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Title:
TREATMENT OF NIDOVIRALES INFECTION WITH ERITORAN
Document Type and Number:
WIPO Patent Application WO/2021/207218
Kind Code:
A1
Abstract:
Embodiments are directed to eritoran or a pharmaceutically acceptable salt thereof for use in methods for treating nidovirales infections in a subject, preferably selected from the group consisting of coronavirus, aterivirus, ronivirus, and mesonivirus.

Inventors:
GUSOVSKY FABIAN (US)
Application Number:
PCT/US2021/025987
Publication Date:
October 14, 2021
Filing Date:
April 06, 2021
Export Citation:
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Assignee:
EISAI R&D MAN CO LTD (JP)
GUSOVSKY FABIAN (US)
International Classes:
A61K31/7024; A61K45/06; A61P11/00; A61P31/14
Domestic Patent References:
WO2005027826A22005-03-31
WO2013148072A12013-10-03
Foreign References:
US5681824A1997-10-28
US8207144B22012-06-26
US6906042B22005-06-14
US201916713027A2019-12-13
US51608207A2007-11-21
US20080227991A12008-09-18
Other References:
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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 [retrieved on 20200909], DOI: 10.1128/aac.00399-20
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 DOI: 10.1128/mBio.00218-12
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 [retrieved on 20210614]
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 DOI: 10.1155/2021/8874339
S. PERLMAN ET AL., NATURE REVIEWS MICROBIOLOGY, vol. 7, 2009, pages 439 - 450
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"Coronaviruses", NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASE, 1 April 2020 (2020-04-01), Retrieved from the Internet
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HANTOUSHZADEH S., ARCH. MED. RES., vol. 51, 2020, pages 347 - 348
INGRAHAM N. E., LANCET RESPIR. ALED., vol. 8, 2020, pages 544 - 546
PATRA R. ET AL., JMED VIROL., vol. 93, 2021, pages 615 - 617
ABOUDOUNYA M. M. ET AL., MEDIATORS INFLAMM., 2021
BHATTACHARYA, M. ET AL., INFECT. GENET. EVOL., vol. 85, 2020, pages 104587
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OPAL: "Effect of Eritoran, an Antagonists ofMD2-TLR4, on Mortality in Patients with Sepsis", JAMA, vol. 309, no. 11, 2013, pages 1154 - 1162
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Attorney, Agent or Firm:
WALTERS, Todd R. et al. (US)
Download PDF:
Claims:
CLAIMS

I claim:

1. 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.

2. The method of claim 1 wherein the therapeutically effective amount of eritoran or a pharmaceutically acceptable salt thereof is an amount sufficient to maintain lung function in a patient.

3. The method of claim 1 wherein the therapeutically effective amount of eritoran or a pharmaceutically acceptable salt thereof is an amount sufficient to improve lung function in a patient.

4. The method of claim 1 further comprising administering to the infected patient a therapeutically effective amount of a second therapeutic agent.

5. The method of claim 4, wherein the second therapeutic agent comprises an antiviral compound, a systemic corticosteroid, or an immune modulatory agent.

6. The method of claim 1 , 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.

7. The method of claim 5, wherein the infected patient tested for the presence of nidovirales infection using PCR, rt-PCR, NAAT, direct antigen detection tests, virus isolation in cell culture, or combinations thereof.

8. The method of claim 1 , further comprising causing a decrease in nidovirales- induced cytokine mRNA or protein levels in the infected patient

9. The method of claim 8, further comprising Causing a decrease in nidovirales- induced cytokine mRNA or protein levels in the infected patient wherein the cytokines comprise TNF-ct, IL-Ιβ, IL-6, EL- 12 p40, KC, IL-10, IL-5, TGF-β or combinations thereof.

10. The method of claim 1 , further comprising causing a decrease in ni do viral es- induced COX-2 mRNA or protein levels in the infected patient

11. The method of claim 1 , further comprising causing a decrease in nidovirales- induced interferon-beta or interferon gamma mRNA levels in the infected patient.

12. The method of claim 1 , wherein the infected patient is administered a therapeutically effective amount of eritoran or a pharmaceutically acceptable salt thereof following the onset of clinical symptoms.

13. The method of claim 12, wherein the clinical symptoms comprise systemic myalgia, headache, cough, fever, pneumonia or combinations thereof.

14. The method of claim 1, wherein eritoran or a pharmaceutically acceptable salt thereof is administered by one of the routes comprising intravenous administration, intraperitoneal administration, intramuscular administration, intracoronary administration, intraarterial administration, intraderm al 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.

15. The method of claim 14, wherein eritoran or a pharmaceutically acceptable salt thereof is administered intravenously.

16. The method of claim I, wherein the effects of administering eritoran or pharmaceutically acceptable salts thereof cause a decrease in viral titers in the infected patient.

17. The method of claim 1 , 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 to about 240 mg, per total dose.

18. The method of claim 1 , wherein the patient is infected with a nidovirales vims selected from the group comprising coronavirus, ateri virus, ronivims, and mesonivirus or combinations thereof

19. The method of claim 18, wherein the nidovirales virus is coronavirus.

20. The method of claim 18, wherein the coronavirus is selected from the group comprising 229E, OC43, NL63, HKU1, SARS-CoV, MERS-CoV, and SARS-CoV-2.

21. The method of claim 20, wherein the coronavirus is SARS-CoV-2.

22. A method for treating a patient infected with a nidovirales vims comprising: administering to the infected patient a composition comprising an active ingredient and a pharmaceutically acceptable carrier wherein the active ingredient comprises a therapeutically effective amount of etitofan or a pharmaceutically acceptable salt thereof.

23. The method of claim 22, wherein the therapeutically effective amount of eritoran or a pharmaceutically acceptable salt thereof is an amount sufficient to maintain lung function in a patient.

24. The method of claim 22, wherein the therapeutically effective amount of eritoran or a pharmaceutically acceptable salt thereof is an amount sufficient to improve lung function in a patient.

25. The method of claim 22, wherein the patient is infected with a nidovirales virus selected from the group comprising coronavirus, aterivirus, ronivims, and mesonivirus or combinations thereof

26. The method of claim 25, wherein the nidovirales vims is coronavirus.

27. The method of claim 25, wherein the coronavirus is selected from the group comprising 229E, OC43, NL63, HKU1, SARS-CoV, MERS-CoV, and SARS-CoV-2.

28. The method of claim 27, wherein the coronavirus is SARS-CoV-2.

29. The method of claim 22, further comprising administering to the infected patient a therapeutically effective amount of a second therapeutic agent.

30. The method of claim 29, wherein the second therapeutic agent comprises an antiviral compound, a systemic corticosteroid, or an immune modulatory agent.

31. The method of claim 22, wherein the infected patient is administered the composition following testing positive for the presence of nidovirales infection.

32. The method of claim 31, wherein the infected patient tested for the presence of nidovirales infection using PCR, rt-PCR, NAAT, direct antigen detection tests, virus isolation in cell culture, or combinations (hereof.

33. The method of claim 22, further comprising causing a decrease in nidovirales- induced cytokine mRNA or protein levels in the infected patient

34. The method of claim 33, further comprising causing a decrease in nidovirales- induced cytokine mRNA or protein levels in the infected patient wherein the cytokines comprise TNF-o, IL-Ιβ, IL-6, EL- 12 p40, KC, IL-10, EL-5, TGF-β or combinations thereof.

35. The method of claim 22, further comprising causing a decrease in nidovirales- induced COX-2 mRNA or protein levels in the infected patient.

36. The method of claim 22, further comprising causing a decrease in nido viral es- induced interferon-beta or interferon gamma mRNA levels in the infected patient.

37. The method of claim 22, wherein the infected patient is administered the composition following (he onset of clinical symptoms.

38. The method of claim 37, wherein the clinical symptoms comprise systemic myalgia, headache, cough, fever, pneumonia or combinations thereof.

39. The method of claim 22, wherein the composition is administered by one of the routes comprising intravenous administration, intraperitoneal administration, intramuscular administration, intracoronary administration, intraarterial administration, intradermal 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 systemicaily absorbed topical or mucosal administration.

40. The method of claim 39, wherein the composition is administered intravenously.

41. The method of claim 22, wherein the effects of administering the composition cause a decrease in viral titers in the infected patient

42. The method of claim 22, wherein the composition administered to the infected patient is a therapeutically effective amount of eritoran or a pharmaceutically acceptable salt thereof in a range of from between about 40 mg to about 300 mg, per total dose.

43. A method for mitigating nidovirales-induced disease comprising: administering to the infected patient a therapeutically effective amount of a TLR4 antagonist wherein the TLR4 antagonist comprises a therapeutically effective amount of eritoran or a pharmaceutically acceptable salt thereof.

44. The method of claim 43, wherein the therapeutically effective amount of a

TLR4 antagonist is an amount sufficient to maintain lung function in a patient.

45. The method of claim 43, wherein the therapeutically effective amount of a

TLR4 antagonist is an amount sufficient to improve lung function in a patient.

46. The method of claim 43, further comprising administering to the infected patient a therapeutically effective amount of an antiviral compound.

47. The method of claim 43, wherein the infected patient is administered a therapeutically effective amount of a TLR4 antagonist following testing positive for the presence of a nidovirales infection.

48. The method of claim 43, wherein the infected patient tested for the presence of nidovirales infection using PCR, rt-PCR, NAAT, direct antigen detection tests, virus isolation in cell culture, or combinations thereof.

49. The method of claim 43, further comprising causing a decrease in nidovirales- induced cytokine mRNA or protein levels in the infected patient

50. The method of claim 49, further comprising causing a decrease in nidovirales- induced cytokine mRNA or protein levels in the infected patient wherein the cytokines comprise TNF-o, IL-Ιβ, EL-6, EL- 12 p40, KC, IL-10, IL-5, TGF-β or combinations tiiereof.

51. The method of claim 43, further comprising causing a decrease in nidovirales- induced COX-2 mRNA or protein levels in the infected patient.

52. The method of claim 43, further comprising causing a decrease in nidovirales induced interferon-beta or interferon gamma mRNA levels in the infected patient.

53. The method of claim 43, wherein the infected patient is administered a therapeutically effective amount of a TLR4 antagonist following the onset of clinical symptoms.

54. The method of claim 53, wherein the clinical symptoms comprise systemic myalgia, headache, cough, fever, pneumonia or combinations thereof.

55. The method of claim 43, wherein the TLR4 antagonist is administered by comprising route selected from the group consisting of intravenous administration, intraperitoneal administration, intramuscular administration, intracoronary administration, intraarterial administration, intradermal administration, transderm al 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, systemically absorbed topical administration, and systemically absorbed mucosal administration.

56. The method of claim 55, wherein the TLR4 antagonist is administered intravenously.

57. The method of claim 43, wherein the effects of administering the TLR4 antagonist cause a decrease in viral titers in the infected patient.

58. The method of claim 43, wherein the therapeutically effective amount of eritoran or a pharmaceutically acceptable salt is present in a range of from between about lpg to about 240 mg, per total dose.

59. The method of claim 43, wherein the patient is infected with a nidovirales virus selected from the group comprising coronavirus, aterivirus, ronivirus, and mesonivirus or combinations thereof

60. The method of claim 59, wherein the nidovirales virus is coronavirus.

61. The method of claim 60, wherein the coronavirus is selected from the group comprising 229E, OC43, NL63, HKU1, SARS-CoV, MERS-CoV, and SARS-CoV-2.

62. The method of claim 61, wherein the coronavirus is SARS-CoV-2.

63. The method of claim 43, wherein the nidovirales-mduced disease is pneumonia.

64. A 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.

65. The method of claim 64, wherein the therapeutically effective amount of a

TLR4 antagonist is administered by a dosing regimen comprising a first and second dose, and subsequent doses, wherein said first dose and second dose are each 10 to approximately 30 mg, and said second dose is administered 12 hours following said first dose; and said subsequent doses are administered once every 12 horns for up to 14 days, and are each 2 mg to approximately 10 mg.

66. The method of claim 65, wherein 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.

67. The method of claim 66, wherein 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.

68. The method of claim 67, wherein 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.

69. A method for improving lung function in a patient infected with coronavims 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.

70. The method of claim 69, wherein the therapeutically effective amount of a

TLR.4 antagonist is administered by a dosing regimen comprising a first and second dose, and subsequent doses, wherein said first dose and second dose are each 10 to approximately 30 mg, and said second dose is administered 12 hours following said first dose; and said subsequent doses are administered once every 12 hours for up to 14 days, and are each 2 mg to approximately 10 mg.

71. The method of claim 70, wherein 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.

72. The method of claim 71, wherein 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.

73. The method of claim 72, wherein additional doses of the 6.56 mg doses are administered at a rate of 3.28 mg¾ over 2 hours until the patient is discharged from a hospital.

74. The method of claim 69, wherein improved lung function is demonstrated by the patient’s reduced need for a ventilator following administration of the TLR4 antagonist.

Description:
TREATMENT OF NIDOVIRALES INFECTION WITH ERITORAN

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of United States Provisional Patent Application No. 63/005,851, filed on April 6, 2020. That application is incorporated by reference as if fully rewritten herein.

BACKGROUND

[0002] Field

[0003] Embodiments relate to compounds and compositions that can be used to treat nidovirales infections in an infected subject

[0004] Background

[0005] In the Northern hemisphere, viral epidemics cause up to 80% of all respiratory illnesses. The most common infections are caused by six viral groups: rhinovirus (RVs), respiratory syncytial virus, influenza virus, parainfluenza virus, coronavirus, and adenovirus.

[0006] 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.

11 : 1708 (2020). Coronaviruses fall within the Nidovirales order of viruses, which also includes Arteriviridae, Roniviridae, and Mesoniviridae.

[0007] 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. 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).

[0008] Activation of the human innate immune cells (macrophages, dendritic cells) through the binding of pathogen-associated molecular pattern (PAMP) from SARS-Cov-2 to cell surface TLRs has been demonstrated to be a vital mediator of COVID-19 immunopathogenesis. Particularly in SARS-CoV-2 infection, major immunopathological consequences leading to death have resulted from the interaction of the SARS-CoV-2 antigens and human TLRs.

[0009] SARS-CoV-2 viral spike protein (S) 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.

[0010] While treatment of specific symptoms improves survival, there is as yet no proven treatment available for COVID-19. Thus, a need exists for new therapeutic drugs that limit the effects of a eoronavirus (e.g., SARS-CoV-2) infection by targeting aspects of the host immune response.

BRIEF SUMMARY

[0011] 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.

[0012] 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.

[0013] 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.

[0014] 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.

[0015] A still further embodiment pertains to a method further comprising administering to the infected patient a therapeutically effective amount of an antiviral compound.

[0016] 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,

[0017] 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.

[0018] A further embodiment pertains to a method further comprising causing a decrease in nidovirales-induced cytokine mRNA levels in the infected patient.

[0019] 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-Ιβ, EL-6, IL-12 p40, KC, IL-10, IL-5, TGF-β 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. [0020] 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.

[0021] 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.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] 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. In a further embodiment, the coronavirus is selected from the group comprising 229E, OC43, NL63, HKU1, SARS-CoV, MERS-CoV, and SARS-CoV-2. In yet a further embodiment, the coronavirus is SARS-CoV-2. In a yet further embodiment the nidovirales-induced disease is pneumonia.

[0026] 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. In a still further embodiment 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.

[0027] In a still further embodiment for treating or preventing pneumonia 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. In a still further embodiment 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. In a still further embodiment 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.

[0028] 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. In a further embodiment 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.

[0029] In a further embodiment 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. In a still further embodiment 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. In a further embodiment 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. In some embodiments improved lung function is demonstrated by the patient’s reduced need for a ventilator following administration of the TLR.4 antagonist.

DETAILED DESCRIPTION

[0030] 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. 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. One of those TLRs, TLRS, has previously been shown to induce production anti-viral cytokines in response to double-stranded RNA produced during influenza infection. 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. Imai et al., Cell, 133: 235-249 (2008)). Previous reports have also indicated that 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.

[0031] 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-met hyl-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.

[0032] 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.

[0033] Molecular crystallographic studies showed that 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. See Akira, et al., “Pathogen Recognition Innate Immunity,” Cell (2006) 124:783-801; Imai, et al., “Identification of Oxidative Stress and TLR4 Receptor Signaling as a Key Pathway of Acute Lung Injury Cell (2008) 133; 235-249. [0034] It was proposed that if an effective inhibitor to LPS could be found, it could become an effective treatment to prevent death from endotoxic shock. Scientists at Eisai developed eritoran (also known as E5564) to inhibit LPS and prevent death from endotoxis shock. Eritoran, when administered in therapeutic amounts, blocked substantially all LPS signaling.

[0035] Phase 1 clinical trials with human volunteers showed that if sufficient amounts of eritoran were given before a LPS IV challenge, LPS-induced activation of toxic reactions was completely blocked. Eritoran was evaluated in 6 further Phase 1 studies in healthy volunteers without clinical or physiologic abnormalities. In Phase 2 trials in patients with sepsis (n=293), eritoran was generally well tolerated with minimal toxicities including phlebitis and injection site pain. See Shirey, et al., “Novel Strategies for Targeting Innate Immune Responses to Influenza, " Mucosal Immunology (2016); 9:1173-1182.

[0036] In 2009-2010, eritoran was tested to determine if it would provide significant benefit in septic shock patients to 28-day mortality. Opal, et al., “Effect of Eritoran, an Antagonists of MD2-TLR4, on Mortality in Patients with Sepsis,” JAMA, 2013; 309:11,1154-1162 The hypothesis was that among patients in the ICU with severe sepsis and organ failure, eritoran would reduce multiorgan failure and to lower mortality rates. Ultimately, there was no difference in the primary endpoint of that trial.

[0037] While clinical trials with eritoran were being conducted, involvement of Toll-Like receptors in other diseases, including viral pathogenesis, was studied. Although 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.

[0038] 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.

[0039] We note that 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. Although 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.

[0040] 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.

[0041] In a recent study, 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.

[0042] 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.

[0043] Compounds suitable for use with the methods reported herein include inhibitors of TLR4. In another embodiment, 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.

[0044] 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. See “Sanofi and Regeneron begin global Kevzara® (sarilumab) clinical trial program in patients with severe COVID-19,” http://www.news.sanofi.us/2020-03-16-Sanofi-and- Regeneron-begm-global-Kevzara-R-sarilumab-clinical-trial-pro gram-in-patients-with-severe- COVID-19 (accessed on April 1, 2020).

[0045] In one embodiment, 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. According to embodiments reported herein, treatment of an infected subject with eritoran or a pharmaceutically acceptable salt thereof dramatically reduces cellular damage in the lung tissue. In addition, treatment with eritoran or a pharmaceutically acceptable salt thereof in the days following infection may lead to reduced systemic effects of coronavirus infection. In one embodiment, coronavirus-induced increases in liver enzyme levels are reduced by treatment with eritoran or a pharmaceutically acceptable salt thereof.

[0046] Acute respiratory viral infection results in the expression of a multitude of cytokines capable of affecting the lungs, and subsequent damage to alveoli and lung tissue results in the lethality seen in more severe respiratory infections, especially those fatalities among young healthy adults. Excessive inflammation triggered by the virus infection can result in significant pathology. In another embodiment, TLR4 is antagonized to decrease expression of coronavirus-induced cytokine RNA expression in coronavirus infected subjects. In one embodiment, 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. Without wishing to be bound to any particular theory, it is believed that coronaviruses infect cells and activate cellular signaling pathways that drive the production of inflammatory cytokines.

[0047] The TLR4 pathway may be targeted by eritoran to reduce production of inflammatory cytokines in subjects infected with coronaviruses. In one embodiment, eritoran or a pharmaceutically acceptable salt thereof is used to reduce coronavirus-induced expression of interferon-beta RNA expression in subjects infected with coronavirus. In another embodiment, eritoran or a pharmaceutically acceptable salt thereof is used to reduce coronavirus-induced expression of interferon-gamma RNA expression in subjects infected with coronavirus. In another embodiment, eritoran treatment of subjects infected with coronavims does not reduce coronavirus-induced expression of interferon-alpha 4. In another embodiment, eritoran treatment of subjects infected with coronavirus does not reduce coronavirus-induced expression of interferon-delta 2. In some embodiments, 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-Ιβ, EL-6, COX-2, IL-12 p40, KC, IL-10, EL-5 and TGF-β.

[0048] In yet another embodiment, 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.

[0049] 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.

[0050] According to one embodiment, 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.

[0051] According to the methods reported herein, 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.

[0052] Administration of eritoran or a pharmaceutically acceptable salt thereof according to embodiments reported here is typically carried out over the course of several days. The efficacy of the compositions reported herein may increase in a dose dependent manner, with higher dosages providing more effective treatment for 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.

[0053] In yet another embodiment, 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.

[0054] In one embodiment, the total dose may be administered over a course of several days until a patient’s lung function has improved. In one embodiment, 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. In another embodiment, 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. In some embodiments, 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. In some embodiments, 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.

In one embodiment, 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,

18, or 20 days. The appropriate amounts of which can be determined by one of skill in the art according to the characteristics of the infected subject and the preferred route of administration. In one embodiment, 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 χ 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).

[0055] In some of the methods reported herein, 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. In other embodiments, 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. In another embodiment, 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. For example, 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.

[0056] In one embodiment, 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.

[0057] In a particular embodiment, 6.56 mg of 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.

[0058] Appropriate frequency of administration may also be determined by one of skill in the art. For example, 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. It will be understood that specific dosage ranges and pharmaceutical formulations may vary according to the method of administration and the specific physical characteristics of the subject being treated. In some embodiments, pharmaceutical formulations contemplated for use herein include those disclosed in U.S. Patent Application Ser. No. 16/713,027.

[0059] In a further embodiment, eritoran or a pharmaceutically acceptable salt thereof may be administered in combination with one or mote additional therapeutic agents. These 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.

[0060] To more clearly and concisely describe the subject matter of the claims, the following definitions are intended to provide guidance as to the meaning of terms used herein. [0061] As used herein, the articles "a” and “an” mean “one or more” or “at least one,” unless otherwise indicated. That is, reference to any element by the indefinite article “a” or “an” does not exclude the possibility that more than one of the element is present.

[0062] Values and ranges are recited in collection with various embodiments herein, e.g. , amount of a compound of formula (I) present in a composition. Values and ranges that fall between the values and ranges listed are intended to be encompassed by embodiments unless explicitly stated otherwise.

[0063] 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.

[0064] “Treatment,” “treat,” or “treating” as used herein, 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). Specifically as used herein, 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. “Treated,” as used herein, refers to the disease or disorder being cured, healed, alleviated, relieved, remedied, ameliorated, or improved.

[0065] Numbers herein that are shown to be “approximate” or stated “approximately” should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Recitation of numerical ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate numerical value falling within the range. Unless otherwise indicated herein, each individual value of a numerical range is incorporated into the present specification its if it were individually recited herein.

[0066] Compounds suitable for use with the methods reported herein are administered in therapeutically effective dosages. The term “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.

[0067] As used herein, 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.

[0068] Furthermore, where the compounds taught herein carry an acidic moiety, 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. Sodium salts of compounds within the scope of formula (I) are described, for example, inU.S. Patent Application Ser. No. 12/516,082 andU.S. Patent Application Publication No. 2008/0227991. 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.

[0069] Other pharmaceutically acceptable 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, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative 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.

In some embodiments, the compound of formula (I) is a sodium salt, e.g., a tetr as odium salt.

[0070] 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. In some embodiments, the subject is a human.

[0071] As used herein, the terms “antagonist” and “inhibitor” refer to molecules or compounds that inhibit the action of a “native” or “natural” molecules or compounds.

[0072] In some embodiments, the compounds described herein are administered systemically. As used herein, “systemic administration” refers to any means by which the compounds described herein can be made systemically available. In some embodiments, 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. In some embodiments, the compounds described herein are administered intravenously. In other embodiments, the compounds described herein are administered orally. In some embodiments, the compounds described herein may be administered intravenously one to five times a week. In some other embodiments, 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).

[0073] Pharmaceutical formulations 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.

[0074] Examples of suitable 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. The 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.

[0075] Methods as reported herein may also be used in combination with other treatment regimes. For example, 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.

[0076] The following are examples of methods and compositions of embodiments reported herein. Other embodiments may be practiced, given the general description provided above.

EXAMPLE

[0077] A Phase Π/ΠΙ Study Of Eritoran In COVID-19 Patients

[0078] The primary objective of a Phase ΙΙ/ΙΠ study for eritoran in COVID-19 patients are:

(a) to demonstrate that intervention with eritoran in patients with COVID19 infection with compromised lung function results in superior efficacy in reduction in any-cause in-hospital mortality and (b) to demonstrate that intervention with eritoran in patients with COVID 19 infection with compromised lung function results in superior efficacy in reduction in total no. of hours on ventilator or increase in the number of ventilator free days as compared to placebo treated patients with standard of care.

[0079] 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;

(b) to evaluate whether eritoran has superior efficacy compared to placebo/standard of care in reducing the time to discharge from ICU in patients with COVED19 infection with compromised lung function; (c) to evaluate whether eritoran has superior efficacy compared to placebo/standard of care in reducing the time to extubation in patients with COVID19 infection with compromised lung function; and (d) to evaluate whether eritoran has superior efficacy compared to placebo/standard of care in reducing the sequential organ failure assessment score (SOFA score) in patients with COVDD19 infection with compromised lung function.

[0080] 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.

[0081] Dose Regimen:

[0082] The dosing regimen includes a 26.24 mg loading dose (6.56 mg/h χ 4 hours, or placebo), a second 13.12 mg loading dose (6.56 mg/h χ 2 hours or placebo) at 12 hours, and up to twenty five 6.56 mg maintenance doses (3.28 mg/h χ 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.

[0083] 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.

[0084] Inclusion/Exclusion Criteria:

[0085] To be included in the study, patients must have a SARS-CoV-2 infection that has been confirmed by local microbiological testing.

[0086] 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 COVID-19 disease; (f) known pregnancy or pregnancy status unknown in child-bearing age (18-55); (g) known immunosuppressive therapy such as cyclosporine or azathioprine; (h) ongoing plan to breastfeed or planning to breastfeed during the 4 days after the investigational product has been administered; (i) known hypersensitivity to active ingredient or any of the excipients; (j) current or prior chemotherapy or other cancer treatment for a minimum of 3 months before hospital admission (unless a longer exclusionary period is specified for an agent used in treatment); (k) neutrophil count < 1000/mm A 3 unless believed due to COVID-19, within the past 14 days; (1) human immunodeficiency virus (HIV)-positive patients with CD4 count <= 50/mm A 3 within 4 weeks of enrollment, or end- stage processes; (m) history of severe congestive heart failure (EF < 35%); (n) history of severe liver disease (Child C); (o) ongoing or planned use of polymyxin B, hemofiltration, endotoxin removal devices, plasma exchange, in the absence of renal impairment; (p) known or estimated weight greater than 150 kg; (q) More than 14 days has elapsed since admission to hospital (if pandemic infection acquired in the community); or (r) More than 14 days have elapsed since symptom onset (if pandemic infection is acquired during this hospital admission).

[0087] Assessments and Endpoints:

[0088] Efficacy is evaluated at each interim analysis. In order to stop early for superiority against control both of the following two conditions (Superiority Criteria) must be met:

1. The intervention is demonstrated superior on the primary endpoint

2. The intervention demonstrates superiority on the key secondary endpoint

[0089] 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.

[0090] 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.

[0091] Although the foregoing has been described in some detail by way of illustration and example for purposes of clarity of understanding, the descriptions and examples should not be construed as limiting the scope of the embodiments as reported herein. The disclosures of all patent and scientific literature cited herein are expressly incorporated in their entirety by reference.