 3-(4- chlorophenyl)-adamantane-1- carboxylic acid (pyridin-4-ylmethyl)amide or a pharmaceutically acceptable salt thereof ranges from about 15.0 mg/kg to about 20.0 mg/kg daily.
  • the method comprises administering orally a solid dosage form comprising the effective amount of the 3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4- ylmethyl)amide or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt of N- ⁇ (2,4,6-triisopropylphenylsulfonyl)-3-amidino- phenylalanine-4-ethoxy-carbonylpiperazide-hydrochloride, N- ⁇ -(2,4,6- triisopropylphenylsulfonyl)-3-hydroxyamidino-phenylalanine-4-ethoxycarbonylpiperazide is a hydrogen sulfate salt.
  • the effective amount of N- ⁇ (2,4,6- triisopropylphenylsulfonyl)-3-amidino-phenylalanine-4-ethoxy-carbonylpiperazide- hydrochloride, N- ⁇ -(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-phenylalanine-4- ethoxy carbonylpiperazide, free base or a pharmaceutically acceptable salt thereof ranges from 200 mg to about 400 mg.
  • the effective amount of N- ⁇ (2,4,6- triisopropylphenylsulfonyl)-3-amidino-phenylalanine-4-ethoxy-carbonylpiperazide- hydrochloride, N- ⁇ -(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-phenylalanine-4- ethoxy carbonylpiperazide, free base or a pharmaceutically acceptable salt thereof is about 231 mg.
  • the effective amount of N- ⁇ (2,4,6-triisopropylphenylsulfonyl)-3-amidino- phenylalanine-4-ethoxy-carbonylpiperazi de-hydrochloride, N- ⁇ -(2,4,6- triisopropylphenylsulfonyl)-3-hydroxyamidino-phenylalanine-4-ethoxycarbonylpiperazide, free base or a pharmaceutically acceptable salt thereof ranges from 50 mg to about 200 mg.
  • the method further comprises confirming if the human is infected with an Ebola virus prior to the administering. In some embodiments, the confirming is performed via a test that detects viral antigens or RNA in a sample of blood. In some embodiments,
  • the confirming is performed via a test that detects viral antigens or RNA in a sample of bodily fluids other than blood.
  • aspects of the disclosure relates to an active ingredient combination for treating Ebola virus infection comprising an effective amount of 3 -(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4- ylmethyl)amide or a pharmaceutically acceptable salt thereof, and an effective amount of remdesivir.
  • the combination is used to inhibit Ebola virus in a patient.
  • an active ingredient combination for treating Ebola virus infection comprising: an effective amount of N- ⁇ (2,4,6-triisopropylphenylsulfonyl)-3- amidino-phenylalanine-4-ethoxy-carbonylpiperazide-hydrochloride, N- ⁇ -(2,4,6- triisopropylphenylsulfonyl)-3-hydroxyamidino-phenylalanine-4-ethoxycarbonylpiperazide, free base or a pharmaceutically acceptable salt thereof, and an effective amount of remdesivir.
  • the pharmaceutically acceptable salt of N- ⁇ -(2,4,6-triisopropylphenylsulfonyl)-3- hydroxyamidino-phenylalanine-4-ethoxycarbonylpiperazide is a hydrogen sulfate salt.
  • the combination is used to inhibit Ebola virus in a patient.
  • an active ingredient combination for treating Ebola virus infection comprising: an effective amount of 3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4- ylmethyl)amide or a pharmaceutically acceptable salt thereof, and an effective amount of N- ⁇ (2,4,6-triisopropylphenylsulfonyl)-3-amidino-phenylalanine-4-ethoxy- carbonylpiperazide-hydrochloride, N- ⁇ -(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino- phenylalanine-4-ethoxycarbonylpiperazide, free base or a pharmaceutically acceptable salt thereof.
  • the combination is used to inhibit Ebola virus in a patient.
  • FIG. 1 shows plate layout of the Opaganib and Remdesivir combination study set-up according to some embodiments.
  • FIG. 2 shows Opaganib and Remdesivir dose response curves and results according to some embodiments.
  • FIG. 3 shows in vitro efficacy Opaganib and Remdesivir combination studies (% inhibition, % cell loss and % inhibition not due to cell death) according to some embodiments.
  • FIG. 4 is a topology synergy map showing significant synergy peaks were observed for Opaganib and Remdesivir according to some embodiments.
  • FIG. 5 is a topology synergy map showing significant synergy peaks were observed for Opaganib and Remdesivir according to some embodiments.
  • FIG. 6 shows plate layout of the Upamostat and Remdesivir combination study set-up according to some embodiments.
  • FIG. 7 shows potency of individual drugs Upamostat and Remdesivir against EBOV.
  • FIG. 8 shows in vitro efficacy Upamostat and Remdesivir combination studies (% inhibition, % cell loss and % inhibition not due to cell death) according to some embodiments.
  • FIG. 9 is a topology synergy map showing significant synergy peaks were observed for Upamostat and Remdesivir according to some embodiments.
  • FIG. 10 is a topology synergy map showing significant synergy peaks were observed for Upamostat and Remdesivir according to some embodiments.
  • FIG. 11 shows dose response curves to determine the potency (EC 50 ), cytotoxicity (CC 50 ) and selectivity index (SI) values.
  • FIG. 12 is a topology synergy map showing significant synergy peaks were observed for Opaganib and Remdesivir for % infection inhibition. Topology shown is corrected Inhibition (Ic).
  • FIG. 13 shows Opaganib and Upamostat dose curve. Upamostat and Opaganib were tested at starting concentration of 60 ⁇ M. Dose response involved three-fold serial dilution, eight different concentrations and four technical replicates either alone or in combination. This combination study was performed in HeLa cells.
  • FIG. 14 is a topology synergy map showing significant synergy peaks were observed for Opaganib and Upamostat for % infection inhibition. Topology shown is corrected Inhibition (Ic).
  • FIG. 15 is a topology synergy map showing significant synergy peaks were observed for Opaganib and Upamostat for % corrected infection inhibition. Topology shown is corrected Inhibition (Ic) (not contributed due to cell loss).
  • FIG. 16 shows survival curves of mice infected with maEBOV and treated with different doses of Opaganib or drug diluent (vehicle).
  • Ebola disease is a rare and often deadly illness, caused by infection by one of a group of four viruses, known as ebolaviruses, that are found primarily in sub-Saharan Africa and are known as: Zaire, Sudan, Tai Forest (formerly Cote d’Irium) and Bundibugyo. Transmission of the disease is mostly through contact with an infected animal (bat or nonhuman primate), or a sick or dead person infected with an ebolavirus.
  • ebolaviruses viruses that are found primarily in sub-Saharan Africa and are known as: Zaire, Sudan, Tai Forest (formerly Cote d’Irium) and Bundibugyo. Transmission of the disease is mostly through contact with an infected animal (bat or nonhuman primate), or a sick or dead person infected with an ebolavirus.
  • the term “agent” refers to a compound having a pharmacological activity - an effect of the agent on an individual.
  • the terms “agent,” “compound,” and “drug” are used interchangeably herein .
  • a “patient” or an “individual” refers to any animal, such as a primate.
  • the primate is a non-human primate.
  • the primate is a human primate. Any animal can be treated using the methods and composition of the present disclosure.
  • agents of the present disclosure when administered together as part of a treatment regimen, provide a therapeutic synergy without accompanying synergistic side effects (e.g., but not limited to, cross-reacting agents).
  • the term “treat” is meant to administer one or more agents of the present disclosure to measurably inhibit the replication of a virus in vitro or in vivo, to measurably decrease the load of a virus in a cell in vitro or in vivo, or to reduce at least one symptom associated with having a filovirus-mediated disease in a patient.
  • the inhibition in replication or the decrease in viral load is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, as determined using a suitable assay.
  • Assays that monitor replication of viruses include, but are not limited to, cytopathic viral assays, reporter-virus and reporter-cell assays, viral replicon assays, and gene-targeted viral assays.
  • an assay that measures CD8 T cell-mediated inhibition of filovirus replication is used to measure the slow or stop in the replication of a virus.
  • Viral load testing can be carried out using nucleic acid amplification based tests (NATs or NAATs) and non-nucleic acid-based tests on blood plasma samples to determine the quantity of virus in a given volume including viral RNA levels in plasma and tissue and total viral DNA.
  • treatment is observed by a trained physician as an appreciable or substantial relief of symptoms in a patient with a filovirus-mediated disease.
  • a decrease in viral replication is accomplished by reducing the rate of RNA polymerization, RNA translation, protein processing or modification, or by reducing the activity of a molecule involved in any step of viral replication (e.g., proteins or coded by the genome of the virus or host important for viral replication).
  • the term “treat” refers to the ability of an agent or agents of the present disclosure to inhibit or suppress replication of a virus, such as an RNA virus.
  • the term “treat” refers to the ability of an agent or agents of the present disclosure to inhibit the cytopathic effect during a RNA virus infection.
  • an “effective amount” is meant the amount of an agent or agents of the present disclosure, alone or in combination with another therapeutic regimen, required to treat a patient with a viral disease (e.g., any virus described herein including an Ebola virus or Marburg virus) in a clinically relevant manner.
  • a viral disease e.g., any virus described herein including an Ebola virus or Marburg virus
  • a sufficient effective amount of an agent or agents used to practice the present disclosure for therapeutic treatment of conditions caused by a virus varies depending upon the manner of administration, the age, body weight, and general health of the patient. Ultimately, the prescribers will decide the appropriate amount and dosage regimen.
  • the effective amount of an agent may be less than the effective amount if the agent were administered in a non-combinatorial (single-agent) therapy. Additionally, an effective amount may be an amount of an agent in a combination therapy of the disclosure that is safe and efficacious in the treatment of a patient having a viral disease over each agent alone as determined and approved by a regulatory authority (such as the U.S. Food and Drug Administration).
  • a treatment exhibits greater efficacy, or is less toxic, safer, more convenient, or less expensive than another treatment with which it is being compared. Efficacy may be measured by a skilled practitioner using any standard method that is appropriate for a given indication.
  • filovirus is meant a virus belonging to the family Fillovirdae.
  • Exemplary filoviruses are Ebola virus and Marburg virus.
  • Ebola or “Ebola hemorrhagic fever” is a disease caused by infection with one of the Ebolavirus strains. Ebola can cause disease in humans and nonhuman primates (monkeys, gorillas, and chimpanzees). Ebola disease in humans is caused by four of five viruses in the genus Ebolavirus. The four are Bundibugyo virus (BDBV), Sudan virus (SUDV), Tai Forest virus (TAFV), and one called, simply, Ebola virus (EBOV, formerly Zaire Ebola virus). The fifth virus, Reston virus (RESTV), is not thought to cause disease in humans, but has caused disease in other primates. These five viruses are closely related to marburgviruses. Marburg virus disease (MVD) is a severe illness of humans and non-human primates caused by either of the two marburgviruses, Marburg virus and Ravn virus.
  • BDBV Bundibugyo virus
  • SUDV Sudan virus
  • TAFV Tai Forest virus
  • EBOV
  • a suitable period of time refers to the period of time starting when a patient begins treatment for a diagnosis of ssRNA viral infection (e.g., but not limited to, Ebola) using a method of the present disclosure, throughout the treatment, and up until when the patient stops treatment due to either a reduction in symptoms associated with ssRNA viral infection (e.g., but not limited to, Ebola) or due to a laboratory diagnosis indicating that the ssRNA viral infection (e.g., but not limited to, Ebola) is under control.
  • a suitable period of time is one (1) week.
  • a suitable period of time is between one (1) week and two (2) weeks.
  • a suitable period of time is two (2) weeks.
  • a suitable period of time is between two (2) weeks and three (3) weeks. In an embodiment, a suitable period of time is three (3) weeks. In an embodiment, a suitable period of time is between three (3) weeks and four (4) weeks. In an embodiment, a suitable period of time is four (4) weeks. In an embodiment, a suitable period of time is between four (4) weeks and five (5) weeks. In an embodiment, a suitable period of time is five (5) weeks. In an embodiment, a suitable period of time is between five (5) weeks and six (6) weeks. In an embodiment, a suitable period of time is six (6) weeks. In an embodiment, a suitable period of time is between six (6) weeks and seven (7) weeks. In an embodiment, a suitable period of time is seven (7) weeks. In an embodiment, a suitable period of time is between seven (7) weeks and eight (8) weeks. In an embodiment, a suitable period of time is eight (8) weeks.
  • cytopathic effects refers to the changes in cell morphology due to a viral infection.
  • cytopathogenesis includes inhibition of host cell gene expression and includes other cellular changes that contribute to viral pathogenesis in addition to those changes that are visible at the microscopic level.
  • in vitro refers to procedures performed in an artificial environment, such as for example, without limitation, in a test tube or cell culture system.
  • an isolate SK enzyme may be contacted with a modulator in an in vitro environment.
  • an isolated cell may be contacted with a modulator in an in vitro environment.
  • in vivo refers to procedures performed within a living organism such as, without limitation, a human, monkey, mouse, rat, rabbit, bovine, equine, porcine, canine, feline, or primate. Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, or 50.
  • the term “about” is understood as within a range of normal tolerance in the art, for example, within 2 standard deviations of the mean. “About” can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein are modified by the term “about”.
  • compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein.
  • ssDNA single-stranded DNA
  • ssDNA single-stranded DNA
  • These viruses have a simple genome: one gene for a viral nucleocapsid protein and another gene for a DNA replication enzyme.
  • the virus with a ssDNA genome also faces a serious replication problem in the host cell. When introduced into cells, these genomes cannot be used to make viral proteins because the only template for transcription is double-stranded DNA. For this reason, the first step after infection is the conversion of the viral ssDNA into dsDNA using host cell DNA polymerase. In some of these viruses, the 3' end of the viral DNA folds back and forms dsDNA by base-pairing with an internal sequence.
  • the primer is built into the genome and the 3' end can be extended to create dsDNA that serves as a template for transcription.
  • the resulting transcripts are translated to make the viral proteins, the replicated viral DNA is converted back into a ssDNA genome, and the virion is packaged for export.
  • RNA viruses can be classified according to the sense or polarity of their RNA into negative- sense (-) and positive-sense (+) RNA viruses.
  • the largest family of viruses is the single stranded negative-sense (-) RNA (“ssRNA”) family of viruses.
  • ssRNA single stranded negative-sense
  • Their viral RNA genome cannot be directly translated, instead the (-) strand is complementary to the viral mRNAs that need to be produced and translated into viral proteins.
  • ssRNA single stranded negative-sense RNA
  • o Family Arenaviridae includes Lassa virus
  • o Family Bunyaviridae includes Hantavirus, Crimean-Congo hemorrhagic fever
  • o Family Ophioviridae includes Influenza viruses
  • o Genus Deltavirus includes Hepatitis D virus o Genus Dichorhavirus o Genus Emaravirus o Genus Nyavirus — includes Nyamanini and Midway viruses o Genus Tenuivirus o Genus Varicosavirus
  • Positive-sense viral RNA is similar to mRNA and thus can be immediately translated by the host cell. Negative-sense viral RNA is complementary to mRNA and thus must be converted to positive-sense RNA by an RNA polymerase before translation. As such, purified RNA of a positive-sense virus can directly cause infection though it may be less infectious than the whole virus particle. Purified RNA of a negative- sense virus is not infectious by itself as it needs to be transcribed into positive-sense RNA; each virion can be transcribed to several positive-sense RNAs. Amtisense RNA viruses resemble negative-sense RNA viruses, except they also translate genes from the positive strand.
  • positive-strand RNA viruses include, but are not limited to, polio virus, Coxsackie virus, and echovirus.
  • negative- strand RNA viruses include, but are not limited to, influenza virus, measles viruses, and rabies virus.
  • the largest family of viruses is the (-) ssRNA family of viruses. Their viral RNA genome cannot be directly translated, instead the (-) strand is complementary to the viral mRNAs that need to be produced and translated into viral proteins. Nature has created hundreds of different (-) ssRNA viruses ranging from the measles and influenza viruses to the rabies and Ebola viruses. Members of this class of virus include Ebola virus and members of the influenza family of viruses.
  • Ebola previously known as Ebola hemorrhagic fever, is a disease caused by infection with one of the Ebola virus strains. Ebola can cause disease in humans and nonhuman primates (monkeys, gorillas, and chimpanzees). Ebola disease in humans is caused by four of five viruses in the genus Ebolavirus. The four are Bundibugyo virus (BDBV), Sudan virus (SUDV), Tai Forest virus (TAFV), and one called, simply, Ebola virus (EBOV, formerly Zaire Ebola virus). The fifth virus, Reston virus (RESTV), is not thought to cause disease in humans, but has caused disease in other primates. These five viruses are closely related to marburgviruses. Currently, no specific therapy is available that has demonstrated efficacy in the treatment of Ebola.
  • BDBV Bundibugyo virus
  • SUDV Sudan virus
  • TAFV Tai Forest virus
  • EBOV formerly Zaire Ebola virus
  • RESTV Reston virus
  • Ebolaviruses contain single-strand, non-infectious RNA genomes. Ebolavirus genomes are approximately 19 kilobase pairs long and contain seven genes in the order 3'-UTR-NP-VP35- VP40-GP-VP 30-VP24-L-5' -UTR. The genomes of the five different ebolaviruses (BDBV, EBOV, RESTV, SUDV, and TAFV) differ in sequence and the number and location of gene overlaps. In general, ebolavirions are 80 nanometers (nm) in width and may be as long as 14,000 nm.
  • the median particle length of ebolaviruses ranges from 974 to 1,086 nm (in contrast to marburgvirions, whose median particle length was measured at 795-828 nm), but particles as long as 14,000 nm have been detected in tissue culture.
  • the viral matrix protein 40 (VP40) is the most abundant protein found in the virions, in infected cells, and also inside the viral nucleocapsid.
  • the nucleoprotein (NP) is associated with the viral genome and assembled into a helical nucleocapside (NC) along with polymerase cofactor (VP35), the transcription activator (VP30), and the RNA-dependent RNA polymerase (L).
  • the viral proteins that comprise the NC catalyze the replication and transcription of the viral genome.
  • a minor viral matrix protein, VP24 is also required for NC assembly. If NP is expressed alone in cells, it assembles together with cellular RNA to form a loose coil-like structure.
  • NP When NP is co- expressed with VP24 and VP35, NC-like structures are formed in the cytoplasm that are morphologically indistinguishable from those seen in infected cells. It has been shown that VP24 and the viral matrix protein VP40 reduce the transcription and replication efficiencies of the EBOV genome, suggesting that VP24 and VP40 are important for the conversion from a transcription and replication-competent NC to one that is ready for viral assembly. VP40 plays a role in the formation and release of the enveloped, filamentous virus-like particles (VLPs) even when expressed alone.
  • VLPs enveloped, filamentous virus-like particles
  • NC-like structures are incorporated into VLPs when VP40 is co-expressed with NP, VP35, and VP24, suggesting that a direct interaction between VP40 and NP is important for the recruitment of NC-like structures to the budding site, the plasma membrane.
  • the interaction between VP40 and NP is also required for the formation of condensed NC-like structures.
  • GP is a surface glycoprotein that forms spikes on virions and plays a crucial role in virus entry into cells by mediating receptor binding and fusion.
  • the ebolavirus life cycle begins with virion attachment to specific cell-surface receptors, followed by fusion of the virion envelope with cellular membranes and the concomitant release of the virus nucleocapsid into the cytosol.
  • Ebolavirus' structural glycoprotein (known as GP1,2) is responsible for the virus' ability to bind to and infect targeted cells.
  • the viral RNA polymerase encoded by the L gene, partially uncoats the nucleocapsid and transcribes the genes into positive- strand mRNAs, which are then translated into structural and nonstructural proteins.
  • the most abundant protein produced is the nucleoprotein, whose concentration in the cell determines when L switches from gene transcription to genome replication.
  • Replication results in full-length, positive-strand antigenomes that are, in turn, transcribed into negative-strand virus progeny genome copy.
  • Newly synthesized structural proteins and genomes self-assemble and accumulate near the inside of the cell membrane. Virions bud off from the cell, gaining their envelopes from the cellular membrane they bud from. The mature progeny particles then infect other cells to repeat the cycle.
  • the Ebola virus genetics are difficult to study due to its virulent nature.
  • Ebola is a filamentous, enveloped, negative-sense RNA strand virus in the family of Filoviridae.
  • the RNA-dependent RNA-polymerase of Ebola virus shares significant sequence homology to other negative-strand RNA viruses, required for both viral transcription and replication of the viral genome.
  • RNA-dependent RNA-polymerase requires a host factor and viral proteins cooperating to accomplish replication and transcription.
  • One of the reasons why Ebola is so deadly is due to its ability to circumvent the immune system while at the same time pro-actively destroying the human body, as a result the immune system is not able to gather a cohesive effort to fight off the disease.
  • monocytes/macrophages in the lymphoid tissues are early and sustained targets of this deadly virus.
  • large amounts of proinflammatory cytokines such as tumor necrosis factor (TNF- ⁇ ) are secreted from infected macrophages and cause disruption of the endothelial barrier.
  • Macrophages and Dendritic cells play a central role in inducing the observed clinical feature of Ebola’s hemorrhagic fever.
  • Secreted cytokines, chemokines, and other mediators alter the blood vessel functions, promote and recruit an influx of inflammatory cells, including additional monocytes/macrophages to the site of the infection.
  • NK Natural Killer
  • CD4+ and CD8+ lymphocytes are the principal cell types affected in Ebola-infected macaques monkeys.
  • An Ebola subject who shows symptoms including, but not limited to, high fever, headache, joint and muscle aches, sore throat, weakness, stomach pain, lethargy, and lack of appetite, can undergo blood and/or tissue tests to confirm an Ebola diagnosis.
  • An Ebola subject who does not show symptoms i.e., is asymptomatic
  • These asymptomatic subjects may have markers in their blood indicating they carry the disease, but they are totally asymptomatic.
  • a subject can be tested for a ssRNA viral infection (e.g., but not limited to, Ebola) within a few days after symptoms begin, or after treatment according to the present disclosure, by collecting a blood or other body fluid sample and testing the sample for detection of viral antigens or RNA in blood and other body fluids using, for example, an antigen-capture enzyme-linked immunosorbent assay (ELISA), using an IgM ELISA (to determine whether the subject has IgM antibodies), using an IgG ELISA (to determine whether the subject has IgG antibodies), using polymerase chain reaction (PCR), or by virus isolation.
  • ELISA antigen-capture enzyme-linked immunosorbent assay
  • IgM ELISA to determine whether the subject has IgM antibodies
  • IgG ELISA to determine whether the subject has IgG antibodies
  • PCR polymerase chain reaction
  • the present disclosure identifies agents and combinations of agents having inhibitory activity against a model filovirus.
  • the present disclosure features compositions and methods for the treatment, of filovirus-mediated disease, e.g., one caused by an Ebola virus or Marburg virus.
  • compositions and methods for treating a patient with a filovirus-mediated disease for example a disease caused by Ebola virus.
  • the method includes administering to the patient a first agent selected from the agents of Table 1, or an analog thereof, in an amount that is effective to treat the patient. In an embodiment, the method further includes administering a second agent selected from the agents of Table 1. In an embodiment, the method further includes administering a third agent selected from the agents of Table 1 Table 1
  • the agents When the methods include administering to a patient more than one active agent, the agents may be administered within 7, 6, 5, 4, 3, 2 or 1 days; within 24, 12, 6, 5, 4, 3, 2 or 1 hours, within 60, 50, 40, 30, 20, 10, 5 or 1 minutes; or substantially simultaneously.
  • the methods of the disclosure may include administering one or more agents to the patient by oral, systemic, parenteral, topical, intravenous, inhalational, or intramuscular administration. In an embodiment, the methods of the disclosure include administering one or more agents to the patient by oral administration.
  • the present disclosure describes a composition including two or more agents selected from the agents of Table 1.
  • the two or more agents are present in amounts that, when administered together to a patient with a filovirus-mediated disease such as a disease caused by Ebola virus, are effective to treat the patient.
  • the composition consists of active ingredients and excipients, and the active ingredients consist of two or more agents selected from agents of Table 1.
  • the present disclosure describes a composition including three or more agents selected from the agents of Table 1.
  • the three or more agents are present in amounts that, when administered together to a patient with a filovirus-mediated disease such as a disease caused by Ebola virus, are effective to treat the patient.
  • the composition consists of active ingredients and excipients, and the active ingredients consist of three or more agents selected from agents of Table 1.
  • Active ingredients or agents useful in the invention include those described herein in any of their pharmaceutically acceptable forms, including isomers, salts, solvates, and polymorphs thereof, as well as racemic mixtures and prodrugs.
  • combination therapies of the present disclosure is suitable to inhibit the viral replication machinery of a ssRNA virus, and is also suitable to inhibit the cytopathic effect during a ssRNA virus infection.
  • a treatment regimen of the present disclosure is suitable to inhibit the viral replication machinery of a ssRNA virus, and is also suitable to inhibit the cytopathic effect during a ssRNA virus infection.
  • Hsp90 interacts with a large number of client proteins that are essential to many cellular processes.
  • Hsp90 interacts with over 200 polypeptides in order to modulate their activity and/or half-life.
  • Hsp90, HspBl, and probably other small Hsps, are global regulators of cell systems.
  • Hsp90 is a host factor for the replication of negative strand viruses and is responsible for proteins folding properly, intracellular disposition, stabilizing proteins against heat stress, and also proteolytic turnover of many essential regulators of cell growth and differentiation.
  • WX-671 or “Mesupron” inhibits the urokinase-type plasminogen activator
  • the compound is N- ⁇ -(2,4,6- triisopropylphenylsulfonyl)-3-hydroxyamidino-phenylalanine-4-ethoxycarbonylpiperazide present as a salt. In an embodiment, the compound is N- ⁇ -(2,4,6-triisopropylphenylsulfonyl)-3- hydroxyamidino-phenylalanine-4-ethoxycarbonylpiperazide present as a sulfate or hydrogen sulfate salt.
  • serine protease inhibitor WX-671 is converted to the active N ⁇ -(2,4,6- triisopropylphenylsulfonyl)-3-amidino-(L)-phenylalanine-4-ethoxycarbonylpiperazide (“WX- UK1”), which inhibits several serine proteases, particularly uPA.
  • the compound is N- ⁇ (2,4,6-triisopropylphenylsulfonyl)-3-amidino- phenylalanine-4-ethoxy-carbonylpiperazide-hydrochloride and in an injectable form to be delivered intravenously or intramuscularly.
  • Upamostat is administered orally at a daily dose of between about 200 mg to about 550 mg. In an embodiment, Upamostat is administered orally at a daily dose of between about 250 mg to about 550 mg. In an embodiment, Upamostat is administered orally at a daily dose of between about 300 mg to about 550 mg. In an embodiment, Upamostat is administered orally at a daily dose of between about 350 mg to about 550 mg. In an embodiment, Upamostat is administered orally at a daily dose of between about 400 mg to about 550 mg. In an embodiment, Upamostat is administered orally at a daily dose of between about 450 mg to about 550 mg.
  • a method for treating a patient having filovirus-mediated disease includes administering to the patient a composition comprising an aryladamantane compound in an amount effective to treat the patient.
  • the filovirus is Ebola virus or Marburg virus.
  • CH 3 O — CH 2 — CH( R 1 ) — CH 3 represents a 2-substituted-1-niethoxypropane compound.
  • the symbol represents the point of attachment of the substituent to a compound.
  • aryl(C 1 -C 6 )alkyl- indicates an alkylaryl group, such as benzyl, attached to the compound at the alkyl moiety.
  • R m optionally substituted with 1, 2 or 3 R q groups indicates that R m is substituted with 1, 2, or 3 R q groups where the R q groups can be the same or different
  • an optionally substituted group may have a substituent at each substitutable position of the group, and each substituent is independent of the other.
  • halogen or halo indicate fluorine, chlorine, bromine, or iodine
  • heteroatom means nitrogen, oxygen or sulfur and includes any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen.
  • nitrogen includes a substitutable nitrogen in a heterocyclic ring As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from nitrogen, oxygen or sulfur, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl).
  • alkyl refers to a saturated aliphatic hydrocarbon including straight chain, branched chain or cyclic (also called “cycloalkyl”) groups.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, iso-, sec- and iert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyI, and the like.
  • the alkyl group has 1 to 20 carbon atoms (whenever a numerical range, e.g.
  • cycloalkyl can be monocyclic, or a polycyclic fused system. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cycolpentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl.
  • the alkyl or cycloalkyl group may be unsubstituted or substituted with 1 , 2, 3 or more substituents.
  • substituents including, without limitation, halo, hydroxy, amino, alkoxy, alkylamino, dialkylamino, cycloalkly, aryl, aryloxy, arylalkyloxy, heterocyclic radical, and (heterocyclic radical)oxy.
  • Examples include fluoromethyl, hydroxyethyl, 2,3-dihydroxyethyl, (2- or 3- furanyl)m ethyl, cyclopropyl methyl, benzyloxyethyl, (3-pyridinyl)rnethyl, (2-thienyl)ethyl, hyroxypropyl, aminocyclohexyl, 2-dimethylaminobutyl, methoxymethyl, N-pyridinylethyl, and diethylaminoethyl .
  • cycloalkylalkyl refers to a C 3 -C 10 cycloalkyl group attached to the parent molecular moiety through an alkyl group, as defined above.
  • alkyl group examples include cyclopropylmethyl and cyclopentylethyb
  • substituents including, without limitation halo, hydroxy, amino, alkoxy, alkylamino, dialkylamino, cycloalkly, aryl, aryloxy, arylalkyloxy, heterocyclic radical, and (heterocyclic radical)oxy.
  • the geometry of the double bond may be
  • E E
  • Z
  • alkenyl groups include ethenyl, propenyl, cis-2-butenyl, trans-2-butenyl, and 2-hyroxy-2-propenyl,
  • alkynyl refers to an aliphatic hydrocarbon having at least one carbon-carbon triple bond, including straight chain, branched chain or cyclic groups having at least one carbon-carbon triple bond.
  • the alkynyl group has 2 to 20 carbon atoms. More preferably, it is a medium size alkynyl having 2 to 10 carbon atoms. Most preferably, it is a lower alkynyl having 2 to 6 carbon atoms.
  • the alkynyl group may be unsubstituted or substituted with 1, 2, 3 or more substituents.
  • unsubstituted aryl groups include phenyl and biphenyl
  • Preferred aryl group substituents include hydrogen, halo, alkyl, haloalkyl, hydroxy and alkoxy.
  • heterocyclyl refers to saturated, partially unsaturated and unsaturated heteroatom-containing ring shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Said heterocyclyl groups may be unsubstituted or substituted at one or more atoms within the ring system.
  • the heterocyclic ring may contain one or more oxo groups.
  • heterocycloalkyl refers to a non-aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur.
  • the heterocycloalkyl ring may be optionally fused to or otherwise attached to other heterocycloalkyl rings and/or non-aromatic hydrocarbon rings.
  • Preferred heterocycloalkyl groups have from 3 to 7 members. Examples of heterocycloalkyl groups include, for example, piperazine, morpholine, piperidine, tetrahydrofuran, pyrrolidine, and pyrazole.
  • heteroaryl refers to an aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur
  • the heteroaryl ring may be fused or otherwise attached to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings or heterocycloalkyl rings.
  • the heteroaryl group may be unsubstituted or substituted at one or more atoms of the ring system, or may contain one or more oxo groups. Examples of heteroaryl groups include, for example, pyridine, furan, thiophene, carbazole and pyrimidine.
  • X is— C(R 3 ,R 4 )N(R 5 )— , — C(O)N(R 4 )— , — N(R 4 )C(O)— , — C(R 4 ,R 5 )— , — N(R 4 )— , — O— , — S— — C(O)— , — S(O) 2 — , — S(O) 2 N(R4)— or— N(R 4 )S(O) 2 — ;
  • groups is optionally substituted with up to 5 groups that are independently (C 1 -C 6 ) alkyl, halogen, haloalkyl, — OC(O)(C 1 -C 6 alkyl), — C(O)O(C 1 -C 6 alkyl), — CONR'R", — OC(O)NR'R", — NR'C(O)R", — CF 3 , — OCF 3 , —OH, C 1 -C 6 alkoxy, hydroxyalkyl, — CN, — CO 2 H, — SH, —S-alkyl, — SOR'R", — SO 2 R', — NO 2 , or NR'R", wherein R' and R" are independently H or (C 1 -C 6 ) alkyl, and wherein each alkyl portion of a substituent is optionally further substituted with 1, 2, or 3 groups independently selected from halogen, CN, OH, and NHz; and R
  • Aryladamantane compounds of Formula I include compounds of formula 1-1 : and pharmaceutically acceptable salts thereof, wherein:
  • R 1 is H, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, aryl, alkylaryl, alkenylaryl, heterocyclyl, heteroaryl, alkylheteroaryl, heterocycloalkyl, alkyl -heterocycloalkyl, acyl, aroyl, halogen, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkanoyl, — COOH, — OH, — SH, — S-alkyl, — CN, — NO 2 , — NH 2 , — CO 2 (alkyl), — OC(O)alkyl, carbamoyl, mono or dialkylaminocarbamoyl, mono or dialkylcarbamoyl, mono or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl
  • R 2 is H, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, aryl, alkylaryl, alkenylaryl, heterocyclyl, heteroaryl, alkylheteroaryl, heterocycloalkyl, alkyl-heterocycloalkyl, acyl, aroyl, halogen, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkanoyl, — COOH, — OH, — SH, — S-alkyl, — CN, — NO 2 , — NH 2 , — CO 2 (alkyl), — OC(O)alkyl, carbamoyl, mono or dialkylaminocarbamoyl, mono or dialkylcarbamoyl, mono or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl,
  • Aryladamantane compounds of Formula I include those of formula II: and pharmaceutically acceptable salts thereof, wherein:
  • Y is — C(R 4 ,R 5 )— , — N(R 4 )— , — O— , or — C(O)— ,
  • R 1 is H, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, aryl, alkylaryl, alkenylaryl, heterocyclyl, heteroaryl, alkylheteroaryl, heterocycloalkyl, alkyl-heterocycloalkyl, acyl, aroyl, halogen, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkanoyl, — COOH, — OH, — SH, — S-alkyl, — CN, — NO 2 , — NH 2 , — CO 2 (alkyl), — OC(O)alkyl, carbamoyl, mono or dialkylaminocarbamoyl, mono or dialkylcarbamoyl, mono or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl,
  • R 2 is H, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, aryl, alkylaryl, alkenylaryl, heterocyclyl, heteroaryl, alkylheteroaryl, heterocycloalkyl, alkyl-heterocycloalkyl, acyl, aroyl, halogen, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkanoyl, — COOH, — OH, — SH, — S-alkyl, — CN, —NO 2 , — NH 2 , — CO 2 (alkyl), — OC(O)alkyl, carbamoyl, mono or dialkylaminocarbamoyl, mono or dialkylcarbamoyl, mono or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl,
  • Y is — C(R 4 ,R 5 ) — or — N(R 4 ) — ,
  • R 2 is H, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, aryl, alkylaryl, alkenylaryl, heterocyclyl, heteroaryl, alkylheteroaryl, heterocycloalkyd, alkyl-heterocycloalkyl, acyl, aroyl, halogen, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkanoyl, — COOH, — OH, — SH, --S-alkyl, ----CN, --NO 2 , --NH 2 , — CO 2 (alkyl), - - OC(O)alkyl, carbamoyl, mono or dialkylaminocarbarnoyl, mono or dialkylcarbamoyl, mono or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl,
  • R 4 and R 5 are independently H or (C 1 -C 6 )alkyl.
  • Representative formula II compounds include:
  • an aryladamantane compound of the present invention is selected from a compound of Formula below: and pharmaceutically acceptable salts thereof, wherein o R 1 is H, Cl or F, o R 2 is H or alkyl; o m is 0, 1 or 2; o n is 1, 2, 3, 4 or 5; o each R 3 is independently H, (O)alkyl --C(O)CH 2 CH 2 C(O)OH, R 4 , ------ C(O)NR 5 R 6 , — P(O)(OR 7 ) 2 or glucosyl, provided that at least one R.i is not H, o wherein
  • ⁇ R 4 is a natural or unnatural amino acid linked through the carboxyl moiety as an ester
  • ⁇ R 5 is H or alkyl
  • ⁇ R 6 is H or alkyl, and each R 7 is independently H or alkyl.
  • the moiety is a catechol with substitution at least one catechol — OH.
  • the moiety is a catechol with substitution at least one catechol — OH.
  • compounds of the invention include:
  • Remdisivir is administered intravenously in the first dose of 200 mg on day 1, and administered intravenously in a second dose of 100 mg on each of the following 9 days. In some embodiments, Remdisivir is administered intravenously once daily. In some embodiments, Remdisivir is administered intravenously over from about 30 to about 120 minutes, is administered in the first dose of 150-250 mg on day 1, and administered in a second dose of 50-150 mg on each of the following 4 days. In some embodiments, the second dose of 50- 150 mg is administered for an additional 1 to 5 days.
  • administration of ABC294640 has a synergistic activity with remdesivir to inhibit the replication machinery of a ssRNA virus infection. In some embodiments, administration of the combination of ABC294640 and remdesivir hinders, restrains or prevents viral infection.
  • administration of ABC294640 and Upamostat has a synergistic activity with an anti-viral drug to inhibit the replication machinery of a ssRNA virus infection.
  • administration of the combination of ABC294640, Upamostat and an anti- viral drug hinders, restrains or prevents viral infection.
  • administration of ABC294640 has a synergistic activity with Upamostat to inhibit the replication machinery of a ssRNA virus infection.
  • Upamostat is administered orally as a solid dosage form. In some embodiments, Upamostat is administered orally one or more times per day.
  • ABC294640 is administered orally as a solid dosage form. In some embodiments, ABC294640 is administered orally one or more times per day. In some embodiments, anti-viral drugs are administered orally or intravenously. In some embodiments, anti-viral drugs are administered orally or intravenously one or more times per day. In some embodiments, anti-viral drugs are administered intravenously. In some embodiments, the anti-viral drug is remdesivir.
  • the present disclosure relates to methods for treating a subject having a ssRNA viral infection, such as Ebola virus or Marburg virus, by concomitantly administering i) a therapeutically effective amount of an anti-viral drug; and ii) a therapeutically effective amount of ABC294640, Upamostat or a combination thereof.
  • a ssRNA viral infection such as Ebola virus or Marburg virus
  • the present disclosure relates to methods for treating a subject having a ssRNA viral infection, such as Ebola virus, by administering i) a therapeutically effective amount of an anti-viral drug; and ii) a therapeutically effective amount of ABC294640.
  • the i) therapeutically effective amount of an anti-viral drug; and ii) therapeutically effective amount of ABC294640 are administered concomitantly.
  • the i) therapeutically effective amount of an anti-viral drug; and ii) therapeutically effective amount of ABC294640 are administered sequentially.
  • the present disclosure relates to methods for treating a subject having a ssRNA viral infection, such as Ebola virus, by administering i) a therapeutically effective amount of an anti-viral drug; and ii) a therapeutically effective amount of upamostat.
  • a ssRNA viral infection such as Ebola virus
  • the i) therapeutically effective amount of an anti-viral drug; and ii) therapeutically effective amount of Upamostat are administered concomitantly.
  • the i) therapeutically effective amount of an anti-viral drug; and ii) therapeutically effective amount of Upamostat are administered sequentially.
  • the present disclosure relates to methods for treating a subject having a ssRNA viral infection, such as Ebola virus, administering i) a therapeutically effective amount of an anti-viral drug; ii) a therapeutically effective amount of ABC294640; iii) a therapeutically effective amount of Upamostat.
  • a ssRNA viral infection such as Ebola virus
  • administering i) a therapeutically effective amount of an anti-viral drug; ii) a therapeutically effective amount of ABC294640; iii) a therapeutically effective amount of Upamostat.
  • the i) therapeutically effective amount of an anti-viral drug; ii) therapeutically effective amount of ABC294640; and iii) therapeutically effective amount of Upamostat are administered sequentially.
  • one, two or more antiviral drugs are administered to the patient in need thereof.
  • the anti-viral drug is remdesivir.
  • the anti-viral drug is a direct antiviral agent.
  • the anti-viral drug is host directed small molecule.
  • the one, two or more antiviral drugs are administered intravenously.
  • the one, two or more antiviral drugs are administered by infusion.
  • the present disclosure relates to methods for treating a subject having a ssRNA viral infection, e.g., but not limited to, Ebola virus, by administering a therapeutically effective amount of an aryladamantane compound.
  • a ssRNA viral infection e.g., but not limited to, Ebola virus
  • the aryladamantane compound is selected from a compound of formula I.
  • aspects of the disclosure relate to a method of treating a human infected with or exposed to an Ebola virus, the method comprising administering to the human, for a suitable period of time, an effective amount of 3 -(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4- ylmethyljamide or a pharmaceutically acceptable salt thereof, and an effective amount of remdesivir.
  • the effective amount of 3-(4-chlorophenyl)-adamantane-1- carboxylic acid (pyridin-4- ylmethyljamide or a pharmaceutically acceptable salt thereof is administered orally.
  • the effective amount of 3-(4-chlorophenyl)- adamantane-1- carboxylic acid (pyridin-4-ylmethyl)amide or a pharmaceutically acceptable salt thereof ranges from about 9.5 mg/kg to about 15.5 mg/kg daily. In some embodiments, the effective amount of 3-(4-chlorophenyl)-adamantane-1- carboxylic acid (pyridin-4-ylmethyl)amide or a pharmaceutically acceptable salt thereof ranges from about 10.5 mg/kg to about 14.5 mg/kg daily.
  • the effective amount of 3-(4-chlorophenyl)-adamantane- 1- carboxylic acid (pyridin-4-ylmethyl)amide or a pharmaceutically acceptable salt thereof ranges from about 11.5 mg/kg to about 13.5 mg/kg daily. In some embodiments, the effective amount of 3-(4-chlorophenyl)-adamantane-1- carboxylic acid (pyridin-4-ylmethyl)amide or a pharmaceutically acceptable salt thereof ranges from about 15.0 mg/kg to about 20.0 mg/kg daily.
  • the method comprises administering orally a solid dosage form comprising the effective amount of the 3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4- ylmethyljamide or a pharmaceutically acceptable salt thereof.
  • remdesivir is administered intravenously.
  • the human weighs more than 40 kg and the effective amount of remdesivir ranges from 50 mg to 250 mg daily.
  • the effective amount of remdesivir ranges from 150 to 250 mg daily on day 1, and 50 mg to 150 mg daily on following days.
  • the method comprises administering intravenously remdesivir over a period of 5 to 10 days.
  • the human weighs from 3.5 kg to less than 40 kg and the effective amount of remdesivir ranges from 2.5 mg/kg to 5 mg/kg daily. In some embodiments, the effective amount of remdesivir ranges is 5 mg/kg daily on day 1, and 2.5 mg/kg daily on following days.
  • the method comprises administering intravenously remdesivir over a period of 5 to 10 days.
  • the method further comprise confirming if the human is infected with an Ebola virus prior to the administering. In some embodiments, the confirming is performed via a test that detects viral antigens or RNA in a sample of blood. In some embodiments, the confirming is performed via a test that detects viral antigens or RNA in a sample of bodily fluids other than blood.
  • aspects of the disclosure relate to a method of treating a human infected with or exposed to an Ebola virus, the method comprising administering to the human, for a suitable period of time, an effective amount of N- ⁇ (2,4,6-triisopropylphenylsulfonyl)-3-amidino-phenylalanine- 4-ethoxy-carbonylpiperazide-hydrochloride, N- ⁇ -(2,4,6-triisopropylphenylsulfonyl)-3- hydroxyamidino-phenylalanine-4-ethoxycarbonylpiperazide, free base or a pharmaceutically acceptable salt thereof, and an effective amount of remdesivir.
  • the pharmaceutically acceptable salt of N- ⁇ (2,4,6-triisopropylphenylsulfonyl)-3-amidino- phenylalanine-4-ethoxy-carbonylpiperazide-hydrochloride, N- ⁇ -(2,4,6- triisopropylphenylsulfonyl)-3-hydroxyamidino-phenylalanine-4-ethoxycarbonylpiperazide is a hydrogen sulfate salt.
  • the effective amount of N- ⁇ (2,4,6- triisopropylphenylsulfonyl)-3-amidino-phenylalanine-4-ethoxy-carbonylpiperazide- hydrochloride, N- ⁇ -(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-phenylalanine-4- ethoxycarbonylpiperazide, free base or a pharmaceutically acceptable salt thereof ranges from 200 mg to about 400 mg.
  • the effective amount of N- ⁇ (2,4,6- triisopropylphenylsulfonyl)-3-amidino-phenylalanine-4-ethoxy-carbonylpiperazide- hydrochloride, N- ⁇ -(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-phenylalanine-4- ethoxy carbonylpiperazide, free base or a pharmaceutically acceptable salt thereof is about 231 mg.
  • remdesivir is administered intravenously.
  • the human weighs more than 40 kg and the effective amount of remdesivir ranges from 50 mg to 250 mg daily. In some embodiments, the effective amount of remdesivir ranges from 150 to 250 mg daily on day 1, and 50 mg to 150 mg daily on following days.
  • the method comprises administering intravenously remdesivir over a period of 5 to 10 days. In some embodiments, the human weighs from 3.5 kg to less than 40 kg and the effective amount of remdesivir ranges from 2.5 mg/kg to 5 mg/kg daily.
  • compositions according to the disclosure or used in the methods of the disclosure may be formulated to release the active compound immediately upon administration or at any predetermined time or time period after administration.
  • the latter types of compositions are generally known as controlled release formulations, which include (i) formulations that create substantially constant concentrations of the agent(s) of the disclosure within the body over an extended period of time; (ii) formulations that after a predetermined lag time create substantially constant concentrations of the agent(s) of the disclosure within the body over an extended period of time; (iii) formulations that sustain the agent(s) action during a predetermined time period by maintaining a relatively constant, effective level of the agent(s) in the body with concomitant minimization of undesirable side effects associated with fluctuations in the plasma level of the agent(s) (sawtooth kinetic pattern); (iv) formulations that localize action of agent(s), e.g., spatial placement of a controlled release composition adjacent to or in the diseased tissue or organ; (v) formulations that achieve convenience of dosing, e.
  • a first agent is delivered orally, and a second agent is delivered intravenously.
  • the dosage of a compound or a combination of compounds depends on several factors, including: the administration method, the type of disease to be treated, the severity of the infection, whether administration first occurs at an early or late stage of infection, and the age, weight, and health of the patient to be treated.
  • the recommended dosage for the anti-viral agent can be less than or equal to the recommended dose as given in the Physician's Desk Reference, 69 th Edition (2015).
  • the compound(s) in question may be administered orally in the form of tablets, capsules, elixirs or syrups, or rectally in the form of suppositories.
  • Parenteral administration of a compound is suitably performed, for example, in the form of saline solutions or with the compound(s) incorporated into liposomes.
  • a solubilizer such as ethanol can be applied.
  • the correct dosage of a compound can be determined by examining the efficacy of the compound in viral replication assays, as well as its toxicity in humans.
  • FIGS. 1-16 show that Opaganib and Upamostat demonstrated distinct synergistic effect when combined individually with remdesivir, significantly improving potency while maintaining cell viability, in an in vitro Ebola virus study.
  • Table 1 In vitro potency of Opaganib against EBOV, MARV and SUDV.
  • Opaganib and Remdesivir (Example la), Opaganib and Remdesivir (Example lb) and Opaganib and Upamostat (a host protease inhibitor)(Example 1c). Upamostat inhibits cell surface proteases required to cleave viral proteins and thereby blocking attachment and uptake of the virus into host cells).
  • MRC-5 cells were treated with individual drugs or combination of two drugs at an appropriate starting concentration. Exemplary Plate layout of the combination study set-up is shown in FIG. 1. A 3-fold serial dilution was performed, 8 different concentration and four technical replicates for each drug combination.
  • each of the compounds were also individually tested at the same concentration in the same plate.
  • the cells were infected with EBOV Duncan/Makona for 48 hours, fixed and subjected to immunofluorescence staining using viral antigen specific antibodies.
  • cell mask deep red and the Hoechst dyes were added to stain the cell cytoplasm and nuclei respectively.
  • Table 3 shows the highest significant peak synergy predicted by all four models (Loewe, HSA, Bliss and ZIP) is at a concentration of Opaganib at 0.74 ⁇ M and Remdesivir at 0.66 ⁇ M at 23% corrected inhibition.
  • Table 4 shows the highest significant peak synergy predicted by all four models (Loewe, HSA, Bliss and ZIP) is at a concentration of Opaganib at 0.74 ⁇ M and Remdesivir at 0.02 ⁇ M at 17% corrected inhibition.
  • Opaganib and Upamostat show a distinct synergy in terms of viral inhibition while maintaining cell viability (i.e., not increasing toxicity), when either is added to remdesivir.
  • Opaganib shows the greatest synergistic effect in combination with remdesivir.
  • Opaganib Twice daily administered Opaganib has previously demonstrated benefit in late-stage clinical studies of patients hospitalized with moderate to severe COVID-19. Opaganib is believed to be the first host-directed molecule to show activity in Ebola virus disease, having recently delivered a statistically significant increase in survival time in an in vivo Ebola virus study.
  • Opaganib a host-directed and potentially broad-acting drug, is a first-in-class, orally administered sphingosine kinase-2 (SPHK2) selective inhibitor with anticancer, anti-inflammatory and antiviral activity.
  • SPHK2 sphingosine kinase-2
  • Opaganib host-directed action is thought to work through the inhibition of multiple pathways, the induction of autophagy and apoptosis, and disruption of viral replication, through simultaneous inhibition of three sphingolipid-metabolizing enzymes in human cells (SPHK2, DES1 and GCS).
  • Opaganib has demonstrated antiviral activity against SARS-CoV-2, multiple variants, and several other viruses, such as Influenza A. Being host-targeted, and based on data accumulated to date, Opaganib is expected to maintain effect against emerging viral variants. In prespecified analyses of Phase 2/3 clinical data in hospitalized patients with moderate to severe COVID-19, oral Opaganib demonstrated improved viral RNA clearance, faster time to recovery and significant mortality reduction in key patient subpopulations versus placebo on top of standard of care.
  • Example 1c- Opaganib and Upamostat Combinations Show Distinct Synergistic Effect against Ebola Upamostat and Opaganib were tested at starting concentration of 60 ⁇ M. Dose response involved three-fold serial dilution, eight different concentrations and four technical replicates either alone or in combination. This combination study was performed in HeLa cells.
  • Table 7 shows the highest significant peak synergy predicted by all four models (Loewe, HSA, Bliss and ZIP) is at a concentration of Opaganib at 2.2 ⁇ M and Upamostat at 6.6 ⁇ M with 46-63 % inhibition.
  • Example 2 Evaluation of the efficacy of Opaganib in mouse model of EBOV infection
  • mice Two independent studies were performed to determine the efficacy of Opaganib in a mouse model of EBOV infection.
  • a mouse model of EBOV infection Two independent studies were performed to determine the efficacy of Opaganib in a mouse model of EBOV infection.
  • maEBOV plaque forming units
  • Treatment with different doses of Opaganib 60 mg/kg, 100 mg/kg and 150 mg/kg was initiated. Doses were chosen based on the lowest dose that demonstrated efficacy in any of our mouse models.
  • mice were exposed via the intraperitoneal (i.p.) route with 100 pfu of maEBOV.
  • Figure 9 shows the combined survival curve generated from two independent studies performed for Vehicle control and Opaganib (150 mg/kg). Mice treated with Opaganib (150 mg/kg) overall showed a 20% survival compared to the vehicle control which showed 10% survival. See FIG. 16.

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Abstract

L'invention concerne des polythérapies pour l'inhibition de la réplication de virus à ARN simple brin, tels que des virus Ebola.
PCT/IB2024/000726 2023-12-20 2024-12-17 Polythérapie pour l'inhibition de virus ebola Pending WO2025133697A2 (fr)

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