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WO2021163549A1 - Compositions et méthodes de traitement d'infections virales - Google Patents

Compositions et méthodes de traitement d'infections virales Download PDF

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Publication number
WO2021163549A1
WO2021163549A1 PCT/US2021/017941 US2021017941W WO2021163549A1 WO 2021163549 A1 WO2021163549 A1 WO 2021163549A1 US 2021017941 W US2021017941 W US 2021017941W WO 2021163549 A1 WO2021163549 A1 WO 2021163549A1
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WO
WIPO (PCT)
Prior art keywords
antibody
subject
antigen
binding fragment
administered
Prior art date
Application number
PCT/US2021/017941
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English (en)
Inventor
Thomas OCCHIPINTI
Naimish Patel
Owen HAGINO
Sumathi Sivapalasingam
David LEDERER
Ned BRAUNSTEIN
David WEINREICH
Chad NIVENS
Original Assignee
Sanofi Biotechnology
Regeneron Pharmaceuticals, Inc.
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Application filed by Sanofi Biotechnology, Regeneron Pharmaceuticals, Inc. filed Critical Sanofi Biotechnology
Publication of WO2021163549A1 publication Critical patent/WO2021163549A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present technology relates to the field of therapeutic treatment of infectious diseases characterized by cytokine release syndrome (a/k/a cytokine storm), such as infection by coronavirus (e.g., 2019-nCoV, SARS-CoV, and MERS-CoV).
  • cytokine release syndrome a/k/a cytokine storm
  • coronavirus e.g., 2019-nCoV, SARS-CoV, and MERS-CoV
  • IL-6R interleukin-6 receptor
  • Cytokine release syndrome (CRS; a/k/a cytokine storm), as related to infectious diseases, is the excessive or uncontrolled release of proinflammatory cytokines in response to the infection.
  • CRS is characterized by increased plasma concentrations of interleukins, interferons, chemokines, colony-stimulating factors (CSFs), and tumor necrosis factor a (TNT a).
  • the present technology relates to methods for treating infectious diseases characterized by CRS in a subject in need thereof comprising administering an effective amount of an antibody, or an antigen-binding fragment thereof, wherein the antibody binds specifically to human IL-6 receptor (hIL-6R).
  • the subject has severe or critical disease.
  • the subject has critical or severe disease.
  • the subject has multi-organ dysfunction.
  • the subject has pneumonia and fever.
  • the present technology relates to methods for reducing one or more symptoms associated with CRS in a subject in need thereof comprising administering an effective amount of an antibody, or an antigen-binding fragment thereof, wherein the antibody binds specifically to hIL-6R.
  • the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH), wherein the VH comprises three heavy chain complementarity-determining regions (HCDRs) (HCDR1, HCDR2 and HCDR3), wherein HCDR1 comprises the amino acid sequence of 8EQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; and HCDR3 comprises the amino acid sequence of 8EQ ID NO: 5, and a light chain variable region (VL), wherein the VL comprises three light chain complementarity-determining regions (LCDRs) (LCDRL LCDR2 and LCDR3), wherein LCDRl comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7: and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.
  • VH heavy chain complementarity-determining regions
  • HCDR1 comprises the amino acid sequence of 8EQ ID NO: 3
  • HCDR2 comprises the amino acid sequence of SEQ ID NO: 4
  • the VH comprises SEQ ID NO: 1 and the VL comprises SEQ ID NO: 2.
  • the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
  • the antibody is sarilumab.
  • the extracellular domain of hIL-6R comprises the amino acid sequence of SEQ ID NO: 11.
  • the antibody or antigen-binding fragment thereof is administered at a dose between about from about 50 mg to about 400 mg, from about 100 mg to about 350 mg, from about 150 rag to about 300 mg, from about 200 mg to about 250 g or from about 700 to about 750 mg. In some embodiments, the antibody is administered at a dose of about 50 mg, 100 mg, 150 g, 200 rag, 300 mg, 350 mg, or 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg or 1000 mg. In some embodiments, the antibody is administered at a dose of about 200 g, 400 mg or 800 mg. In some embodiments, the antibody is administered at a dose of about 150 mg or about 200 mg of the antibody. In some embodiments, the antibody is administered at a dose between about 2 mg/kg to about 4 mg/kg
  • the antibody or antigen-binding fragment thereof is administered subcutaneously. In some embodiments, the antibody is administered intravenously. In some embodiments, the antibody is administered daily, once a week, twice a week, or every two weeks.
  • the antibody or antigen-binding fragment thereof comprises a VH, wherein the VH comprises three HCDRs (HCDR1, HCDR2 and HCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 14; HCDR2 comprises the amino acid sequence of SEQ ID NO: 15; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 16, and a VL, wherein the VL comprises three LCDRs (LCDR1 , LCDR2 and LCDR3), wherein LCDR1 comprises the amino acid sequence of SEQ ID NO: 17; LCDK2 comprises the amino acid sequence of SEQ ID NO: 18; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 19.
  • the VH comprises SEQ ID NO: 12 and the VL comprises SEQ ID NO: 13.
  • the antibody is tocilizumab.
  • the antibody or antigen-binding fragment thereof is administered at 8 mg per kg, 10 mg per kg, or 12 mg per kg. In some embodiments, the antibody is administered at 162 g. In some embodiments, the antibody is administered subcutaneously or intravenously. In some embodiments, the antibody is administered daily, once a week, twice a week, or every two weeks.
  • the infectious diseases characterized by CRS is an infection by coronavirus, H1N1, H1N2, II3N1, H3N2, H2N3, H5NI, or respiratory syncytial vims (RSV)
  • the coronavirus is selected from 2019-nCoV (also referred to herein as “COVID-19”), SARS-CoV, and MERS-CoV.
  • CRS results from an infection by coronavirus, H1N1, H1N2, H3N1, H3N2, 112N3, H5N1, or RSV.
  • the subject has severe disease.
  • the subject has severe disease.
  • the subject has multi-organ dysfunction.
  • the subject has pneumonia.
  • the subject has fever.
  • the CRS is characterized by increased plasma concentrations of one or more cytokines selected from interleukins, interferons, chemokines, CSFs, and TNFa.
  • the interleukins are selected from IL-ia, IL-Ib, IL-1RA, IL-2, IL-6, IL-7, IL-8, IL-9, IE- 10, and 11. ⁇ 18.
  • the interferons are selected from IFNa, IRNb, IFNy, IFN-lI, IFV-X2, and INR-l3.
  • the chemokines are selected from CXCR3 ligands, CXCL8, CXCL9, CXCLIO, CXCL11, CCL2 (monocyte chemoattractant protein 1 [MCP-1]), CCL3, CCL4, bFGF, PDGF, VEGF, and CCL11 (eotaxin).
  • the CSFs are selected from granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), and granulocyte colony-stimulating factor (G-CSF).
  • the CR8 is characterized by increased plasma concentrations of IL-Ib, IL-IRA, IL-2, IL-7, IL-8, IL-9, IL-IQ, bFGF, GM-CSF, G-CSF, interferon-g- inducible protein 10, IFNy, CXCL10, CCL2, Ci 1.3 CCL4, PDGF, VEGF, MCP-1, macrophage inflammatory ' protein 1 alpha, and/or TNFa
  • the CRS is characterized by increased plasma concentrations of interleukins 2, 7, and 10, granulocyte-colony stimulating factor, interferon-y-inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1 alpha, and/or TNFa.
  • the CRS is characterized by increased plasma concentrations of platelet-derived growth factor (PDGF).
  • PDGF platelet-derived growth factor
  • the CRS is characterized by increased plasma concentrations of vascular endothelial growth factor (VEGF).
  • VEGF vascular endothelial growth factor
  • the CRS is characterized by increased plasma concentrations of basic fibroblast growth factor (bFGF).
  • the subject in need thereof is suffering from one or more symptoms selected from pneumonia, bronchitis, fever, coughing, productive cough, runny nose, sneezing, breathlessness, sharp or stabbing chest pain during deep breaths, chills, exacerbated asthma, increased rate of breathing, acute respiratory' distress syndrome (ARDS), RNAaemia (detectable RNA in the bloodstream), acute cardiac injuryy shock, myalgia, fatigue, sputum production, rusty colored sputum, bloody sputum, swelling of lymph nodes, middle ear infection, joint pain, wheezing, headache, hemoptysis, diarrhea, dyspnea, redness, swelling or edema, pain, loss of function, organ dysfunction, multi-organ system failure, acute kidney injury', confusion, malnutrition, blue-tinged skin, sepsis, hypotension, hypertension, hypothermia, hypoxemia, leukocytosis, leukopenia, lymphopenia, thrombocyto
  • the subject in need thereof has pulmonary complications characterized by abnormalities in chest CT images.
  • the subject in need thereof exhibits ground-glass opacity and subsegmental areas of consolidation in chest CT images.
  • the subject in need thereof exhibits multiple lobular and subsegmental areas of consolidation in chest CT images.
  • the subject in need thereof exhibits bilateral involvement of ground-glass opacity and subsegmental areas of consolidation in chest CT images.
  • the subject in need thereof exhibits bilateral involvement of multiple lobular and subsegmental areas of consolidation in chest CT images.
  • the subject in need thereof has elevated levels, relative to a healthy subject, of aspartate aminotransferase (AST). In some embodiments, the subject in need thereof has elevated levels, relative to a healthy subject, of D-dimer In some embodiments, the subject in need thereof has elevated levels, relative to a healthy subject, of hypersensitive troponin I (hs-cTnl). In some embodiments, the subject in need thereof has elevated levels, relative to a healthy subject, of proeaicitonin levels, such as, e.g., a procalcitonin level greater than 0.5 ng'inL. In some embodiments, the subject in need thereof has an elevated prothrombin time relative to a healthy subject.
  • AST aspartate aminotransferase
  • AST aspartate aminotransferase
  • the subject in need thereof has elevated levels, relative to a healthy subject, of D-dimer
  • the subject in need thereof has elevated levels, relative to a healthy subject, of hypersensitive troponin I (hs
  • the subject in need thereof is an adult.
  • An adult is a human subject greater than, or equal to, 18 years of age.
  • the subject in need thereof is greater than or equal to 18 years of age and less than or equal to 59 years of age.
  • the subject in need thereof is 60 years of age or older.
  • the subject in need thereof is younger than 18 years of age.
  • the subject in need thereof is greater than, or equal to, 12 years of age.
  • the subject achieves a reduction in C -reactive protein levels within four days from treatment with the antibody.
  • the subject in need thereof has a long-term or pre-existing medical condition, for example, but not limited to, heart disease, lung disease, diabetes, cancer and/or high blood pressure.
  • a long-term or pre-existing medical condition for example, but not limited to, heart disease, lung disease, diabetes, cancer and/or high blood pressure.
  • the subject in need thereof has the pre-existing medical condition is heart disease, lung disease, diabetes, cancer and/or high blood pressure. In some embodiments, the subject in need thereof has a weakened immune system.
  • administration of at least one of the antibodies or antigen binding fragments thereof reduces or eliminates the need for mechanical ventilation, invasive mechanical ventilation, high intensity oxygen therapy, supplemental oxygen and/or hospitalization.
  • administration of at least one antibody or antigen-binding fragment thereof reduces the plasma concentration of one or more cytokines.
  • administration of at least one anti body or antigen-binding fragment thereof treats or ameliorates one or more symptoms selected from the group consisting of pneumonia, bronchitis, fever, coughing, productive cough, runny nose, sneezing, breathlessness, sharp or stabbing chest pain during deep breaths, chills, exacerbated asthma, increased rate of breathing, acute respiratory distress syndrome (ARDS), RNAaemia (detectable RNA in the bloodstream), acute cardiac injury, shock, myalgia, fatigue, sputum production, rusty colored sputum, bloody sputum, swelling of lymph nodes, middle ear infection, joint pain, wheezing, headache, hemoptysis, diarrhea, dyspnea, redness, swelling or edema, pain, loss of function, organ dysfunction, multi-organ system failure, acute kidney injury, confusion, malnutrition, blue-tinged skin, sepsis, hypotension, hypertension, hypothermia, hypoxemia, leukocytosis, leukocytos
  • administration of at least one antibody or antigen-binding fragment thereof reduces levels of AST in a subject. In some embodiments the administration of the at least one antibody reduces levels of alanine aminotransferase in a subject. In some embodiments, administration of at least one antibody or antigen-binding fragment thereof reduces levels of D-dimer in a subject. In some embodiments, administration of at least one antibody or antigen-binding fragment thereof reduces levels of hypersensitive troponin I (hs- cTnl) in a subject. In some embodiments, administration of at least one antibody or antigen binding fragment thereof reduces procalcitonin levels in a subject. In some embodiments, administration of at least one antibody or antigen-binding fragment thereof reduces prothrombin lime in a subject.
  • administration of at least one antibody or antigen-binding fragment thereof reduces and/or eliminates one or more pulmonary complications characterized by abnormalities in chest CT images. In some embodiments, administration of at least one antibody or antigen-binding fragment thereof reduces the incidence of death in a subject infected with an infectious disease characterized by CRS. In some embodiments, administration of at least one antibody or antigen-binding fragment thereof reduces and/or eliminates the need for mechanical ventilation, invasive mechanical ventilation, high intensity oxygen therapy, supplemental oxygen and/or hospitalization in the subject
  • the subject on a ventilator at baseline no longer requires invasive mechanical ventilation within 22 days after treatment with the antibody or antigen binding fragment thereof.
  • the subject achieves at least a 1-point improvement on the 7- point ordinal scale in clinical status within 22 days after treatment with the antibody or antigen-binding fragment thereof.
  • one or more active compounds are administered with at least one antibody or antigen-binding fragment thereof.
  • one or more active compounds is selected from analgesics, decongestants, expectorants, antihistamines, mucokinetics, and cough suppressants.
  • one or more antiviral therapies are administered with at least one antibody or antigen-binding fragment thereof.
  • the administration may be prior to the antibody or antigen-binding fragment thereof administration, concurrently with the antibody or antigen-binding fragment thereof administration, or following the antibody administration.
  • one or more antiviral therapies may be administered by using one or more antiviral agents.
  • the antiviral agents are selected from remdesivir, hydroxychloroquinine, galidesivir, oseltamivir, paramivir, zanamivir, ganciclovir, acyclovir, ribavirin, lopinavir, ritonavir, favipiravir, darunavir or a combination thereof.
  • the subject was previously administered an antiviral therapy by administering one or more antiviral agents.
  • the antiviral agents are selected from remdesivir, hydroxychloroquinine, galidesivir, oseltamivir, paramivir, zanamivir, ganciclovir, acyclovir, ribavirin, lopinavir, ritonavir, favipiravir, darunavir or a combination thereof.
  • the subject has elevated IL-6 levels and/or high CRP levels. In some embodiments, the high CRP levels of the subject are reduced at day 4 after treatment with sarilumab.
  • This disclosure further provides a method of determining if a subject with infectious disease characterized by CRS has an increased propensity for effective treatment of CRS or reducing one or more symptoms associated with CRS comprising measuring a concentration of CRP in a serum sample from the subject wherein if the serum sample has a concentration of CRP greater than the upper limit of normal, the subject has an increased propensity for effective treatment of CRS or reducing one or more symptoms associated with CRS.
  • the disclosure provides a method of determining if a subject with infectious disease characterized by CRS has an increased propensity for effective treatment of CRS or reducing one or more symptoms associated with CRS comprising measuring a concentration of IL-6 in a serum sample from the subject wherein if the serum sample has a concentration of IL-6 greater than the upper limit of normal, the subject has an increased
  • the present technology relates to a method for treating coronavirus infection in a subject in need thereof comprising administering an effective amount of an antibody, or an antigen binding fragment thereof, the antibody binds specifically to human 11,-6 receptor (hIL-6R).
  • the antibody or antigen binding fragment thereof comprises a VH, wherein the VH comprises three HCDRs (HCDR1, HCDR2 and HCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 3, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 4, and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, and a VL, wherein the VL comprises three LCDRs (LCDR1, LCDR2 and LCDRS), wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 6, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.
  • the VH comprises SEQ ID NO: 1 and the VL comprises SEQ ID NO: 2.
  • the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
  • the antibody is sarilumab.
  • the antibody or antigen binding fragment thereof is administered at a dose from about 50 mg to about 400 mg, from about 100 mg to about 350 mg, from about 150 mg to about 300 mg, from about 200 mg to about 250 mg or from about 750 to about 750 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered at a dose of about 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 rng, 550 rng, 600 rng, 650 rng, 700 rng, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg or 1000 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered at a dose of about 200, 400 or 800 g.
  • the antibody or antigen binding fragment thereof is administered at a dose between about 2 mg/kg to about 4 mg/kg. In some embodiments, the antibody or antigen binding fragment thereof is administered subcutaneously. In some embodiments, the antibody or antigen binding fragment thereof is administered intravenously. In some embodiments, the antibody or antigen binding fragment thereof is administered daily, once a week, twice a week, or every two weeks.
  • the antibody or antigen binding fragment thereof comprises a VH, wherein the VH comprises three HCDRs (HCDR1, HCDR2 and HCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 14, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 15, and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 16, and a VL, wherein the VL comprises three LCDRs (LCDR1, LCDR2 and LCDR3), wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 17, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 18, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 19.
  • the VH comprises SEQ ID NO: 12 and the VL comprises SEQ ID NO: 13.
  • the antibody is tocilizumab.
  • the antibody or antigen binding fragment thereof is administered at 8 mg per kg, 10 mg per kg, or 12 mg per kg. In some embodiments, the antibody or antigen binding fragment thereof is administered at 162 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered subcutaneously or intravenously.
  • the coronavirus is selected from 2019-nCoV, SARS-CoV, and
  • the subject in need thereof is suffering from one or more symptoms selected from pneumonia, bronchitis, fever, coughing, productive cough, runny nose, sneezing, breathlessness, sharp or stabbing chest pain during deep breaths, chills, exacerbated asthma, increased rate of breathing, acute respiratory distress syndrome (ARDS), RNAaemia (detectable RNA in the bloodstream), acute cardiac injury, shock, myalgia, fatigue, sputum production, rusty colored sputum, bloody sputum, swelling of lymph nodes, middle ear infection, joint pain, wheezing, headache, hemoptysis, diarrhea, dyspnea, redness, swelling or edema, pain, loss of function, organ dysfunction, multi-organ system failure, acute kidney injury, confusion, malnutrition, blue-tinged skin, sepsis, hypotension, hypertension, hypothermia, hypoxemia, leukocytosis, leukopenia, lymphopenia, thrombocytopenia
  • the administration of at least one of the antibodies or antigen binding fragments reduces the plasma concentration of one or more cytokines.
  • at least one of the antibodies or antigen-binding fragments treats or ameliorates one or more symptoms selected from pneumonia, bronchitis, fever, coughing, productive cough, runny nose, sneezing, breathlessness, sharp or stabbing chest pain during deep breaths, chills, exacerbated asthma, increased rate of breathing, acute respiratory distress syndrome (ARDS), RNAaemia (detectable RNA in the bloodstream), acute cardiac injury, shock, myalgia, fatigue, sputum production, rusty colored sputum, bloody sputum, swelling of lymph nodes, middle ear infection, joint pain, wheezing, headache, hemoptysis, diarrhea, dyspnea, redness, swelling or edema, pain, loss of function, organ dysfunction, multi-organ system failure, acute kidney injury, confusion, malnutrition, blue-tinged skin,
  • the one or more active compounds are administered with at least one of the antibodies or antigen-binding fragments.
  • the one or more active compounds is selected from analgesics, decongestants, expectorants, antihistamines, mucokinetics, and cough suppressants.
  • the subject was previously administered an antiviral therapy by administering one or more antiviral agents.
  • the antiviral agent is selected from remdesivir, hydroxychloroquinine, galidesivir, oseltamivir, paramivir, zanamivir, ganciclovir, acyclovir, ribavirin, lopinavir, ritonavir, favipiravir, and darunavir, or any combinations thereof.
  • the subject is greater than or equal to 12 years of age. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than, or equal to, 18 years of age. In some embodiments, the subject is greater than, or equal to, 18 years of age and less than, or equal to, 59 years of age. In some embodiments, the subject is 60 years of age or older. In some embodiments, the subject achieves a reduction in C ⁇ reactive protein levels within four days from treatment with the antibody or antigen binding fragment thereof.
  • the present technology relates to a method for reducing one or more symptoms associated with coronavirus infection in a subject in need thereof comprising administering an effective amount of an antibody or an antigen binding fragment thereof wherein the antibody binds specifically to human IL-6 receptor (hIL-6R).
  • the antibody or antigen binding fragment thereof comprises a VH, wherein the VH comprises three HCDRs (HCDRl, HCDR2 and HCDR3), wherein the HCDR!
  • the VH comprises SEQ ID NO: 1 and the VL comprises SEQ ID NO: 2.
  • the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.
  • the antibody is sarilumab.
  • the antibody or antigen binding fragment thereof is administered at a dose from about 50 mg to about 400 mg, from about 100 mg to about 350 mg, from about 150 mg to about 300 g, from about 200 mg to about 250 mg or from about 700 to about 750 mg. In some embodiments, the antibody or antigen binding fragment thereof is admin stered at a dose about 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg or 1000 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered at. a dose about 200, 400 or 800 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered at a dose between about 2 mg/kg to about 4 mg/kg.
  • the antibody or antigen binding fragment thereof is administered subcutaneously. In some embodiments, the antibody or antigen binding fragment thereof is administered intravenously. In some embodiments, the antibody or antigen binding fragment thereof is administered daily, once a week, twice a w'eek, or every two weeks.
  • the antibody or antigen binding fragment thereof comprises a VH, wherein the VH comprises three HCDRs (HCDRl, HCDR2 and HCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 14, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 15, and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 16, and a VL, wherein the VL comprises three LCDRs (LCDR1, LCDR2 and LCDR3), wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 17, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 18; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 19.
  • the VH comprises SEQ ID NO: 12 and the VL comprises SEQ ID NO: 13.
  • the antibody is tocilizumab.
  • the antibody or antigen binding fragment thereof is administered at 8 mg per kg, 10 mg per kg, or 12 mg per kg. In some embodiments, the antibody or antigen binding fragment thereof is administered at 162 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered subcutaneously or intravenously.
  • the coronavirus is selected from 2019-nCoV, SARS-CoV, and
  • the subject in need thereof is suffering from one or more symptoms selected from pneumonia, bronchitis, fever, coughing, productive cough, runny nose, sneezing, breathlessness, sharp or stabbing chest pain during deep breaths, chills, exacerbated asthma, increased rate of breathing, acute respiratory distress syndrome (ARDS), RNAaemia (detectable RNA in the bloodstream), acute cardiac injury, shock, myalgia, fatigue, sputum production, rusty colored sputum, bloody sputum, swelling of lymph nodes, middle ear infection, joint pain, wheezing, headache, hemoptysis, diarrhea, dyspnea, redness, swelling or edema, pain, loss of function, organ dysfunction, multi-organ system failure, acute kidney injury, confusion, malnutrition, blue-tinged skin, sepsis, hypotension, hypertension, hypothermia, hypoxemia, leukocytosis, leukopenia, lymphopenia, thrombocytopenia
  • the administration of at least one of the antibodies or antigen binding fragments reduces the plasma concentration of one or more cytokines.
  • at least one of the antibodies or antigen-binding fragments treats or ameliorates one or more symptoms selected from pneumonia, bronchitis, fever, coughing, productive cough, runny nose, sneezing, breathlessness, sharp or stabbing chest pain during deep breaths, chilis, exacerbated asthma, increased rate of breathing, acute respiratory distress syndrome (ARDS), RNAaemia (detectable KNA in the bloodstream), acute cardiac injury, shock, myalgia, fatigue, sputum production, rusty colored sputum, bloody sputum, swelling of lymph nodes, middle ear infection, joint pain, wheezing, headache, hemoptysis, diarrhea, dyspnea, redness, swelling or edema, pain, loss of function, organ dysfunction, multi-organ system failure, acute kidney injury, confusion, malnutrition, blue-tinged skin,
  • the one or more active compounds are administered with at least one of the antibodies or antigen-binding fragments.
  • the one or more active compounds is selected from analgesics, decongestants, expectorants, antihistamines, mucokinetics, and cough suppressants.
  • the subject was previously administered an antiviral therapy by administering one or more antiviral agents.
  • the antiviral agent is selected from remdesivir, hydroxychloroquinine, galidesivir, oseltamivir, paramivir, zanamivir, ganciclovir, acyclovir, ribavirin, lopinavir, ritonavir, favipiravir, and darunavir, or any combinations thereof.
  • the subject is greater than or equal to 12 years of age. In some embodiments, the subject is an adult. In some embodiments, the subject is greater than, or equal to, 18 years of age. In some embodiments, the subject is greater than, or equal to, 18 years of age and less than, or equal to, 59 years of age. In some embodiments, the subject is 60 years of age or older.
  • the subject achieves a reduction in C-reactive protein levels within four days from treatment with the antibody or antigen binding fragment thereof.
  • the subject in need has pulmonary complications characterized by abnormalities in chest CT images.
  • At least one of the antibodies or antigen-binding fragments treats or ameliorates the pulmonary complications characterized by abnormalities in the chest CT images.
  • the subject in need has, relative to a healthy subject, elevated levels of aspartate aminotransferase (AST), elevated levels of alanine aminotransferase (ALT), elevated levels of D-dimer, elevated levels of hypersensitive troponin I (hs-cTnl), elevated levels of proealcitonin, and/or elevated prothrombin time.
  • AST aspartate aminotransferase
  • ALT alanine aminotransferase
  • D-dimer elevated levels of D-dimer
  • elevated levels of hypersensitive troponin I (hs-cTnl) elevated levels of proealcitonin
  • prothrombin time elevated prothrombin time.
  • At least one of the antibodies or antigen-binding fragments treats or ameliorates one or more symptoms selected from the elevated levels of AST, elevated levels of ALT, elevated levels of D-dimer, elevated levels of hypersensitive troponin I (bs-cTni), elevated levels of proealcitonin, and/or elevated prothrombin time.
  • the subject has a pre-existing medical condition.
  • the pre-existing medical condition is heart disease, lung disease, diabetes, cancer and/or high blood pressure.
  • the subject has a weakened immune system.
  • the administration of at least one of the antibodies or antigen binding fragments reduces or eliminates the need for mechanical ventilation, invasive mechanical ventilation, high intensity oxygen therapy, supplemental oxygen and/or hospitalization.
  • the subject on a ventilator at baseline no longer requires invasive mechanical ventilation within 22 days after treatment with the antibody or antigen binding fragment thereof.
  • the subject achieves at least a I -point improvement on the 7- poinl ordinal scale in clinical status within 22 days after treatment with the antibody or antigen binding fragment thereof. In some embodiments, the administration of at least one of the antibodies or antigen binding fragments reduces the incidence of death.
  • the method further comprises administering one or more antiviral agents.
  • the antiviral agent is selected from remdesivir, hydroxychloroquinine, galidesivir, oseltamivir, paramivir, zanamivir, ganciclovir, acyclovir, ribavirin, lopinavir, ritonavir, favipiravir, and darunavir, or any combinations thereof
  • the subject has high IL-6 levels.
  • administering an effective amount of the antibody or antigen binding fragment thereof is not associated with new safety findings. In some embodiments, administering an effective amount of the antibody or antigen-binding fragment thereof does not result in hypersensitivity events.
  • Figure 1 shows atrial profile mITT-modified intent! on-to-treat.
  • Figure 2 shows the primary endpoint - time to improvement of >2 points in clinical status of assessment from baseline on a 7-point ordinal scale (Kap!an-Maier curves; day 29 analysis).
  • Figure 3 shows proportions of subjects in each 7-point ordinal scale category' over time.
  • Figure 3A shows proportions of subjects in each 7-point ordinal scale category over time among all patients.
  • Figure 3B shows proportions in each 7-point ordinal scale category over time among severely ill patients.
  • Figure 3C shows proportions in each 7-point ordinal scale category over time among critically ill patients (C). Scores: 1 — Death; 2 — Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation;
  • Figure 4 shows Kaplan-Meier curves of placebo and sarilumab treated subject population.
  • Figure 4A shows Kaplan-Meier curves of time to >2 ⁇ point clinical improvement on the 7-point ordinal scale in with severe disease.
  • Figure 4B shows Kaplan-Meier curves of time to >2-point clinical improvement on the 7-point ordinal scale in with critical disease.
  • Figure 4C shows survival in patients with severe disease.
  • Figure 4D shows survival in patients with critical disease.
  • Figure 4E shows time to discharge due to recovery in patients with severe disease.
  • Figure 4F shows time to discharge due to recovery in patients with critical disease.
  • Figure 5 shows sariiumab concentration, pharmacodynamic markers, and laboratory findings potentially related to CQVTD-19 severity, over time.
  • Figure 5 A shows Mean (8D) serum sariiumab concentration by treatment and number of doses received.
  • Figure 5B show's CRP concentration.
  • Figure 5C shows median IL- ⁇ concentration.
  • Figure 5D shows sIL-6R concentration.
  • Figure 5E show's neutrophil count.
  • Figure 5F shows neutrophil to lymphocyte ratio.
  • Figure 5G show's D-dimer concentration.
  • COVTD- 19 coronavirus disease 19.
  • CRP C-reactive protein.
  • IL interleukin.
  • sIL-6R soluble IL-6 receptor.
  • Figure 6 show's frequencies of initiations over time and by treatment group.
  • Figure 6A shows systemic corticosteroids.
  • Figure 6B shows dexamethasone.
  • Figure 6C shows antiviral agents.
  • Figure 6D show's hydroxychioroquine/chloroquine.
  • Figure 6E show's systemic antibacterial agents.
  • Figure 7 show's proportion of patients with selected medication use over calendar time.
  • CQ chloroquine
  • CS corti costeroid
  • HCQ hydroxychloroquine.
  • Figure 8 shows a flow chart of the screening, enrollment, randomization and inclusion in analysis.
  • Figure 9 shows the distributions of organ support free days.
  • Figure 9 A shows the cumulative proportion (y-axis) for each intervention group by day (x-axis) with death listed first.
  • Figure 9B shows the organ support free days as horizontally stacked by intervention group.
  • Figure 9C show's the cumulative proportion (y-axis) for each intervention group by day (x-axis) with death listed first.
  • Figure 9D shows the organ support free days as horizontally stacked by intervention group.
  • Figure 10 shows time to event analysis.
  • Figure 10A show's the Kaplan-Meier curves for survival by individual intervention group.
  • Figure 10B shows the survival with tocilizumab and sariiumab intervention groups pooled together.
  • Figure IOC shows the time to intensive care unit discharge by individual intervention group.
  • Figure 10D shows the time to hospital discharge by individual intervention group.
  • Figure 11 show's a flow diagram for Phase 2 and Phase 3 of a study provided herein.
  • the term “about” in quantitative terms refers to plus or minus 10% of the value it modifies (rounded up to the nearest whole number if the value is not sub- dividable, such as a number of molecules or nucleotides). For example, the phrase “about 100 mg” would encompass 90 mg to 110 mg, inclusive; the phrase “about 2500 mg” would encompass 2250 g to 2750 g. When applied to a percentage, the term “about” refers to plus or minus 10% relative to that percentage. For example, the phrase “about 20%” would encompass 18-22% and “about 80%” would encompass 72-88%, inclusive.
  • a or “an” entity refers to one or more of that entity; for example, "a symptom,” is understood to represent one or more symptoms.
  • the terms “a” (or “an”), “one or more,” and “at least one” can be used interchangeably herein.
  • a “symptom” associated with an infectious disease characterized by CHS includes any clinical or laboratory (e.g, diagnostic) manifestation associated with such infectious disease and is not limited to what the subject can feel or observe.
  • the symptoms described herein are of coronavirus infection.
  • these coronaviruses are selected from 2019-nCoV, SARS-CoV, and MERS- CoV.
  • the symptoms include cytokine release syndrome (CRS; a/k/a cytokine storm).
  • CRS is a systemic inflammatory response that can occur in response to coronavirus infection.
  • Symptoms of CRS include fever, fatigue, loss of appetite, muscle and joint pain, nausea, vomiting, d arrhea, rashes, fast breathing, rapid heartbeat, low blood pressure, seizures, headache, confusion, delirium, hallucinations, tremor, and loss of coordination.
  • patients with “severe disease” require supplemental oxygen administration by nasal cannula, simple face mask, or other similar oxygen delivery device.
  • the disease is COVID-19.
  • patients with “critical disease” require supplemental oxygen delivered by non-rebreather mask or high-flow nasal cannula or the use of invasive or non-invasive ventilation or require treatment in an intensive care unit.
  • the disease is COVID-19.
  • the term “subpopulation” refers to subjects (e.g., patients) having one or more defined characteristics that are present in a subset of subjects.
  • a population can comprise, for example, and without limitation, severe patients, patients requiring supplemental oxygen (e.g., patients requiring supplemental oxygen by nasal cannula, patients requiring supplemental oxygen by face mask, or the like), critical patients, patients requiring mechanical ventilation (e.g., patients requiring noninvasive or invasive mechanical ventilation), patients requiring extracorporeal support, a patients requiring intensive respiratory' support, patients requiring extracorporeal membrane oxygenation (ECMQ), or subjects having any combinations of these conditions.
  • severe patients patients requiring supplemental oxygen (e.g., patients requiring supplemental oxygen by nasal cannula, patients requiring supplemental oxygen by face mask, or the like)
  • critical patients e.g., patients requiring mechanical ventilation (e.g., patients requiring noninvasive or invasive mechanical ventilation)
  • patients requiring extracorporeal support e.g., patients requiring
  • a population or subpopulation can comprise subjects having one or more of the following, including, but not limited to, elevated C-reactive protein levels, one or more abnormalities in chest CT images, elevated levels of aspartate aminotransferase (AST), elevated levels of alanine aminotransferase (ALT), elevated levels of D-dimer, elevated levels of hypersensitive troponin I (hs-cTnl), elevated levels of procalcitonin, elevated prothrombin time, and the like.
  • AST aspartate aminotransferase
  • ALT alanine aminotransferase
  • hs-cTnl hypersensitive troponin I
  • procalcitonin elevated procalcitonin
  • elevated prothrombin time and the like.
  • a population or subpopulation can also comprise subjects having one or more pre existing medical conditions such as, e.g., heart disease, lung disease, diabetes, cancer, high blood pressure, and the like.
  • a subpopulation includes subjects having one or more severe symptoms of a disease described herein, e.g., a coronavirus infection.
  • a subpopulation includes subjects requiring supplemental oxygen, e.g., oxygen administered by face mask or by a nasal cannula.
  • a subpopuiation includes subjects that have one or more critical symptoms of a disease described herein, e.g., a coronavirus infection.
  • a subpopuiation includes subjects requiring extracorporeal support, e.g., ECMQ.
  • a subpopulation includes subjects requiring intensive respiratory support, e.g., non-invasive mechanical ventilation and/or invasive mechanical venti lati on.
  • amino acid sequence of SEQ ID NO: 1 is:
  • amino acid sequence of SEQ ID NO: 3 is RFTFDDYA.
  • amino acid sequence of SEQ ID NO: 4 is I8WN8GRJ.
  • amino acid sequence of SEQ ID NO: 5 is AKGRDSFDI.
  • amino acid sequence of SEQ ID NO: 6 is QGIS8W.
  • amino acid sequence of SEQ ID NO: 7 is GAS.
  • amino acid sequence of SEQ ID NO: 8 is QQANSFPYT.
  • amino acid sequence of SEQ ID NO: 9 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • amino acid sequence of SEQ ID NO: 12 is, VQLQESGPGLVRPSQTLSLTCTVSGYSrrSDHAWSWVRQPPGRGLEWIGYISYSGITT YN
  • amino acid sequence of SEQ ID NO: 13 is DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGV PSRF SGSGSGTDFTFTIS SLQPEDIATY Y CQQGNTLP YTF GQGTKVEIKRT VAAPS VFBF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS L S S TLTL SK AD YEKHK VY ACE VTHQ GL S SP VTK SFNRGEC .
  • the amino acid sequence of SEQ ID NO: 14 is, SDHAWS
  • the amino acid sequence of SEQ ID NO: 15 is, YISYSGITTYNPSLK
  • the amino acid sequence of SEQ ID NO: 16 is, SLARTTAMDY
  • the amino acid sequence of SEQ ID NO: 17 is, RASQDISSYLN
  • the amino acid sequence of SEQ ID NO: 18 is, YTSRLHS
  • the amino acid sequence of SEQ) ID NO: 19 is, QQGNTLPYT High IL-6 anci CRP levels
  • high IL-6 levels and “high interleukin-6 levels,” used interchangeably herein, refer to levels of IL-6 in a sample(s) from a subject that are, in one embodiment, a level of IL-6 in a sampie(s) from a subject having infectious diseases characterized by CRS who more likely to achieve a clinically meaningful response following administration of a human anti-IL-6R antibody, or antigen-binding portion thereof, e.g., sarilurnab.
  • a high IL-6 level is greater than about 1.5 times the upper limit of normal (i.SxULN); greater than about 1.75xUL,N; about 2xULN; about 2.25xULN; about 2.5xULN; about 2.75xULN; about 2.80xULN; about 2.85x!JLN; about 2.90xlILN; about 2.95xULN; or greater than about 3xULN.
  • the upper limit of normal of IL-6 in the serum of a subject is about 12.5 pg/m!. Ranges and values intermediate to the above recited ranges and values are also contemplated to be part of the invention.
  • high IL-6 levels are greater than about 15 pg/m!, e.g., about
  • 750 pg/ml between about 30 and about 750 pg/ml; between about 40 and about 750 pg/ml; between about 45 and about 750 pg/ml; between about 50 and about 750 pg/ml; between about 55 and about 750 pg/ml; between about 60 and about 750 pg/ml; between about 65 and about 750 pg/ml; between about 70 and about 750 pg/ml; between about 75 and about 750 pg/ml; between about 80 and about 750 pg/ml; between about 85 and about 750 pg/ml; between about 90 and about 750 pg/ml; between about 95 and about 750 pg/ml; between about 100 and about 750 pg/ml; between about 105 and about 750 pg/ml; between about 15 and about 800 pg/ml; between about 20 and about 800 pg/ml; between about 25 and about 700 pg
  • high IL-6 levels are greater than about 35 pg/ml, e.g, about 35 pg/ml to about 800 pg/ml. Ranges and values intermediate to the above recited ranges and values are also contemplated to be part of the invention.
  • a subject having high C-reactive protein (CRP) level has a concentration of CRP in serum of greater than about 20 mg/L, e.g., about. 20 mg/L; 25 mg/L; 30 mg/L; 35 mg L; 40 mg/L; 45 mg/L; 50 mg/L; 55 mg/L; 60 mg/L; 65 mg/L; 70 mg/L; 75 mg/L; 80 mg/L; 85 mg/L; 90 mg/L; 95 mg L; 100 mg/L; 105 mg/L; 110 mg/L; 120 mg/L;
  • 65 and about 400 mg/L between about 70 and about 400 mg/L; between about 75 and about 400 mg/L; between about 80 and about 400 mg/L; between about 85 and about 400 mg/L; between about 90 and about 400 mg/L; between about 95 and about.
  • the dose of anti-IL-6R antibody administered to the subject is from about 10 mg to about 600 mg. In some embodiments, the dose of the antibody administered to the subject is from about 25 mg to about 200 rng. In various embodiments, the dose of the antibody administered to the subject is from about 60 mg to about 200 mg.
  • the present invention includes (but is not limited to) methods wherein about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 g, about 60 mg, about 65 mg, about 70 g, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 nig, about 200, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 rng, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 nig, about
  • the IL-6R antibody is administered at a dose of from about 25 to 150 mg once a week or 40 mg to 200 rag every other week. In some embodiments, the IL- 6R antibody is administered at a dose of from 25 to 50 mg once per week or once every other week. In some embodiments, the IL-6R antibody is administered at a dose of from 50 to 75 mg once per week or once every other week. In some embodiments, the IL-6R antibody is administered at a dose of from 75 to 100 mg once per week or once every other week. In some embodiments, the IL-6R antibody is administered at a dose of from 100 to 125 mg once per week or once ever)-’ other week.
  • the IL-6R antibody is administered at a dose of from 125 to 150 mg once per week or once every other week. In some embodiments, the IL-6R antibody is administered at a dose of from 150 to 175 mg once per week or once every other week. In some embodiments, the IL-6R antibody is administered at a dose of from 175 to 200 mg once per week or once every other week. In some embodiments, the IL-6R antibody is administered at a dose of 100 mg once a week. In some embodiments, the IL-6R antibody is administered at a dose of 150 ng once a week. In some embodiments, the IL-6R antibody is administered at a dose of 200 mg once a week.
  • the IL-6R antibody is administered at a dose of from 100 to 150 mg once a week. In some embodiments, the IL-6R antibody is administered at a dose of from 100 to 200 mg once every' two v/eeks. In some embodiments, the IL-6R antibody is administered at a dose of from 150 to 200 mg once every two weeks. In some embodiments, the IL-6R antibody is administered at a dose of about 100 or about 150 mg once every two weeks. In some embodiments, the IL-6R antibody is administered at a dose of about 100, 150 or 200 mg once every two rveeks. In some embodiments, the IL-6R antibody is administered at a dose of 100 rng once every two weeks. In some embodiments, the IL-6R antibody is administered at a dose of 150 mg once every two weeks. In some embodiments, the IL-6R antibody is administered at a dose of 200 rng once every two weeks.
  • the amount of anti-IL-6R antibody that is administered to the patient may be expressed in terms of milligrams of antibody per kilogram of patient body weight (i.e., mg/kg).
  • the methods of the present invention include administering an anti-IL- 6R antibody to a patient at a daily dose from about 0.01 to about 100 mg/kg, from about 0.1 to about 50 mg/kg, or from about 1 to about 10 mg/kg of patient body weight.
  • the anti-hIL6R antibody is sarilumab and is administered from about 2 mg/kg to about 4 mg/kg.
  • the anti-hIL6R antibody is sarilumab and is administered from about 2 mg/kg to about 3 mg/kg.
  • the anti-hIL6R antibody is sarilumab and is administered from about 2.5 mg/kg to about 4 mg/kg. In various embodiments, the anti-hIL6R antibody is sarilumab and is administered from about 2 mg/kg to about 3 mg/kg at a frequency of once a week (qw) or once every two weeks (q2w). In some embodiments, the anti-hIL6R antibody is administered at a dose of about 2 mg/kg to 4 mg/kg at a frequency of once a week (qw) or once every two weeks (q2w).
  • the anti-hIL6R antibody is administered at a dose of about 2.5 mg/kg to 4 mg/kg at a frequency of once a week (qw) or once every two weeks (q2w). In various embodiments, the anti-hIL6R antibody is administered at a dose of about 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5 or 5.0 mg/kg. In some embodiments, the anti-hIL6R antibody comprises a VH and a VL, wherein the VH comprises the three CDRs found within the sequence of SEQ ID NO:l and wherein the VL comprises the three CDRs found within the sequence of SEQ ID NO:2. In other embodiments, the anti-hIL6R antibody is sarilumab.
  • the methods of the present invention include administering multiple doses of an anti- 11.-0 R antibody to a patient over a specified time course.
  • the anti-IL-6R antibody can be administered about 1 to 5 times per day, about 1 to 5 times per week, about 1 to 5 times per month or about 1 to 5 times per year.
  • the methods of the invention include administering a first dose of anti-IL-6R antibody to a patient at a first time point, followed by administering at least a second dose of anti-IL-6R antibody to the patient at a second time point.
  • the first and second doses may contain the same amount of anti-IL-6R antibody.
  • the first and second doses may each contain from about 1(3 mg to about 500 mg, from about 20 mg to about 300 mg, from about 100 g to about 200 mg, or from about 100 mg to about 150 mg of the antibody.
  • the time between the first and second doses may be from about a few hours to several weeks.
  • the second time point i.e. , the time when the second dose is administered
  • the second time point can be about 1 hour, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks or longer after the first time point.
  • the second time point is about 1 week or about 2 weeks.
  • Third and subsequent doses may be similarly administered throughout the course of treatment of the patient.
  • the invention provides methods of using therapeutic compositions comprising anti- IL-6R antibodies or antigen-binding fragments thereof and, optionally, one or more additional therapeutic agents.
  • the therapeutic compositions of the invention will be administered with suitable carriers, excipients, and other agents that are incorporated into formulations to provide improved transfer, delivery, tolerance, and the like.
  • suitable carriers, excipients, and other agents that are incorporated into formulations to provide improved transfer, delivery, tolerance, and the like.
  • a multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, incorporated herein by reference in its entirety.
  • formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTIN), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et ai. "Compendium of excipients for parenteral formulations" PDA (1998) I Pharm Sci Technol 52:238-311, incorporated herein by reference in its entirety.
  • Various delivery systems are known and can be used to administer the pharmaceutical composition of the invention, e.g., encapsulation in liposomes, microparticles, microcapsules, receptor mediated endocytosis (see, e.g., Wu etal. (1987) J Biol. Chem. 262:4429-4432, incorporated herein by reference in its entirety).
  • Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes.
  • composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g, oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local.
  • the IL-6R antibody can be administered subcutaneously.
  • the pharmaceutical composition can also be delivered in a vesicle, such as a liposome (see Danger (1990) Science 249:1527-1533, incorporated herein by reference in its entirety).
  • a vesicle such as a liposome
  • the pharmaceutical composition can be delivered in a controlled release system, for example, with the use of a pump or polymeric materials.
  • a controlled release system can be placed in proximity of the composition’s target, thus requiring only a fraction of the systemic dose.
  • the injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular injections, local injection, drip infusions, etc. These injectable preparations may be prepared by methods publicly known. For example, the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections.
  • aqueous medium for injections there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g, polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc.) " .
  • an alcohol e.g., ethanol
  • a polyalcohol e.g., propylene glycol, polyethylene glycol
  • a nonionic surfactant e.g, polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)
  • oily medium there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc.
  • a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc.
  • the antibody is formulated as described herein and in international publication number WO2011/085158, incorporated herein by reference in its entirety.
  • the antibody is administered as an aqueous buffered solution at about pH 60 containing about 21 niM histidine, about 45 mM arginine, about 0.2% (w/v) polysorbate 20, about 5% (w/v) sucrose, and between about 100 mg/mL and about 200 rag/mL of the antibody.
  • the antibody is administered as an aqueous buffered solution at about pH 6.0 containing a h out 21 m M hi sti di ne, about 45 mM arginine, about 0.2% (w/v) polysorbate 20, about 5% (w/v) sucrose, and at least about 130 mg/mL of the antibody.
  • the antibody is administered as an aqueous buffered solution at about pH 60 containing about 21 mM histidine, about 45 mM arginine, about 0.2% (w/v) polysorbate 20, about 5% (w/v) sucrose, and about 131.6 mg/niL of the antibody.
  • the antibody is administered as an aqueous buffered solution at about pH 60 containing about 21 mM histidine, about 45 mM arginine, about 0 2% (w/v) polysorbate 20, about 5% (w/v) sucrose: and about 175 mg/mL of the antibody.
  • the antibody is administered as an aqueous buffered solution at pH 6 0 containing
  • sucrose 5% (w/v) sucrose, and between 100 mg/mL and 200 mg/mL, of the antibody.
  • the antibody is administered as an aqueous buffered solution at pH 6.0 containing
  • the antibody is administered as an aqueous buffered solution at pH 6 0 containing
  • the antibody is administered as an aqueous buffered solution at pH 6.0 containing
  • the pharmaceutical compositions for oral or parenteral use described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients.
  • dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.
  • one or more active compounds are administered with at least one of the antibodies or antigen-binding fragments.
  • the administration may be prior to the antibody administration, concurrently with the antibody administration, or following the antibody administration.
  • at least one of the antibodies or antigen binding fragments is formulated in a pharmaceutical composition that comprises the one or more active compounds selected from, but not limited to, analgesics, decongestants, expectorants, antihistamines, mucokinetics, and cough suppressants.
  • one or more antiviral therapy is administered with at least one of the antibodies or antigen-binding fragments.
  • the administration may be prior to the antibody administration, concurrently with the antibody administration, or following the antibody administration.
  • one or more antiviral therapy may be administered by using one or more antiviral agents.
  • the antiviral agents are selected from remdesivir, hydroxychJoroquinine, galidesivir, oseltamivir, paramivir, zanamivir, ganciclovir, acyclovir, ribavirin, lopinavir, ritonavir, favipiravir, darunavir or a combination thereof.
  • analgesics include, but are not limited to, acetaminophen and the non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, ibuprofen, and naproxen sodium.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • decongestants include, but are not limited to, ephedrine, phenylephrine, pseudoephedrine, and oxymetazoline.
  • expectorants include, but are not limited to, acetylcysteine and guaifenesin.
  • antihistamines include, but are not limited to, chlorpheniramine maleate, diphenhydramine, brompheniramine, ioratadine, cetirizine, and doxylamine succinate.
  • cough suppressants i.e., antitussives
  • dextromethorphan guaifenesin
  • codeine pholcodine
  • noscapine butamirate
  • phenylephrine phenylephrine
  • mucokinetics include, but are not limited to, earbocisteine, ambroxol, and bromhexine.
  • the subject being treated by the methods described herein was previously administered an antiviral therapy using one or more antiviral agents.
  • the antiviral agents previously administered are selected from remdesivir, hydroxy chi oroquinine, galidesivir, oseltamivir, paramivir, zanamivir, ganciclovir, acyclovir, ribavirin, lopinavir, ritonavir, favipiravir, darunavir or a combination thereof.
  • the anti-IL-6R antibody (or pharmaceutical formulation comprising the antibody) can be administered to the patient using any acceptable device or mechanism.
  • the administration can be accomplished using a syringe and needle or with a reusable pen and/or autoinjector delivery device.
  • the methods of the present invention include the use of numerous reusable pen and/or autoinjector deliver ⁇ ' devices to administer an anti ⁇ IL ⁇ 6R antibody (or pharmaceutical formulation comprising the antibody).
  • Examples of such devices include, but are not limited to AUTOPEN (Owen Murnford, Inc., Woodstock, UK), DISETRONIC pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOGMIX 75/25 pen, HU VIA LOG pen, HUMALIN 70/30 pen (Eli Lilly and Co., Indianapolis, IN), NQVQPEN I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR (Novo Nordisk, Copenhagen, Denmark), BD pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN, OPTIPEN PRO, OPTIPEN STARLET, and OPTICLIK (Sanofi-Aventis, Frankfurt, Germany).
  • Examples of disposable pen and/or autoinjector delivery devices having applications in subcutaneous deliver ⁇ ' of a pharmaceutical composition of the present invention include, but are not limited to the SOLOSTAR pen (Sanofi-Aventis), the FLEXPEN (Novo Nordisk), and the KWIKPEN (Eli Lilly), the SURECLICK Autoinjector (Amgen, Thousand Oaks, CA), the PENLET (Hase!meier, Stuttgart, Germany), the EPIPEN (Dey, L.P.), and the HLTMIRA Pen (Abb Vie Inc., North Chicago, IL), to name only a few.
  • the patients treated with an anti-IL-6R antibody or pharmaceutical formulation comprising the antibody
  • administration of the anti-IL-6R antibody did not worsen the symptoms of patients.
  • the patients treated with an anti-IL-6R antibody showed a decline in mean CRP.
  • reduction in CRP was shown at day 4 or later after treatment with anti- IL-6R antibody.
  • the patients treated with an anti-IL-6R antibody showed improvements during the first 2 weeks of treat ent.
  • the patients treated with an anti-IL-6R antibody showed a mean ALT elevation at day 7 (Figure 5H).
  • the patients treated with an anti-IL-6R antibody showed a shorter median time to improvement.
  • the median time is 2 days shorter. (12 days vs 10 days).
  • safety is demonstrated using routine safety procedures and/or routine safety assessments known in the art.
  • safety procedures and assessments include clinical laboratory' testing (e.g., white cell count including ANC, hemoglobin, platelets, creatinine, total bilirubin, ALT, AST), targeted physical examination, and concomitant medication review are performed.
  • safety is assessed by investigator reports of adverse events (AEs), serious AEs, AEs of special interest (infusion-related reactions; hypersensitivity reactions, absolute neutrophil count ⁇ 500/mrn 3 with or without concurrent invasive infection; increase in ALT of at least 3 -fold ULN or in excess of 3-fold ULN and at least 2-fold over the baseline level; invasive bacterial or fungal infections of clinical significance with confirmed diagnosis based on the investigator’s assessment with appropriate diagnostic workups and consultations; symptomatic overdose), and clinical laboratory' parameters including lymphocyte count, neutrophil count, and ALT on days 1, 4, 7, 15, 21, and 29 (if still hospitalized).
  • no new safety signals for sarilumab is observed in patient with CQVID-19.
  • the safety objectives of a study is to evaluate the safety of sarilumab through hospitalization compared to the control arm as assessed by incidence of: (1) Serious adverse events (SAEs); (2) Grade 4 neutropenia (ANC ⁇ 500/mm 3 ); (3) Grade 4 neutropenia (ANC ⁇ 500/mm 3 ) with concurrent severe or life-threatening bacterial, invasive fungal, or opportunistic infection; (4) Grade >2 infusion-related reactions; (5) Grade >2 hypersensitivity reactions; (6) Increase in alanine transaminase (ALT) or aspartate aminotransferase (AST) >3X ULN (for patients with normal baseline) or >3X ULN AND at least 2-fold increase from baseline value (for patients with abnormal baseline); and (7) Invasive bacterial or fungal infections of clinical significance with confirmed diagnosis based on the investigator’s assessment with appropriate diagnostic workups and consultations.
  • SAEs Serious adverse events
  • ANC ⁇ 500/mm 3 Grade 4 neutropenia
  • NCT04315298 evaluates the clinical efficacy of sarilumab relative to the control arm in adult patients hospitalized with COVID-19 regardless of disease severity
  • NCT04327388 evaluates the efficacy of sarilumab in adult patients hospitalized with severe or critical COVID-19.
  • NCT04357860 trial evaluates the efficacy of early sarilumab administration in hospitalized patients infected with COVID-19 with pulmonary' infiltrates and are at high risk of developing acute respiratory distress syndrome (ARDS).
  • ARDS acute respiratory distress syndrome
  • NCT04324073 evaluates the therapeutic effect and tolerance of sarilumab in patients with moderate, severe pneumonia or critical pneumonia associated with COVID-19.
  • NCT04386239 is a clinical trial designed for evaluating clinical efficacy of sarilumab in adult patients hospitalized due to severe COVID-19 pneumonia.
  • NCT04359901 evaluates the efficacy of Sarilumab for moderate COVID-19 disease.
  • NCT04341870 is directed to combination therapy using sarilumab, hydroxychloroquine and azithromycin.
  • NCT04357808 is directed to testing the efficacy of subcutaneous sarilumab in hospital zed patients with moderate-severe COVID-19 infection.
  • NCT02735707 evaluates the efficacy of sarilumab in adult patients hospitalized with severe or critical COVID-19 and pneumonia.
  • Example 1 Sarilumah treatment of hospitalized patients with severe or critical COVID-19: a multinational, randomized, adaptive, phase 3, double-blind, placebo- controlled trial
  • This study was an adaptive, phase 2/3, multicenter, randomized, double-blinded trial. Because of the uncertainties of assessing treatment efficacy in COVID- 19 pneumonia at the time of study design, the initial protocol allowed adaptations such as modification of the provisional phase 3 endpoints, sample size re-estimation before entering phase 3, or closing a dose group while the study remained blinded. Patients were assessed daily while hospitalized until discharge, or death, with a final follow-up on day 60.
  • the trial was monitored by an external independent data monitoring committee (IDMC) with ongoing access to unblinded clinical data.
  • IDMC independent data monitoring committee
  • the protocol was approved by the institutional review boards at each participating hospital and by national ethics committees, as required by local and national regulations.
  • the study was carried out in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and the World Medical Association’s Declaration of Helsinki and its amendments. 17
  • AST aspartate aminotransferase
  • ALT' alanine aminotransferase
  • UPN upper limit of normal
  • immunosuppressants including, but not limited to, IL-6 inhibitors or Janus kinase inhibitors within 30 days of baseline; anti-CD20 agents without evidence of B-cell recovery to baseline levels or IL-1 receptor antagonist (anakinra) within 1 week of baseline; ⁇ abatacept within 8 weeks of baseline;
  • ® alkylating agents including cyclophosphami de, within 6 months of baseline; cyclosporine, azathioprine, mycopheno!ate mofetil, leflunomide, or methotrexate within 4 weeks of baseline; ® intravenous (IV) immunoglobulin within 5 months of baseline;
  • systemic chronic (e.g., oral ) corticosteroids for a condition not related to COVID-19 at doses higher than prednisone 10 rng/day or equivalent at screening;
  • Eligible patients were randomized (2:2:1) to IV sariiumab 400 mg, sarilumab 200 mg, or placebo according to a central randomization scheme using permuted blocks of 5 and implemented through an interactive response technology (IRT). Randomization w3 ⁇ 4s stratified by severity of illness (severe or critical) and use of systemic corticosteroids (yes or no). Patients, care providers, outcomes assessors, and investigators remained blinded to patients’ assigned intervention throughout the course of the study. An unblinded pharmacist was responsible for the preparation and dispensation of ail study interventions.
  • IRT interactive response technology
  • Sariiumab 400 mg, sariiumab 200 mg, or placebo were prepared according to instructions provided in the pharmacy manual.
  • the hospital pharmacist added the contents of prefi!led syringes (PFS) of sariiumab 200 mg solution for subcutaneous injection supplied by the sponsor into a specified volume of locally sourced 0-9% NaCl solution for IV infusion (two syringes for the 400-mg dose, one syringe for the 200-mg dose, and 0-9% NaCl solution for the placebo dose) to produce an IV bag containing a colorless solution to be administered by blinded hospital staff as a single IV infusion.
  • PFS prefi!led syringes
  • Efficacy assessments included daily assessment of clinical status until discharge, body temperature (day 1-3: four times a day, day 4-29: twice a day), oxygen administration (day 1-3: four times a day; day 4-29: results recorded as assessed), resting oxygen saturation (SpCh; day 1-3: four times a day; day 4-29: results recorded as assessed), and National Early- Warning Score 2 (NEWS2).
  • Safety procedures and assessments included clinical laboratory testing (performed locally at each hospital), targeted physical examination, and concomitant medication review'. Vital signs were recorded daily until discharge. Surveillance testing for bacterial and fungal infection was performed locally, on days 7 and 15.
  • nasopharyngeal when feasible
  • blood samples were collected at baseline and on days 7, 15, 21, and 29, or on the day of hospital discharge and analyzed by the local laboratories and a central laboratory, respectively.
  • Serum IL-6 and other biomarkers were analyzed in a central laboratory.
  • Blood samples were also taken for measurement of sariiumab concentration.
  • all clinical data were entered by investigators at each site into an electronic clinical research form (eCRF) and validated remotely by the sponsor’s monitoring team.
  • the primary efficacy endpoint was time from baseline to clinical improvement of >2 points on a 7-point ordinal scale, with numerical values defined as follows: 1 . -Death; 2 .
  • the original phase 2 primary endpoint was the time to resolution of fever for at least 48 hours without antipyretics or until discharge (original protocol).
  • the unanticipated rapid rate of enrolment made the plan to use the phase 2 analysis to select phase 3 efficacy endpoints unfeasible.
  • the primary' and key secondary endpoints for phase 3, as described above, were adopted a priori in the Amended protocol 04.
  • time-to-event endpoints by treatment e.g., time to improvement of >1 point on the 7-point scale, fever resolution, or discharge from hospital
  • score changes at specific time points e.g., proportion with 1 -point improvement/worsening
  • event durations e.g., mechanical ventilation, hospitalization
  • AEs adverse events
  • serious AEs AEs of special interest (infusion -related reactions; hypersensitivity reactions; absolute neutrophil count ⁇ 50G/mm 3 with or without concurrent invasive infection; increase in ALT of at least 3- fold ULN or in excess of 3-fold ULN and at least 2-fold over the baseline level, invasive bacterial or fungal infections of clinical significance with confirmed diagnosis based on the investigator’s assessment with appropriate diagnostic workups and consultations; symptomatic overdose), and clinical laboratory parameters including lymphocyte count, neutrophil count, and ALT on days 1, 4, 7, 15, 21, and 29 (if still hospitalized).
  • the modified intention-to-treat (rnlTT) and safety populations included all randomized patients treated with study medication.
  • Primary analysis was planned at day 29 and final analysis at day 60
  • Analysis of the primary endpoint (rnlTT) involved a stratified log-rank test with treatment as a fixed factor.
  • Estimation of treatment effect was provided as hazard ratio (HR), generated using a stratified Cox proportional hazards model with treatment as a covariate.
  • HR hazard ratio
  • Patients without improvement were censored at the last observation time point; patients who took rescue medication in the study without prior improvement were censored at rescue medication start date. Patients who died were deemed no improvement starting from death date.
  • the proportional hazards assumption was assessed by visual inspection of the plot of log(-log(survival)) versus log(surviva!
  • systemic corticosteroids including dexamethasone
  • antiviral medications including antiviral medications, antibacterial medications (including azithromycin), and hydroxychloroquine/ chi oroquine prior to, prior to and during, and after first infusion of study medication did not differ substantially across treatment arms (Table 3).
  • the proportions of patients discharged due to recovery by day 29 were 83-3% (placebo), 79-2% (sarilumab 200 mg), and 79-2% (sarilumab 400 mg) and the percentages of patients alive at day 60 were 89-3%, 89-3%, and 89-6%, respectively (Table 5). Additional secondary' endpoints related to fever, oxygenation, and hospital status are presented in the supplementary materials (Table 5).
  • CRP C-reactive protein
  • neutrophil counts were considered pharmacodynamic markers of systemic IL-6 signalling inhibition.
  • the decline in mean CRP was steeper in the sariiumab arms than in the placebo arm, with a rebound at day 7 in the 200-mg arm and day 15 in the 400-mg arm ( Figure 5B).
  • neutrophil counts were decreased in the sariiumab arms and lower for a longer period of time with the 400-mg dose than the 200-mg dose, hut again appeared to increase after day 4 in the 200-mg arm and after day 15 in the 400-mg arm.
  • neutrophil counts were stable through day 7 but were higher at day 15 (Figure 5E).
  • the imrnunomodulation may be beneficial for the most serious cases of COVID-19.
  • a numerical difference in survival favoring sarilumab was seen in patients who required intensive respiratory support (oxygen by nonrebreather mask or high-flow nasal cannula, use of invasive or noninvasive ventilation), or treatment in an intensive care unit.
  • CRP C-reactive protein
  • neutrophil counts w3 ⁇ 4re considered pharmacodynamic markers of systemic IL-6 signalling inhibition.
  • the decline in mean CRP was steeper in the sarilumab arms than in the placebo arm, with a rebound at day 7 in the 200-mg arm and day 15 in the 400-mg ami ( Figure 5B).
  • the high CRP levels of the subject are reduced at day 4 after treatment with sarilumab.
  • a Phase 1 safety study is performed for male or female patients who are 12 years of age or older at the time of the study and hospitalized with illness of any duration with evidence of pneumonia by chest radiograph, chest computed tomography or chest auscultation (rales, crackles) and fever documented in the medical record and meets at least one of the following at baseline:
  • an antiviral therapy including one or more antiviral drugs selected from remdesivir, hydroxychloroquinine, galidesivir, oseltamivir, paramivir, zanamivir, ganciclovir, acyclovir, ribavirin, lopinavir, ritonavir, favipiravir, darunavir or a combination thereof.
  • antiviral drugs selected from remdesivir, hydroxychloroquinine, galidesivir, oseltamivir, paramivir, zanamivir, ganciclovir, acyclovir, ribavirin, lopinavir, ritonavir, favipiravir, darunavir or a combination thereof.
  • AH patients have laboratory- confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as per country diagnosis assessment (or other commercial or public health assay) within 2 weeks prior to enrollment and no alternative explanation for current clinical condition.
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • antiviral drugs such as remdesivir, hydroxychloroquinine, galidesivir, oseltamivir, paramivir, zanamivir, ganciclovir, acyclovir, ribavirin, lopinavir, ritonavir, favipiravir, darunavir or a combination thereof.
  • ANC absolute neutrophil count
  • AST aspartate transaminase
  • ALT alanine transaminase
  • IL-6 interleukin-6
  • JKi Janus kinase inhibitors
  • Sarilumab is also administered intravenously one time to all eligible patients.
  • the primary endpoint is change from baseline on clinical status according to WHO master protocol 7-point ordinal scale.
  • the secondary endpoints are (a) resolution of fever for at least 48 hours without antipyretics (b) decrease m 7-point ordinal scale (c) decrease in National Early Warning System 2 (NEWS) score (d) decreased need for/obviation of supplemental oxygen use (e) obviation of ventilator use (f) obviation of medically necessary hospitalization (g) death or any other serious adverse event.
  • NEWS National Early Warning System 2
  • sarilumab will prevent or reduce death, the need for mechanical ventilation, supplemental oxygen and/or hospitalization, fever for at least 48 hours without antipyretics and lead to decrease in 7-point ordinal scale, and/or National Early Warning System 2 (NEWS) score, and reduce or ameliorate one or more symptoms of SARS-CoV-2 infection (for example, pneumonia, bronchitis, fever, coughing, productive cough, runny nose, sneezing, breathlessness, sharp or stabbing chest pain during deep breaths, chills, exacerbated asthma, increased rate of breathing, acute respiratory distress syndrome (ARDS), RNAaemia (detectable RNA in the bloodstream), acute cardiac injury, shock, myalgia, fatigue, sputum production, rusty colored sputum, bloody sputum, swelling of lymph nodes, middle ear infection, joint pain, wheezing, headache, hemoptysis, diarrhea, dyspnea, redness, swelling or edema, pain, loss of SARS-CoV
  • Example 3 lnterleukin-6 Receptor Antagonists in Critically III Patients with Covid-19 Preliminar report
  • REMAP-CAP is an international, adaptive platform trial designed to determine best treatment strategies for patients with severe pneumonia in both pandemic and non-pandemic settings.
  • a 'domain' covers a common therapeutic area (e.g., antiviral therapy) and contains two or more interventions (including control e.g. 'no antiviral'). Patients are randomized to one intervention in each domain for which they are eligible.
  • the REMAP-CAP trial is defined by a master ('core') protocol with individual appendices for each domain, regional governance and adaptations for a declared pandemic. The trial was overseen by a blinded International Trial Steering Committee (ITSC) and an unblinded independent Data and Safety Monitoring Board (DSMB). The trial was approved by relevant regional ethics committees and is conducted in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. Writen or verbal informed consent, in accordance with regional legislation, is obtained from all patients or their surrogates. Participants
  • the Immune Modulation Therapy domain included five interventions: two IL-6 receptor antagonists, tocilizumab and sanlumab; an IL-1 receptor antagonist, anakinra; and interferon beta- la; as well as control (no immune modulation).
  • Investigators at each site selected a priori at least two interventions, one of which had to be control, to which patients would be randomized. Participants were randomized via centralized computer program to each intervention (available at the site) starting with balanced assignment for tocilizumab, sari!umab or control (e.g. 1 : 1 if two interventions available, 1 :1:1 if three interventions available).
  • Tocilizumab at a dose of 8 mg/kg of actual body weight (up to a maximum of 800 mg), was administered as an intravenous infusion over one hour; this dose could be repeated 12-24 hours later at the discretion of the treating clinician.
  • Sanlumab 400 mg, was administered as an intravenous infusion once only. All investigational drugs were dispensed by local pharmacies and were open-label
  • the primary outcome was respiratory and cardiovascular organ support-free days up to day 21.
  • This composite ordinal outcome all deaths within hospital were assigned the worst outcome (-1).
  • respiratory and cardiovascular organ support-free days were calculated up to day 21, such that a higher number represents faster recovery.
  • This outcome was used m a recent Food and Drug Administration approved trial and 1.5 days was considered a minimally clinically important difference.
  • REMAP-CAP uses a Bayesian design with no maximum sample size. Regular, interim analyses are conducted and randomization continues, potentially with response-adaptive randomization with preferential assignment to those interventions that appear most favorable, until a pre-defined statistical trigger was met.
  • the primary analysis was generated from a Bayesian cumulative logistic model, which calculated posterior probability distributions of the 21 -day organ support-free days (primary outcome) based on evidence accumulated in the trial and assumed prior knowledge in the form of a prior distribution.
  • Prior distributions for individual treatment effects 'ere neutral.
  • the primary model adjusted for location (site, nested within country'), age (categorized into six groups), sex, and time-period (two-week epochs).
  • the model contained treatment effects for each intervention within each domain and pre-specified treatment-by-treatment interactions across domains.
  • the treatment effects for tocilizumab and sari!umab were “nested” in the model with a hierarchical prior distribution sharing a common mean and variance. This prior structure facilitates dynamic borrowing between the two 11,-6 receptor antagonists that borrows more information when the observed effects are similar and less when they are different.
  • the primary analysis was conducted on all severe state patients with Covid-19 randomized to any domain (and with complete follow-up).
  • the inclusion of additional patients enrolled outside the Immune Modulation Therapy domain allowed maximal incorporation of all information, providing the most robust estimation of the coefficients of all covariates, as per the principle of the REMAP-CAP design.
  • the model included covariate terms reflecting each patient’s domain eligibility, such that the estimate of an intervention’s effectiveness, relative to any other intervention within that domain, was generated from those patients that might have been eligible to be randomized to those interventions within the domain.
  • the cumulative log odds for the primary outcome was modeled such that a parameter >0 reflects an increase in the cumulative log odds for the organ support-free days outcome, indicating benefit. There was no imputation of missing outcomes.
  • the model was fit using a Markov Cham Monte Carlo algorithm that drew iteratively (10,000 draws) from the joint posterior distribution, allowing calculation of odds ratios with their 95% credible intervals (CrX) and the probability that each intervention (including control) was optimal in the domain, that an intervention was superior compared with control (efficacy), that two non-control interventions 'ere equivalent, or an intervention w3 ⁇ 4s futile compared with control.
  • An odds ratio >1 represents improved survival and/or more organ support-free days.
  • the pre-defmed statistical triggers for trial conclusions and disclosure of results were: a >99% posterior probability that an intervention was optimal compared with all other interventions; an inferiority conclusion if ⁇ 0.25% posterior probability that an intervention was optimal; an intervention efficacy if >99% posterior probability the odds ratio was >1 compared with control; intervention futility if ⁇ 5% posterior probability the odds ratio was >1.2 compared with control, or equivalence if >90% probability the odds ratio was between 1/1.2 and 1.2 for two non-control interventions.
  • Analysis of the primary outcome was then repeated in a second model using only data from those patients enrolled in domains that had stopped and were unblinded at the time of analysis with no adjustment for assignment in other ongoing domains.
  • the secondary outcomes were also analyzed in this second model.
  • One subgroup analysis based on terciles of serum C- reaetive protein (CRP) at inclusion, was pre-specified. Pre-specified analyses are listed in the statistical analysis plan. Data management and summaries were created using R version 3.6.0, the primary analysis was computed in R version 4.0.0 using the rstan package version 2.21.1. Additional data management and analyses w3 ⁇ 4re performed in SQL 2016, SPSS version 26, and Stata version 14.2.
  • ® b only included patients when tocilizumab and/or sarilumab was a randomization option
  • ® L contraindications include hypersensitivity, raised ALT/AST, or thrombocytopenia, or pregnancy.
  • tocilizumab group 92% received at least one dose, and 29% received a second dose at the discretion of the treating clinician.
  • Figure 9 A the cumulative proportion (y-axis) for each intervention group by day (x- axis), with death listed first is shown. Curves that rise more slowly are more favorable.
  • Figure 9B the organ support-free days as horizontally stacked proportions by intervention group are shown. In this figure, red represents worse outcomes and blue represents better outcomes.
  • Figures 9C and 9D are similar figures with the tocilizumab and sarilumab interventions pooled together. The median adjusted odds ratio is 1.65 (95% credible interval 1.27 to 2.14) yielding >99.9% probability of superiority compared with control.
  • Tocilizumab and sarilumab were effective across ail secondary outcomes, including 90-day survival, time to ICU and hospital discharge, and improvement m the World Health Organization (WHO) ordinal scale at day 14. Similar effects were seen in all CRP subgroups.
  • WHO World Health Organization
  • IL-6 receptor antagonists tocilizumab and sarilumab
  • current standard of care which included corticosteroids in the majority of patients (>80%).
  • Benefit was consistent across primary and secondary outcomes, and across subgroups and secondary analyses. Both an improved time to clinical improvement and a reduction in mortality was observed.
  • a Phase 2/3, randomized, double-blind, placebo-controlled trial used an adaptive design to evaluate the safety and efficacy of adding sariiumab to usual supportive care, compared to supportive care plus placebo, m 463 adults, hospitalized with serious complications from COVED- 19, in the Phase 2 portion of the study.
  • patients were hospitalized with laboratory-confirmed COVED- 19 that is classified as severe or critical, or who were suffering from multi-organ dysfunction. Ail patients had pneumonia and fever. After receiving the study dose, patients were assessed for 60 ⁇ 7 days, or until hospital discharge or death.
  • Phase 2 the primary objective was to evaluate the clinical efficacy of sariiumab relative to the control arm in adult patients hospitalized with COVED- 19 regardless of severity strata.
  • the total sample size for Phase 2 was to be approximately 460 patients.
  • patients were randomized 2:2:1 into three groups: sariiumab high dose, sariiumab low dose and placebo, (for example, 400 mg IV sariiumab, 200 mg IV sariiumab, or placebo). Randomization was stratified by severity of illness (severe, critical, multi-system organ dysfunction, immunocompromised) and use of systemic corticosteroids for COVID-19.
  • Patients with severe disease required supplemental oxygen administration by nasal cannula, simple face mask, or other similar oxygen delivery device;
  • Phase 3 helping to determine the endpoints, patient numbers and doses.
  • the second, larger part of the trial evaluates the expected improvement longer-term outcomes, including preventing death and reducing the need for mechanical ventilation, supplemental oxygen and/or hospitalization.
  • An In ependent Data Monitoring Committee (IDMC) reviewed ail available data.
  • the primary objective of the Phase 3 study is to evaluate the clinical efficacy of sarilumab relative to the control arm in adult patients hospitalized with critical COVTD-19.
  • the Phase 3 portion of the study was divided into three cohorts: Cohort 1 - patients enrolled into the following treatment arms and strata:
  • Phase 3 Cohort 1 interim analysis was added to allow s an earlier determination of significant benefit and serves as the basis for this EUA request.
  • ICU intensive care unit
  • the secondary safety objectives of the study were to evaluate the safety of sarilumab through hospitalization (up to Day 29 if patient is still hospitalized) compared to the control arm as assessed by incidence of:
  • ALT alanine transaminase
  • AST aspartate aminotransferase
  • Exhibit A and Exhibit C disclose additional details of the clinical trial protocol.
  • the severity categories are:
  • TB tuberculosis
  • the primary end-point of the Phase 2 study was the percent change from baseline m C- reactive protein (CRP) levels at Day 4 in patients with serum IL-6 levels greater than the upper limit of normal.
  • CRP C- reactive protein
  • the primary endpoint for Phase 3 was the time to improvement (2 points) in clinical status assessment from baseline using the 7-point ordinal scale in patients with a serum IL-6 level greater than the upper limit of normal.
  • the 7-point ordinal scale will also be assessed as a secondary endpoint Phase 2.
  • the ordinal scale is an assessment of the clinical status.
  • the scale is as follows:
  • This adaptive Phase 2/3 study allowed for adaptation of the primary endpoint for Phase 3 following the preliminary analysis of the Phase 2 portion of the study.
  • the primary end point in Phase 3, cohort 1 was the proportion of patients with at least a 1 -point improvement in clinical status from baseline to Day 22 using the 7-point ordinal scale in patients with critical COVID-19 receiving mechanical ventilation at baseline
  • the primary endpoint of Cohort 2 was the proportion of patients with at least 1 -point improvement m clinical status from baseline to Day 22 using the 7-point ordinal scale in patients with critical COVID-19 receiving mechanical ventilation at baseline.
  • the primary end point of Cohort 3 was the proportion of patients with at least I -point improvement in clinical status from baseline to Day 22 using the 7-point ordinal scale in patients with COVTD-19 on high-intensity oxygen therapy* without mechanical ventilation at baseline
  • High -intensity oxygen therapy is defined as the use of non-rebreather mask with an oxygen flow rate of at least 101, /min; use of a high flow device with at least 50% Fi02, or use of non-invasive ventilation (e.g., BiPAPTM) or CPAP to treat hypoxemia.
  • non-invasive ventilation e.g., BiPAPTM
  • CPAP CPAP
  • the Sponsor may present nominal p-valnes for key secondary endpoints at the interim without formal testing at interim.
  • the secondary safety endpoints are:
  • Phase 2 ami 3 Exploratory Endpoints
  • the exploratory endpoints are: 1. Qualitative and quantitative PCR for SARS-CoV-2 in OP/NP swab on Days 1, 4, and 29
  • Serum CRP was measured at each site’s local laboratory according to the schedule m Table 9.
  • Tests may include:
  • a typical blood chemistry panel is shown below:
  • Pregnancy testing was performed using urine or serum samples at screening in women of childbearing potential. A positive pregnancy test was not exclusionary for study participation but was recorded.
  • Culture results (bacterial, fungal, or viral) including specimen source (BAL, tracheal aspirate, sputum, blood, urine, etc.) was performed as part of patients’ workup for new infection should be reported to the Sponsor.
  • specimen source BAL, tracheal aspirate, sputum, blood, urine, etc.
  • Surveillance bacterial and fungal blood cultures Blood samples were collected on Day 7 and Day 15 for blood cultures.
  • Serum samples were collected to measure cytokines and biomarkers such as IL-6, soluble XL-6R and were analyzed by a central laboratory.
  • Nasopharyngeal (NP)/oropharyngeal (OP) swabs were used to collect secretions from patients to determine presence or absence of SARS-CoV-2 virus and to explore relative quantitation of viral load as an exploratory measure.
  • viral sequencing was m some cases performed if sufficient sample was available to determine the sequence and variations. Detailed instructions for blood/OP and NP swab sample collections are in the laboratory manual provided to study sites.
  • Samples for measurement of sari!umab and sIL-6R in serum were collected at visits listed in Table 9. These samples were analyzed either by the Sponsor or a central laboratory. Leftover sampl es may be stored for up to 15 years after the study completion for future biomarker research. Results may be reported outside the CSR.
  • Biomarker samples were collected at time points according to Table 9. PD marker/Biornarker measurements were performed to determine the target pathway of IL-6 inhibition and the impact on pneumonia and respiratory illness associate with viral infection and pathology. Relative quantitation of viral load and viral sequencing w3 ⁇ 4re evaluated in some cases using methodologies that include but may not be limited to RT-PCR and sequencing. Additional biomarkers related to antiviral immunity, including but not limited to neutralizing antibodies were also measured in some circumstances. These samples may be stored for up to 15 years after the study completion for exploratory biomarker research to better understand CO VXD- 19 and related pulmonary disorders, predictive or prognostic markers associated with sarilumab efficacy and safety in COVID-19 patients. Results may be reported outside the CSR.
  • Efficacy procedures and assessments include serum CRP measurement, body temperature, oxygen administration (FiC ) and oxygenation (Sp0 2 ) clinical data assessment, National Early Warning Score2 (NEWS2), ACVPU scale, and biospecimens for biomarker analysis and virology.
  • Safety procedures and assessments include laboratory testing, vital signs, limited physical examination, and targeted medication review.
  • EOS end of study
  • Oxygen administration and oxygenation Sp02 must be measured after 5 minutes of rest (sitting or supine) and must be measured simultaneously with oxygen administration and ventilation data. Record oxygen flow rate (L/min) for patients receiving nasal cannula, simple face mask, or non-rebreather mask. Record Fi02 for patients receiving high flow nasal cannula, non-invasive ventilation, mechanical ventilation, or extracorporeal membrane oxy genation.
  • Temperature may be measured using the following methods: oral, rectal, tympanic, or temporal according to local hospital protocols and according to the manufacturer ’ s instructions for use of the device. Body temperature should be measured using the same method each time. Temperature should be measured predose after at least 5 minutes of rest (supine or sitting).
  • chest CT images will be collected as part of a separate effort related to this study for predictive exploratory analysis and may be provided in a separate study report.
  • CBC is required prior to randomization (standard of care labs may be used). After Day E CBC will not be performed as a study procedure. When CBC is performed as part of the patient’s clinical care the results will be entered in eCRF.
  • LFTs and creatinine are required prior to randomization (standard of care labs may be used). After Day 1, LFTs and creatinine will not be 10 performed as a study procedure. When chemistries are performed as part of the patient’s clinical care, the results will be entered in eCRF.
  • EOT end-of-infusion
  • the Day 1 pre-dose sample and Day 29 or Early Termination PK sample may be used for ADA analysis.
  • genomic DN A/R A The sample for genomic DN A/R A should be collected on Day 1 or may be collected at any visit.
  • a sample size of approximately 200 total patients in all disease seventy strata with high baseline ! L-6 levels (80 in each of the 2 sarilumab groups and 40 on placebo) provided at least 90% power using a two-sample t-test to detect an effect size of 0.633 (i.e., -6.6% mean difference, sarilumab minus placebo, with a standard deviation of 10.43%) for percent change from baseline in CRP levels at Day 4.
  • 0.633 i.e., -6.6% mean difference, sarilumab minus placebo, with a standard deviation of 10.43%) for percent change from baseline in CRP levels at Day 4.
  • the Phase 3 portion of the study required a total of approximately 300 patients with high baseline IL-6 to provide 90% power for pairwise comparisons between each sarilumab dose (400 mg IV or 200 mg IV; n-120 each) and placebo (n ⁇ 6Q) using a log-rank test at a 2-sided significance level of 0.05.
  • This study planned to enroll approximately 400 patients in Phase 3 portion (across all IL-6 levels and severity of illness) in order to have 300 patients m the severe and critical strata to test the primary hypothesis m high IL-6 patients.
  • the number of patients enrolled has been revised based on the observed distribution of baseline IL-6 levels in Phase 2. Only critical patients will be enrolled in the Phase 3 portion of the study at 400 g IV of sarilumab.
  • the study analysis plan was based on the analysis of 2 populations; modified intention- to-treat (mITT) population defined as randomized and treated patients with high baseline IL-6 levels and intention-to-treat (ITT) population defined as all randomized and treated patients. Supportive analyses could also be performed using the per protocol set (PPS) population.
  • mITT modified intention- to-treat
  • ITT intention-to-treat
  • PPS per protocol set
  • the primary efficacy analysis was a pairwise comparison between sarilumab 400 mg IV and placebo with respect to percent change from baseline in CRP levels (natural log scale) at Day 4, in patients with COVID-19 disease. Missing values of CRP levels at Day 4 were imputed by Day 3 or Day 5 levels when available, in this order of priority.
  • Hypothesis test of superiority of sarilumab versus placebo was done using an analysis of covariance (ANCOVA) model with treatment group, severity of illness and systemic corticosteroid used as fixed effects, and baseline logfCRP) as a covariate. Treatment effect was reported as difference in mean percent change from baseline in CRP levels (natural log scale) at Day 4. P-values were compared to 0.05 (2-sided) level of significance and 95% confidence levels reported.
  • the primary efficacy analysis will be a pairwise comparison between sarilumab 400 mg IV and placebo with respect to the primary endpoint of time-to- improvement in clinical status assessment from baseline using the 7-point ordinal scale defined as time from randomization to an improvement of 2 points (from the status at randomization) in patients within the severe and critical strata having high baseline IL-6 levels (mITT), followed by patients within the severe and critical strata with all IL-6 levels (ITT).
  • Hypothesis test of superiority of sarilumab versus placebo will be done using the stratified generalized Wilcoxon test with seventy of illness and systemic corticosteroid use as stratification factors. Treatment effect will be reported as difference in median times-to- resolution of fever using Kaplan-Meier estimate and hazard ratio using Cox proportional hazards model. P-values will be compared to 0.05 (2-sided) level of significance and 95% confidence levels reported.
  • Phase 3 The final primary efficacy analysis for Phase 3 will be decided after confirmation or modification of the endpoints using Phase 2 data.
  • the primary endpoint and the key secondary endpoint will be tested at 0.05 (2-sided) significance level in a hierarchical manner. P- values for other secondary endpoints will be reported for descriptive purpose and compared against 0.05 (2-sided) level of significance. Therefore, no multiplicity adjustment is needed for Phase 2.
  • Baseline characteristics included standard demography (e.g., age, race, weight, height, etc.), disease characteristics, medical history, and medication histor for each patient.
  • Chronic hypercapnic respiratory failure is defined as the presence of both of the following criteria:
  • the efficacy variables included serum CRP, body temperature, gas exchange/oxygen requirement, requirement for ventilation support, ICU admissions, days of hospitalization, 7- point ordinal scale score (to assess clinical status), and NEWS 2 specified in the study endpoints, survival/mortality status
  • Safety variables included incidence of AES is, SAEs, and laboratory safety test results (white cell count including ANC, hemoglobin, platelets, creatinine, total bilirubin, ALT, AST).
  • the PK variable was the concentration of sarilumab and siL-6R m serum at each time point specified in Table 9.
  • Exploratory endpoint variables included measurement of SARS-CoV-2 in OP or NP swabs over time using RT-PCR. Qualitative (positive or negative) or relative quantitation of viral copies were evaluated. Pharmacodynamic variables included the time to reach a negative OP or NP RT-PCR result.
  • Additional biomarker testing included, but was not be limited to, evaluation of inflammatory cytokines in serum, and ANC.
  • Pharmacodynamic variables included the time to nadir (or peak), mean and median change from baseline, mean and median percent change from baseline, and area under the curve (AUC) of mean change, median for IL-6 and ANC.
  • Kevzara rapidly lowered C-reactive protein, a key marker of inflammation, meeting the primary endpoint (see Table 12).
  • Analysis of clinical outcomes in the Phase 2 trial was exploratory and pre-specified to focus on the “severe” and “critical” groups. Patients were classified as “severe” if they required oxygen supplementation without mechanical or high-flow oxygenation; or “critical” if they required mechanical ventilation or high-flow oxygenation or required treatment in an intensive care unit.
  • 7 -point scale consists of: 1) death; 2) hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 4) hospitalized, requiring supplemental oxygen; 5) hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVTD-19 related or otherwise); 6) hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) discharged from hospital.
  • ECMO extracorporeal membrane oxygenation
  • Phase 3 Cohort 1 a greater proportion of patients with critical COVTD-19 receiving mechanical ventilation at baseline had at least a 1 -point improvement on the 7-point ordinal scale, in clinical status from baseline to Day 22 after treatment with sarilumab 400 mg IV compared to placebo. This result was statistically significant and is clinically meaningful to both patients and healthcare providers as a 1 -point improvement indicates that patients (on a ventilator at baseline) no longer require invasive mechanical ventilation.

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Abstract

La présente invention concerne des compositions et des méthodes de traitement de maladies infectieuses, y compris celles caractérisées par le syndrome de libération de cytokines, à l'aide d'un anticorps qui se lie spécifiquement au récepteur de l'interleukine-6 humaine (hIL-6R).
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WO2023064759A1 (fr) * 2021-10-11 2023-04-20 The Board Of Regents Of The University Of Oklahoma Compositions et procédés pour le traitement d'une maladie infectieuse par coronavirus-19 (covid-19)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023064759A1 (fr) * 2021-10-11 2023-04-20 The Board Of Regents Of The University Of Oklahoma Compositions et procédés pour le traitement d'une maladie infectieuse par coronavirus-19 (covid-19)
CN114525235A (zh) * 2022-02-25 2022-05-24 郑州大学 一种提高人表皮生长因子分泌生产效率的方法
CN114525235B (zh) * 2022-02-25 2023-07-14 郑州大学 一种提高人表皮生长因子分泌生产效率的方法

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