WO2021203001A1 - Procédé de traitement de patients infectés par une infection virale avec un inhibiteur de l'enzyme activant le petit modificateur de type ubiquitine - Google Patents

Procédé de traitement de patients infectés par une infection virale avec un inhibiteur de l'enzyme activant le petit modificateur de type ubiquitine Download PDF

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WO2021203001A1
WO2021203001A1 PCT/US2021/025581 US2021025581W WO2021203001A1 WO 2021203001 A1 WO2021203001 A1 WO 2021203001A1 US 2021025581 W US2021025581 W US 2021025581W WO 2021203001 A1 WO2021203001 A1 WO 2021203001A1
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pharmaceutically acceptable
acceptable salt
administered
day
compound
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PCT/US2021/025581
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English (en)
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Dennis Huszar
Igor PROSCURSHIM
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Millennium Pharmaceuticals, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present disclosure relates to methods of therapeutically or prophylactically treating a subject with a viral infection such as coronavirus disease (COVID).
  • COVID coronavirus disease
  • the present disclosure provides methods for therapeutically or prophylactically treating a viral infection by administering a small ubiquitin-like modifier (SUMO) activating enzyme (SAE) inhibitor, such as Compound 1-263 a.
  • SAE small ubiquitin-like modifier activating enzyme
  • Coronaviruses are common, diverse viruses that infect many mammalian and avian species. Coronaviruses infections can result in respiratory, gastrointestinal, and central nervous system diseases. Coronavirus virions comprise an envelope, a helical capsid, and a single-stranded and positive-sense RNA genome. The coronavirus genome is the largest among all RNA viruses and typically ranges between 27 and 32 kb. (Lig, F., J. Vir. 89(4):1954-64 (2015)).
  • Coronaviruses belong to the Coronaviridae family in the order of Nidovirales and can be classified into at least three major genera: alpha, beta, and gamma (formerly group
  • Alphacoronaviruses include human coronavirus NL63 (HCoV- NL63), porcine transmissible gastroenteritis coronavirus (TGEV), PEDV, and porcine respiratory coronavirus.
  • Betacoronaviruses include SARS-CoV, MERS-CoV, bat coronavirus HKU4, mouse hepatitis coronavirus (MHV), bovine coronavirus (BCoV), human coronavirus OC43, and SARS-CoV-2. (Lig, F., J. Vir. 89(4): 1954-64 (2015)).
  • HCoV-NL63 is a prevalent human respiratory pathogen that is often associated with common colds in healthy adults and acute respiratory diseases in young children.
  • Coronaviruses can also result in more severe health problems.
  • Two betacoronavirues, SARS-CoV and MERS-CoV are highly pathogenic human pathogens.
  • SARS-CoV caused the SARS epidemic in 2002 to 2003, which resulted in over 8,000 infections and a fatality rate of approximately 10%.
  • MERS-CoV emerged in 2012 and at the end of November 2019, 2,494 laboratory-confirmed cases of MERS had been confirmed by the World Health Organization (WHO), including 858 associated deaths — a fatality rate of 34.4%.
  • WW Health Organization, MERS Situation Update, (Nov. 2019) available at http://applicatiots.emxO.who.int/docs/BMRPUB-CSR-241-2019- EN .pdf 1 ).
  • SARS-CoV2 is a betacoronavirus and related to SARS-CoV and MERS-CoV. SARS-CoV2 infection results in COVID-19, which affects the lower respiratory tract and manifests as pneumonia. (Sohrabi, C., et ah, Int. ./. Surgery , 76, 71-76 (2020)).
  • SARS-CoV2 infected patients develop mild symptoms such as dry cough, sore throat, and fever. The majority of symptoms have spontaneously resolve. However, some infected patients have developed various fatal complications including organ failure, septic shock, pulmonary oedema, severe pneumonia, and Acute Respiratory Distress Syndrome (ARDS). (Sohrabi, C., et ah, Int. J. Surgery , 76, 71-76 (2020)).
  • COVID-19 continues to rise. COVID-19 was declared a pandemic by the WHO in 2020. There are currently no effective treatments or vaccines available for COVID-19. (Sohrabi, C., et ak, Int. J. Surgery , 76, 71-76 (2020)).
  • Small ubiquitin-like modifier (SUMO) activating enzyme (SAE) inhibitors are an example of small molecules that may be used for targeted therapies.
  • SUMO is a member of the ubiquitin-like protein (Ubl) family that covalently conjugate to cellular proteins in a manner similar to ubiquitin (Ub)-conjugation (Kerscher, O. et al, Annu Rev Cell Dev Biol. 22:159-80 (2006)).
  • Mammalian cells express three major SUMO isoforms: SUMOl, SUM02, and SUM03.
  • SUM02 and SUM03 share approximately 95% amino acid sequence homology but have approximately 45% sequence homology with SUMOl (Kamitani, T., et al., J Biol Chem. 273(18): 11349-53 (1998)).
  • SUMO proteins can conjugate to a single lysine residue of a protein (monosumoylation) or to a second SUMO protein that is already conjugated to a protein forming a SUMO chain (polysumoylation ).
  • SUM02/3 can form such chains because they possess internal consensus SUMO modification sites (Tatham, M. H., et al., J Biol Chem. 276(38):35368-74 (2001)).
  • An additional isoform, SUM04 is found in kidney, lymph node and spleen cells, but it is not known whether SUM04 can conjugate to cellular proteins.
  • SAE is activated in an ATP-dependent manner by SAE (see, for example, U.S. Patent Application Publication No. 2010/0160177 Al (FIG. IB), U.S. Patent 9,434,765 B2 (FIG. 2), and Gareau, J.R., et al, Nat Rev Mol Cell Biol. 11:861-871 (2010) ( Figure 1)).
  • SAE is a heterodimer that consists of SAE1 (SUMO- activating enzyme subunit 1) and SAE2 (UBA2).
  • SAE like other El activating enzymes, uses ATP to adenylate the C-terminal glycine residue of SUMO.
  • a thioester intermediate is then formed between the C-terminal glycine of SUMO and a cysteine residue in SAE2.
  • SUMO is transferred from the El to the cysteine residue of the SUMO conjugating enzyme (E2), UBC9.
  • E2 SUMO conjugating enzyme
  • Ubc9 is currently the only known conjugating enzyme for SUMO and functions with SUMOl, SUM02, and SUM03 proteins.
  • SUMO proteins then conjugate to the target protein, either directly or in conjunction with an E3 ligase, through isopeptide bond formation with the epsilon amino group of a lysine side chain on a target protein.
  • SUMO E3 ligases including PIAS (protein inhibitor of activated signal transducer and activator of transcription protein) proteins and Ran-binding protein 2 (RanBP2), and polycomb 2 (Pc2), have been identified (Johnson, E. S., and Gupta, A. A, Cell. 106(6):735-44 (2001); Pichler, A., etal, Cell. 108(1): 109-20 (2002); Kagey, M. H., et al, Cell. 113(1): 127-37 (2003)).
  • SUMO modulates the function, subcellular localization, complex formation and/or stability of substrate proteins (Miiller, S., et al, Nat Rev Mol Cell Biol.
  • SENPs de-sumoylating enzymes
  • SAE-initiated SUMO-conjugation plays a major role in regulating diverse cellular processes, including cell cycle regulation, transcriptional regulation, cellular protein targeting, maintenance of genome integrity, chromosome segregation, and protein stability (Hay, R. T Mol Cell. 18(1):1-12 (2005); Gill, G, Genes Dev. 18(17):2046-59 (2004)).
  • SUMO-conjugation causes changes in the subcellular localization of RanGAPl by targeting it to the nuclear pore complex (Mahajan, R., el al ., Cell. 88(1):97-1070 (1997)).
  • Sumoylation counteracts ubiquitination and subsequently blocks the degradation of IKB, thereby negatively regulating NF-kB activation (Desterro, J. M., et al., Mol Cell. 2(2):233-9 (1998)). Sumoylation has been reported to play an important role in transcription exhibiting both repressive and stimulatory effects. Many of the transcriptional nodes that are modulated play important roles in cancer. For example, sumoylation stimulates the transcriptional activities of transcription factors such as p53 and HSF2 (Rodriguez, M. S., et al., EMBO J. 18(22):6455-61 (1999); Goodson, M. L., et al., J Biol Chem.
  • SUMO-conjugation represses the transcriptional activities of transcription factors such as LEF (Sachdev, S., et al., Genes Dev. 15(23):3088-103 (2001)) and c-Myb (Bies, J., et al., J Biol Chem. 277(11):8999- 9009 (2002)).
  • LEF Senddev, S., et al., Genes Dev. 15(23):3088-103
  • c-Myb Bies, J., et al., J Biol Chem. 277(11):8999- 9009 (2002).
  • SUMO-conjugation controls gene expression and growth control pathways that are important for cancer cell survival.
  • Compound 1-263 described herein, is presently formulated as an intravenous (IV) injectable solution, and is a first in class small molecule inhibitor of SUMOylation.
  • SUMOylation is a post-translational modification that attaches a SUMO protein to protein substrates, regulating their activity, subcellular localization and stability.
  • Compound I-263a inhibits SUMOylation by forming an irreversible adduct with SUMO when SUMO is bound to Sumo Activating Enzyme (SAE), preventing its ligation to substrate proteins.
  • SAE Sumo Activating Enzyme
  • the present disclosure relates to methods of therapeutically or prophylactically treating a subject suffering from a viral infection, comprising administering to the subject a therapeutically effective amount of an active agent, wherein the active agent is I-263a or a pharmaceutically acceptable salt thereof.
  • the active agent is I-263a.
  • the viral infection is caused by a virus selected from the group consisting of at least one alphacoronavirus, at least one betacoronavirus, and at least one deltacoronavirus.
  • the at least one alphacoronavirus is selected from the group consisting of human coronavirus NL63 (HCoV-NL63), porcine transmissible gastroenteritis coronavirus (TGEV), PEDV, and porcine respiratory coronavirus.
  • HCV-NL63 human coronavirus NL63
  • TGEV porcine transmissible gastroenteritis coronavirus
  • PEDV porcine respiratory coronavirus
  • the at least one betacoronavirus is selected from the group consisting of SARS-CoV, MERS-CoV, bat coronavirus HKU4, mouse hepatitis coronavirus (MHV), bovine coronavirus (BCoV), human coronavirus OC43, and SARS- CoV-2.
  • the betacoronavirus is SARS-CoV2.
  • the viral infection is COVID-19.
  • the subject is greater than 55 years old. In some embodiments, the subject further has cardiovascular disease, diabetes, chronic respiratory disease, hypertension, cancer, or combinations thereof.
  • the therapeutically effective amount is between about 3 mg and about 90 mg. Additional suitable doses are provided below. Suitable doses include 3, 5, 10, 15, 20, 25, 40, 60, 75 or 90 mg. In some embodiments, the therapeutically effective amount is 40 mg. In some embodiments, the therapeutically effective amount is 60 mg.
  • the 1-263 a or the pharmaceutically acceptable salt thereof is administered as a single dose.
  • the I-263a or the pharmaceutically acceptable salt thereof is administered once in a seven-day treatment cycle.
  • the I-263a or the pharmaceutically acceptable salt thereof is administered twice in a seven-day treatment cycle.
  • the I-263a or the pharmaceutically acceptable salt thereof is administered on day 1 and day 4 of the seven-day treatment cycle.
  • the seven-day treatment cycle is repeated at least once.
  • the treatment cycle is followed by one- week rest. In some embodiments, the treatment cycle is followed by two-week rest.
  • the 1-263 a or the pharmaceutically acceptable salt thereof is administered on Days 1, 4, 8, and 11 of a 3-week cycle. In some embodiments, the I- 263a or the pharmaceutically acceptable salt thereof is administered on Days 1, and 4 of a 3-week cycle. In some embodiments, the I-263a or the pharmaceutically acceptable salt thereof is administered on Days 1, and 8 of a 3-week cycle.
  • the I-263a or the pharmaceutically acceptable salt is administered orally, systemically, parenterally, topically, mucosally, intramuscularly, intravenously, intraperitoneally, intradermally, subcutaneously, intranasally, intravaginally, intrarectally, transdermally, sublingually, via an aerosol route, or via inhalation.
  • the 1-263 a or the pharmaceutically acceptable salt thereof is administered intravenously.
  • the I-263a or the pharmaceutically acceptable salt thereof is formulated as a 10 mg/ml solution.
  • the 1-263 a or the pharmaceutically acceptable salt thereof is administered over a time period of up to 4 hours. In some embodiments, the I-263a or the pharmaceutically acceptable salt thereof is administered over a time period of 60 + 10 minutes.
  • the method further comprises determining presence of the virus in a nasopharyngeal or blood sample from the subject before or after administering the 1-263 a or the pharmaceutically acceptable salt thereof.
  • the presence of the virus is determined by PCR.
  • the method further comprises determining National Early
  • Warning Score of the subject before or after administering the I-263a or the pharmaceutically acceptable salt thereof.
  • administering the I-263a or the pharmaceutically acceptable salt thereof induces Type-I IFN gene expression. In some embodiments, administering the I-263a or the pharmaceutically acceptable salt thereof induces immune cell activation. In some embodiments, administering the I-263a or the pharmaceutically acceptable salt thereof induces cytokine or chemokine production.
  • the present disclosure relates to methods of therapeutically or prophylactically treating a subject suffering from a viral infection, comprising administering to the subject a therapeutically effective amount of an active agent, wherein the active agent is I-263a or a pharmaceutically acceptable salt thereof and at least one additional active agent.
  • the active agent is I-263a.
  • the at least one additional active agent is an antiviral agent, an antibiotic, a corticosteroid, interferon beta Bl, tocilizumab or a combination thereof.
  • the antibiotic is azithromycin.
  • the antiviral agent is selected from the group consisting of chloroquine, hydroxychloroquine, remdesivir, bortezomib, ixazomib, ponatinib, lopinavir/ritonavir, darunavir/cobicistat antiviral IgG, antiviral IgM, anti-IL-6 agents, azidothymidine (AZT), or pharmaceutically acceptable salts thereof, and combinations thereof.
  • the viral infection is caused by a virus selected from the group consisting of at least one alphacoronavirus, at least one betacoronavirus, and at least one deltacoronavirus.
  • the at least one alphacoronavirus is selected from the group consisting of human coronavirus NL63 (HCoV-NL63), porcine transmissible gastroenteritis coronavirus (TGEV), PEDV, and porcine respiratory coronavirus.
  • the at least one betacoronavirus is selected from the group consisting of SARS-CoV, MERS-CoV, bat coronavirus HKU4, mouse hepatitis coronavirus (MHV), bovine coronavirus (BCoV), human coronavirus OC43, and SARS- CoV-2.
  • the betacoronavirus is SARS-CoV2.
  • the viral infection is COVID-19.
  • the therapeutically effective amount of I-263a is between about 3 mg and about 90 mg. In some embodiments, the therapeutically effective amount of I-263a is 40 mg. In some embodiments, the therapeutically effective amount of I-263a is 60 mg.
  • the 1-263 a or the pharmaceutically acceptable salt thereof is administered as a single dose.
  • the I-263a or the pharmaceutically acceptable salt thereof is administered once in a seven-day treatment cycle.
  • the I-263a or the pharmaceutically acceptable salt thereof is administered twice in a seven-day treatment cycle.
  • the I-263a or the pharmaceutically acceptable salt thereof is administered on day 1 and day 4 of the seven-day treatment cycle.
  • the seven-day treatment cycle is repeated at least once.
  • the treatment cycle is followed by one- week rest. In some embodiments, the treatment cycle is followed by two-week rest.
  • the 1-263 a or the pharmaceutically acceptable salt thereof is administered on Days 1, 4, 8, and 11 of a 3-week cycle. In some embodiments, the I- 263a or the pharmaceutically acceptable salt thereof is administered on Days 1, and 4 of a 3-week cycle. In some embodiments, the I-263a or the pharmaceutically acceptable salt thereof is administered on Days 1, and 8 of a 3-week cycle.
  • the I-263a or the pharmaceutically acceptable salt is administered orally, systemically, parenterally, topically, mucosally, intramuscularly, intravenously, intraperitoneally, intradermally, subcutaneously, intranasally, intravaginally, intrarectally, transdermally, sublingually, via an aerosol route, or via inhalation.
  • the pharmaceutically acceptable salt thereof is administered intravenously.
  • the pharmaceutically acceptable salt thereof is formulated as a 10 mg/ml solution.
  • the 1-263 a or the pharmaceutically acceptable salt thereof is administered over a time period of up to 4 hours. In some embodiments, the I-263a or the pharmaceutically acceptable salt thereof is administered over a time period of 60 + 10 minutes.
  • the method further comprises determining presence of the virus in a nasopharyngeal or blood sample from the subject before or after administering the 1-263 a or the pharmaceutically acceptable salt thereof.
  • the presence of the virus is determined by PCR.
  • the method further comprises determining National Early
  • Warning Score of the subject before or after administering the I-263a or the pharmaceutically acceptable salt thereof.
  • administering the I-263a or the pharmaceutically acceptable salt thereof induces Type-I IFN gene expression. In some embodiments, administering the I-263a or the pharmaceutically acceptable salt thereof induces immune cell activation. In some embodiments, administering the I-263a or the pharmaceutically acceptable salt thereof induces cytokine or chemokine production.
  • the at least one additional active agent is administered orally, systemically, parenterally, topically, mucosally, intramuscularly, intravenously, intraperitoneally, intradermally, subcutaneously, intranasally, intravaginally, intrarectally, transdermally, sublingually, via an aerosol route, or via inhalation.
  • the chloroquine, hydroxychloroquine, or the pharmaceutically acceptable salt thereof is administered in an amount between 300 mg and 500 mg. In some embodiments, the chloroquine, hydroxychloroquine, or the pharmaceutically acceptable salt thereof is administered once or twice daily for up to 5 days.
  • the at least one additional active agent is administered simultaneously with the 1-263 a or the pharmaceutically acceptable salt thereof. In some embodiments, the at least one additional active agent is administered prior to administering the I-263a or the pharmaceutically acceptable salt thereof. In some embodiments, the at least one additional active agent is administered after administering the 1-263 a or the pharmaceutically acceptable salt thereof.
  • FIG. 1 is a drawing showing the mechanism of I-263a inhibition of the
  • COVID-19 refers to a disease caused by SARS-CoV2 characterized by dry cough, sore throat, and fever. And in serious cases, organ failure, septic shock, pulmonary oedema, severe pneumonia, and Acute Respiratory Distress Syndrome (ARDS).
  • ARDS Acute Respiratory Distress Syndrome
  • the term "effective amount” or “therapeutically effective amount” refers to an amount of a compound, or combination of one or more compounds that, when administered (either sequentially or simultaneously) elicits the desired biological or medicinal response, e.g., either destroys the target cancer cells or slows or arrests the progression of the cancer in a patient.
  • the therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the patient and disease condition being treated, e.g., the weight and age of the patient, the severity of the disease condition, the manner of administration and the like, which may readily be determined by one skilled in the art.
  • the term also applies to a dose that will induce a particular response in target cells, e.g., reduction of platelet adhesion and/or cell migration.
  • prophylactically treating refers to administering to a subject exposed to, or potentially exposed to a virus, such as SARS-CoV2, an amount of an active agent, such as Compound 1-263 a, capable of preventively mitigating a subject’s viral load or preventively mitigating or substantially reducing symptoms associated with an illness or disease caused by a viral infection.
  • an active agent such as Compound 1-263 a
  • the term “therapeutically treating” refers to administering to a subject with a viral infection an amount of an active agent, such as Compound 1-263 a, capable of providing a therapeutic benefit such as amelioration of symptoms, prevention of an increased viral load, or a decrease in viral load.
  • an active agent such as Compound 1-263 a
  • Viral load may be detected by methods well-known in the art, such as determining viral RNA levels in a nasopharyngeal or blood sample from the subject.
  • subject generally means a mammal (e.g., human) who has been diagnosed with, exhibits symptoms of, or is otherwise believed to be afflicted with a disease, disorder, or condition (such as cancer).
  • 1-263 a or a pharmaceutically acceptable salt thereof, and at least one additional active agent to a subject at the same time, or at two different time points that are separated by no more than 2 hours.
  • the simultaneous administration of the I-263a or a pharmaceutically acceptable salt thereof, and at least one additional active agent may be in a single dosage form or in separate dosage forms.
  • the terms “prior to administration” and “after administration” refer to the administration of the I-263a or a pharmaceutically acceptable salt thereof, and at least one additional active agent as disclosed herein, to a patient at two different time points that are separated by more than 2 hours, e.g., about 3 hours, about 4 hours, about 5 hours, about 8 hours, about 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days or even longer.
  • the term “intermission” refers to a period that is subsequent to the administration of one or more particular pharmaceutically active ingredients to a patient in an intermittent regimen. Intermission refers to a rest period wherein a particular pharmaceutically active ingredient is not administered for at least one day.
  • structures depicted herein are meant to include chemical entities which differ only in the presence of one or more isotopically enriched atoms.
  • chemical entities having the present structure except for the replacement of a hydrogen atom by a deuterium or tritium, or the replacement of a carbon atom by a 1 3 C- or 14 C-enriched carbon are within the scope of the invention.
  • stereochemical configuration Unless stereochemical configuration is denoted, structures depicted herein are meant to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Therefore, unless otherwise indicated, single stereochemical isomers as well as enantiomeric, racemic and diastereomeric mixtures of the present chemical entities are within the scope of the invention.
  • the diastereoisomeric or enantiomeric excess of the compound is at least 99.0%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9%.
  • I-263a is also known as TAK-981.
  • Compounds described herein may be in the form of a pharmaceutically acceptable salt.
  • such salts are derived from inorganic or organic acids or bases.
  • suitable salts see, e.g., Berge et al., J Pharm. Sci., 1977, 66, 1 19 and Remington: The Science and Practice of Pharmacy, 20th Ed., A. Gennaro (ed.), Lippincott Williams & Wilkins (2000).
  • Suitable acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, lucoheptanoate, glycerophosphate, hemi sulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3 -phenyl propionate, picrate, pivalate, propionate, succinate,
  • suitable base addition salts include ammonium salts; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; salts with organic bases, such as dicyclohexylamine salts, N-methyl D- glucamine; and salts with amino acids such as arginine, lysine, and the like.
  • salts anions adipate, alginate, aminosalicylate, anhydromethylenecitrate, arecoline, aspartate, bisulfate, butylbromide, camphorate, digluconate, dihydrobromide, disuccinate, glycerophosphate, hemisulfate, hydrofluoride, hydroiodide, methylenebis(salicylate), napadisylate (1,5 naphthalene ⁇ di sulfonate), oxalate, pectinate, persulfate, phenylethylbarbiturate, picrate, propionate, thiocyanate, tosylate and undecanoate; organic cations benethamine (N benzylphenethylamine), clemizole (1 p chloro benzyl-2 pyrrolildine-G ylmethylbenzimidazole), diethylamine, piperazine and t
  • the innate immune response the first line of defense against pathogens, limits viral replication during initial infection especially for respiratory infections and also induces adaptive immune responses responsible for viral clearance and maintenance (memory).
  • Viruses detected by innate immune receptors trigger signaling cascades such as nuclear factor kappa B (NF-KB)-dependent cytokine responses, interferon regulatory factor (IRF)-dependent IFN-a/b responses, and inflammasome/caspase-1 -dependent IL- 1b responses.
  • IFN-a/b are the major cytokines that limit viral replication playing a key immunomodulatory role activating innate immune effector cells as well as dendritic cells, promoting the priming, and sustaining the expansion of, naive T cells.
  • SUMOylation has been shown to play a key role in regulating innate immune responses .
  • a net inhibitory effect of SUMOylation on type 1 interferon (IFN) expression has been demonstrated (Decque, A., et al., Nat. Immunol., 17(2): 140-49 (2016); Crowl, JT, et al., Proc. Natl. Acad. Sci USA, 115(26):6798-6803 (2016)).
  • Type I IFN signaling has been shown to be central to the mechanism of action of TAK-981.
  • Ex vivo analyses have demonstrated Type I IFN-dependent activation of macrophages (upregulation of CD80, CD86 and FcgR’s) and NK cells (upregulation of CD69 and CD107) by TAK-981, resulting in enhanced phagocytic and cytotoxic activity, respectively, against Daudi target cells.
  • TAK-981 also promoted maturation of mouse bone marrow-derived dendritic cells (DCs) and human PBMC-derived DCs, upregulating the T cell co-stimulatory markers CD40, CD80, and CD86 and promoting release of type 1 IFNs and pro-inflammatory chemokines.
  • DCs mouse bone marrow-derived dendritic cells
  • PBMC-derived DCs human PBMC-derived DCs
  • TAK-981 has been shown to enhance antigen cross presentation and T cell priming by DCs, generating T cell dependent anti-tumor immune responses.
  • TAK-981 has also been shown to directly stimulate T cells ex vivo, upregulating expression of Type I IFNs and in OT-1 T cells enhancing sensitivity and response to antigen.
  • I-263a or a pharmaceutically acceptable salt thereof may be administered alone, or in combination with at least one additional agent.
  • 1-263 a and the at least one additional active agent may be administered in a single dosage form or as separate dosage forms.
  • the at least one additional active agent antibody may be administered prior to, at the same time as, or following administration of I-263a or a pharmaceutically acceptable salt thereof.
  • Administration of an effective amount of Compound I-263a in humans can provide formation of a Compound 1-263 a-SUMO adduct, inhibition of SUMOylation, and may increase in Type I IFN signaling and lymphocyte activation.
  • the administration of Compound I-263a may induce a Type I IFN response in patients with COVID-19, including cancer patients with COVD-19 and non cancer patients with COVID-19, and this may result in improved SARS-CoV-2 clearance by the immune system.
  • one or more doses of I-263a or a pharmaceutically acceptable salt thereof may be administered prior to the at least one additional active agent.
  • the at least one additional active agent is administered prior to the administration of Compound I-263a or a pharmaceutically acceptable salt thereof.
  • the administration in "combination" of Compound I-263a or a pharmaceutically acceptable salt thereof and at least one additional active agent refers not only to simultaneous or sequential administration of the agents, but also to the administration of the agents during a single treatment cycle, as understood by one skilled in the art.
  • Compound 1-263 a or a pharmaceutically acceptable salt thereof is administered in combination with the at least one additional active agent, a therapeutically effective amount of the combination is administered.
  • Compound I-263a may be administered by any method known to one skilled in the art.
  • Compound I-263a may be administered in the form of a pharmaceutical composition of I-263a and a pharmaceutically acceptable carrier, such as those described herein.
  • the pharmaceutical composition is suitable for oral administration.
  • the pharmaceutical composition is a tablet or a capsule that is suitable for oral administration.
  • the pharmaceutical composition is a liquid dosage form suitable for oral administration.
  • the pharmaceutical composition is suitable for intravenous administration.
  • the pharmaceutical composition is suitable for subcutaneous administration.
  • these compositions optionally further comprise one or more additional therapeutic agents.
  • the at least one additional active agent may be administered by any method known to one skilled in the art.
  • the at least one additional active agent is administered intravenously (IV).
  • the at least one additional active agent is administered subcutaneously (SC).
  • the at least one additional active agent is administered orally.
  • the at least one additional active agent may be administered in the form of a second composition, in some embodiments, a pharmaceutical composition of the at least one additional active agent and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is suitable for oral administration.
  • the pharmaceutical composition is a tablet or a capsule that is suitable for oral administration.
  • the pharmaceutical composition is a liquid dosage form suitable for oral administration. In some embodiments, these compositions optionally further comprise one or more additional therapeutic agents.
  • the amounts or suitable doses of the methods of this disclosure depends upon a number of factors, including the nature of the severity of the condition to be treated, the particular inhibitor, the route of administration and the age, weight, general health, and response of the individual patient.
  • the suitable dose level is one that achieves a therapeutic response as measured by tumor regression, or other standard measures of disease progression, progression free survival or overall survival.
  • the suitable dose level is one that achieves this therapeutic response and also minimizes any side effects associated with the administration of the therapeutic agent.
  • the suitable dose levels may be ones that prolong the therapeutic response and/or prolong life.
  • a suitable dose of Compound I-263a and at least one additional active agent may be taken at any time of the day or night.
  • a suitable dose of each agent is taken in the morning.
  • a suitable dose of each agent is taken in the evening.
  • a suitable dose of each of the agents is taken both in the morning and the evening.
  • a suitable dose of each agent may be taken with or without food.
  • a suitable dose of an agent is taken with a meal.
  • a suitable dose of an agent is taken while fasting.
  • Compound 1-263 a or a pharmaceutically acceptable salt thereof is administered as a single dose. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered every other day. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered once every three days. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered on a twice-weekly schedule. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered on a three times a week schedule. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered on a weekly schedule. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered on a once every two weeks schedule.
  • Compound 1-263 a or a pharmaceutically acceptable salt thereof is administered at least 3 times on alternate days within a 7-day cycle. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered on day 1 and day 4 of a 7-day cycle. In some embodiments, Compound I- 263a or a pharmaceutically acceptable salt thereof is administered on consecutive days in a 7-day cycle followed by an intermission. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered for 2 consecutive days followed by an intermission of 5 consecutive days for at least one 7-day cycle.
  • Compound I-263a or a pharmaceutically acceptable salt thereof is administered for 3 consecutive days followed by an intermission of 4 consecutive days for at least one 7-day cycle. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered for 4 consecutive days followed by an intermission of 3 consecutive days for at least one 7-day cycle. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered for 5 consecutive days followed by an intermission of 2 consecutive days for at least one 7-day cycle. In some embodiments, there will be periods of rest between one or more of the 7-day treatment cycles. In some embodiments, there will be a 7-day rest between one or more of the 7-day treatment cycles.
  • a treatment cycle is about 7 days to about 56 days, or more.
  • a treatment cycle is 7 days, 14 days, 21 days, 28 days, 35 days, 42 days, 49 days, or 56 days.
  • a treatment cycle is 14 days, 21 days, 28 days, or 35 days.
  • there will be periods of rest within or between one or more of the treatment cycles For example, in some embodiments, there will be a period of rest at the end of the treatment cycle. In some embodiments, there will be a period of rest between the second and third treatment cycle but not the first and second treatment cycle.
  • Dosing schedules include, for example, administering Compound I-263a once during a treatment schedule, e.g., on day 1 of a 21 day cycle, twice during a treatment cycle, e.g., on days 1 and 15 of a 21 day cycle or on days 1 and 15 of a 28 day cycle, three times during a treatment cycle, e.g., on days 1, 8 and 15 of a 21 day cycle or on days 1, 8 and 15 of a 28 day cycle, four times during a treatment cycle, e.g., on days 1, 4, 8, and 11 of a 14 days cycle, days 0, 3,
  • Day 0 of a treating cycle is one day immediately before the day that the treatment cycle starts.
  • Other dosage schedules are encompassed by the present invention.
  • Compound 1-263 a or a pharmaceutically acceptable salt thereof is administered within a 14-day cycle. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered twice weekly on days on 0,
  • Compound 1-263 a or a pharmaceutically acceptable salt thereof is administered twice weekly on days on 1, 4, 8, and 11 of the 14 day cycle. [0084] In some embodiments, Compound 1-263 a or a pharmaceutically acceptable salt thereof is administered within a 21 day cycle. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered twice weekly on days on 1,
  • Compound I-263a or a pharmaceutically acceptable salt thereof is administered twice weekly on days on 1, 4, 8, and 11 of the 21 day cycle. In some embodiments, Compound 1-263 a or a pharmaceutically acceptable salt thereof is administered twice weekly on days on 1, and 4 of the 21 day cycle. In some embodiments, Compound 1-263 a or a pharmaceutically acceptable salt thereof is administered twice weekly on days on 1, and 8 of the 21 day cycle.
  • Compound 1-263 a or a pharmaceutically acceptable salt thereof is administered within a 28 day cycle. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered twice weekly on days on 1,
  • Compound I-263a or a pharmaceutically acceptable salt thereof is administered twice weekly on days on 1, 8, 15, and 22 of the 28 day cycle.
  • the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg to about 200 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg to about 100 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg to about 50 mg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg to about 10 mg.
  • the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg to about 5 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 1 mg to about 3 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 2 mg to about 5 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 5 mg to about 10 mg.
  • the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 5 mg to about 15 mg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 10 mg to about 20 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 15 mg to about 25 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 20 mg to about 30 mg.
  • the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 25 mg to about 35 mg. In some embodiments, the amount of Compound I- 263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 30 mg to about 40 mg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 35 mg to about 45 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 40 mg to about 50 mg.
  • the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 55 mg to about 65 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 50 mg to about 100 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 90 mg to about 150 mg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 140 mg to about 200 mg.
  • the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 3 mg to about 160 mg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 1 mg. In some embodiments, the amount of Compound I- 263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 2 mg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 3 mg.
  • the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 4 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 6 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 8 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 10 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 12 mg. All dosing amounts refer to the amount of Compound I-263a administered, and do not include the weight amount of any pharmaceutically acceptable salt.
  • the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 1 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 3 mg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 6 mg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 10 mg. In some embodiments, the amount of Compound I- 263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 15 mg.
  • the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 25 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 40 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 60 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 90 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 120 mg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 160 mg.
  • the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg/kg to about 200 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg/kg to about 100 mg/kg. In some embodiments, the amount of Compound I- 263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg/kg to about 50 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg/kg to about 10 mg/kg.
  • the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg/kg to about 5 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 1 mg/kg to about 3 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 2 mg/kg to about 5 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 5 mg/kg to about 10 mg/kg.
  • the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 5 mg/kg to about 15 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 10 mg/kg to about 20 mg/kg. In some embodiments, the amount of Compound I- 263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 15 mg/kg to about 25 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 20 mg/kg to about 30 mg/kg.
  • the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 25 mg/kg to about 35 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 30 mg/kg to about 40 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 35 mg/kg to about 45 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 40 mg/kg to about 50 mg/kg.
  • the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 55 mg/kg to about 65 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 50 mg/kg to about 100 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 90 mg/kg to about 150 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 140 mg/kg to about 200 mg/kg.
  • the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 1 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 2 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 3 mg/kg.
  • the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 2.5 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 4 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 5 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 6 mg/kg.
  • the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 7.5 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 8 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 10 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 12 mg/kg.
  • the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 12.5 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 15 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 17.5 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 20 mg/kg.
  • the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 25 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 30 mg/kg. All dosing amounts refer to the amount of Compound 1-263 a administered, and do not include the weight amount of any pharmaceutically acceptable salt.
  • the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 1 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 3 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 6 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 7.5 mg/kg.
  • the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 10 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 15 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 25 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 40 mg/kg.
  • the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 60 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 90 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 120 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 160 mg/kg.
  • the at least one additional active agent is an antiviral agent, an antibiotic, a corticosteroid, interferon beta Bl, or tocilizumab.
  • the antibiotic is azithromycin.
  • the antiviral agent is chloroquine, hydroxychloroquine, remdesivir, bortezomib, ixazomib, ponatinib, lopinavir/ritonavir, darunavir/cobicistat antiviral IgG, antiviral IgM, anti-IL-6 agents, or azidothymidine (AZT).
  • the at least one additional active agent is chloroquine or hydroxylchloroquine. In some embodiments, between 300 mg and 500 mg of the chloroquine or hydroxychloroquine is administered to the subject one or twice daily for up to 5 days.
  • the at least one additional active agent is administered on a daily schedule. In some embodiments, the at least one additional active agent is administered every other day. In some embodiments, the at least one additional active agent is administered once every three days. In some embodiments, the at least one additional active agent is administered on a twice-weekly schedule. In some embodiments, the at least one additional active agent is administered on a three times a week schedule. In some embodiments, the at least one additional active agent is administered on a weekly schedule. In some embodiments, the at least one additional active agent is administered on a once every two weeks schedule. In some embodiments, the at least one additional active agent is administered on a once every three weeks schedule. In some embodiments, the at least one additional active agent is administered on a once every four weeks schedule.
  • compositions suitable for administration can be formulated into pharmaceutical compositions suitable for administration.
  • the pharmaceutical compositions may comprise pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable excipient includes, but are not limited to, any and all solvents, dispersion media, or other liquid vehicles, dispersion or suspension aids, diluents, granulating and/or dispersing agents, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, binders, lubricants or oil, coloring, sweetening or flavoring agents, stabilizers, antioxidants, antimicrobial or antifungal agents, osmolality adjusting agents, pH adjusting agents, buffers, chelants, cyoprotectants, and/or bulking agents, as suited to the particular dosage form desired.
  • any of the therapeutic agents described herein may be in the form of a pharmaceutically acceptable salt.
  • such salts are derived from inorganic or organic acids or bases.
  • suitable salts see, e.g., Berge et ah, J. Pharm. Sci., 1977, 66, 1 19 and Remington: The Science and Practice of Pharmacy, 20th Ed., A. Gennaro (ed.), Lippincott Williams & Wilkins (2000).
  • Suitable acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, lucoheptanoate, glycerophosphate, hemi sulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2 hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2 naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3 phenyl propionate, picrate, pivalate, propionate, succinate
  • Suitable base addition salts include ammonium salts; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; salts with organic bases, such as dicyclohexylamine salts, N methyl D glucamine; and salts with amino acids such as arginine, lysine, and the like.
  • salts anions adipate, alginate, aminosalicylate, anhydromethylenecitrate, arecoline, aspartate, bisulfate, butylbromide, camphorate, digluconate, dihydrobromide, disuccinate, glycerophosphate, hemisulfate, hydrofluoride, hydroiodide, methylenebis(salicylate), napadisylate (1,5 naphthalene ⁇ di sulfonate), oxalate, pectinate, persulfate, phenylethylbarbiturate, picrate, propionate, thiocyanate, tosylate and undecanoate; organic cations benethamine (N benzylphenethylamine), clemizole (1 p chloro benzyl-2 pyrrolildine-G ylmethylbenzimidazole), diethylamine, piperazine and t
  • compositions may comprise pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier refers to a material that is compatible with a recipient subject (a human) and is suitable for delivering an active agent to the target site without terminating the activity of the agent.
  • the toxicity or adverse effects, if any, associated with the carrier preferably are commensurate with a reasonable risk/benefit ratio for the intended use of the active agent.
  • compositions include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates or carbonates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene polyoxypropylene block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates or carbonates
  • glycine, sorbic acid, potassium sorbate partial glyceride mixture
  • compositions for use in the methods of the present disclosure may be manufactured by methods well known in the art such as conventional granulating, mixing, dissolving, encapsulating, lyophilizing, or emulsifying processes, among others.
  • Compositions may be produced in various forms, including granules, precipitates, or particulates, powders, including freeze dried, rotary dried or spray dried powders, amorphous powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions.
  • Formulations may contain stabilizers, pH modifiers, surfactants, solubilizing agents, bioavailability modifiers and combinations of these.
  • compositions are formulated for pharmaceutical administration to a human being.
  • Such compositions may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intraperitoneal, intramuscular, intra articular, intra synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intravenously or subcutaneously.
  • the compositions are administered orally.
  • the compositions are administered intravenously.
  • the intravenous administration can be intravenous infusion or intravenous injection.
  • the compositions are administered by an intravenous infusion.
  • the compositions are administered by an intravenous injection.
  • the compositions are administered by subcutaneous injection.
  • the compositions are administered by intravenous infusion and then subsequently administered by subcutaneous injection.
  • the anti- CD38 antibody is coadministered with human hyaluronidase subcutaneously.
  • These formulations may be designed to be short acting, fast releasing, or long acting.
  • the compositions may be administered in a local rather than systemic means, such as administration (e.g., by injection) at a tumor site.
  • compositions may be prepared as liquid suspensions or solutions using a liquid, such as an oil, water, an alcohol, and combinations of these. Solubilizing agents such as cyclodextrins may be included. Pharmaceutically suitable surfactants, suspending agents, or emulsifying agents, may be added for oral or parenteral administration. Suspensions may include oils, such as peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. Suspension preparations may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides.
  • Suspension formulations may include alcohols, such as ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol; ethers, such as poly(ethyleneglycol); petroleum hydrocarbons such as mineral oil and petrolatum; and water.
  • alcohols such as ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol
  • ethers such as poly(ethyleneglycol)
  • petroleum hydrocarbons such as mineral oil and petrolatum
  • Sterile injectable forms of these pharmaceutical compositions may be aqueous or oleaginous suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono or di glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • oils such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • compositions may be formulated for parenteral administration by injection such as by bolus injection or continuous infusion.
  • a unit dosage form for injection may be in ampoules or in multi dose containers.
  • compositions may be orally administered in any orally acceptable dosage form including capsules, tablets, aqueous suspensions or solutions.
  • aqueous suspensions When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • useful diluents include lactose and dried cornstarch.
  • carriers that are commonly used include lactose and com starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • Coatings may be used for a variety of purposes, e.g., to mask taste, to affect the site of dissolution or absorption, or to prolong drug action. Coatings may be applied to a tablet or to granulated particles for use in a capsule.
  • these pharmaceutical compositions may be administered in the form of suppositories for rectal administration.
  • suppositories may be prepared by mixing the agent with a suitable non irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract may be affected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically transdennal patches may also be used.
  • the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of the present disclosure include mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical compositions may be formulated in a suitable lotion or cream containing the active component(s) suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzyl alkonium chloride.
  • the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
  • compositions may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • a compound of formula I-263a is formulated as a solution for intravenous infusion.
  • a compound of formula I-263a is formulated in a solution with a buffering agent or a PH modifying agent, and a cyclodextrin, such as a beta-cyclodextrin.
  • the solution includes phosphoric acid and Captisol (betadex sulfobutyl ether sodium) in water.
  • a compound of formula I-263a is formulated as a drug product, wherein the drug product contains compound 1-263 a in a solution of phosphoric acid and Captisol (betadex sulfobutyl ether sodium) in water.
  • the drug product is packaged with a volume of 10 mL of compound I-263a sterile solution.
  • kits are any article of manufacture (e.g., a package or container) comprising at least one reagent or chemotherapeutic agent.
  • a kit for use in the methods herein may comprise I-263a or a pharmaceutically acceptable salt thereof.
  • the kit may further include at least one additional active agent.
  • the at least one additional active agent in the kit is an antiviral agent, an antibiotic, a corticosteroid, interferon beta Bl, or tocilizumab.
  • the antibiotic is azithromycin.
  • the antiviral agent is chloroquine, hydroxychloroquine, remdesivir, bortezomib, ixazomib, ponatinib, lopinavir/ritonavir, darunavir/cobicistat antiviral IgG, antiviral IgM, anti-IL-6 agents, or azidothymidine (AZT).
  • the present disclosure relates to a kit comprising a medicament for use in treating a viral infection in a subject in need of such treatment.
  • the kit comprises a medicament comprising I-263a, and instructions for administering I- 263a and at least one additional active agent.
  • the kit may contain a medicament comprising 1-263 and at least one additional active agent and instructions for administering 1-263 and at least one additional active agent, wherein the medicament is in single dosage form or in separate dosage forms.
  • a kit comprising 1-263 and at least one additional active agent may further include another component or reagent.
  • a reagent in the kit may be a diluent for preparing the I-263a for administration.
  • a reagent in the kit may be a diluent for preparing the at least one additional active agent for administration.
  • a component in the kit may be a vessel for mixing the combination of the 1-263 and the at least one additional active agent.
  • I-263a will be administered intravenously as a 10 mg/ml solution. The solution will be administered over a time of 60 + 10 minutes. The administration time may be expanded to up to 4 hours. I-263a will be administered on days 1 and 4 of a 21-day treatment cycle. After the treatment cycle viral load will be detected by PCR analysis of nasopharyngeal or blood samples. If PK, pharmacodynamics, decrease in viral load and safety data are supportive, the schedule can be modified but cannot exceed administration on days 1, 4, 8 and 11. A ramp-up schedule may also be evaluated.
  • the subject s National Early Warning Score (NEWS) score will be evaluated during and after the 21 -day treatment cycle.
  • a NEWS score evaluates a subject’s respiration rate, peripheral blood, supplemental oxygen, temperature, systolic blood pressure, heart rate and level of consciousness. Higher NEWS scores are associated with increased likelihood of death or admission to an intensive care unit.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Virology (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

La présente invention concerne des procédés, des compositions pharmaceutiques et des kits pour le traitement thérapeutique ou prophylactique d'un sujet atteint d'une infection virale. Le procédé comprend l'administration au sujet d'une quantité thérapeutiquement efficace d'I-263a ou d'un sel pharmaceutiquement acceptable de celui-ci.
PCT/US2021/025581 2020-04-03 2021-04-02 Procédé de traitement de patients infectés par une infection virale avec un inhibiteur de l'enzyme activant le petit modificateur de type ubiquitine WO2021203001A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130213398A1 (en) * 2010-08-23 2013-08-22 Michael M. Lipp Dry powder formulations and methods for treating pulmonary diseases
US20130245032A1 (en) * 2010-11-09 2013-09-19 Sanford-Burnham Medical Research Institute at Lake Nona Bicyclic and tricyclic inhibitors of sumoylation enzymes and methods of their use
US20160009744A1 (en) * 2014-07-01 2016-01-14 Millennium Pharmaceuticals, Inc. Heteroaryl compounds useful as inhibitors of sumo activating enzyme
WO2020014139A1 (fr) * 2018-07-09 2020-01-16 Millennium Pharmaceuticals, Inc. Administration d'inhibiteur d'enzyme d'activation sumo et anticorps anti-cd20

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130213398A1 (en) * 2010-08-23 2013-08-22 Michael M. Lipp Dry powder formulations and methods for treating pulmonary diseases
US20130245032A1 (en) * 2010-11-09 2013-09-19 Sanford-Burnham Medical Research Institute at Lake Nona Bicyclic and tricyclic inhibitors of sumoylation enzymes and methods of their use
US20160009744A1 (en) * 2014-07-01 2016-01-14 Millennium Pharmaceuticals, Inc. Heteroaryl compounds useful as inhibitors of sumo activating enzyme
WO2020014139A1 (fr) * 2018-07-09 2020-01-16 Millennium Pharmaceuticals, Inc. Administration d'inhibiteur d'enzyme d'activation sumo et anticorps anti-cd20

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