WO2021207218A1 - Traitement d'une infection à nidovirales à l'aide d'éritoran - Google Patents

Traitement d'une infection à nidovirales à l'aide d'éritoran Download PDF

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WO2021207218A1
WO2021207218A1 PCT/US2021/025987 US2021025987W WO2021207218A1 WO 2021207218 A1 WO2021207218 A1 WO 2021207218A1 US 2021025987 W US2021025987 W US 2021025987W WO 2021207218 A1 WO2021207218 A1 WO 2021207218A1
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administration
administered
patient
dose
nidovirales
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Fabian Gusovsky
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Eisai R&D Management Co., 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
    • A61K31/7024—Esters of saccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • Embodiments relate to compounds and compositions that can be used to treat nidovirales infections in an infected subject
  • Coronaviruses are a genus in the Coronaviridae family and are pleomorphic, enveloped viruses. See S. Perlman et al., Nature Reviews Microbiology, 7:439-450 (2009). Coronaviruses contain a single stranded, 5 '-capped, positive strand RNA molecule that ranges from 26-32 kb and that contains at least 6 open reading frames. Coronaviruses use host proteins as part of their replication strategies. Immune, metabolic, stress, cell cycling, and other cellular pathways are activated by infection. See Tang Y. et al., Front. Immunol.
  • Coronaviruses fall within the Nidovirales order of viruses, which also includes Arteriviridae, Roniviridae, and Mesoniviridae.
  • Coronaviruses usually cause mild to moderate upper-respiratory tract illnesses, like the common cold, in people. See “Coronaviruses,” National Institute of Allergy and Infectious Disease, https://www.niaid.nLh.gov/diseases-conditions/coronavimses (accessed on April 1, 2020); and Lee, J.S., et al., Sci. Immunol. 5 (2020). There are hundreds of coronaviruses that affect animal species. Seven coronaviruses are known to cause human disease.
  • coronaviruses Four of these coronaviruses are mild: viruses 229E, OC43, NL63 and HKUl; three of the coronaviruses can have more serious outcomes in people: SARS-CoV (causing severe acute respiratory syndrome), which emerged in late 2002 and disappeared by 2004; MERS- CoV (causing Middle East respiratory syndrome), which emerged in 2012 and remains in circulation in camels; and SARS-CoV-2 (also known as 2019-nCoV), which emerged in December 2019.
  • COVED- 19 disease is caused by the eoronavirus known as SARS-CoV-2 (also known as 2019-nCoV).
  • SARS-CoV-2 has been shown to cause mild to fatal symptoms in the human population. See Hantoushzadeh S. et aL, Arch. Med. Res. 51 : 347-348 (2020) and Ingraham N. E. et aL, Lancet Respir. Med. 8; 544-546 (2020).
  • SARS-CoV-2 viral spike protein binds with the extracellular domain of various TLRs including TLR1, TLR4, and TLR6, with the strongest binding with TLR4, The S protein plays a crucial role in host cell receptor binding and fusion properties leading to virus entry. See Patra R. et aL, JMed Virol. 93:615-617 (2021); Aboudounya M. M. et aL, Mediators Inflamm. 2021: ID 8874339; Bhattacharya, M. et aL, Infect. Genet. Evol. 85: 104587 (2020).
  • SARS-CoV-2 S proteins resemble features of class I viral proteins, wherein they are constituted of 2 subunits, S 1 , containing the receptor binding domain (RBD) and S2, containing the fusion entry domain. Binding of the RBD to the host cell receptor induces conformational changes resulting in activation of the protease cleavage site upstream of the fusion domain followed by release and activation of the S2 fusogenic domain. These conformational changes allow SARS-CoV-2 to infiltrate a cell and begin replication. See Khanmohammadi S. et aL, J Med Virol. 1—5 (2021). SARS-CoV-2 S protein contains a furin cleavage site located at the boundary of SI and S2 enabling rapid processing of the S protein during biosynthesis in host cells.
  • Embodiments relate, at least in part, to a compound of formula (I) or pharmaceutically acceptable salts thereof, that can be used to treat nidovirales infections in an infected subject. More specifically, embodiments relate to eritoran or a pharmaceutically acceptable salt thereof that can be used to treat subjects infected with nidovirales to limit the effects and duration of infection.
  • the compound of formula (I) can reduce nidovirales-induced cytokine production and reduce nidovirales-associated pathology.
  • the compound of formula (1) can prevent the decrease in lung function or can improve lung function in a patient infected with a nidovirales virus.
  • One embodiment pertains to a method for treating a patient infected with a nidovirales virus comprising administering to the infected patient a therapeutically effective amount of eritoran or a pharmaceutically acceptable salt thereof.
  • Another embodiment pertains to a method for treating a patient infected with a nidovirales virus comprising administering to the infected patient a composition comprising an active ingredient and a pharmaceutically acceptable carrier wherein the active ingredient comprises eritoran or a pharmaceutically acceptable salt thereof.
  • a further embodiment pertains to a method for mitigating nidovirales-induced disease comprising administering to the infected animal a therapeutically effective amount of a TLR4 antagonist, wherein the TLR4 antagonist comprises eritoran or a pharmaceutically acceptable salt thereof.
  • a still further embodiment pertains to a method further comprising administering to the infected patient a therapeutically effective amount of an antiviral compound.
  • a still yet further embodiment pertains to a method wherein the infected patient is administered a therapeutically effective amount of eritoran or a pharmaceutically acceptable salt thereof following testing positive for the presence of nidovirales infection,
  • Another embodiment pertains to a method wherein the infected patient tested for the presence of nidovirales infection using PCR, rt-PCR, nucleic acid amplification tests (NAAT), direct antigen detection tests, virus isolation in cell culture, or combinations thereof.
  • PCR rt-PCR
  • NAAT nucleic acid amplification tests
  • a further embodiment pertains to a method further comprising causing a decrease in nidovirales-induced cytokine mRNA levels in the infected patient.
  • Another embodiment pertains to a method further comprising causing a decrease in nidovirales-induced cytokine mRNA or protein levels in the infected patient wherein the cytokines comprise TNF-a, IL- ⁇ , EL-6, IL-12 p40, KC, IL-10, IL-5, TGF- ⁇ or combinations thereof
  • Another embodiment pertains to a method further comprising causing a decrease in nidovirales-induced COX-2 mRNA or protein levels in the infected patient.
  • Another embodiment pertains to a method further comprising causing a decrease in nidovtrales-induced interferon-beta or interferon gamma mRNA levels in the infected patient.
  • a further embodiment pertains to a method wherein the infected patient is administered a therapeutically effective amount of eritoran or a pharmaceutically acceptable salt thereof following the onset of clinical symptoms, wherein the clinical symptoms comprise systemic myalgia, headache, cough, fever, pneumonia or combinations thereof.
  • a further embodiment pertains to a method wherein the composition is administered by one of the routes comprising intravenous administration, intraperitoneal administration, intramuscular administration, intracoronary administration, intraarterial administration, mtradermal administration, transdermal delivery, intratracheal administration, subcutaneous administration, intraarticular administration, intraventricular administration, inhalation, intracerebral, nasal, naval, oral, intraocular, pulmonary administration, impregnation of a catheter, by suppository and direct injection into a tissue, or systemically absorbed topical or mucosal administration.
  • routes comprising intravenous administration, intraperitoneal administration, intramuscular administration, intracoronary administration, intraarterial administration, mtradermal administration, transdermal delivery, intratracheal administration, subcutaneous administration, intraarticular administration, intraventricular administration, inhalation, intracerebral, nasal, naval, oral, intraocular, pulmonary administration, impregnation of a catheter, by suppository and direct injection into a tissue, or
  • a further embodiment pertains to a method wherein the effects of administering eritoran or pharmaceutically acceptable salts thereof prevent a decrease in lung function or cause an improvement in lung function in the infected patient.
  • a further embodiment pertains to a method wherein the infected patient is administered a therapeutically effective amount of eritoran or a pharmaceutically acceptable salt thereof in a range of from between about 1 pg to about 240 mg, per total dose.
  • a further embodiment pertains to a method wherein the patient is infected with a nidovirales virus selected from the group comprising coronavirus, aterivims, ronivirus, and mesonivims or combinations thereof.
  • the coronavirus is selected from the group comprising 229E, OC43, NL63, HKU1, SARS-CoV, MERS-CoV, and SARS-CoV-2.
  • the coronavirus is SARS-CoV-2.
  • the nidovirales-induced disease is pneumonia.
  • a further embodiment includes method for treating or preventing pneumonia in a patient infected with coronavirus comprising: administering to the infected patient a therapeutically effective amount of a TLR4 antagonist, wherein the TLR4 antagonist comprises eritoran or a pharmaceutically acceptable salt thereof.
  • the therapeutically effective amount of a TLR4 antagonist is administered by a dosing regimen comprising a first and second dose, and subsequent doses, wherein the first dose and second dose are each 10 to approximately 30 mg, and the second dose is administered 12 hours following said first dose; and wherein the subsequent doses are administered once every 12 hours for up to 14 days, and are each 2 mg to approximately 10 mg.
  • the therapeutically effective amount of a TLR4 antagonist is administered by a dosing regimen comprising a first and second dose, and subsequent doses, each given at 12 hour intervals, wherein the first dose is approximately 26 to approximately 27 mg, the second dose is approximately 13 to approximately 14 mg, and up to twenty eight doses each of approximately 6 to approximately 7 mg.
  • the therapeutically effective amount of a TLR4 antagonist is administered by a dosing regimen comprising a first and second dose, and subsequent doses, each given at 12 hour intervals, wherein the first dose is 26.24 mg administered at a rate of 6.56 mg/h over 4 hours, the second dose is 13,12 mg administered at a rate of 6.56 mg/h over 2 hours, and up to twenty five 6.56 mg doses administered at a rate of 3.28 mg/h over 2 hours.
  • additional doses of the 6.56 mg doses are administered at a rate of 3.28 mg/h over 2 hours until the patient is discharged from a hospital.
  • a further embodiment provides a method for improving lung function in a patient infected with coronavirus comprising: administering to the infected patient a therapeutically effective amount of a TLR4 antagonist, wherein the TLR4 antagonist comprises eritoran or a pharmaceutically acceptable salt thereof.
  • the therapeutically effective amount of a TLR4 antagonist is administered by a dosing regimen comprising a first and second dose, and subsequent doses, wherein the first dose and second dose are each 10 to approximately 30 mg, and the second dose is administered 12 hours following the first dose; and subsequent doses are administered once every 12 hours for up to 14 days, and are each 2 mg to approximately 10 mg.
  • the therapeutically effective amount of a TLR4 antagonist is administered by a dosing regimen comprising a first and second dose, and subsequent doses, each given at 12 hour intervals, wherein the first dose is approximately 26 to approximately 27 mg, the second dose is approximately 13 to approximately 14 mg, and up to twenty eight doses each of approximately 6 to approximately 7 mg.
  • the therapeutically effective amount of a TLR4 antagonist is administered by a dosing regimen comprising a first and second dose, and subsequent doses, each given at 12 hour intervals, wherein the first dose is 26.24 mg administered at a rate of 6.56 mg/h over 4 hours, the second dose is 13.12 mg administered at a rate of 6.56 mg/h over 2 hours, and up to twenty- five 6.56 mg doses administered at a rate of 3.28 mg/h over 2 hours.
  • additional doses of the 6.56 mg doses are administered at a rate of 3.28 mg/h over 2 hours until the patient is discharged from a hospital.
  • improved lung function is demonstrated by the patient’s reduced need for a ventilator following administration of the TLR.4 antagonist.
  • the innate immune system is the first line of defense against invading microorganisms.
  • Immune competent cells such as macrophages, dendritic cells, neutrophils, and endothelial cells recognize pathogen-associated molecular patterns (PAMPS) on the surface of pathogens, as diverse as Gram-positive and Gram-negative bacteria, viruses, fungi, and Mycoplasma.
  • PAMPS pathogen-associated molecular patterns
  • the toll-like receptors (TLRs) are a family of closely related receptors that trigger cellular innate immune signaling pathways in response to discreet stimuli defined by conserved PAMPS. To date, ten different human TLRs have been identified.
  • TLR4 is typically associated with activating innate immune signaling in response to lipopolysaccharide (LPS) produced during infection by Gram-negative bacteria. It was previously shown, however, that TLR4-deficient mice were strongly resistant to infection by a mouse-adapted strain of influenza, A/PR/8/34. (Q.M. Nhu et al., Mucosal Immunology, Vol. 3, No. 1 : 29-39, (2010)). TLR4 mutant mice have also been shown to display natural resistance to acid-induced acute lung injury. (Y.
  • TLR4-/- mice are resistant to lethal influenza challenge. Shirey et al., Nature 497(7450): 498-502 (2013). Furthermore, Shirey et al. demonstrated that blocking TLR4 signaling protected mice from lethal influenza challenge following treatment of mice with the TLR4 antagonist, eritoran. However, there are no studies indicating whether inhibition of TLR4 in infected subjects may provide potential therapeutic effects following coronavirus infection.
  • Eritoran also known as E5564, compound 1287, SGEA or (a-D-Glucopyranose, 3-0- decyl-2-deoxy-6-0-[2-deoxy-3-0-[(3R)-3-methoxydecyl)-6-0-methyl-2-[[ ⁇ - 1 lZ)-l-oxo-l 1- octadecenyl)ammo]-4-0-phosphcmo-p-D-glucopyranosyl]-2-[( 1 ,3-dioxotetradecyl)amino]- 1 - (dihydrogen phosphate)) has previously been shown to be an effective antagonist of TLR4.
  • Eritoran is described as compound 1 in U.S. Pat. No. 5,681,824, which is incorporated herein by reference for its description of compound 1 and methods of making same.
  • Eritoran has the structure of formula (I): and may be provided as one of a number of pharmaceutically acceptable salts.
  • Sodium salts of eritoran are described, for example, in U.S. Pat. No. 8,207,144, which is incorporated herein by reference in its entirety for the description of such salt forms and methods for preparing same.
  • the compound of formula (I) may be prepared in the form of a micelle, as described in U.S. Pat No. 6,906,042, which is incorporated herein by reference in its entirety for the description of such micelles and methods for preparing same.
  • Eritoran was originally recognized as potentially useful for its activity against bacterial endotoxin, a toxic substance called Hpopolysaccharide (LPS). Some mechanisms of innate immune activation are attributable to LPS. See Brade, H., et al., Endotoxin in Health and Disease. 1999; Marcel Dekker, New York.
  • LPS signaling requires multiple components. These include a hexameric complex of two LPS molecules, two myeloid differentiation factor 2 (MD2) adaptor proteins, and two molecules of the cell bound receptor Toll-like receptor 4 (TLR4). When properly aligned these molecules form a signaling complex that activates immune cells expressing TLR.4. This results in an influx of acute phase proteins and mediators and terminates in fatal endotoxic shock.
  • MD2 myeloid differentiation factor 2
  • TLR4 cell bound receptor Toll-like receptor 4
  • TLR4 was originally believed to only be relevant to LPS signaling, TLR4 interaction was later found in other tissue injury and in non-bacterial pathogens. See Baily, et al., “Inflammatory Response to Installation of Oxidized Surfactant in a Rat Model of Surfactant Deficiency,” J. Appl. Physiol. (2004); 96: 164- 1680; Fei Zhou, et al., “Clinical Course and Risk Factors for Mortality of Adults with COVID-19 in Wuhan. China: A Retrospective Cohort Study,” Lancet (2020) 395:1054-1062.
  • Eritoran blocks TLR4 signaling and functions similar to tlr4-/tlr4- mice, which are refractory from death from acid-induced lung injury, oxidative stress and lung injury due to oxidized phospholipids (OxPL).
  • the intracellular adapter molecule used to pair with TLR4 in the lung is TRIP (Toll-like Receptor-domain-containing adaptor-inducing interferon-beta), and not MyD88.
  • TLR4 expression in mildly injured lung tissue exacerbates the inflammatory process when exposed to oxidized phospholipids. Eritoran’s inhibition of TLR4 limits acute lung injury to a variety of injurious stimuli.
  • eritoran is not known to be a direct antiviral agent for treatment of SARS-CoVl or SARS-CoV2, the production of oxidized phospholipids in response to influenza, H1N1, H3N2, SARS-CoVl, and avian influence H5N could create a plausible mechanism of action for use of eritoran in treatment of SARS-CoV2.
  • Eritoran as a TLR4 inhibitor, may protect injured lung tissue from the continuous pro-inflammatory damage induced by SARS-CoV2 related oxidized phospholipids. Lung injury in COVID-19 occurs over several days to two weeks or more, allowing eritoran ample time to affect the inflammatory response.
  • the spike protein of COVID-19 (the major infective protein of SARS-CoV-2) strongly binds with the ACE2 receptors protein from human and bat origin.
  • Cell surface TLRs, especially TLR4 was most likely to be involved in recognizing molecular patterns from SARS-CoV-2 to induce inflammatory response.
  • Molecular docking studies demonstrated significant binding of the native spike protein of SARS-CoV-2 to TLR1, TLR4, and TLR6. See Choudbury, et aL, “ha Silico Studies on the Comparative Characterization of the Interactions of SARS-CoV-2 Spike Glycoprotein with ACE2 Receptor Homologs and Human TLRs,” J. Med. Virology (2020) 1-9.
  • Embodiments reported herein are directed to methods of treating respiratory virus infections and more particularly, for treating infections by nidovirales viruses.
  • Another embodiment provides a method of treating coronavirus infection in an animal by administering to the animal an inhibitor of TLR4.
  • One embodiment pertains to methods to treat coronavirus infection in an animal by administering to the animal a therapeutically effect amount of eritoran or a pharmaceutically acceptable salt thereof.
  • Another embodiment pertains to methods to treat coronavirus infection by reducing viral replication in an infected host by inhibiting TLR4.
  • Compounds suitable for use with the methods reported herein include inhibitors of TLR4.
  • methods are practiced using eritoran or a pharmaceutically acceptable salt thereof to inhibit TLR4 signaling.
  • Eritoran is a synthetic lipid A analog that interferes with LPS signaling through TLR4. Eritoran and pharmaceutically acceptable salts thereof competitively inhibit LPS to bind the hydrophobic pocket of MD-2. Kim, H.M. et aL, Cell 130:906-917 (2007). When bound, eritoran or a pharmaceutically acceptable salt thereof prevents TLR4 dimerization and intracellular signaling.
  • Eritoran was previously found to have an excellent safety profile in humans and, thus, makes it a suitable compound for early pharmaceutical intervention in infected patients. Opal, S.M. et al.,JAMA 309(11):1154-1162 (2013). Further, because eritoran targets TLR4, which is upstream of IL-6, administering eritoran may provide broader protection against SARS- CoV-2-induced inflammation than current clinical COVID-19 therapies that target IL-6 alone.
  • treatment with eritoran or a pharmaceutically acceptable salt thereof decreases coronavirus induced pathology.
  • Symptoms associated with respiratory virus infection, and more particularly associated with coronavirus infection include among others systemic myalgia, headache, cough, fever and pneumonia. Frequently, coronavirus infection leads to cellular damage to the lungs.
  • treatment of an infected subject with eritoran or a pharmaceutically acceptable salt thereof dramatically reduces cellular damage in the lung tissue.
  • treatment with eritoran or a pharmaceutically acceptable salt thereof in the days following infection may lead to reduced systemic effects of coronavirus infection.
  • coronavirus-induced increases in liver enzyme levels are reduced by treatment with eritoran or a pharmaceutically acceptable salt thereof.
  • TLR4 is antagonized to decrease expression of coronavirus-induced cytokine RNA expression in coronavirus infected subjects.
  • the TLR4 antagonist, eritoran or a pharmaceutically acceptable salt thereof may result in a decrease in the production of coronavirus-induced cytoldne RNA expression in infected subjects.
  • the TLR4 pathway may be targeted by eritoran to reduce production of inflammatory cytokines in subjects infected with coronaviruses.
  • eritoran or a pharmaceutically acceptable salt thereof is used to reduce coronavirus-induced expression of interferon-beta RNA expression in subjects infected with coronavirus.
  • eritoran or a pharmaceutically acceptable salt thereof is used to reduce coronavirus-induced expression of interferon-gamma RNA expression in subjects infected with coronavirus.
  • eritoran treatment of subjects infected with coronavims does not reduce coronavirus-induced expression of interferon-alpha 4.
  • eritoran treatment of subjects infected with coronavirus does not reduce coronavirus-induced expression of interferon-delta 2.
  • eritoran treatment of infected subjects may be used to decrease coronavirus-induced expression of specific species of interferon without affecting the expression of other species of interferon. Methods and compositions reported herein may also be used for decreasing TLR4-mediated expression of TNF-a, IL- ⁇ , EL-6, COX-2, IL-12 p40, KC, IL-10, EL-5 and TGF- ⁇ .
  • the effects of eritoran or a pharmaceutically acceptable salt thereof result in decreased coronavirus replication in infected subjects compared to untreated subjects. While not wishing to be bound to any particular theory, it is believed that eritoran or a pharmaceutically acceptable salt thereof s inhibitory effects on TLR4 signaling produces a cellular environment that is less suitable to virus growth.
  • Methods and compounds reported herein may be used to treat any strain of coronavirus infection. According to one embodiment, the methods pertain to treatment of SARS-CoV-2 infection. In addition, methods and compounds herein may also be used to treat other nidovirales infections.
  • a method as reported herein includes detecting the presence of coronavims infection in the respiratory specimens of a subject.
  • a number of different laboratory diagnostic tests can be used for detecting the presence of coronavimses in respiratory specimens, including direct antigen detection tests, vims isolation in cell culture, detection of coronavims-specific RNA by real-time reverse transcriptase-polymerase chain reaction (rRT-PCR) or others.
  • treatment may begin within up to about 6 days following infection with coronavirus or up to 7 days following the onset of clinical symptoms. See Bouadma, L. et al., Intensive Care Medicine 46:579-582 (2020) at Fig, 1 for time windows for interventions. According to a preferred embodiment, treatment may begin within up to about 4 days following the onset of clinical symptoms from a coronavims infection. According to a more preferred embodiment, treatment may begin within up to about 2 days following infection with coronavims.
  • Embodiments relate to methods of treating subjects suffering front a virus infection, or more specifically subjects suffering from coronavirus infection.
  • a total dose may be administered from between approximately lpg to approximately 1000 mg. In one embodiment, a total dose may be administered from between approximately 1 pg to approximately 400 mg. In another embodiment a total dose may be administered from between approximately 1 pg to approximately 300 mg. In yet another embodiment, a total dose may be administered from between approximately 1 pg to approximately 250 mg.
  • a total dose may be administered from between approximately 1 pg to approximately 125 mg. In yet another embodiment, a total dose may be administered from between approximately 1 pg to approximately 150 mg. In yet another embodiment, a total dose may be administered from between approximately 1 pg to approximately 200 mg. In another embodiment, a total dose may be administered between approximately 100 pg to approximately 250 mg. In another embodiment, a total dose may be administered between approximately 1 mg and approximately 300 mg. In another embodiment, a total dose may be administered between approximately 40 mg and approximately 300 mg. In another embodiment, a total dose may be administered between approximately 50 mg and approximately 250 mg. In another embodiment, a total dose may be administered between approximately 175 mg and approximately 250 mg. In another embodiment, a total dose may be administered between approximately 200 mg and approximately 220 mg.
  • the total dose may be administered over a course of several days until a patient’s lung function has improved.
  • the dosing regimen includes a first and second dose (“loading dose”) from between lpg to approximately 50 mg, lpg to approximately 40 mg, lpg to approximately 30 mg, lpg to approximately 20 mg, 1 pg to approximately 15 mg, or 1 pg to approximately 10 mg.
  • the first and second loading dose amounts may be the same or different.
  • the dosing regimen includes a first and second dose each from between approximately 10 mg to approximately 50 mg, approximately 10 mg to approximately 40 mg, approximately 10 mg to approximately 30 mg, approximately 25 mg to approximately 28 mg, or approximately 26 mg to approximately 27 mg.
  • the second loading dose is one-half of the first loading dose, e.g., the first dose is approximately 26 mg and the second dose is approximately 13 mg.
  • the first and second doses are administered 12 hours apart.
  • the loading dose is followed by a subsequent lower dose (“maintenance dose”) given once every 12 Ins from between lgg to approximately 20 mg, lpg to approximately 15 mg, lpg to approximately 10 mg, lpgto approximately 8 mg, lpg to approximately 6 mg, or lpg to approximately 4 mg.
  • each of the maintenance doses is from between approximately lOOpg to approximately 20 mg, approximately 1 mg to approximately 15 mg, approximately 2 mg to approximately 10 mg, approximately 4 mg to approximately 8 mg, or approximately 6 mg to approximately 7 mg, each administered 12 hours apart.
  • the maintenance dose is continued until a patient’s lung function has improved, e.g., over the course of 4, 6, 8, 10, 12, 14, 16,
  • the dosing regimen includes a 26.24 mg loading dose (6.56 mg/h x 4 hours), a second 13.12 mg loading dose (6.56 mg/h ⁇ 2 hours) at 12 hours, and up to twenty eight 6.56 mg maintenance doses (3.28 mg/h * 2 hours) one every 12 hours thereafter up to 14 days (or until cessation of hospital care).
  • eritoran or a pharmaceutically acceptable salt thereof may also be administered to patients by intravenous infusion over a period of 12- 100 hours, e.g., 60-80 or 72 hours.
  • the infusion dosage rate may vary, for example, 0.001-0.5 mg/kg body weight/hour, e.g., 0.01-0.2 mg/kg/hour or 0.03-0.1 mg/kg/hour.
  • the infusion of eritoran or a pharmaceutically acceptable salt thereof can, if desired, be preceded by a bolus injection of eritoran or a pharmaceutically acceptable salt thereof, which can be given at a dosage of 0.001-0.5 mg/kg body weight.
  • the total amount of eritoran or a pharmaceutically acceptable salt thereof administered to a patient can be, for example, 50-600 mg of drug, e.g., 150-500 mg, by infusion over a period of 60-80 hours.
  • eritoran or a pharmaceutically acceptable salt thereof may be administered to patients by intravenous infusion over a period of 1-10 hours for a total daily dose of between 1 — 20 mg.
  • the total amount of eritoran or pharmaceutically acceptable salt thereof administered to a patient may be between about 1 and about 10 mg in a daily dose, administered by intravenous infusion over a period of up to 5 hours.
  • the total amount of eritoran or a pharmaceutically acceptable salt thereof administered to a patient is 5 mg in a daily dose, administered by intravenous infusion over a period of about 1 hour. In one embodiment, the total amount of eritoran or a pharmaceutically acceptable salt thereof administered to a patient is 5mg in a daily dose, administered by intravenous infusion over a period of about 4 hours.
  • the quantity and method of administration may vary during the course of treatment. For example, a patient may first receive eritoran or a pharmaceutically acceptable salt thereof by intravenous injection during the initial stage of infection to be followed by inhalation methods of administration for a series of days, including up to about 14 days post-infection.
  • eritoran is reconstituted in D5 W for administration by infusion.
  • the typical eritoran dosage form is a sterile, white, freeze-dried cake or powder, containing 6.56 mg of eritoran in a clear glass vial.
  • the eritoran is reconstituted with sterile water for injection, USP.
  • the resulting solution which is clear and colorless, is diluted with 5% dextrose injection, USP, before IV infusion.
  • Appropriate frequency of administration may also be determined by one of skill in the art.
  • the drug may be administered 1 -4 times per day, preferably 2 - 4 times per day.
  • Administration may be continuous over a selected period of time or may be in a series of spaced doses.
  • Administration of the drug may continue until symptoms of the infection have disappeared. In some cases, it may be preferable to continue administration for several days. In one embodiment, administration may continue for several days after clinical symptoms of infection have disappeared.
  • specific dosage ranges and pharmaceutical formulations may vary according to the method of administration and the specific physical characteristics of the subject being treated.
  • pharmaceutical formulations contemplated for use herein include those disclosed in U.S. Patent Application Ser. No. 16/713,027.
  • eritoran or a pharmaceutically acceptable salt thereof may be administered in combination with one or mote additional therapeutic agents.
  • additional therapeutic agents may be, for example, an antiviral compound intended to be active against COVID-19 infection, a systemic corticosteroid, or an immune modulatory agent intended to influence host response to COVID- 19 infection.
  • Administration of two agents in combination could be sequential or simultaneous administration, either separately or in a single dosage form.
  • the term “effective amount” of a compound refers to a sufficient amount of the compound that provides a desired effect but with no- or acceptable-toxicity. This amount may vary from subject to subject, depending on the species, age, and physical condition of the subject, the severity of the disease that is being treated, the particular compound used, its mode of administration, and the like. A suitable effective amount may be determined by one of ordinary skill in the art.
  • Treatment are defined as the application or administration of a therapeutic agent to a subject, or to an isolated tissue or cell line from a subject.
  • the subject generally has a disease or disorder, a symptom of disease or disorder or a predisposition toward a disease or disorder (e.g., coronavirus).
  • treatment is directed at subjects already infected with a virus, such as coronavirus, as opposed to subjects that have not yet been infected.
  • the purpose of treatment is generally to cure, heal, alleviate, relieve, remedy, ameliorate, or improve such disease, disorder, or symptoms.
  • Treatment refers to the disease or disorder being cured, healed, alleviated, relieved, remedied, ameliorated, or improved.
  • therapeutically effective amount is used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. This response may occur in a tissue, system (animal including human) that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et ah , describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).
  • the salts can be prepared in situ during the final isolation and purification of the compounds taught herein, or separately by reacting a free base or free acid function with a suitable reagent, as described generally below. For example, a free base function can be reacted with a suitable acid.
  • suitable pharmaceutically acceptable salts thereof may, include metal salts such as alkali metal salts, e.g., sodium or potassium salts; and alkaline earth metal salts, e.g., calcium or magnesium salts.
  • metal salts such as alkali metal salts, e.g., sodium or potassium salts
  • alkaline earth metal salts e.g., calcium or magnesium salts.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such its acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such its acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, peroxine sodium sulf
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • the compound of formula (I) is a sodium salt, e.g., a tetr as odium salt.
  • the term “subject” refers to an animal, preferably a mammal, and most preferably a human, who is the object of treatment, observation or experiment.
  • the mammal may be selected from the group consisting of mice, rats, hamsters, gerbils, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, giraffes, platypuses, primates, such as monkeys, chimpanzees, and apes.
  • the subject is a human.
  • the terms “antagonist” and “inhibitor” refer to molecules or compounds that inhibit the action of a “native” or “natural” molecules or compounds.
  • systemic administration refers to any means by which the compounds described herein can be made systemically available.
  • systemic administration encompasses intravenous administration, mtraperitoneal administration, intramuscular administration, intracoronary administration, intraarterial administration (e.g., into a carotid artery), intradermal administration, subcutaneous administration, transdermal delivery, intratracheal administration, subcutaneous administration, mtraarticular administration, intraventricular administration, inhalation (e.g., aerosol), intracerebral, nasal, naval, oral, intraocular, pulmonary administration, impregnation of a catheter, by suppository and direct injection into a tissue, or systemically absoibed topical or mucosal administration.
  • Mucosal administration includes administration to the respiratory tissue, e.g., by inhalation, nasal drops, ocular drop, etc.; anal or vaginal routes of administration, e.g., by suppositories; and the like.
  • the compounds described herein are administered intravenously.
  • the compounds described herein are administered orally.
  • the compounds described herein may be administered intravenously one to five times a week.
  • the compounds described herein may be administered orally one or more times a day (e.g., once a day, twice a day or three times a day).
  • compositions suitable for use as reported herein may also include excipients, preservatives, pharmaceutically acceptable carriers and combinations thereof, die term “pharmaceutically acceptable carrier or excipient” means a carrier or excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable carrier or excipient” as used in the specification and claims includes both one and more than one such carrier or excipient.
  • excipients include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, saline, syrup, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and polyacrylic acids such as Carbopols.
  • compositions can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying agents; suspending agents; preserving agents such as methyl-, ethyl-, and propyl-hydroxy-benzoates; pH adjusting agents such as inorganic and organic acids and bases; sweetening agents; and flavoring agents.
  • lubricating agents such as talc, magnesium stearate, and mineral oil
  • wetting agents such as talc, magnesium stearate, and mineral oil
  • emulsifying agents such as methyl-, ethyl-, and propyl-hydroxy-benzoates
  • pH adjusting agents such as inorganic and organic acids and bases
  • sweetening agents such as inorganic and organic acids and bases
  • flavoring agents such as talc, magnesium stearate, and mineral oil.
  • Methods as reported herein may also be used in combination with other treatment regimes.
  • one embodiment pertains to combination therapy in which eritoran or a pharmaceutically acceptable salt thereof is used in combination with one or more antiviral drugs.
  • the secondary objectives of the study are: (a) to evaluate whether eritoran has superior efficacy compared to placebo/standard of care on improvement in Sp02 within 48h of treatment initiation in patients with COVID 19 infection with compromised lung function;
  • This Phase H/III study is a multicenter, multiple dose, randomized, double-blind, placebo-controlled, parallel-group study in PCR positive COVID-19 patients admitted to hospitals with compromised lung function.
  • Approximately 400 subjects will be randomized to 2 treatment groups in a ratio of 1 : 1 and will receive eritoran or placebo according to the following schedule.
  • Subjects receiving eritoran will receive it intravenously after 7 mg/vial of eritoran is reconstituted using D5W (dextrose 5% in water).
  • Subjects receiving placebo will receive saline control solution intravenously.
  • Approximately 600 subjects will be screened to provide 400 randomized subjects.
  • the dosing regimen includes a 26.24 mg loading dose (6.56 mg/h ⁇ 4 hours, or placebo), a second 13.12 mg loading dose (6.56 mg/h ⁇ 2 hours or placebo) at 12 hours, and up to twenty five 6.56 mg maintenance doses (3.28 mg/h ⁇ 2 hours or placebo) one every 12 hours thereafter up to 14 days (or until cessation of hospital care).
  • Matching placebo will be administered on the same schedule. Dosing will be stopped if a patient is discharged from a hospital. Dosing may continue at the Physician's discretion for another maintenance cycle.
  • the end of the study will be the date of the clinical database lock, i.e., when all study data are collected and data validation is completed.
  • the maximum estimated period for each subject on study is anticipated to be approximately 30 days.
  • Patients may be excluded from the study for any one of the following reasons: (a) patient has already received any dose of one or more of any form of eritoran or apremilast or other immune modulators (anakinra, apremilast, interferon, sarilumab, tocilizumab, crisaborole or roflumilast) during the hospitalization of the study; (b) patient is on long-term therapy or has been randomized in a trial evaluating an immune modulation agent for confirmed COVID-19 infection, where the protocol of that trial requires ongoing administration of Investigational Product with any of those immune modulators prior to this hospital admission; (c) the treating clinician believes that participation in the domain would not be in the best interests of the patient; (d) known active current or history of mycobacterial disease; (e) patients receiving a mean dose of >0.5 mg/kg prednisone or equivalent dose of another agent) in the 7 days prior to eligibility assessment, except if used as a treatment for septic shock or severe CO
  • Each intervention will be evaluated for efficacy on the Superiority Criteria compared to the respective control arm in the primary analysis population (only blinded patients). If there is a greater than 99% posterior probability that an intervention is superior to the control arm, then it will be declared superior based on the above criteria.
  • the Primary endpoint is a composite of in-hospital mortality and the number of days free of organ failure support while admitted to an ICU through 21 days from the time of enrollment.
  • the key secondary endpoint is a dichotomous endpoint for the 28-day recovery status.
  • the domain-specific key secondary endpoint is defined as a 28-day recovery. A patient is considered recovered if they are alive on day 28 and free of respiratory or cardiovascular support on day 28. Patients that have died or remain on respiratory or cardiovascular support on day 28 will be considered as not recovered.

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Abstract

Des modes de réalisation concernent l'éritoran ou un sel pharmaceutiquement acceptable de celui-ci, destiné à être utilisé dans des procédés de traitement d'infections à nidovirales chez un sujet, de préférence choisies dans le groupe constitué par le coronavirus, l'atérivirus, le ronivirus et le mésonivirus.
PCT/US2021/025987 2020-04-06 2021-04-06 Traitement d'une infection à nidovirales à l'aide d'éritoran WO2021207218A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5681824A (en) 1995-06-05 1997-10-28 Eisai Co., Ltd. Substituted liposaccharides useful in the treatment and prevention of endotoxemia
WO2005027826A2 (fr) * 2003-07-14 2005-03-31 Eisai, Co, Ltd. Methodes de traitement du syndrome respiratoire aigu severe
US6906042B2 (en) 2000-02-18 2005-06-14 Eisai Co., Ltd. Micelles
US20080227991A1 (en) 2006-11-22 2008-09-18 Eisai R&D Management Co., Ltd. Sodium salt of disaccharide compound, production method and use of same
WO2013148072A1 (fr) * 2012-03-28 2013-10-03 University Of Maryland Administration d'eritoran ou des sels pharmaceutiquement acceptables de celui-ci pour traiter des infections à orthomyxovirus

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5681824A (en) 1995-06-05 1997-10-28 Eisai Co., Ltd. Substituted liposaccharides useful in the treatment and prevention of endotoxemia
US6906042B2 (en) 2000-02-18 2005-06-14 Eisai Co., Ltd. Micelles
WO2005027826A2 (fr) * 2003-07-14 2005-03-31 Eisai, Co, Ltd. Methodes de traitement du syndrome respiratoire aigu severe
US20080227991A1 (en) 2006-11-22 2008-09-18 Eisai R&D Management Co., Ltd. Sodium salt of disaccharide compound, production method and use of same
US8207144B2 (en) 2006-11-22 2012-06-26 Eisai R & D Management Co., Ltd. Sodium salt of disaccharide compound, production method and use of same
WO2013148072A1 (fr) * 2012-03-28 2013-10-03 University Of Maryland Administration d'eritoran ou des sels pharmaceutiquement acceptables de celui-ci pour traiter des infections à orthomyxovirus

Non-Patent Citations (31)

* Cited by examiner, † Cited by third party
Title
"Coronaviruses", NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASE, 1 April 2020 (2020-04-01), Retrieved from the Internet <URL:https://www.niaid.nih.gov/disea.ses-conditions/coronaviruses>
ABOUDOUNYA M. M. ET AL., MEDIATORS INFLAMM., 2021
ABOUDOUNYA MOHAMED M. ET AL: "COVID-19 and Toll-Like Receptor 4 (TLR4): SARS-CoV-2 May Bind and Activate TLR4 to Increase ACE2 Expression, Facilitating Entry and Causing Hyperinflammation", MEDIATORS OF INFLAMMATION., vol. 2021, 14 January 2021 (2021-01-14), GB, pages 1 - 18, XP055813605, ISSN: 0962-9351, Retrieved from the Internet <URL:https://downloads.hindawi.com/journals/mi/2021/8874339.pdf> DOI: 10.1155/2021/8874339 *
AKIRA: "Pathogen Recognition Innate Immunity", CELL, vol. 124, 2006, pages 783 - 801, XP003018351, DOI: 10.1016/j.cell.2006.02.015
ANONYMOUS: "Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community- Acquired Pneumonia - TREMAP-CAP", CLINICALTRIALS.GOV, 8 October 2020 (2020-10-08), pages 1 - 21, XP055813353, Retrieved from the Internet <URL:https://www.clinicaltrials.gov/ct2/show/record/NCT02735707?term=eritoran&cond=covid&draw=2&rank=1> [retrieved on 20210614] *
BAILY ET AL.: "Inflammatory Response to Installation of Oxidized Surfactant in a Rat Model of Surfactant Deficiency", J, APP/. PHYSIOL., vol. 96, 2004, pages 164 - 1680
BHATTACHARYA, M. ET AL., INFECT. GENET. EVOL., vol. 85, 2020, pages 104587
BOUADMA, L, INTENSIVE CARE MEDICINE, vol. 46, 2020, pages 579 - 582
BRADE, H.: "Endotoxin in Health and Disease", 1999, MARCEL DEKKER
CHANNAPPANAVAR RUDRAGOUDA ET AL: "Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology", SEMINARS IN IMMUNOPATHOLOGY, SPRINGER BERLIN / HEIDELBERG, DE, vol. 39, no. 5, 2 May 2017 (2017-05-02), pages 529 - 539, XP037066447, ISSN: 1863-2297, [retrieved on 20170502], DOI: 10.1007/S00281-017-0629-X *
CHOUDBURY: "In Silico Studies on the Comparative Characterization of the Interactions of SARS-CoV-2 Spike Glycoprotein with ACE2 Receptor Homologs and Human TLRs", J. MED. VIROLOGY, 2020, pages 1 - 9
FEI ZHOU ET AL.: "Clinical Course and Risk Factors for Mortality of Adults with COVID-19 in Wuhan, China: A Retrospective Cohort Study", LANCET, vol. 395, 2020, pages 1054 - 1062
HANTOUSHZADEH S., ARCH. MED. RES., vol. 51, 2020, pages 347 - 348
IMAI YUMIKO: "Identification of Oxidative Stress and Toll-like Receptor 4 Signaling as a Key Pathway of Acute Lung Injury", CELL, 18 April 2018 (2018-04-18), pages 235 - 249, XP055813791, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112336/pdf/main.pdf> [retrieved on 20210615] *
INGRAHAM N. E., LANCET RESPIR. ALED., vol. 8, 2020, pages 544 - 546
KHANMOHAMMADI S. ET AL., J MED VIROL., 2021, pages 1 - 5
KIM, H.M., CELL, vol. 130, 2007, pages 906 - 917
LEE, J.S. ET AL., SCI. IMMUNOL., vol. 5, 2020
MIGUEL ANGEL MARTINEZ: "Compounds with therapeutic potential against novel respiratory 2019 coronavirus", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 9 March 2020 (2020-03-09), United States, XP055729045, Retrieved from the Internet <URL:https://aac.asm.org/content/aac/64/5/e00399-20.full.pdf> [retrieved on 20200909], DOI: 10.1128/aac.00399-20 *
OPAL, S.M., JAMA, vol. 309, no. 11, 2013, pages 1154 - 1162
OPAL: "Effect of Eritoran, an Antagonists ofMD2-TLR4, on Mortality in Patients with Sepsis", JAMA, vol. 309, no. 11, 2013, pages 1154 - 1162
PATRA R. ET AL., JMED VIROL., vol. 93, 2021, pages 615 - 617
Q.M. NHU ET AL., MUCOSAL IMMUNOLOGY, vol. 3, no. 1, 2010, pages 29 - 39
RALLABHANDI PRASAD ET AL: "Respiratory Syncytial Virus Fusion Protein-Induced Toll-Like Receptor 4 (TLR4) Signaling Is Inhibited by the TLR4 Antagonists Rhodobacter sphaeroides Lipopolysaccharide and Eritoran (E5564) and Requires Direct Interaction with MD-2", MBIO, vol. 3, no. 4, 31 August 2012 (2012-08-31), US, pages 1 - 8, XP055813884, ISSN: 2161-2129, Retrieved from the Internet <URL:https://journals.asm.org/doi/pdf/10.1128/mBio.00218-12> DOI: 10.1128/mBio.00218-12 *
S. M. BERGE: "pharmaceutically acceptable salts", J. PHARMACEUTICAL SCIENCES, vol. 66, 1977, pages 1 - 19
S. PERLMAN ET AL., NATURE REVIEWS MICROBIOLOGY, vol. 7, 2009, pages 439 - 450
SANOFI AND REGENERON BEGIN GLOBAL KEVZARA® (SARILUMAB) CLINICAL TRIAL PROGRAM IN PATIENTS WITH SEVERE COVRD-19, 1 April 2020 (2020-04-01), Retrieved from the Internet <URL:http:,,/www.news.saiiofi.us,''A'020-03-16-Sanofi-and-Regeneron-begin-global-Kevzara-R-sarilumab-clinical-trial-program-in-patients-with-severe-COVID-19>
SHIREY ET AL., NATURE, vol. 497, no. 7450, 2013, pages 498 - 502
SHIREY: "Novel Strategies for Targeting Innate Immune Responses to Influenza", MUCOSAL IMMUNOLOGY, vol. 9, 2016, pages 1173 - 1182, XP055420280, DOI: 10.1038/mi.2015.141
TANG Y., FRONT. IMMUNOL., vol. 11, 2020, pages 1708
Y. IMAI ET AL.: "Identification of Oxidative Stress and TLR4 Receptor Signaling as a Key Pathway of Acute Lung Injury", CELL, vol. 133, 2008, pages 235 - 249

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