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WO2021163549A1 - Compositions and methods for treating viral infections - Google Patents

Compositions and methods for treating viral infections 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
Other languages
French (fr)
Inventor
Thomas OCCHIPINTI
Naimish Patel
Owen HAGINO
Sumathi Sivapalasingam
David LEDERER
Ned BRAUNSTEIN
David WEINREICH
Chad NIVENS
Original Assignee
Sanofi Biotechnology
Regeneron Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanofi Biotechnology, Regeneron Pharmaceuticals, Inc. filed Critical Sanofi Biotechnology
Publication of WO2021163549A1 publication Critical patent/WO2021163549A1/en

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Classifications

    • 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

The present disclosure provides compositions and methods of treating infectious diseases, including those characterized by cytokine release syndrome, using an antibody that specifically binds human interleukin-6 receptor (hIL-6R).

Description

COMPOSITIONS AND METHODS FOR TREATING VIRAL INFECTIONS
RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application Nos 62/976,998, filed February 14, 2020, 62/986,564, filed March 6, 2020, 62/990,353, filed March 16, 2020, 63/003,860, filed April 1, 2020, 63/015,646, filed April 26, 2020, 63/039,380, filed June 15, 2020, and 63/115,509, filed November 18, 2020, and EP Provisional Application No. 21315021.2, filed February 12, 2021, each of which is incorporated herein by reference in its entirety.
FIELD
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). Certain aspects of the present technology relate to the use of interleukin-6 receptor (IL-6R) antagonists, such as anti-IL-6R antibodies, to treat infectious diseases characterized by cytokine storm.
BACKGROUND
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).
SUMMARY
In one aspect, 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). In some embodiments, the subject has severe or critical disease. In some embodiments, the subject has critical or severe disease. In sonic embodiments, the subject has multi-organ dysfunction. In some embodiments, the subject has pneumonia and fever. In another aspect, 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.
In some embodiments, 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.
In some embodiments, the VH comprises SEQ ID NO: 1 and the VL comprises SEQ ID NO: 2.
In some embodiments, 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.
In some embodiments, the antibody is sarilumab.
In some embodiments, the extracellular domain of hIL-6R comprises the amino acid sequence of SEQ ID NO: 11.
In some embodiments, 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
In some embodiments, 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.
In some embodiments, 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.
In some embodiments, the VH comprises SEQ ID NO: 12 and the VL comprises SEQ ID NO: 13.
In some embodiments, the antibody is tocilizumab.
In some embodiments, 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.
In some embodiments, the infectious diseases characterized by CRS is an infection by coronavirus, H1N1, H1N2, II3N1, H3N2, H2N3, H5NI, or respiratory syncytial vims (RSV) In some embodiments, the coronavirus is selected from 2019-nCoV (also referred to herein as “COVID-19”), SARS-CoV, and MERS-CoV. In some embodiments, CRS results from an infection by coronavirus, H1N1, H1N2, H3N1, H3N2, 112N3, H5N1, or RSV. In some embodiments, the subject has severe disease. In some embodiments, the subject has severe disease. In some embodiments, the subject has multi-organ dysfunction. In some embodiments, the subject has pneumonia. In some embodiments, the subject has fever.
In some embodiments, the CRS is characterized by increased plasma concentrations of one or more cytokines selected from interleukins, interferons, chemokines, CSFs, and TNFa. In some embodiments, 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. In some embodiments, the interferons are selected from IFNa, IRNb, IFNy, IFN-lI, IFV-X2, and INR-l3. In some embodiments, 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). In some embodiments, 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).
In some embodiments, 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
In some embodiments, 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. In some embodiments, the CRS is characterized by increased plasma concentrations of platelet-derived growth factor (PDGF). In some embodiments, the CRS is characterized by increased plasma concentrations of vascular endothelial growth factor (VEGF). In some embodiments, the CRS is characterized by increased plasma concentrations of basic fibroblast growth factor (bFGF). In some embodiments, 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, thrombocytopenia, nasal congestion, sore throat, unwillingness to drink, convulsions, ongoing vomiting, extremes of temperature, decreased level of consciousness, abdominal pain, and secondary' infection.
In some embodiments, the subject in need thereof has pulmonary complications characterized by abnormalities in chest CT images. In some embodiments, the subject in need thereof exhibits ground-glass opacity and subsegmental areas of consolidation in chest CT images. In some embodiments, the subject in need thereof exhibits multiple lobular and subsegmental areas of consolidation in chest CT images. In some embodiments, the subject in need thereof exhibits bilateral involvement of ground-glass opacity and subsegmental areas of consolidation in chest CT images. In some embodiments, the subject in need thereof exhibits bilateral involvement of multiple lobular and subsegmental areas of consolidation in chest CT images.
In some embodiments, 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.
In some embodiments, the subject in need thereof is an adult. An adult is a human subject greater than, or equal to, 18 years of age. In some embodiments, 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. In some embodiments, the subject in need thereof is 60 years of age or older.
In some embodiments, the subject in need thereof is younger than 18 years of age.
In some embodiments, the subject in need thereof is greater than, or equal to, 12 years of age.
In some embodiments, the subject achieves a reduction in C -reactive protein levels within four days from treatment with the antibody.
In some embodiments, 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.
In some embodiments, 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.
In some embodiments, 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.
In some embodiments, administration of at least one antibody or antigen-binding fragment thereof reduces the plasma concentration of one or more cytokines.
In some embodiments, 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, leukopenia, lymphopenia, thrombocytopenia, nasal congestion, sore throat, unwillingness to drink, convulsions, ongoing vomiting, extremes of temperature, decreased level of consciousness, abdominal pain, and secondary infection.
In some embodiments, 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.
In some embodiments, 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
In some embodiments, 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.
In some embodiments, 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. In some embodiments, one or more active compounds are administered with at least one antibody or antigen-binding fragment thereof. In some embodiments, one or more active compounds is selected from analgesics, decongestants, expectorants, antihistamines, mucokinetics, and cough suppressants.
In some embodiments, 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. In some embodiments, one or more antiviral therapies may be administered by using one or more antiviral agents. In some embodiments the antiviral agents are selected from remdesivir, hydroxychloroquinine, galidesivir, oseltamivir, paramivir, zanamivir, ganciclovir, acyclovir, ribavirin, lopinavir, ritonavir, favipiravir, darunavir or a combination thereof.
In some embodiments, the subject was previously administered an antiviral therapy by administering one or more antiviral agents. In some embodiments, the antiviral agents are selected from remdesivir, hydroxychloroquinine, galidesivir, oseltamivir, paramivir, zanamivir, ganciclovir, acyclovir, ribavirin, lopinavir, ritonavir, favipiravir, darunavir or a combination thereof.
In some embodiments, 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.
In another aspect, 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
/ propensity for effective treatment of CRS or reducing one or more symptoms associated with CRS.
In another aspect, 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). In some embodiments, 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.
In some embodiments, the VH comprises SEQ ID NO: 1 and the VL comprises SEQ ID NO: 2. In some embodiments, 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.
In some embodiments, the antibody is sarilumab.
In some embodiments, 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. 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. 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. In some embodiments, 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. In some embodiments, the VH comprises SEQ ID NO: 12 and the VL comprises SEQ ID NO: 13.
In some embodiments, the antibody is tocilizumab.
In some embodiments, 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.
In some embodiments, the coronavirus is selected from 2019-nCoV, SARS-CoV, and
MERS-CoV.
In some embodiments, 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, nasal congestion, sore throat, unwillingness to drink, convulsions, ongoing vomiting, extremes of temperature, decreased level of consciousness, abdominal pain, and secondary infection. In some embodiments, the subject has severe to critical disease. In some embodiments, the subject has critical disease. In some embodiments, the subject has multi-organ dysfunction. In some embodiments, the subject has pneumonia and fever.
In some embodiments, the administration of at least one of the antibodies or antigen binding fragments reduces the plasma concentration of one or more cytokines. In some embodiments, 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, sepsis, hypotension, hypertension, hypothermia, hypoxemia, leukocytosis, leukopenia, lymphopenia, thrombocytopenia, nasal congestion, sore throat, unwillingness to drink, convulsions, ongoing vomiting, extremes of temperature, decreased level of consciousness, abdominal pain, and secondary infection.
In some embodiments, the one or more active compounds are administered with at least one of the antibodies or antigen-binding fragments. In some embodiments, the one or more active compounds is selected from analgesics, decongestants, expectorants, antihistamines, mucokinetics, and cough suppressants.
In some embodiments, the subject was previously administered an antiviral therapy by administering one or more antiviral agents. In some embodiments, the antiviral agent is selected from remdesivir, hydroxychloroquinine, galidesivir, oseltamivir, paramivir, zanamivir, ganciclovir, acyclovir, ribavirin, lopinavir, ritonavir, favipiravir, and darunavir, or any combinations thereof.
In some embodiments, 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.
In another aspect, 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). In some embodiments, the antibody or antigen binding fragment thereof comprises a VH, wherein the VH comprises three HCDRs (HCDRl, HCDR2 and HCDR3), wherein the HCDR! 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, LCDK2 and LCDR3), 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. In some embodiments, the VH comprises SEQ ID NO: 1 and the VL comprises SEQ ID NO: 2. in some embodiments, 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.
In some embodiments, the antibody is sarilumab.
In some embodiments, 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.
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 w'eek, or every two weeks.
In some embodiments, 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. In some embodiments, the VH comprises SEQ ID NO: 12 and the VL comprises SEQ ID NO: 13.
In some embodiments, the antibody is tocilizumab.
In some embodiments, 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.
In some embodiments, the coronavirus is selected from 2019-nCoV, SARS-CoV, and
MERS-CoV.
In some embodiments, 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, nasal congestion, sore throat, unwillingness to drink, convulsions, ongoing vomiting, extremes of temperature, decreased level of consciousness, abdominal pain, and secondary infection. In some embodiments, the subject has severe to critical disease. In some embodiments, the subject has severe to critical disease. In some embodiments, the subject has multi-organ dysfunction. In some embodiments, the subject has pneumonia and fever.
In some embodiments, the administration of at least one of the antibodies or antigen binding fragments reduces the plasma concentration of one or more cytokines. In some embodiments, 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, sepsis, hypotension, hypertension, hypothermia, hypoxemia, leukocytosis, leukopenia, lymphopenia, thrombocytopenia, nasal congestion, sore throat, unwillingness to drink, convulsions, ongoing vomiting, extremes of temperature, decreased level of consciousness, abdominal pain, and secondary' infection.
In some embodiments, the one or more active compounds are administered with at least one of the antibodies or antigen-binding fragments. In some embodiments, the one or more active compounds is selected from analgesics, decongestants, expectorants, antihistamines, mucokinetics, and cough suppressants.
In some embodiments, the subject was previously administered an antiviral therapy by administering one or more antiviral agents. In some embodiments, the antiviral agent is selected from remdesivir, hydroxychloroquinine, galidesivir, oseltamivir, paramivir, zanamivir, ganciclovir, acyclovir, ribavirin, lopinavir, ritonavir, favipiravir, and darunavir, or any combinations thereof.
In some embodiments, 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. In some embodiments, the subject in need has pulmonary complications characterized by abnormalities in chest CT images.
In some embodiments, at least one of the antibodies or antigen-binding fragments treats or ameliorates the pulmonary complications characterized by abnormalities in the chest CT images.
In some embodiments, 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.
In some embodiments, 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.
In some embodiments, the subject has a pre-existing medical condition. In some embodiments, the pre-existing medical condition is heart disease, lung disease, diabetes, cancer and/or high blood pressure. In some embodiments, the subject has a weakened immune system.
In some embodiments, 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. In some embodiments, 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.
In some embodiments, 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.
In some embodiments, the method further comprises administering one or more antiviral agents. In some embodiments, the antiviral agent is selected from remdesivir, hydroxychloroquinine, galidesivir, oseltamivir, paramivir, zanamivir, ganciclovir, acyclovir, ribavirin, lopinavir, ritonavir, favipiravir, and darunavir, or any combinations thereof
In some embodiments, the subject has high IL-6 levels.
In some embodiments, 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.
BRIEF DESCRIPTION OF THE DRAWING
Aspects, features, benefits, and advantages of the embodiments described herein will be apparent with regard to the following description, appended claims, and accompanying drawings where:
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;
3. Hospitalized, on non-invasive ventilation or high-flow oxygen devices, 4. Hospitalized, requiring supplemental oxygen; 5 — Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise), 6. Hospitalized, not requiring supplemental oxygen - no longer requiring ongoing medical care; 7 — Not hospitalized. ECMO=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-ό 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. Figure 5H shows ALT concentration. Data are mean (SE), except where otherwise indicated. ALT=alanine aminotransferase. 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.
DETAILED DESCRIPTION
As used 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. Moreover, where “about” is used herein in conjunction with a quantitative term it is understood that in addition to the value plus or minus 10%, the exact value of the quantitative term is also contemplated and described. For example, the term “about 23 %” expressly contemplates, describes, and includes exactly 23%.
It is to be noted that the term "a" or “an" entity refers to one or more of that entity; for example, "a symptom," is understood to represent one or more symptoms. As such, the terms “a" (or "an"), "one or more," and "at least one" can be used interchangeably herein.
Furthermore, "and/or" where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and/or" as used in a phrase such as "A and/or B" herein is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Likewise, the term "and/or" as used in a phrase such as "A, B, and/or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).
It is understood that wherever aspects are described herein with the language “comprising," otherwise analogous aspects described in terms of "consisting of’ and/or "consisting essentially of’ are also provided.
As used 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. In some embodiments, the symptoms described herein are of coronavirus infection. In some embodiments, these coronaviruses are selected from 2019-nCoV, SARS-CoV, and MERS- CoV. In some embodiments, 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.
As used herein, patients with “severe disease” require supplemental oxygen administration by nasal cannula, simple face mask, or other similar oxygen delivery device.
In some embodiments, the disease is COVID-19.
As used herein, 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. In some embodiments, the disease is COVID-19.
As used herein, 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.
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.
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. In particularly exemplary embodiments, a subpopulation includes subjects having one or more severe symptoms of a disease described herein, e.g., a coronavirus infection. In particularly exemplary embodiments, a subpopulation includes subjects requiring supplemental oxygen, e.g., oxygen administered by face mask or by a nasal cannula.
In particularly exemplar)'’ embodiments, a subpopuiation includes subjects that have one or more critical symptoms of a disease described herein, e.g., a coronavirus infection.
In particularly exemplary embodiments, a subpopuiation includes subjects requiring extracorporeal support, e.g., ECMQ.
In particularly exemplary embodiments, a subpopulation includes subjects requiring intensive respiratory support, e.g., non-invasive mechanical ventilation and/or invasive mechanical venti lati on.
Sequences
The amino acid sequence of SEQ ID NO: 1 is:
EVQLVESGGGLVQPGRSLRLSCAASRFTFDDYAMHWVRQAPGKGLEWVSGISWNS
GRI
GYADSVKGRFTISRDNAENSLFLQMNGLRAEDTALYYCAKGRDSFDIWGQGTMVT vss.
The amino acid sequence of SEQ ID NO: 2 is
DIQMTQ SPS S V S AS V GDRVTITCRASQGI S SWLAW Y QQKPGKAPKLLI Y GAS SLESGV PSRFSGSGSGTDFTLTISSLQPEDFASYYCQQANSFPYTFGQGTKLEIK.
The amino acid sequence of SEQ ID NO: 3 is RFTFDDYA.
The amino acid sequence of SEQ ID NO: 4 is I8WN8GRJ.
The amino acid sequence of SEQ ID NO: 5 is AKGRDSFDI.
The amino acid sequence of SEQ ID NO: 6 is QGIS8W.
The amino acid sequence of SEQ ID NO: 7 is GAS.
The amino acid sequence of SEQ ID NO: 8 is QQANSFPYT.
The amino acid sequence of SEQ ID NO: 9 is
EVOLVESGGGLVOPGRSLRLSCAASRFTFDDYAMITWVROAPGKGLEWVSGISWNS
GRIGYADSVKGRFTISRDNAENSLFLOMNGLRAEDTALYYCAKGRDSFDIWGOGTM
VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF
PAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP
CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVH
NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG
QPREPQ V YTLPP SRDELTKN Q VSLTCLVKGF YP SDIAVEWESNGQPENNYKTTPP VX
DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK. The amino acid sequence of SEQ ID NO: 10 is
DIQMTQ SP S S VS AS VGDRYTIT CRASOGIS S WL AW YQQKPGKAPKLLIY GAS S
LESGVPSRFSGSGSGTDFTLTISSLOPEDFASYYCOOANSFPYTFGOGTKLEIKRTVAA
PSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK
DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC.
The sequence of SEQ ID NO: 11 is
MVAVGCALLAALLAAPGAALAPRRCPAQEVARGVLTSLPGDSVTLTCPGVEPEDNA
TVHWVLRKPAAGSHPSRWAGMGRRLLLRSVQLHDSGNYSCYRAGRPAGTVHLLVD
VPPEEPQLSCFRKSPLSNVVCEWGPRSTPSLTTKAVLLVRKFQNSPAEDFQEPCQYSQ
ESQKF SCQLAVPEGD S SF YIVSMC VAS SVGSKF SKTQTFQGCGILQPDPPANITVTAY
ARNPRWLSVTWQDPHSWNSSFYRLRFELRYRAERSKTFTTWMVKDLQHHCVIHDA
WSGLRHVVQLRAQEEFGQGEWSEWSPEAMGIPWTESRSPPAENEVSTPMQALTTN
KDDDNILFRD S ANAT SLP VQD .
The amino acid sequence of SEQ ID NO: 12 is, VQLQESGPGLVRPSQTLSLTCTVSGYSrrSDHAWSWVRQPPGRGLEWIGYISYSGITT YN
PSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTV
S S ASTKGPS WPLAPS SKSTSGGT A ALGCLVKDYFPEP VTV S WN SGALTSGVHTFP A V
LQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA
PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK
TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG.
The 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
The terms “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.
In another embodiment, 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.
In another embodiment, high IL-6 levels are greater than about 15 pg/m!, e.g., about
20 pg/ml; 25 pg/ml; 30 pg/ml; 35 pg/ml; 40 pg/ml; 45 pg/ml; 50 pg/ml; 55 pg/ml; 60 pg/ml; 65 pg/ml; 70 pg/ml, 75 pg/ml; 80 pg/ml; 85 pg/ml, 90 pg/ml; 95 pg/ml; 100 pg/ml; 105 pg/ml; 110 pg/ml; 120 pg/ml; 130 pg/ml; 140 pg/ml; 150 pg/ml; 160 pg/ml; 170 pg/ml; 180 pg/ml, 190 pg/ml; 200 pg/ml; 210 pg/ml; 220 pg/ml; 230 pg/ml, 240 pg/ml; 250 pg/ml; 260 pg/ml; 270 pg/ml; 280 pg/ml; 290 pg/ml; 300 pg ml; 310 pg/ml; 320 pg/ml; 330 pg/ml; 340 pg/ml; 350 pg/ml; 360 pg/ml, 370 pg/ml, 380 pg/ml; 390 pg/ nl; 400 pg/ml; 410 pg/ml; 420 pg/ml; 430 pg/ml; 440 pg/ml; 450 pg/ml; 460 pg/ml; 470 pg/ml; 480 pg/ml; 490 pg/ml; 500 pg/ml; 510 pg/ml; 520 pg/ml; 530 pg/ml; 540 pg/ml; 550 pg/ml; 560 pg/ml; 570 pg/ml; 580 pg/ml; 590 pg/rnl; 600 pg/ml; 610 pg/ml; 620 pg/ml; 630 pg/ml, 640 pg/ml; 650 pg/ml; 660 pg/ml; 670 pg/ml; 680 pg/ml; 690 pg/ml; 700 pg/ml; 710 pg/ml: 720 pg/ml; 730 pg/ml; 740 pg/ml; 750 pg/ml; 760 pg/ml, 770 pg ml, 780 pg/ml; 790 pg/rnl; or about 800 pg/rnl; e.g., between about 15 and about 800 pg/ml; between about 20 and about 800 pg/ml; between about 25 and about 800 pg/ml; between about 30 and about 800 pg/rnl; between about 35 and about 800 pg/ml; between about 40 and about 800 pg/ml; between about 45 and about 800 pg/ml; between about 50 and about 800 pg ml, between about 55 and about 800 pg/ml; between about 60 and about 800 pg/ml; between about 65 and about 800 pg/ml; between about 70 and about 800 pg/ml; between about 75 and about 800 pg/ml; between about 80 and about 800 pg/ml; between about 85 and about 800 pg/rnl; between about 90 and about 800 pg/ml; between about 95 and about 800 pg/ml; between about 100 and about 800 pg/ml; between about 105 and about 800 pg/ml; between about 15 and about 800 pg/ml; between about 20 and about 800 pg/ml; between about 25 and 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/ml; between about 30 and about 700 pg/ml; between about 40 and about 700 pg/ml; between about 45 and about 700 pg/ml; between about 50 and about 700 pg/ml; between about 55 and about 700 pg/ml; between about 60 and about 700 pg/ml; between about. 65 and about 700 pg/ml; between about 70 and about 700 pg/ml; between about 75 and about 700 pg/ml; between about 80 and about 700 pg/ml; between about 85 and about 700 pg/ml; between about 90 and about 700 pg/ml; between about 95 and about 700 pg/ml; between about 100 and about 700 pg/ml; or between about 105 and about 700 pg/ml. In one embodiment, 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.
In another embodiment, 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;
130 mg/L; 140 mg/L; 150 mg/L; 160 mg/L; 170 mg/L; 180 mg/L; 190 mg/L; 200 mg/L; 210 mg L; 220 mg/L; 230 mg/L; 240 mg/L; 250 mg/L; 260 mg/L; 270 mg/L; 280 mg/L; 290 mg/L; 300 mg/L; 310 mg/L; 320 mg/L; 330 mg L; 340 mg/L; 350 mg/L; 360 mg/L; 370 mg/L; 380 mg/L; 390 mg/L; or about 400 pg/ml; e.g., between about 15 and about 400 mg/'L; between about 20 and about 400 mg/L; between about 25 and about 400 mg/L; between about 30 and about 400 mg/L; between about 35 and about 400 mg/L; between about 40 and about 400 mg/L; between about 45 and about 400 mg/L; between about 50 and about 400 mg/L; between about 55 and about 400 mg/L; between about 60 and about 400 mg/L; between about. 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. 400 mg/L; between about 100 and about 400 mg/L; between about 105 and about 400 mg/L; between about 20 and about 350 mg/L; between about 25 and about 350 mg/L; between about 30 and about 350 rng/L; between about 40 and about 350 mg/L, between about 45 and about 350 mg/L; between about 50 and about 350 mg/L; between about 55 and about 350 mg/L; between about 60 and about 350 mg/L; between about 65 and about 350 mg/L; between about 70 and about 350 mg L; between about 75 and about 350 mg/L; between about 80 and about 350 mg/L; between about 85 and about 350 mg/L; between about 90 and about 350 mg/L; between about 95 and about 350 mg/L; between about 100 and about 350 mg/L; between about 105 and about 350 mg/L; between about 20 and about 300 mg/L; between about 25 and about 300 mg L; between about 30 and about 300 mg/L; between about 40 and about 300 mg/L; between about 45 and about 300 mg/L; between about 50 and about 300 mg/L; between about 55 and about 300 mg/L, between about 60 and about 300 mg/L; between about 65 and about 300 mg/L; between about 70 and about 300 mg/L; between about 75 and about 300 mg L; between about 80 and about 300 mg/L; between about 85 and about 300 mg/L; between about 90 and about 300 mg/L; between about 95 and about 300 mg/L; between about 100 and about 300 mg/L; or between about 105 and about 300 mg/L. Ranges and values intermediate to the above recited ranges and values are also contemplated to be part of the invention.
Methods of Administration and Formulations
In some embodiments, 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.
For example, 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 270 mg, about 275 mg, about 280 rng, about 285 nig, about 290 rng, about 295 nig, about 300, about 325 nig, about 350 rag, about 375 nig, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg or more of anti-IL-6R antibody is administered to the patient per week or once ever)-’ two weeks.
In some embodiments, 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. In some embodiments, 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. In some embodiments, 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). For example, 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. In certain embodiments, the anti-hIL6R antibody is sarilumab and is administered from about 2 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. In certain embodiments, 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). In some embodiments, 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. For example, 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. In certain embodiments, 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, in certain embodiments, may contain the same amount of anti-IL-6R antibody. For instance, 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. For example, the second time point (i.e. , the time when the second dose is administered) can be from about 1 hour to about 7 weeks after the first time point (i.e., the time when the first dose is administered). According to certain exemplary embodiments of the present invention, 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.
In certain embodiments, 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. 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. These 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. The 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). In certain situations, the pharmaceutical composition can be delivered in a controlled release system, for example, with the use of a pump or polymeric materials. In another embodiment, 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. As the 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.)". As the 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. The injection thus prepared can be filled in an appropriate ampoule.
In some embodiments, the antibody is formulated as described herein and in international publication number WO2011/085158, incorporated herein by reference in its entirety.
In some embodiments, 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.
In some embodiments, 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.
In some embodiments, 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.
In some embodiments, 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.
In some embodiments, the antibody is administered as an aqueous buffered solution at pH 6 0 containing
21 mM histidine,
45 mM arginine,
0.2% (w/v) polysorbate 20,
5% (w/v) sucrose, and between 100 mg/mL and 200 mg/mL, of the antibody.
In some embodiments, the antibody is administered as an aqueous buffered solution at pH 6.0 containing
21 mM histidine,
45 mM arginine,
0 2% (w/v) polysorbate 20,
5% (w/v) sucrose, and at least 130 mg/mL of the antibody.
In some embodiments, the antibody is administered as an aqueous buffered solution at pH 6 0 containing
21 mM histidine,
45 mM arginine,
0.2% (w/v) polysorbate 20,
5% (w/v) sucrose, and 131.6 mg/mL of the antibody.
In some embodiments, the antibody is administered as an aqueous buffered solution at pH 6.0 containing
21 mM histidine,
45 mM arginine, 0.2% (w/v) polysorbate 20,
5% (w/v) sucrose; and 175 mg/mL of the antibody.
In some embodiments, 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. By way of example, but not by limitation, in some embodiments, such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.
In some embodiments, 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. In some embodiments, 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.
In some embodiments, 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. In some embodiments, one or more antiviral therapy may be administered by using one or more antiviral agents. In some embodiments the antiviral agents are selected from remdesivir, hydroxychJoroquinine, galidesivir, oseltamivir, paramivir, zanamivir, ganciclovir, acyclovir, ribavirin, lopinavir, ritonavir, favipiravir, darunavir or a combination thereof.
In some embodiments, analgesics include, but are not limited to, acetaminophen and the non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, ibuprofen, and naproxen sodium.
In some embodiments, decongestants include, but are not limited to, ephedrine, phenylephrine, pseudoephedrine, and oxymetazoline.
In some embodiments, expectorants include, but are not limited to, acetylcysteine and guaifenesin.
In some embodiments, antihistamines include, but are not limited to, chlorpheniramine maleate, diphenhydramine, brompheniramine, ioratadine, cetirizine, and doxylamine succinate. In some embodiments, cough suppressants (i.e., antitussives) include, but are not limited to, dextromethorphan, guaifenesin, codeine, pholcodine, noscapine, butamirate, and phenylephrine.
In some embodiments, mucokinetics include, but are not limited to, earbocisteine, ambroxol, and bromhexine.
In some embodiments, the subject being treated by the methods described herein was previously administered an antiviral therapy using one or more antiviral agents. In some embodiments 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.
In accordance with the methods disclosed herein, the anti-IL-6R antibody (or pharmaceutical formulation comprising the antibody) can be administered to the patient using any acceptable device or mechanism. For example, 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. In some embodiments, the patients treated with an anti-IL-6R antibody (or pharmaceutical formulation comprising the antibody) exhibited few if any adverse events. In some embodiments, administration of the anti-IL-6R antibody (or pharmaceutical formulation comprising the antibody) did not worsen the symptoms of patients. In some embodiments, the patients treated with an anti-IL-6R antibody (or pharmaceutical formulation comprising the antibody) showed a decline in mean CRP. In some embodiments, reduction in CRP was shown at day 4 or later after treatment with anti- IL-6R antibody.
In some embodiments, the patients treated with an anti-IL-6R antibody (or pharmaceutical formulation comprising the antibody) showed improvements during the first 2 weeks of treat ent.
In some embodiments, the patients treated with an anti-IL-6R antibody (or pharmaceutical formulation comprising the antibody) showed a mean ALT elevation at day 7 (Figure 5H).
In some embodiments, the patients treated with an anti-IL-6R antibody (or pharmaceutical formulation comprising the antibody) showed a shorter median time to improvement. In some embodiments, the median time is 2 days shorter. (12 days vs 10 days).
In some embodiments, safety is demonstrated using routine safety procedures and/or routine safety assessments known in the art. In some embodiments, 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. In some embodiments, 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/mrn3 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). In some embodiments, no new safety signals for sarilumab is observed in patient with CQVID-19. In so e embodi ents, 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/mm3); (3) Grade 4 neutropenia (ANC<500/mm3) 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. In certain exemplary embodiments, sarilumab was not associated with new safety findings. In other exemplary embodiments, no hypersensitivity events were observed with sarilumab.
Several clinical trials are ongoing to determine the efficacy and safety of sarilumab (Kevzara) for the treatment of viral infection caused by SARS-COV-2. For example, the objective of NCT04315298 is to evaluate 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).
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.
Examples
Example 1: Sarilumah treatment of hospitalized patients with severe or critical COVID-19: a multinational, randomized, adaptive, phase 3, double-blind, placebo- controlled trial
Objective
The efficacy and safety of sari!umab, an interleukin-6 receptor inhibitor, in severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support.) CQVTD-19 was assessed.
Study design
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. 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
Patients
Inclusion Criteria
This study enrolled patients aged 18 years or older at the time of signing informed consent who had been hospitalized for laboratory-confirmed SARS-CoV-2 infection in any specimen within 2 weeks prior to randomization and with evidence of pneumonia by chest imaging or chest auscultation and no alternative explanation for current clinical presentation. Patients also had to meet criteria for severe disease (defined as administration of supplemental oxygen by nasal cannula, simple face mask, or another similar device) or critical disease (defined as need for supplemental oxygen delivered by nonrebreather mask or high-flow nasal cannula, use of invasive or noninvasive ventilation, or treatment in an intensive care unit). Before participating in the trial, informed consent w¾s obtained from all patients or their legally authorized/appointed representatives, as specified by local law and in compliance with or exceeding ethics committee requirements.
Exclusion Criteria
Patients were excluded from the study if they had at least one of the following:
• in the investigator’ s opini on: o a low probability of surviving 48 hours or remaining at the investigational site beyond 48 hours, o dy sfunction of >2 organ systems o need for extracorporeal life support, or o renal replacement therapy at screening,
* absolute neutrophil count <2000/mm3;
® aspartate aminotransferase (AST) or alanine aminotransferase (ALT') exceeding 5 -fold upper limit of normal (ULN) at screening;
® platelets <50,0Q0/mm3 at screening; known active, incompletely treated, suspected or known extrapulmonary tuberculosis;
® prior or concurrent use of immunosuppressants at screening, 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;
® tumor necrosis factor a inhibitors within 2-8 w?eeks 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;
® use of 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;
® suspected or known active systemic bacterial or fungal infections within 4 w'eeks of screening.
Randomization and masking
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 w¾s 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.
Procedures
Sariiumab 400 mg, sariiumab 200 mg, or placebo were prepared according to instructions provided in the pharmacy manual. After confirming the randomization number accessed via IRT, 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. Patients could have the IV infusion stopped for a safety-related issue, in which case they did not continue with dosing. An option for a second dose existed (within the assigned treatment arm) within 24-48 hours of the first dose, based on the investigator’s benefit-risk assessment (Amended protocol 02; April 8, 2020).
Clinical and laboratory monitoring
Efficacy assessments
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. In addition to the positive SARS-CoV-2 result required for inclusion, nasopharyngeal (when feasible) and 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. Other than central laboratory results, 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. Outcomes
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.
Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation;
3 — Hospitalized, on noninvasive ventilation or high-flow oxygen devices, 4 — Hospitalized, requiring supplemental oxygen; 5 — Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise), 6 — Hospitalized, not requiring supplemental oxygen - no longer requiring ongoing medical care; 7 — Not hospitalized. Discharge prior to day 29 was considered as a 2-point improvement. The key secondary efficacy endpoint was the proportion of patients alive at day 29.
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). However, the unanticipated rapid rate of enrolment made the plan to use the phase 2 analysis to select phase 3 efficacy endpoints unfeasible. As a result, the primary' and key secondary endpoints for phase 3, as described above, were adopted a priori in the Amended protocol 04.
Other secondary efficacy endpoints included differences in 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), and event durations (e.g., mechanical ventilation, hospitalization).
Safety was assessed by investigator reports of adverse events (AEs), serious AEs, AEs of special interest (infusion -related reactions; hypersensitivity reactions; absolute neutrophil count <50G/mm3 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).
Statistical analysis
This study addressed the null hypothesis of no difference in time to >2-point improvement on the 7-point scale between a sarilumab dose group and placebo. In sample size determination, approximately 400 patients, randomized 2:2:1, were estimated to provide >90% power for pairwise comparison between each sarilumab dose (approximately 160 patients each) and placebo (approximately 80 patients) using a log-rank test of superiority at a two-sided significance level of 0-05. Assumptions, based in part on the results of a placebo- controlled study remdesivir in China (Wang Y, Zhang D, Du G, et al. “Remdesivir in adults with severe COVID-19: a randomized, double-blind, placebo-controlled, multicenter trial,” Lancet 2020; 395, pp. 1569-78) included accrual duration of 3 months, each patient being followed up for >29 days, and proportions of patients with 2 -point improvement at day 15 being 45% for placebo and 70% for sarilumab.
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. 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! time) to determine whether curves were parallel among treatments. Analysis of the key secondary endpoint (niff T) involved a Cochran- Mantei-Haenszel test, with estimation of treatment effect reported as the difference in percentage of patients alive at day 29 (sarilumab - placebo). An administrative interim analysis was prespecified for a point in time when approximately 50% of total planned patients (approximately 200) reached day 15. Multiplicity was addressed for the primary' and key secondary endpoints for the primary analysis at day 29, by means of hierarchical testing (1. Primary endpoint sarilumab 400 mg vs placebo; 2, Key secondary endpoint sarilumab 400 mg vs placebo; 3. Primary' endpoint sarilumab 200 mg vs placebo; 4. Key secondary endpoint sarilumab 200 mg vs placebo).
Resuits
The study was conducted at 45 sites in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain (Table 2). Of 431 patients who were screened, 420 were randomized and 416 received treatment (placebo, n=84; sarilumab 200 mg, n=I59; sarilumab 400 mg, n=T73) (Figure 1). Within each treatment group, fewer than 10% of patients received a second blinded infusion of the assigned treatment.
Baseline demographic, clinical, and laboratory' characteristics were overall similar among the treatment groups, with exceptions including sex distribution, ferritin concentration, and proportions of patients with fever and obesity (Table 1). Median age was 59.0 years (interquartile range [IQR] 50.0-68.0 years) and 37% of participants were women. According to investigator-reported severity, 61% had severe disease and 39% had critical disease. Two (0.5%) patients randomized into the severe disease stratum were recorded in the eCRF as having multisystem organ dysfunction because they required renal replacement therapy. Fever was reported in 52% of patients. Median duration of hospitalization before dosing was 3.0 days (IQR 2,0-4.0 days). Use of systemic corticosteroids (including dexamethasone), 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).
For the primary endpoint of time to improvement of >2 points on a 7-point clinical assessment scale, no significant difference was observed between sarilumah doses and placebo up to day 29 (Figure 2). Although the between-group differences were not significant, median time to improvement was 2 days longer in the placebo group compared with the sarilumab groups (12 days vs. 10 days) (Table 4). In addition, no significant differences were observed in the overall proportions of patients alive at day 29 (placebo, 91.7%; sarilumab 200 mg, 89.9%; sarilumab 400 mg, 91.9%) (Table 4).
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).
Pre-specified analysis of day 29 data shotved a numerical but nonsignificant difference in survival between sarilumab 400 mg (88%) and placebo (79%; difference +9%, 95% Cl -7-7 to 25-5, p 0-25) for the sickest patients in this trial, those with critical disease (Table 4).
In patients with either severe or critical disease, differences between sarilumab 400 mg and placebo on the 7-point clinical status scale w'ere larger during the first 2 wrecks of treatment than during the second 2 weeks (Figure 2). The time-concentration plot of sarilumab concentration following IV infusion showed an initially rapid decline over the first 4 days and a slower decline from day 7 onward, with nearly complete elimination by day 21 even among patients who received two doses of 400 mg within the first. 48 hours (Figure 5A).
Changes in C-reactive protein (CRP) and 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). As expected with IL-6 receptor inhibition, 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. In the placebo arm, neutrophil counts were stable through day 7 but were higher at day 15 (Figure 5E). Neutrophil/lymphocyte ratios (Figure 5F) and D-dimer (Figure 5G) concentrations did not appear to be influenced by sariiumab concentration, and mean ALT elevation only appeared higher than placebo in the sariiumab arms at day 7 (Figure 5FI) The concentration-time plots for IL-6 (Figure 5C) and soluble IL-6 receptor (sIL-6K) (Figure 5D) were consistent with w'hat has been previously reported for sariiumab following subcutaneous injection. Mean sIL- 6R concentration in the placebo arm remained low up to day 29.
The rates of treatment-emergent AEs, infections (including serious infections), and treatment-emergent AEs leading to death were similar among the treatment groups (Table 6). In sarilumab-treated patients, the types of AEs of special interest were generally consistent with the established safety profile of sariiumab and the IV route of administration and occurred more frequently than in the placebo group.
Because standards of care for hospitalized patients with COVTD-19 evolved over the course of the trial, in a post hoc analysis the proportions of patients initiating or continuing selected medications were plotted by w'eek of study conduct (Figure 6). Use of systemic corticosteroids appeared to wane during the first 6 weeks of study conduct, then increased to a peak usage in 70% of patients 13 weeks after the first randomized patient started receiving a corticosteroid (Figure 6A). This uptick in corticosteroid usage coincided with increased enrolment of patients with critical disease. Over the course of the study, initiation of systemic corticosteroids did not appear to be related to treatment arm (Figure 6A). Use of antiviral medications (Figure 6C), hydroxyehloroquine/chloroquine (Figure 6D), and combinations (Figure 7) declined over the course of the tri al. For the medications of interest, changes in background therapy appeared balanced across the treatment arms. In subgroup analyses (not presented), no significant interactions between use of systemic corticosteroids, antiviral medications, antibiotic medications, or hydroxyehloroquine/chloroquine and time to clinical improvement >2 points or survival at day 29 were identified. Only two patients each were treated with remdesivir or convalescent plasma during the trial.
In this multinational, randomized, placebo-controlled study of patients with severe or critical COVID-19 who were receiving the local standard of care, there was no demonstrated benefit of IV sarilumab over placebo. The treatment groups had similar rates of serious infections and AEs leading to death, and types of AEs were consistent with prior clinical trial experience with sarilumab. No new safety signals for sarilumab were observed in these patients with CQVID-19.
The imrnunomodulation may be beneficial for the most serious cases of COVID-19. Results of a large, open-label, controlled trial of dexamethasone (n=2104) versus usual care (n::::4321) for hospitalized patients with COVID-19 suggest the magnitude of survival benefit is related to intensity of respiratory support. 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. The differences in treatment response between patients with severe disease and critical disease may be qualitatively reflected in the different evolution of clinical status over the course of the trial; i.e., earlier improvement in the sarilumab arms among severely ill patients up to day 15, and greater proportions of patients surviving after day 15 among critically ill patients (Figure 3A-C). Kapian-Meier time-to- event curves up to day 60 also suggest more rapid improvement and earlier discharge due to improvement in the sarilumab arms than the placebo arm among the patients with severe disease; and higher probability of survival among sarilumab-treated patients than placebo- treated in the critically ill group (Table 4, Figure 4A-F).
Survival at day 29 was possibly higher by 9% in the sarilumab aims than in the placebo arm for patients who required noninvasive or invasive mechanical ventilation or ECMQ at baseline. Therefore, the results of this study do not exclude the possibility of a benefit from targeted imrnunomodulation in hospitalized patients with COVID-19 pneumonia with critical illness and suggest that subsequent randomized trials of targeted immunomodulatory therapies in this disease focus on critically ill patients and are adequately powered to assess survival as a primary endpoint. Safety w¾s assessed and observed by investigator reports of adverse events (AEs), serious AEs, AEs of special interest and clinical laboratory parameters including lymphocyte count, neutrophil count, and ALT on days 1, 4,
7, 15, 21, and 29. A greater proportion of patients with critical COVID-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. This same endpoint was analyzed in patients in the overall critical stratum regardless of the use of mechanical ventilation at baseline as a key secondary endpoint and again demonstrated that sarilumab 400 nig IV, compared to placebo, had a greater proportion of patients who had improvement in their oxygenation requirements. The treatment groups had similar rates of serious infections and AEs leading to death, and types of AEs were consistent with prior clinical trial experience with sarilumab. No new safety signals for sarilumab w^ere observed in these patients with COVID-19
Changes in C-reactive protein (CRP) and neutrophil counts w¾re 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). For some of the subjects, the high CRP levels of the subject are reduced at day 4 after treatment with sarilumab.
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Example 2: Evaluation of the Efficacy am! Safety of Sarilumab in Hospitalized Patients With COVID-19
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:
(1) Patients with severe disease requiring supplemental oxygen administration by nasal cannula, simple face mask, or other similar oxygen delivery device; or
(2) Patients with critical disease requiring 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; or
(3) Patients with multi-system organ dysfunction and are on vasopressors, extracorporeal life support, or renal replacement therapy; and/or
(4) Patients were previously treated with 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.
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.
All patients were previously administered an antiviral therapy with one or more antiviral drugs, such as remdesivir, hydroxychloroquinine, galidesivir, oseltamivir, paramivir, zanamivir, ganciclovir, acyclovir, ribavirin, lopinavir, ritonavir, favipiravir, darunavir or a combination thereof.
Patients were excluded from the study if in the opinion of the in vestigator, unlikely to survive for <48 hours from screening; • presence of any of the following abnormal laboratory values at screening: absolute neutrophil count (ANC) less than 2000 mm3, aspartate transaminase (AST) or alanine transaminase (ALT) greater than 5 x the upper limit of normal (ULN), platelets < 50,000 per mm3; or
• treatment with anti-interleukin (IL)-6, other anti-IL-6R antagonists, or with Janus kinase inhibitors (JAKi) in the past 30 days or plans to receive during the study period.
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.
After receiving the study dose, patients are assessed for 60 days, or until hospital discharge or death.
It is anticipated that treatment with 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 function, organ dysfunction, multi-organ system failure, acute kidney injury, confusion, malnutrition, blue-tinged skin, sepsis, hypotension, hypertension, hypothermia, hypoxemia, leukocytosis, leukopenia, lymphopenia, thrombocytopenia, nasal congestion, sore throat, unwillingness to drink, convulsions, ongoing vomiting, extremes of temperature, decreased level of consciousness, abdominal pam, and secondary infection) are compare to untreated control patients. This study will show that sarilumab is useful in the treatment of SARS-CoV-2 in patients previously treated with antiviral therapies.
Example 3: lnterleukin-6 Receptor Antagonists in Critically III Patients with Covid-19 Preliminar report
Objective
The effectiveness of sarilumab on survival and organ support in critically ill patients with Covid-19 in a Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community- Acquired Pneumonia (REMAP-CAP) was assessed as described in Gordon et al (“Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 -Preliminary Report,” 2021, medRxiv 2021.01.07.21249390, doi: https://doi.org/10.1101/2021.01.07.21249390).
Trial Design and Oversight
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.
Patients eligible for the platform were assessed for eligibility and potentially randomized to multiple interventions across multiple domains. 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
Critically ill patients, aged > 18 years, with suspected or confirmed Covid-19, admitted to an intensive care unit (ICU) and receiving respiratory or cardiovascular organ support, were classified as severe state and were eligible for enrollment in the Covid-19 Immune Modulation Therapy domain. Exclusion criteria included presumption that death was imminent with lack of commitment to full support, and prior participation in REMAP-CAP within 90 days.
Randomization
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
Procedures
Other aspects of patient management were provided per each site’s standard of care. In addition to assignments in this domain, participants could be randomized to other interventions within other domains, depending on domains active at the site, patient eligibility, and consent (see www'. remapcap.org). After randomization to the Corticosteroid domain for Covid-19 closed, corticosteroids were allowed as per recommended standard of care.
Although clinical staff were aware of individual patient intervention assignment, neither they nor the IT SC were provided any information about aggregate patient outcomes. Outcome Measures
The primary outcome was respiratory and cardiovascular organ support-free days up to day 21. In this composite ordinal outcome, all deaths within hospital were assigned the worst outcome (-1). Among survivors, 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.
Statistical Analysis
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. Importantly, not all patients w¾re eligible for all domains nor for ail interventions (dependent on active domains and interventions at the site, eligibility criteria, and patient/surrogate consent). Therefore, 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 w¾s 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 w¾re performed in SQL 2016, SPSS version 26, and Stata version 14.2.
Results
At a scheduled interim analysis, the independent DSMB reported that tocilizumab had met the statistical trigger for efficacy (posterior probability 99.75%, odds ratio 1.87, 95%CrI 1.20, 2.76) based on an interim analysis of patients as of October 28, 2020. 2,046 patients had been randomized in at least one domain m the severe disease state of REMAP-CAP, and 895 had been randomized in the Immune Modulation Therapy domain (366 to tocilizumab, 48 to sarilumab, 412 to control and 69 to other interventions within the domain) in 113 sites across six countries (Figure 8). Figure 8 shows a flow chart of the screening, enrollment, randomization and inclusion m analysis, and the figure includes the following superscripts:
® a = patients met more than one ineligibility criterion;
® b = only included patients when tocilizumab and/or sarilumab was a randomization option;
• c = other interventions included anakinra, interferon (31a, and no immune modulation when tocilizumab and/or sarilumab was not available as a randomization option;
• d = the primary analysis of alternative interventions within the immune modulation domain was estimated from a model that adjusts for patient factors and for assignment to interventions in other domains. To obtain the most reliable estimation of the effect of these patient factors and of other interventions on the primary outcome, all patients enrolled in the severe COVID-19 cohort (for whom there was consent and follow-up) are included. Importantly, however, the model also factors eligibility for the immune modulation domain and its interventions, such that the final estimate of an immune modulation domain intervention’s effectiveness relative to any other within that domain is generated from those patients that might have been eligible to be randomized to those interventions within the domain; and
® L = contraindications include hypersensitivity, raised ALT/AST, or thrombocytopenia, or pregnancy.
Thirty patients subsequently withdrew consent, and 11 patients had missing primary outcome data. Following a subsequent interim analysis, the D8MB reported that sarilumab had also met the statistical trigger for efficacy and so these results are also reported.
Baseline characteristics were balanced across intervention groups and typical of a critically ill population with Covid-19 (Table 7). All but three patients were receiving respiratory support at the time of randomization, including high flow nasal oxygen (28.8%), noninvasive (41.5%) and invasive (29.4%) mechanical ventilation. The majority of patients (n::::707) were enrolled after June 172020 and the announcement of the dexamethasone result from the RECOVERY trial (“The Recovery Collaborative Group. Dexamethasone m Hospitalized Patients with Covid-19 - Preliminar Report”. N Engl J Med 2020, incorporated herein by reference in its entirety) and of these patients, 93.3% (610/654) were treated with corticosteroids at enrollment or within the following 48 hours. Of the 158 patients recruited before June 17, 2020, 107 were randomized in the previously published Corticosteroid domain within REMAP- CAP, 41 allocated to a seven-day course of hydrocortisone and 39 to shock dependent hydrocortisone. Remdesivir use was recorded in 32.8% (265/807) of patients.
In the tocilizumab group, 92% received at least one dose, and 29% received a second dose at the discretion of the treating clinician. In the sarilumab group, 90% received the allocated drug and in the control group, and 2% were given one of the immune modulating drugs outside the trial protocol.
Primary Outcome
Median organ support-free days were 10 (interquartile range [IQR] -1, 16), 11 (IQR 0,
16) and 0 (IQR -1, 15) for tocilizumab, sarilumab and control groups, respectively (Table 8 and Figures 9A-9D).
In 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. In 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. The median adjusted odds ratios from the primary analysis, using a Bayesian cumulative logistic model, were 1.64 (95% credible interval, 1.25 to 2.14) and 1.76 (95% credible interval, 1 .17 to 2.91) for the tocilizumab and sarilumab groups compared with control, yielding >99.9% and 99.5% probabilities of superiority compared with control, respectively. 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.
Compared with control, median adjusted odds ratios (primary model) were 1.64 (95%CrI 1.25, 2.14) for tocilizumab and 1.76 (95%Crl 1.17, 2.91) for sarilumab, yielding >99.9% and 99.5% posterior probabilities of superiority. Hospital mortality w¾s 28.0% (98/350) for tocilizumab, 22,2% (10/45) for sarilumab and 35.8% (142/397) for control. The hospital mortality pooling both IL-6 receptor antagonists was 27.3% (108/395). Compared with control, median adjusted odds ratios for hospital survival were 1.64 (95%CrI 1.14, 2.35) for tocilizumab and 2.01 (95% Crl 1.18, 4.71) for sanlumab, yielding 99.6% and 99.5% posterior probabilities of superiority. The estimates of the treatment effect for patients treated either with tocilizumab or sarilumab and corticosteroids in combination -were greater than for any intervention on its own, indicating the benefit of using both IL-6 receptor antagonists and corticosteroids together in this critically ill population.
Secondary Outcomes The secondary outcomes are listed in Table 8 and Figures 10A-10D. 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.
There were nine serious adverse events reported in the tocilizumab group including one secondary bacterial infection, five bleeds, two cardiac events and one deterioration in vision. There were 11 serious adverse events in the control group, four bleeds and seven thromboses; and no serious adverse events in the sarilumab group.
Analysis in critically ill patients ith Covid-19, the IL-6 receptor antagonists, tocilizumab and sarilumab, are both effective compared with 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.
Table 7: Baseline Characteristics of Participants in the Immune Modulation Therapy domain*
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Table 8. Primary and Secondary Outcomes
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Example 4; Sariiumab treatment of hospitalized patients with serious complications from CO V ID- 19
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. To enter the trial, 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.
Objectives:
In the Phase 2 study, 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. In this part of the trial, 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. (1) Patients with severe disease required supplemental oxygen administration by nasal cannula, simple face mask, or other similar oxygen delivery device;
(2) Patients with critical disease required supplemental oxygen delivered by non rebreather mask or high-flow nasal cannula or the use of invasive or non-invasive ventilation or require treatment m an intensive care unit; (3) Patients with multi-system organ dysfunction were on vasopressors, extracorporeal life support, or renal replacement therapy; and
(4) Immune compromised patients could be on immunosuppressant treatments.
The Phase 2 findings were utilized in an adaptive manner to determine transition into
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:
- Hospitalized patients with COVTD-19 meeting severe, critical, MSOD, or immunocompromised criteria
Prior to IDMC Recommendation 3 treatment arms: placebo, 200 g sarilumab, or 400 mg sarilumab
- 4 disease severity strata: severe, critical, multiple system organ dysfunction (MSOD), immunocompromised
Post IDMC Recommendation
- 2 treatment arms: placebo, 400 mg sarilumab
- 1 disease stratum: critical
• Cohort 2 - patients on mechanical ventilation at baseline randomized (1:1) to placebo or 800 mg sarilumab on top of standard of care
• Cohort 3 - patients not on mechanical ventilation at baseline but on high intensity oxygen therapy at baseline randomized (1 : 1) to placebo or 800 mg sarilumab on top of standard of care - High intensity oxygen therapy was defined as the use of non-rebreather mask with an oxygen flow rate of at least 10 L/min; use of a high flow nasal device with at least 50% FiOh or use of non-invasive ventilation or continuous positive airway pressure (CPAP) to treat hypoxemia.
A Phase 3 Cohort 1 interim analysis was added to allows an earlier determination of significant benefit and serves as the basis for this EUA request.
An interim analysis was performed once approximately 110 patients in the Phase 3 Cohort 1 critical stratum requiring mechanical ventilation at baseline and randomized to 400 mg or placebo are enrolled, with a data lock point 22 days later. Interim analysis for tins data lock wall be conducted in all critical Phase 3 patients who were enrolled until the first dose date of the last 110th patient in Cohort 1 critical stratum randomized to sarilumab 400 mg or placebo wdio w¾s on a ventilator at baseline.
The secondary objectives of the Phase 2 and Phase 3 studies are summarized below:
1. Evaluate the clinical efficacy of sarilumab compared to the control arm in all disease severity levels and by clinical severity
2. Evaluate the clinical efficacy of sarilumab compared to the control arm by baseline IL-6 level
3. Evaluate changes in the National Early Warning Score 2 (NEWS2)
4. Evaluate the duration of predefined symptoms and signs (if applicable)
5. Evaluate the duration of supplemental oxygen dependency (if applicable)
6. Evaluate the incidence of new mechanical ventilation use during the study
7. Evaluate the duration of new mechanical ventilation use during the study
8. Evaluate need for admission into intensive care unit (ICU)
9. Evaluate duration of hospitalization (days)
10. Evaluate the 28-day mortality rate.
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:
• Serious adverse events (SAEs)
® Grade 4 neutropenia (ANC<5Q0/mnr,) • Grade 4 neutropenia (ANC<500/mm3) with concurrent severe or life-threatening bacterial, invasive fungal, or opportunistic infection
• Grade >2 infusion-related reactions
• Grade >2 hypersensitivity reactions
• 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)
• Invasive bacterial or fungal infections of clinical significance with confirmed diagnosis based on the investigator’s assessment with appropriate diagnostic workups and consultations
An individual patient completed the study approximately 60 days from screening to follow-up on Day 60 ±7 days. (Figure 11 )
Exhibit A and Exhibit C disclose additional details of the clinical trial protocol.
Randomization
For Phase 2 and Phase 3 Cohort 1 , randomization is stratified by:
• Severity of illness at enrollment Severe disease Critical disease Multi -system organ dysfunction immunocompromised Systemic corticosteroids (Yes/No)
The severity categories are:
1. Severe disease
Requires supplemental oxygen administration by nasal cannula, simple face mask, or other similar oxygen delivery device 2. Critical disease:
* Requires supplemental oxygen requiring delivered by non-rebreather mask or high-flow nasal cannula, OR
* Use of invasive or non-invasive ventilation, OR
* Requiring treatment in an ICU
3. Multi-system organ dysfunction:
* Multi-system organ dysfunction: use of vasopressors, extracorporeal life support, or renal replacement therapy
4. Immunocompromised
* Immunocompromised patients (or on immunosuppressant treatments)
Phase 2 and Phase 3: Exploratory Objectives
The exploratory objectives of the study were to:
1. Evaluate the virologic changes in the treatment arms compared to the control arm as assessed by:
• Percent of patients with SARS-COV-2 detectable in oropharyngeal (OP) or nasopharyngeal (NP) sample
• Quantitative SARS-CoV-2 virus in the OP or NP sample
• Development of SARS-CoV-2 variants in OP or NP sample
• Quantitative SARS-CoV-2 virus in blood
2. To evaluate the cytokine profile and additional biomarkers that may be associated with efficacy and safety associated with sarilumab treatment and antiviral immunity
3. Evaluate the incidence of new or worsening laboratory-confirmed serious secondary infections in the treatment arms as compared to the control arm
4. To characterize the concentrations of sarilumab and sIL-6R m serum over time patients will not be recalled after discharge for any missing exploratory assessments.
Exclusion Criteria
A patient who met any of the following criteria was excluded from the study: 1. In the opinion of the investigator, not expected to survive for more than 48 hours from screening.
2. Presence of any of the following abnormal laboratory values at screening: absolute neutrophil count (ANC) less than 2000 min’, AST or ALT greater than 5 x ULN, platelets <50,000 per mm3.
3. Treatment with anti-IL-6, anti-IL-6R antagonists, or with Janus kinase inhibitors (JAKi) in the past 30 days or plans to receive during the study period.
4. Current treatment with the simultaneous combination of leflunoniide and methotrexate.
5. Exclusion criteria related to tuberculosis (TB). a. Known active TB or a history of incompletely treated TB. b. Suspected or known extrapulmonary TB.
6. Patients with suspected or known active systemic bacterial or fungal infections. Note: Patients with a history of positive bacterial or fungal cultures but on enrollment did not have suspected or known active systemic bacterial or fungal infections may be enrolled.
7. Patients who have received immunosuppressive antibody therapy within the past 5 months, including intravenous immunoglobulin or plans to receive during the study period.
8. Participation in a double-blind clinical research study evaluating an investigational product or therapy within 3 months and less than 5 half-lives of investigational product prior to the screening visit.
Exception: The use of remdesivir, hydroxychloroquine, or other treatments being used for COVTD-19 treatments in the context of an open-label study or compassionate use protocol was permitted.
End-points:
Phase 2
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. The primary endpoint for Phase 3 described below were determined after review of Phase
2 data.
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:
• Death;
• Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO);
• Hospitalized, requiring non-invasive ventilation or high flow oxygen devices;
• Hospitalized, requiring supplemental oxygen;
• Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise)
• Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care
• Not hospitalized
Phase 3 Cohort 1
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
An interim analysis was performed once for the approximately 110 patients in the Phase
3 Cohort 1 between enrollment and the data lock point 22 days later. Interim analysis for this data lock will be conducted in all critical Phase 3 patients who ware enrolled until the first dose date of the last 110 patient in Cohort 1 critical stratum randomized to sarilumab 400 mg or placebo who w¾s on a ventilator at baseline. The primary efficacy endpoint was tested at interim analysis at the 0.005 (2-sided) significance level.
Phase 3 Cohort 2
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.
Phase 3 Cohort 3
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., BiPAP™) or CPAP to treat hypoxemia. The secondary end-points are summarized as below.
Key Secondary Efficacy Endpoint Phase 2 only:
1. Time to improvement (2 points) in clinical status assessment from baseline on the 7-point ordinal scale in severe or critical patients with serum IL-6 level greater than the upper limit of normal
2. Time to improvement (2 points) in clinical status assessment from baseline on the 7-point ordinal scale reporting in severe or critical patients with all IL-6 levels.
Phase 3:
The primary and key secondary endpoints for the final Phase 3 Cohort 1 analyses are presented in Table 10, Should the interim analysis be positive, the alpha from the interim analysis will be reallocated and added to the alpha for the planned key secondary endpoints which will allow them to be tested at a significance level of 0.05. Table 11 summarizes the primary and secondary end points for all cohorts in Phase 3.
Table 10: Phase 3 Cohort 1 Primary ami Key Secondary Endpoints
Figure imgf000083_0001
† If the interim analysis results for primary endpoint are statistically significant, then the Sponsor may decide to stop the cohort earlier for efficacy and the alpha used at interim will be reallocated to test the key secondary endpoints at the full a=0.05 (2-sided) if the interim analysis on the primary endpoint is not significant, the Sponsor will continue the follow-up of cohort and any interim results on the secondary' endpoints will be exploratory. The Sponsor may present nominal p-valnes for key secondary endpoints at the interim without formal testing at interim.
Table 11: Phase 3 Primary and Secondary efficacy end points
Figure imgf000084_0001
Figure imgf000085_0001
Phase 2 and Phase 3: Other Secondary Endpoints Efficacy
1. Time to resolution of fever for at least 48 hours without antipyretics or until discharge, whichever is sooner, in patients with documented fever >38°C (oral), >38.4°C (rectal or tympanic), or >37.6°C (temporal or axillary) at Baseline
(Resolution of fever is defined as postbaseline body temperature <37.2°C (oral), or <376°C (rectal or tympanic) or <36.8°C (temporal or axillary)
2. Time to resolution of fever defined as above for at least 48 hours without antipyretics or until discharge, whichever is sooner, in patients defined as above, by clinical seventy
3. Time to resolution of fever (defined as above) for at least 48 hours without antipyretics or until discharge, whichever is sooner, in patients defined as above, by baseline IL-6 levels
4. Time to improvement in oxygenation (increase in SpCh/FiCh of 50 or greater compared to the nadir SpCh/FiO?.) for at least 48 hours or until discharge, whichever is sooner
5. Time to improvement in oxygenation (increase in Sp02/Fi02 of 50 or greater compared to the nadir Sp02/Fi02) for at least 48 hours or until discharge, whichever is sooner, by clinical severity
6. Time to improvement oxygenation (increase in 8p02/Fi02 of 50 or greater compared to the nadir 8p()2/Fi02) for at least 48 hours or until discharge, whichever is sooner, by baseline IL-6 level
7. Time to resolution of fever (as defined above) and improvement in oxygenation (as defined above)
8. Mean change in the 7-point ordinal scale from baseline to Days 3, 5, 8, 11 , 15, and 29 (or until discharge)
9. Percentage of patients in each clinical status category using the 7-point ordinal scale at Days 3, 5, 8, 11, 15, and 29
10. Time to discharge or to a NEVVS2 of <2 and maintained for 24 hours, whichever occurs first
11. Change from baseline to Days 3, 5, 8, 11, 15, and 29 in NEWS2 12. Days with fever (>38°C °C [oral], >38.4°C [rectal or tympanic], or >37.6°C [temporal or axillary])
13. Proportion of patients alive, off oxygen at Day 29
14. Days of resting respiratory rate >24 breaths/min (recorded at least once each day)
15. Days of hypoxemia (Sp()2 <93% on room air, or requiring supplemental oxygen, or mechanical ventilatory' support)
16. Days of supplemental oxygen use
17. Time to saturation >94% on room air
18. Ventilator free days in the first 28 days (to Day 29)
19. Initiation of mechanical ventilation, non-invasive ventilation, or use of high flow nasal cannula (for those not requiring these interventions at baseline)
20. Admission into an ICU (among those not in an ICU at baseline)
21. Days of hospitalization among survivors
22. Ail-cause mortality
23. Change from baseline in serum CRP levels (Phase 3 only)
Other Secondary Safety Endpoints
The secondary safety endpoints are:
1. Incidence of serious adverse events
2. Incidence of Grade 4 neutropenia (ANC <500/mnr)
3. The incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic infection
4. The incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic infection in patients with Grade 4 neutropenia (ANC<500/mmJ)
5. The incidence of hypersensitivity reactions, infusion reactions, gastrointestinal perforation
6. White cell count, hemoglobin, platelets, creatinine, total bilirubin, ALT, AST, on Days 1, 4, 5, 8, 11, 15 and 29 (if still hospitalized)
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
2. Time to 2 consecutive negative OP/NP swab PCR results for SARS-CoV-2
3. Qualitative and quantitative PCR for SARS-CoV-2 in blood on Days 1, 4, and 29
4. Change from baseline m circulating cytokines on Days 4, 7, and 29
5. Change from baseline in serum CRP levels
6. Concentrations of serum sarilumab and sIL-6R Laboratory Assessments
Serum CRP was measured at each site’s local laboratory according to the schedule m Table 9.
All patients should have had white blood cell count, platelet count, AST, and ALT measured prior to randomization. If these laboratory tests were not performed as part of the patient’s clinical care, they may be performed as study procedures in the site’s local laboratory.
After randomization, when patients enrolled in this study undergo laboratory testing as part of their standard-of-eare, the results of these tests will be provided to the Sponsor, as indicated.
Certain tests that are not necessarily part of the patient’s standard-of-care will also be collected as part of this study, as indicated laboratory test results that may be recorded are Table 9. Tests may include:
Blood Chemistry
The results of blood chemistry testing that was performed as part of the patient’s standard-of-care were shared with the Sponsor. These samples were analyzed. LFTs and creatinine are required prior to randomization (standard of care labs may be used). After Day 1, LFTs and creatinine were not performed as a study procedure. When chemistries w¾re performed as part of the patient’s clinical care, the results w¾re entered in eCRF.
A typical blood chemistry panel is shown below:
Figure imgf000088_0001
Figure imgf000089_0001
Hematology
The results of hematology testing that was performed as part of the patient's standard-of- eare was shared with the Sponsor. These samples were analyzed by a local laboratory. CBC was required prior to randomization (standard of care labs may be used). After Day 1, CBC was not performed as a study procedure. When CBC was performed as part of the patient’s clinical care, the results were entered in eCRF.
A typical hematology panel is shown below:
Figure imgf000089_0002
Other Laboratory Tests Screening.·
Patients eligible for study participation tested positive for SARS-CoV-19 RT-PCR. This test was performed as part of standard-of-care and the results were provided to the Sponsor. Safety.
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. Surveillance bacterial and fungal blood cultures: Blood samples were collected on Day 7 and Day 15 for blood cultures.
Biomarkers/Research Samples:
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. In addition to RT-PCR to quantify viral load, 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.
Drus Concentration and Measuremen ts
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.
Pharmacodynamic and Exploratory Biomarker Procedures
In this study, research assessments were performed to explore how sarilumab may modify the clinical manifestations and pathology associated with COVID-19 and how the IL-6 signaling pathway may be modulated.
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 w¾re 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 Assessments
Efficacy procedures and assessments include serum CRP measurement, body temperature, oxygen administration (FiC ) and oxygenation (Sp02) 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.
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Figure imgf000092_0001
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Figure imgf000093_0001
Figure imgf000094_0001
Footnotes:
1. Screening and baseline may occur on the same day. Assessments that are noted for both visits should only be assessed once. Medical history' should include collecting onset of pneumonia symptoms. Body temperature, Sp02, and Fi02 must be collected at randomizatio n.
2. Patients will have an end of study (EOS) assessment to collect data on survival and history of hospital re -admission. This assessment may be performed by j 5 phone.
3. Patients discharged prior to Day 29 will have a follow-up phone call on Day 29 to collect data on survival and history of hospital re-admission and do not need to be recalled to the hospital for a visit.
4. Patients discharged prior to or after Day 29 should have a sample collected. If day of discharge is not Day 29 and coincides wish another visit, the Day 29 assessments should he performed.
10 5. Patients will be re-dosed
6. 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.
7. Clinical Status Assessment using the 7 -point ordinal scale
15 8. 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).
9. If available in the medical record, 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.
10. ECG only if feasible. Historical ECG from current hospital admission is acceptable.
11. Targeted medications
5 12. Adverse events: Only SAEs and AESIs will be recorded in eCRF.
13. Pregnancy testing to be performed in women of childbearing potential (WOCBP) only. Serum or urine pregnancy test are both acceptable.
14. Hematology: 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.
15. Blood Chemistry'. 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.
16. Surveillance blood cultures for bacteria and fungi, should be performed weekly for patients who have had a sustained ANC <1000/mE for >48 hours postrandomization.
17. All samples should be collected before study drug administration except post-infusion PK and sIL-6R samples: so * PK and sIL-6R samples collected on dosing days for the initial dose and for the FIRST repeat dose are mandatory'. Samples for subsequent doses are requested
15 if sufficient PPI are available:
- One predose (as ciose to initiation of treatment as reasonable) and
- One within 60 minutes after the end-of-infusion (EOT). The EOI sample or flush should be collected from the arm, contralateral to that used for IV infusion, if possible. If not medically feasible, the sample can be drawn from the same arm. If the sample cannot be obtained within 60 minutes of the end of infusion, the time from end of infusion should be provided in the CRT
20 - Day 4 samples are mandatory (if PPE and appropriate lab facilities are available).
* The Day 1 pre-dose sample and Day 29 or Early Termination PK sample may be used for ADA analysis.
18. Swab and tests will be for exploratory analysis only not for inclusion or diagnosis.
19. Separate consent is required for participation in the optional genomic sub-study and collection of a blood sample for (DNA/RNA). The sample for genomic DN A/R A should be collected on Day 1 or may be collected at any visit.
Statistical analysis
For the Phase 2 portion of the study, 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. These assumptions were approximated from the CRP data on tocilizumab in the China CQVTD-19 study (Xu, 2020). Total sample size for Phase 2 was expected to be larger than 200 to include patients with all baseline IL-6 levels.
Assumed median time-to-improvement (2 point) in clinical status (in severe or critical COVID-19 patients with high baseline IL-6) follows an exponential survival distribution with difference between sari!umab and placebo median times assumed to be 2 days (5 days in placebo and 3 days in sarilumab group), accrual duration is 1 year (-365 days) and each patient was followed for a period of at least 29 days. With a 2:2: 1 randomization ratio (sarilumab 400 mg IV : sarilumab 200 mg IV : placebo), 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.
For the Phase 2 portion of the study, 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.
To determine the success of the Phase 2 portion of the trial, first the data in patients with high baseline IL-6 was analyzed (mITT). If the treatment difference was statistically significant, then the key secondary endpoint, time to improvement (2 points) in clinical status on the 7-point ordinal scale, was tested as specified below for the primary endpoint m Phase 3. If this is statistically significant, similar analyses were done between sarilumab 400 mg IV and placebo on the data for the full Phase 2 ITT population (that is, without regard to baseline IL-6 levels).
For the Phase 3 study, 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.
The final primary efficacy analysis for Phase 3 will be decided after confirmation or modification of the endpoints using Phase 2 data. In Phase 2, 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.
Based on Phase 2 results, adaptations are made to the Phase 3 portion of the study. Study Variables
A. Demographic and Baseline Characteristics
Baseline characteristics included standard demography (e.g., age, race, weight, height, etc.), disease characteristics, medical history, and medication histor for each patient.
The site investigator assessed the patient for a history of chronic hypercapnic respiratory failure (e.g., due to chronic obstructive pulmonary disease) at the screening visit. Chronic hypercapnic respiratory failure is defined as the presence of both of the following criteria:
1. Documented current or historical PaCC >45 mm Hg (measured from arterial blood gas analysis), and
2. A clinician has documented a history of chronic hypercapnic respiratory failure m the medical record (Note that there are many ways to document this: chronic hypercapnic respiratory failure, CO2 retainer, chronic hypercapnia, chronic alveolar hypoventilation, etc.).
B. Efficacy Variables
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
C. Safety Variables
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).
D. Pharmacokinetic Variables
The PK variable was the concentration of sarilumab and siL-6R m serum at each time point specified in Table 9.
E. Pharmacodynamic and Other Biomarker Variables
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.
Results:
Preliminary analysis of the Phase 2 portion of the trial demonstrated that 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.
In the preliminary Phase 2 analysis, Kevzara had no notable benefit on clinical outcomes when combining the “severe” and “critical” groups. However, there were negative trends for most outcomes m the “severe” group, while there were positive trends for all outcomes in the “critical” group (see table below). During a further review of the discontinued “severe” group it was revealed that the negative trends in the Phase 2 (n=T26) were not reproduced in Phase 3 (n=276), and that clinical outcomes were balanced across all treatment groups. Outcomes for the “severe” group were better than expected regardless of treatment assignment: for example, m the Phase 2 portion, approximately 80% were discharged, 10% of patients died and 10% remain hospitalized.
Table 12; IJ.S. Kevzara Trial - Phase 2 Efficacy Results
Figure imgf000099_0001
Figure imgf000100_0001
Footnotes:
3. 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.
Safety
Based on data from the Phase 2 interim analysts, sanlurnab 400 mg IV was not associated with new safety findings. Transient increase in transaminase levels were observed at higher rates in sarilumab patients compared to placebo. Grade 4 neutropenia was rare. The primary risk of hypersensitivity reactions is a common risk seen with all protein therapeutics. When reviewing the signs and symptoms reported during and after infusion in the phase 2 interim analysis, only 1 infusion reaction was observed that was moderate in severity and resolved. There were no hypersensitivity events observed with sarilumab. Other safety events analyzed did not yield any significant safety findings.
Benefits
In 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.
This same endpoint was analyzed in patients in the overall critical stratum regardless of the use of mechanical ventilation at baseline as a key secondary endpoint and again demonstrated that sarilumab 400 mg IV, compared to placebo, had a greater proportion of patients who had improvement in their oxygenation requirements.
One skilled in the art will appreciate further features and advantages of the invention based on the above-described embodiments. Accordingly, the invention is not to be limited by what has been particularly shown and described, except as indicated by the appended claims. All publications and references cited herein are expressly incorporated herein by reference m their entirety for all purposes.

Claims

1. A method for treating coronavirus infection in a subject in need thereof composing administering an effective amount of an antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof binds specifically to human IL- 6 receptor (I1XL-6R), and wherein the antibody or antigen-binding fragment thereof comprises a VH, wherein the VH comprises three HCDRs (HCDRL HCDR2 and HCDR3), wherein HCDR1 comprises the ammo acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, and a VL, wherein the VL comprises three LCDRs (LCDR1, LCDR2 and LCDR3), wherein LCDR1 comprises the ammo 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.
2. The method of claim 1, wherein the VH comprises SEQ ID NO: 1 and the VI, comprises SEQ ID NO: 2
3. The method of claim 2, wherein 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.
4. The method of claim 2, wherein the antibody is sarilumab.
5. The method of any one of claims 1 -4, wherein 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 rng.
6. The method of any one of claims 1-4, wherein 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 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg or 1000 mg.
7. The method of any one of claims 1-4, wherein the antibody or antigen- binding fragment thereof is administered at a dose of about 200 mg, 400 mg or 800 mg.
8. The method of any one of claims 1-4, wherein the antibody or antigen-binding fragment thereof is administered at a dose between about 2 nig/'kg to about 4 mg/kg.
9. The method of any one of claims 1-8, wherein the antibody or antigen- binding fragment thereof is administered subcutaneously.
10. The method of any one of claims 1-8, wherem the antibody or antigen-binding fragment thereof is administered intravenously.
11. The method of any one of claims 1-10, wherein the antibody or antigen-binding fragment thereof is administered daily, once a week, twice a week, or once every two weeks.
12. The method of claim 1, wherein the coronavirus is selected from the group consisting of
2019-nCoV, SARS-CoV, and MERS-CoV.
13. The method of any one of claims 1-12, wherein the subject is suffering from 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 inj ury, 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, nasal congestion, sore throat, unwillingness to drink, convulsions, ongoing vomiting, extremes of temperature, decreased level of consciousness, abdominal pa , and secondary infection.
14. The method of any one of claims 1-13, wherein the subject has severe to critical disease.
15. The method of any one of claims 1-13, wherein the subject has critical disease.
16. The method of any one of claims 1-13, wlierein the subject has multi-organ dysfunction.
17. The method of any one of claims 1-13, wlierein the subject has pneumonia and fever.
18. The method of any one of claims 1-17, wlierein the administration of the antibody or antigen-binding fragment thereof reduces the plasma concentration of one or more cytokines.
19. The method of any one of claims 1-18, wherein administration of the antibody or antigen- biding 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 pam 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 pam, wheezing, headache, hemoptysis, diarrhea, dyspnea, redness, swelling or edema, pam, 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, nasal congestion, sore throat, unwillingness to drink, convulsions, ongoing vomiting, extremes of temperature, decreased level of consciousness, abdominal pain, and secondary infection.
20. The method of any one of claims 1-19, wherein one or more active compounds are administered with the antibody or antigen-binding fragment thereof.
21. The method of claim 20, wherein the one or more active compounds is selected from the group consisting of analgesics, decongestants, expectorants, antihistamines, mucokinetics, and cough suppressants.
22. The method of any one of claims 1-21, wherein the subject w¾s previously administered an antiviral therapy by administering one or more antiviral agents.
23. The method of claim 22, wherein the antiviral agent is selected from the group consisting of remdesivir, liydroxyeiiloroquinine, galidesivir, oseltamivir, paramivir, zanamivir, ganciclovir, acyclovir, ribavirin, lopinavir, ritonavir, favipiravir, and darunavir, or any combinations thereof.
24. The method of any one of claims 1-23, wherein the subject is greater than or equal to 12 years of age.
25. The method of any one of claims 1-24, wherein the subject is an adult.
26. The method of any one of claims 1-25, wherein the subject is greater than or equal to 18 years of age.
27. The method of any one of claims 1-26, wherein the subject is greater than or equal to 18 years of age and less than or equal to 59 years of age.
28. The method of any one of claims 1-26, wherein the subject is 60 years of age or older.
29. The method of any one of claims 1-28, wherein the subject achieves a reduction in C- reactive protein levels within four days from treatment with the antibody.
30. 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 (ML-6R), wherein the antibody or antigen-binding fragment thereof comprises a VH, and wherein the VH comprises three HCDRs (HCDR1, 11CDR2 and HCDR3), wherein HCDR1 comprises the ammo acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, and a VL, wherein the VL comprises three LCDRs (LCDRl, LCDR2 and LCDR3), wherein LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2. comprises the ammo acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.
31. The method of claim 30, wherein the VH comprises SEQ ID NO: 1 and the VL comprises SEQ ID NO: 2.
32. The method of claim 31, wherein 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
33. The method of claim 31, wherein the antibody is sarilumab.
34. The method of any one of claims 30-33, wherein the antibody or antigen-binding fragment thereof is administered at a dose from about 50 mg to about 400 mg, from about 100ng to about 350 rng, from about 150 mg to about 300 rng, from about 200 mg to about 250 mg or from about 700 to about 750 mg.
35. The method of any one of claims 30-33, wherein the antibody or antigen-binding fragment thereof is administered at a dose about 50 rng, 100 mg, 150 mg, 200 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 rng, 600 mg, 650 rng, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg or 1000 mg.
36. The method of any one of claims 30-33, wherein the antibody or antigen-binding fragment thereof is administered at a dose about 200 mg, 400 mg or 800 mg.
37. The method of any one of claims 30-33, wherein the antibody or antigen-binding fragment thereof is administered at a dose between about 2 mg/kg to about 4 mg/kg.
38. The method of any one of claims 30-37, wherein the antibody or antigen- binding fragment thereof is administered subcutaneously.
39. The method of any one of claims 30-37, wherein the antibody or antigen-binding fragment thereof is administered intravenously.
40. The method of any one of claims 30-39, wherein the antibody or antigen-binding fragment thereof is administered daily, once a week, twice a week, or every two weeks.
41. The method of any one of claims 30-40, wherein the subject is suffering from 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), aeute 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, nasal congestion, sore throat, unwillingness to drink, convulsions, ongoing vomi ting, extremes of temperature, decreased level of consciousness, abdominal pain, and secondary infection.
42. The method of any one of claims 30-41, wherein the subject has severe to critical disease.
43. The method of any one of claims 30-41, wherein the subject has critical disease.
44. The method of any one of claims 30-41, wherein the subject has multi-organ dysfunction.
45. The method of any one of claims 30-41, wherein the subject has pneumonia and fever.
46. The method of any one of claims 30-45, wherein the administration of the antibody or antigen-bmding fragment thereof reduces the plasma concentration of one or more cytokines.
47. The method of any one of claims 30-46, wherein administration of the antibody 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 m 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, nasal congestion, sore throat, unwillingness to drink, convulsions, ongoing vomiting, extremes of temperature, decreased level of consciousness, abdominal pain, and secondary infection.
48. The method of any one of claims 30-47, wherein one or more active compounds are administered with the antibody or antigen-binding fragment thereof.
49. The method of claim 48, wherein the one or more active compounds are selected from the group consisting of analgesics, decongestants, expectorants, antihistamines, mucokineties, and cough suppressants.
50. The method of any one of claims 30-49, wherein the subject was previously administered an antiviral therapy by administering one or more antiviral agents.
51. The method of claim 50, wherein the antiviral agent is selected from the group consisting of remdesivir, hydroxychloroquinme, gahdesivir, oseltamivir, paramivir, zanamivir, ganciclovir, acyclovir, ribavirin, lopmavir, ritonavir, favipiravir, and darunavir, or any combinations thereof.
52. The method of any one of claims 30-51, wherein the subject is greater than or equal to 12 years of age.
53. The method of any one of claims 30-52, wherein the subject is an adult.
54. The method of any one of claims 30-53, wherein the subject is greater than or equal to 18 years of age.
55. The method of any one of claims 30-54, wherein the subject is greater than or equal to 18 years of age and less than or equal to 59 years of age.
56. The method of any one of claims 30-54, wherein the subject is 60 years of age or older.
57. The of any one of claims 30-56, wherein the subject achieves a reduction in C-reaetive protein levels within four days from treatment with the antibody or antigen-binding fragment thereof.
58. The method of any one of claims 1-57, wherein the subject has pulmonary complications characterized by abnormalities in chest computed tomography (CT) images.
59. The method of claim 58, wherein administration of the antibody or antigen-binding fragment thereof treats or ameliorates the pulmonary complications characterized by abnormalities in the chest CT images.
60. The method of any one of claims 1-59, wherein the subject 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 procalcitomn, and/or elevated prothrombin time.
61. The method of claim 60, wherein administration of the antibody or antigen-binding fragment thereof treats or ameliorates one or more symptoms selected from the elevated levels of AST, elevated levels of ALT, elevated levels ofD-dmier, elevated levels of hypersensitive troponin I (hs-cTnl), elevated levels of procalcitonin, and/or elevated prothrombin time.
62. The method of claim 1-61, wherein the subject has a pre-existing medical condition.
63. The method of claim 62, wherein the pre-existing medical condition is heart disease, lung disease, diabetes, cancer and/or high blood pressure
64. The method of any one of claims i -63, wherein the subject has a w eakened immune system.
65. The method of any one of claims 1-64, wherein administration of the antibody or antigen- binding fragment thereof reduces or eliminates the need for mechanical ventilation, invasive mechanical ventilation, high intensity oxygen therapy, supplemental oxygen and/or hospitalization.
66. The method of claim 65, wherein 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.
67. The method of any one of claims 1-66, wherein 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.
68. The method of any one of claims 1-67, wherein administration of the antibody or antigen- binding fragment thereof reduces the incidence of death.
69. The method of any one of claims 1-68, further comprising administering one or more antiviral agents.
70. The method of claim 69, wherein the antiviral agent is selected from the group consisting of remdesivir, hydroxychloroquinine, gaiidesivir, oseltamivir, paramivir, zanamivir, ganciclovir, acyclovir, ribavirin, lopinavir, ritonavir, favipiravir, and darimavir, or any combinations thereof.
71. The method of any of the preceding claims, wherein the subject has elevated IL-6 levels.
72. The method of any of the preceding claims, wherein administering the antibody or antigen- binding fragment thereof is not associated with new safety findings.
73. The method of any of the preceding claims, wherein administering the antibody or antigen-binding fragment thereof does not result in hypersensitivity events.
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