WO2021207697A1 - Traitement d'une lésion pulmonaire aiguë - Google Patents

Traitement d'une lésion pulmonaire aiguë Download PDF

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Publication number
WO2021207697A1
WO2021207697A1 PCT/US2021/026713 US2021026713W WO2021207697A1 WO 2021207697 A1 WO2021207697 A1 WO 2021207697A1 US 2021026713 W US2021026713 W US 2021026713W WO 2021207697 A1 WO2021207697 A1 WO 2021207697A1
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Prior art keywords
patient
treatment
dociparstat
sodium
level
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PCT/US2021/026713
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English (en)
Inventor
Stephen Marcus
Thomas Preston Kennedy
William Garrett NICHOLS
Ernest Randall Lanier, Jr.
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Cantex Pharmaceuticals, Inc.
Chimerix, Inc.
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Publication of WO2021207697A1 publication Critical patent/WO2021207697A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • ALI acute lung injury
  • ALI caused by viral respiratory infections, including ALI caused by infection with coronavirus, notably infection with SARS-CoV-2.
  • Patients with acute lung injury are at risk of progressing to intubation, with a particularly difficult and unpredictable treatment course made especially bleak by the potential for rationing of mechanical ventilators.
  • ALI is associated with cellular infiltration of the airways and inflammation.
  • High mobility group box protein 1 (HMGB1) and interleukin-6 (IL-6) are among the pro-inflammatory cytokines implicated in ALI.
  • agents that specifically inhibit IL-6 such as tocilizumab
  • agents that are more generally anti-inflammatory such as hydroxychloroquine
  • coronavirus infections there presently are no proven effective treatments for severe ALI, including that caused by coronavirus infections, especially agents that prevent the progression to intubation.
  • ALI acute lung injury
  • ARDS acute respiratory distress syndrome
  • ALI concomitant pneumonia
  • ARDS with concomitant pneumonia comprising: administering an effective amount of dociparstat sodium to a patient who has or is at risk for acute lung injury (ALI), acute respiratory distress syndrome (ARDS), ALI with concomitant pneumonia, or ARDS with concomitant pneumonia.
  • cytokine release syndrome CRS
  • methods of treating a patient who has a confirmed or suspected viral lung infection comprising: administering a therapeutically effective amount of dociparstat sodium to a patient suffering from a viral lung infection.
  • methods of treating a patient who has or is at risk for cytokine release syndrome comprising: administering an effective amount of dociparstat sodium to a patient who has, or is at risk for, CRS.
  • the patient has a viral infection.
  • the infection is by a virus selected from the group consisting of coronavirus, influenza virus, rhinovirus, respiratory syncytial virus, metapneumo virus, adenovirus, and boca virus.
  • the virus is a coronavirus selected from the group consisting of coronavirus OC43, coronavirus 229E, coronavirus NL63, coronavirus HKU1, middle east respiratory syndrome beta coronavirus (MERS-CoV), severe acute respiratory syndrome beta coronavirus (SARS-CoV), and SARS-CoV-2 (COVID-19).
  • coronavirus OC43 coronavirus 229E
  • coronavirus NL63 coronavirus HKU1
  • coronavirus HKU1 middle east respiratory syndrome beta coronavirus
  • SARS-CoV severe acute respiratory syndrome beta coronavirus
  • COVID-19 SARS-CoV-2
  • the coronavirus is SARS-CoV-2 (COVID-19).
  • the virus is an influenza virus selected from the group consisting of parainfluenza virus 1, parainfluenza virus 2, parainfluenza virus 3, parainfluenza virus 4, influenza A virus, and influenza B virus.
  • the patient has or is at risk for ALI. In some embodiments, the patient has or is at risk of ARDS. In some embodiments, the patient has or is at risk for ALI with concomitant pneumonia or ARDS with concomitant pneumonia.
  • the dociparstat sodium is administered intravenously.
  • the dociparstat sodium is administered by inhalation.
  • the dociparstat sodium is administered as a 4 mg/kg intravenous (IV) bolus followed by continuous infusion of 0.25-0.375 mg/kg/hr for at least seven days.
  • the dociparstat sodium is administered as a 4 mg/kg IV bolus followed by 0.25 mg/kg/hr continuous IV infusion for at least seven days.
  • the dociparstat sodium is administered as a 4 mg/kg IV bolus followed by 0.325 mg/kg/hr continuous IV infusion for at least seven days.
  • the dociparstat sodium is administered as a 4 mg/kg IV bolus followed by 0.375 mg/kg/hr continuous IV infusion for at least seven days.
  • the patient is not hospitalized.
  • the patient is hospitalized.
  • the patient is not on a ventilator.
  • the administration of dociparstat sodium reduces or eliminates the patient’s need for assisted ventilation.
  • the patient has a body temperature of greater than 37.5 °C prior to first administration of dociparstat sodium.
  • the body temperature of the patient is measured at one or more sites selected from the group consisting of an oral cavity, a rectal cavity, axilla area, and tympanic membrane.
  • the method reduces the body temperature of the patient below pre treatment levels.
  • the patient has a pre-treatment C-creative protein (CRP) level greater than 2 mg/L.
  • CRP C-creative protein
  • the patient has a pre-treatment CRP level greater than 5 mg/L. [0027] In some embodiments, the patient has a pre-treatment CRP level greater than 10 mg/L. [0028] In some embodiments, the patient has a pre-treatment CRP level greater than 20 mg/L. [0029] In some embodiments, the patient has a pre-treatment CRP level greater than 30 mg/L. [0030] In some embodiments, the patient has a pre-treatment CRP level greater than 40 mg/L. [0031] In some embodiments, the method reduces the patient’s serum CRP levels below pre treatment levels.
  • the post-treatment CRP level is no more than 45 mg/L.
  • the post-treatment CRP level is no more than 40 mg/L.
  • the post-treatment CRP level is no more than 35 mg/L.
  • the post-treatment CRP level is no more than 30 mg/L.
  • the post-treatment CRP level is no more than 20 mg/L.
  • the post-treatment CRP level is no more than 10 mg/L.
  • the post-treatment CRP level is no more than 5 mg/L.
  • the post-treatment CRP level is no more than 1 mg/L.
  • the method reduces the CRP level by at least 10% as compared to pre-treatment levels.
  • the CRP level is decreased by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% as compared to pre-treatment levels.
  • the patient has a pre-treatment free IL-6 level in serum of at least 2 pg/ml.
  • the patient has a pre-treatment free IL-6 level in serum of at least 2.5 pg/ml, 3 pg/ml, 4 pg/ml, 5 pg/ml, 10 pg/ml, 20 pg/ml, 30 pg/ml, 40 pg/ml, 50 pg/ml, 60 pg/ml, 70 pg/ml, 80 pg/ml, 90 pg/ml, 100 pg/ml, 150 pg/ml or 200 pg/ml.
  • the method reduces the patient’s free IL-6 levels in serum below pre-treatment levels.
  • the free IL-6 level in serum is decreased by at least 10% as compared to pre-treatment levels. [0046] In some embodiments, the free IL-6 level in serum is decreased by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% as compared to pre-treatment levels.
  • the patient has a pre-treatment neutrophil-to-lymphocyte ratio (NLR) greater than 2.0.
  • NLR neutrophil-to-lymphocyte ratio
  • the patient has a pre-treatment NLR greater than 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0.
  • the patient has a pre-treatment D-Dimer level that is elevated above baseline.
  • the patient has a pre-treatment sepsis-induced coagulopathy (SIC) total score of 4 or more with total score of prothrombin time and coagulation exceeding 2.
  • SIC sepsis-induced coagulopathy
  • the patient has a post-treatment NLR less than 3.18.
  • the administration of dociparstat sodium decreases the NLR by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% as compared to pre-treatment levels.
  • the patient has a pre-treatment respiration rate on ambient air of fewer than 12 breaths or more than 20 breaths per minute.
  • the method improves the respiration rate of the patient.
  • the patient has a post-treatment respiration rate between 12 to 20 breaths per minute.
  • the patient has a pre-treatment oxygen saturation level on ambient air of no more than 93%.
  • the patient has a pre-treatment oxygen saturation level on ambient air of no more than 85%, 80%, 75%, 70%, 65% or 60%.
  • the method improves the oxygen saturation level of the patient on ambient air by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% as compared to pre treatment levels.
  • the method reduces the patient’s need for supplemental oxygen.
  • the patient is older than 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59 years of age.
  • the patient is older than 60 years of age.
  • the patient is younger than 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, or 50 years of age.
  • the method further comprises administering an effective amount of at least one second therapeutic agent selected from the group consisting of: an antiviral agent, antibacterial agent, an angiotensin receptor blocker (ARB), an IL-6 inhibitor, hydroxychloroquine, chloroquine, and COVID-19 immune serum or plasma.
  • at least one second therapeutic agent is an antiviral agent.
  • the antiviral agent is favipiravir.
  • the second therapeutic agent is remdesivir.
  • the at least one second therapeutic agent is an antibacterial agent.
  • the antibacterial agent is selected from the group consisting of azithromycin, tobramycin, aztreonam, ciprofloxacin, meropenem, cefepime, cetadizine, imipenem, piperacillin-tazobactam, amikacin, gentamicin and levofloxacin.
  • the antibacterial agent is azithromycin.
  • the at least one second therapeutic agent is an ARB.
  • the ARB is losartan.
  • the ARB is valsartan.
  • the at least one second therapeutic agent is an IL-6 inhibitor.
  • the IL-6 inhibitor is selected from the group consisting of: an anti- IL-6 receptor antibody or an antigen binding fragment thereof, an anti-IL-6 antibody or an antigen binding fragment thereof, and a JAK/STAT inhibitor.
  • the IL-6 inhibitor is an anti-IL-6 receptor antibody, or antigen binding fragment thereof.
  • the anti-IL-6 receptor antibody is tocilizumab or sarilumab.
  • the IL-6 inhibitor is an anti-IL-6 antibody, or antigen binding fragment thereof.
  • the anti-IL-6 antibody is selected from the group consisting of ziltivekimab, siltuximab, gerilimzumab, sirukumab, clazakizumab, olokizumab, VX30 (VOP- R003; Vaccinex), EB-007 (EBI-029; Eleven Bio), and FM101 (Femta Pharmaceuticals, Lonza).
  • the IL-6 inhibitor is a JAK/STAT inhibitor.
  • the JAK/STAT inhibitor is selected from the group consisting of ruxolotinib, tofacitinib, and baricitinib.
  • a method of treating a patient comprising: intravenously administering a therapeutically effective amount of dociparstat sodium to a patient with confirmed or suspected infection with SARS-CoV-2, wherein the patient is not on a ventilator.
  • the patient has a pre-treatment CRP level greater than 2 mg/L and has a pre-treatment body temperature greater than 37.5°C.
  • the patient has a pre-treatment neutrophil-to-lymphocyte ratio (NLR) greater than 2.0.
  • NLR neutrophil-to-lymphocyte ratio
  • the patient has a pre-treatment D-Dimer level that is elevated above baseline.
  • the patient has a pre-treatment sepsis-induced coagulopathy (SIC) total score of 4 or more with total score of prothrombin time and coagulation exceeding 2.
  • SIC sepsis-induced coagulopathy
  • the patient has a pre-treatment respiration rate on ambient air of fewer than 12 breaths or more than 20 breaths per minute.
  • the patient has a pre-treatment oxygen saturation level on ambient air of no more than 93%.
  • the patient is older than 50 years of age.
  • the patient is older than 60 years of age.
  • the patient prior to treatment is not receiving oral or intravenous anticoagulation or low molecular weight heparin (other than unfractionated heparin).
  • the dociparstat sodium is administered as a 4 mg/kg IV bolus followed by continuous IV infusion of 0.25-0.375 mg/kg/hr for at least seven days.
  • the dociparstat sodium is administered as a 4 mg/kg IV bolus followed by 0.25 mg/kg/hr continuous IV infusion for at least seven days.
  • the dociparstat sodium is administered as a 4 mg/kg IV bolus followed by 0.325 mg/kg/hr continuous IV infusion for at least seven days.
  • the dociparstat sodium is administered as a 4 mg/kg IV bolus followed by 0.375 mg/kg/hr continuous IV infusion for at least seven days.
  • the method further comprises administering an effective amount of at least one second therapeutic agent, wherein each of the at least one second therapeutic agent is selected from the group consisting of: an antiviral agent, an antibacterial agent, an angiotensin receptor blocker (ARB), an IL-6 inhibitor, hydroxychloroquine, chloroquine, and COVID-19 immune serum or plasma.
  • each of the at least one second therapeutic agent is selected from the group consisting of: an antiviral agent, an antibacterial agent, an angiotensin receptor blocker (ARB), an IL-6 inhibitor, hydroxychloroquine, chloroquine, and COVID-19 immune serum or plasma.
  • kits comprising a container comprising dociparstat sodium, and instructions for using the kit.
  • the kit further comprises a separate container comprising normal saline.
  • the kit further comprises materials suitable for intravenous administration.
  • FIGURE 1 is a table of primary and secondary endpoints for phase 1 and phase 2 dociparstat sodium trials for the treatment of severe COVID-19.
  • FIGURE 2 is a table showing exemplary biomarkers and levels indicating ALI.
  • FIGURE 3 is a Kaplan-Meier plot reporting time to first invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) for patients treated with dociparstat sodium (DSTAT) or placebo (PBO). Patients with any invasive mechanical ventilation or ECMO were counted as event. All other patients were censored.
  • ECMO extracorporeal membrane oxygenation
  • FIGURE 4 is a Kaplan-Meier plot reporting duration of first invasive mechanical ventilation or ECMO for patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • FIGURE 5 reports hemoglobin values over time for patients treated with dociparstat sodium (DSTAT) or placebo (PBO). “Early Tx DC (TXDC)” denotes early treatment discontinuation visit.
  • FIGURE 6 reports platelet values over time for patients treated with dociparstat sodium (DSTAT) or placebo (PBO). “Early Tx DC (TXDC)” denotes early treatment discontinuation visit.
  • FIGURE 7 reports activated partial thromboplastin time (aPTT) over time for patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • aPTT partial thromboplastin time
  • DTAT dociparstat sodium
  • PBO placebo
  • FIGURE 8 reports prothrombin time (PT) over time for patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • Early Tx DC (TXDC) denotes early treatment discontinuation visit.
  • FIGURE 9 reports prothrombin international normalized ratio (INR) values over time for patients treated with dociparstat sodium (DSTAT) or placebo (PBO). “Early Tx DC (TXDC)” denotes early treatment discontinuation visit.
  • FIGURE 10 reports D-dimer values over time for patients treated with dociparstat sodium (DSTAT) or placebo (PBO). “Early Tx DC (TXDC)” denotes early treatment discontinuation visit.
  • FIGURE 11 reports anti-XA values over time for patients treated with dociparstat sodium (DSTAT) or placebo (PBO). “Early Tx DC (TXDC)” denotes early treatment discontinuation visit.
  • FIGURE 12 reports aspartate aminotransferase (AST) values over time for patients treated with dociparstat sodium (DSTAT) or placebo (PBO). “Early Tx DC (TXDC)” denotes early treatment discontinuation visit.
  • FIGURE 13 reports alanine aminotransferase (ALT) values over time for patients treated with dociparstat sodium (DSTAT) or placebo (PBO). “Early Tx DC (TXDC)” denotes early treatment discontinuation visit.
  • FIGURE 14 reports total bilirubin values over time for patients treated with dociparstat sodium (DSTAT) or placebo (PBO). “Early Tx DC (TXDC)” denotes early treatment discontinuation visit.
  • FIGURE 15 reports creatinine values over time for patients treated with dociparstat sodium (DSTAT) or placebo (PBO). “Early Tx DC (TXDC)” denotes early treatment discontinuation visit.
  • FIGURE 16 reports creatinine clearance values over time for patients treated with dociparstat sodium (DSTAT) or placebo (PBO). “Early Tx DC (TXDC)” denotes early treatment discontinuation visit.
  • FIGURE 17 is a Kaplan-Meier plot reporting time to invasive ventilation, ECMO, or all cause mortality for patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • FIGURE 18 is a Kaplan-Meier plot reporting time to all-cause mortality for patients treated with dociparstat sodium (DSTAT) or placebo (PBO). Patients who died were counted as event. All other patients were censored.
  • DTAT dociparstat sodium
  • PBO placebo
  • FIGURE 19 is a Kaplan-Meier plot reporting time to clinical improvement for patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • Clinical improvement is defined as at least a two-grade improvement from baseline on the NIAID ordinal scale. Patients with a clinical improvement were counted as event. Subjects without a clinical improvement or deaths occurring prior to the positive event were censored.
  • FIGURE 20 is a Kaplan-Meier plot reporting time to hospital discharge for patients treated with dociparstat sodium (DSTAT) or placebo (PBO). Patients discharged from the hospital were counted as event. Patients who remained hospitalized or died in the hospital were censored.
  • DTAT dociparstat sodium
  • PBO placebo
  • FIGURE 21 shows measured values of the biomarker HMGB1 over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • FIGURE 22 shows measured values of the biomarker IL-6 over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • FIGURE 23 shows measured values of the biomarker serum amyloid A (SAA) over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • FIGURE 24 shows measured values of the biomarker antithrombin III (AT-III) over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • FIGURE 25 shows measured values of the biomarker Ficolin-3 over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • FIGURE 26 shows measured values of the biomarker IL-10 over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • FIGURE 27 shows measured values of the biomarker IL-18 over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • FIGURE 28 shows measured values of the biomarker IL-2 over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • FIGURE 29 shows measured values of the biomarker IL-8 over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • FIGURE 30 shows measured values of the biomarker LRG1 over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • FIGURE 31 shows measured values of the biomarker MIP1 alpha over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • FIGURE 32 shows measured values of the biomarker MIP-lb over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • FIGURE 33 shows measured values of the biomarker MCP-1 over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • FIGURE 34 shows measured values of the biomarker Nr-C AM over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • FIGURE 35 shows measured values of the biomarker Neuropilin-1 overtime in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • FIGURE 36 shows measured values of the biomarker NAP -2 over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • FIGURE 37 shows measured values of the biomarker PEDF over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • FIGURE 38 shows measured values of the biomarker RAGE over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • FIGURE 39 shows measured values of the biomarker SHBG over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • FIGURE 40 shows measured values of the biomarker Sortilin over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • FIGURE 41 shows measured values of the biomarker SOD-1 over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • FIGURE 42 shows measured values of the biomarker TAFI over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • FIGURE 43 reports time to hospital discharge for patients treated with dociparstat sodium (DSTAT) or placebo (PBO).
  • ALI Viral infection of the lungs, and the subsequent inflammatory response to clear the invading viral pathogens, including cytokine release syndrome (CRS, colloquially known as “cytokine storm”), significantly contributes to the morbidity and mortality of patients suffering from ALI. ALI can also occur independently of viral infection.
  • CRS cytokine release syndrome
  • Dociparstat sodium (also known as DSTAT, CX-01, O-desulfated heparin, 2-0, 3-0- desulfated heparin, ODSH; and previously known as PGX-100) is a glycosaminoglycan derived from porcine heparin that retains the polyanionic and anti-inflammatory properties of unfractionated heparin but has significantly reduced anticoagulant activity (Rao et al, Am. J. Physiol. Cell Physiol. 299:C97-C110, 2010). As described herein, provided are methods for treating or preventing ALI, CRS, and/or respiratory viral infections by administering an effective amount of dociparstat sodium.
  • patient and “subject” are used interchangeably, and may be taken to mean any living organism which may be treated with compounds of the present invention.
  • patient and “subject” include, but are not limited to, any non human mammal, primate and human.
  • a “therapeutically effective amount” of a composition is an amount sufficient to achieve a desired therapeutic effect, and therefore does not require cure or complete remission.
  • the terms "treat,” “treated,” “treating”, or “treatment” as used herein have the meanings commonly understood in the medical arts, and therefore do not require cure or complete remission, and therefore include any beneficial or desired clinical results.
  • Nonlimiting examples of such beneficial or desired clinical results are prolonging survival as compared to expected survival if not receiving treatment, reduced probability of requiring intubation and mechanical ventilation, reduced number of days on mechanical ventilation, reduced days in the ICU, reduced days of total hospitalization.
  • preventing refers to inhibiting the full development of a disease.
  • IL-6 interleukin 6
  • IL-6 polypeptide refers to a human polypeptide or fragment thereof having at least about 85% or greater amino acid identity to the amino acid sequence provided at NCBI Accession No. NP_000591 and having IL-6 biological activity.
  • IL-6 is a pleotropic cytokine with multiple biologic functions.
  • Exemplary IL-6 biological activities include immunostimulatory and pro-inflammatory activities.
  • IL-6 antagonist is used synonymously with “IL-6 inhibitor” and refers to an agent that is capable of decreasing the biological activity of IL-6.
  • IL- 6 antagonists include agents that decrease the level of IL-6 polypeptide in serum, including agents that decrease the expression of an IL-6 polypeptide or nucleic acid; agents that decrease the ability of IL-6 to bind to the IL-6R; agents that decrease the expression of the IL-6R; and agents that decrease signal transduction by the IL-6R receptor when bound by IL-6.
  • the IL-6 antagonist decreases IL-6 biological activity by at least about 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or even 100%.
  • IL-6 antagonists include IL-6 binding polypeptides, such as anti-IL-6 antibodies and antigen binding fragments or derivatives thereof; IL-6R binding polypeptides, such as anti-IL-6R antibodies and antigen binding fragments or derivatives thereof; and synthetic chemical molecules, such as JAK1 and JAK3 inhibitors.
  • IL-6 antibody or “anti-IL-6 antibody” refers to an antibody that specifically binds IL-6 ligand.
  • Anti-IL-6 antibodies include monoclonal and polyclonal antibodies that are specific for IL-6 ligand, and antigen-binding fragments or derivatives thereof. IL-6 antibodies are described in greater detail below.
  • C-reactive protein refers to a polypeptide or fragment thereof having at least about 85% or greater amino acid identity to the amino acid sequence provided at NCBI Accession No. NP_000558 and having complement activating activity. CRP levels increase in response to inflammation, and can be measured with an hsCRP (high-sensitivity C- reactive protein) test.
  • biological sample refers to any tissue, cell, fluid, or other material derived from an organism (e.g., human subject). In certain embodiments, the biological sample is serum or blood.
  • pre- treatment means prior to the first administration of dociparstat sodium according the methods described herein. Pre-treatment does not exclude, and often includes, the prior administration of treatments other than dociparstat sodium.
  • post-treatment means after the administration of dociparstat sodium according to the methods described herein. Post-treatment includes after any administration of dociparstat sodium at any dosage described herein. Post-treatment also includes after the bolus treatment phase of dociparstat sodium, and also after continuous administration of dociparstat sodium at any dosage described herein.
  • biomarker also refers to any measurable characteristic of biological processes (e.g., protein, nucleic acid).
  • the present disclosure provides a method of treating a patient who has or is at risk for acute lung injury (ALI), acute respiratory distress syndrome (ARDS), ALI with concomitant pneumonia, or ARDS with concomitant pneumonia.
  • the method comprises administering an effective amount of dociparstat sodium to a patient who has or is at risk for acute lung injury (ALI), acute respiratory distress syndrome (ARDS), ALI with concomitant pneumonia, or ARDS with concomitant pneumonia.
  • the present disclosure provides a method of treating a patient who has a confirmed or suspected viral lung infection.
  • the method comprises administering a therapeutically effective amount of dociparstat sodium to a patient suffering from a viral lung infection.
  • the patient has or is at risk for ALL
  • the patient has or is at risk of ARDS.
  • the patient has or is at risk for ALI with concomitant pneumonia or ARDS with concomitant pneumonia.
  • the present disclosure provides a method of treating a patient who has or is at risk for cytokine release syndrome (CRS), the method comprising administering an effective amount of dociparstat sodium to a patient who has or is at risk for CRS.
  • CRS cytokine release syndrome
  • the patient who has or is at risk for CRS is determined to have or at risk for ALI, ARDS, ALI with concomitant pneumonia, or ARDS with concomitant pneumonia.
  • the patient who has or is at risk for CRS has confirmed or suspected viral lung infection.
  • the present disclosure is based at least in part on the ability of an effective amount of dociparstat sodium to alleviate, diminish or prevent one or more of the symptoms associated with these conditions, including CRS, as described herein below.
  • the patient has a confirmed or suspected viral lung infection.
  • the infection is by a virus selected from coronavirus, influenza virus, rhinovirus, respiratory syncytial virus, metapneumovirus, adenovirus, and boca virus.
  • the virus is a coronavirus.
  • the virus is any one or combination of the following coronaviruses: coronavirus OC43, coronavirus 229E, coronavirus NL63, coronavirus HKU1, middle east respiratory syndrome beta coronavirus (MERS-CoV), severe acute respiratory syndrome beta coronavirus (SARS-CoV), and SARS- CoV-2 (COVID-19).
  • the virus is SARS-CoV-2.
  • the patient has severe acute respiratory syndrome (SARS).
  • the patient has middle eastern respiratory syndrome (MERS).
  • the patient has coronavirus disease 2019 (COVID-19).
  • the virus is an influenza virus.
  • the virus is any one or combination of the following influenza viruses: parainfluenza virus 1, parainfluenza virus 2, parainfluenza virus 3, parainfluenza virus 4, influenza A virus, and influenza B virus.
  • viral infection has been or is concomitantly confirmed by detection of viral genetic material in a fluid sample from the patient.
  • viral infection has not been or is not concomitantly confirmed by detection of viral genetic material in a fluid sample from the patient, but is suspected based on clinical presentation and history.
  • treatment is initiated before confirmation by detection of viral genetic material.
  • treatment is initiated before confirmation by detection of viral genetic material, and viral infection is later confirmed by detection of viral genetic material or virus-specific IgM and/or IgG in the patient’s serum.
  • the patient has fever.
  • the patient has a body temperature greater than 37.5°C.
  • the body temperature is 37.6°C or greater, 37.7°C or greater, 37.8°C or greater, 37.9°C or greater, 38°C or greater, 38.1°C or greater, 38.2°C or greater, 38.3°C or greater, 38.4°C or greater, 38.5°C or greater, 38.6°C or greater, 38.7°C or greater, 38.8°C or greater, 38.9°C or greater, 39°C or greater, 39.1°C or greater, 39.2°C or greater, 39.3°C or greater, 39.4°C or greater, 39.5°C or greater, 39.6°C or greater, 39.7°C or greater, 39.8°C or greater, 39.9°C or greater, 40°C or greater, 40.1°C or greater, 40.2°C or greater, 40.3
  • the patient has a body temperature greater than 37.5°C for 24 hours or more, 48 hours or more, 72 hours or more, 96 hours or more, 5 days or more, 6 days or more, 1 week or more, 1.5 weeks or more, or 2 weeks or more.
  • the body temperature is measured from clinically accessible measurement sites on the patient.
  • the measurement site is the patient’s forehead, temple, and/or other external body surfaces.
  • the measurement site is the oral cavity, rectal cavity, axilla area, or tympanic membrane.
  • the patient has a blood oxygen saturation level (SpCh) of less than 95%. In some embodiments, the patient has a blood oxygen saturation level (SpCh) of less than 94%. In some embodiments, the patient has a blood oxygen saturation level (SpCh) of 93% or less. In some embodiments, the patient has an SpCh level of 92% or less, 91% or less, 90% or less, 85% or less, 80% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, or 25% or less. In some embodiments, the patient requires mechanical ventilation and/or supplemental oxygen.
  • the patient has pneumonia.
  • the patient is hospitalized.
  • the patient is on a ventilator. In some embodiments, the patient is not on a ventilator.
  • SIC Sepsis-Induced Coagulopathy
  • the patient has elevated pre-treatment levels of d-dimer above baseline (e.g. >1 pg/ml, or as exemplified in Figures 1-2, or elevated at or above the upper limit of normal).
  • the patient has elevated pre-treatment levels of sepsis- induced coagulopathy (SIC) total score of 4 or more with total score of prothrombin time and coagulation exceeding 2, or a score at or above the upper limit of normal.
  • SIC sepsis- induced coagulopathy
  • the patient has elevated pre-treatment levels of serum C-Reactive Protein (CRP).
  • CRP serum C-Reactive Protein
  • the patient has a pre-treatment CRP level of at least 2 mg/L. In some embodiments, the patient has a pre-treatment CRP level of at least 5 mg/L. In some embodiments, the patient’s pre-treatment CRP level is at least 2 mg/L, 2.5 mg/ L, 3 mg/L, 3.5 mg/L, 4 mg/L, 4.5 mg/L, or 5 mg/L. In some embodiments, the patient has pre-treatment CRP levels of at least 7.5 mg/L, 10 mg/L, 12.5 mg/L, or 15 mg/L. In certain embodiments, the patient’s pre-treatment CRP level is at least 7.5 mg/L.
  • the patient has a pre-treatment CRP level of at least 10 mg/L. In certain embodiments, the patient has a pre treatment CRP level of at least 12.5 mg/L. In certain embodiments, the patient has a pre treatment CRP level of at least 15 mg/L. In certain preferred embodiments, the patient has a pre treatment CRP level of at least 10 mg/L. In some embodiments, the patient has pre-treatment CRP levels of at least 20 mg/L, 25 mg/L, 30 mg/L, 35 mg/L, 40 mg/L, 45 mg/L, or 50 mg/L. In certain embodiments, the patient’s pre-treatment CRP level is at least 20 mg/L.
  • the patient has a pre-treatment CRP level of at least 25 mg/L. In certain embodiments, the patient has a pre-treatment CRP level of at least 30 mg/L. In certain embodiments, the patient has a pre-treatment CRP level of at least 35 mg/L. In certain embodiments, the patient’s pre-treatment CRP level is at least 40 mg/L. In certain embodiments, the patient has a pre-treatment CRP level of at least 45 mg/L. In certain embodiments, the patient has a pre-treatment CRP level of at least 50 mg/L. In certain preferred embodiments, the patient has a pre-treatment CRP level of at least 40 mg/L.
  • the patient has elevated pre treatment serum levels of IL-6.
  • the patient has a pre-treatment serum IL- 6 level of at least 2 pg/ml.
  • the patient has a pre-treatment serum IL-6 level of at least 2 pg/ml, at least 3 pg/ml, at least 4 pg/ml, at least 5 pg/ml, at least 6 pg/ml, at least 7 pg/ml, at least 8 pg/ml, at least 9 pg/ml, at least 10 pg/ml, at least 11 pg/ml, at least 12 pg/ml, at least 13 pg/ml, at least 14 pg/ml, or at least 15 pg/ml.
  • the patient has a pre-treatment serum IL-6 level of at least 2.5 pg/ml. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 4 pg/ml. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 5 pg/ml. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 7.5 pg/ml. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 10 pg/ml. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 12.5 pg/ml.
  • the patient has a pre-treatment serum IL-6 level of at least 15 pg/ml. In some embodiments, the patient has a pre-treatment serum IL-6 level of at least 20 pg/ml. In various embodiments, the patient has a pre-treatment serum IL-6 level of at least 20 pg/ml, at least 30 pg/ml, at least 40 pg/ml, at least 50 pg/ml, at least 60 pg/ml, at least 70 pg/ml, at least 80 pg/ml, at least 90 pg/ml, at least 100 pg/ml, at least 150 pg/ml, or at least 200 pg/ml.
  • the patient has a pre-treatment serum IL-6 level of at least 30 pg/ml. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 40 pg/ml. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 50 pg/ml. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 75 pg/ml. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 100 pg/ml. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 150 pg/ml. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 200 pg/ml.
  • the patient has elevated pre-treatment serum levels of CRP and elevated pre-treatment IL-6 levels.
  • the patient has a pre-treatment serum IL-6 level of at least 2 pg/ml and a pre-treatment CRP level of at least 2 mg/L.
  • the patient has a pre-treatment serum IL-6 level of at least 2 pg/ml and a pre treatment CRP level of at least 2.5 mg/L.
  • the patient has a pre-treatment serum IL-6 level of at least 2 pg/ml and a pre-treatment CRP level of at least 5 mg/L.
  • the patient has a pre-treatment serum IL-6 level of at least 2 pg/ml and a pre treatment CRP level of at least 10 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 4 pg/ml and a pre-treatment CRP level of at least 2 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 4 pg/ml and a pre treatment CRP level of at least 2.5 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 4 pg/ml and a pre-treatment CRP level of at least 5 mg/L.
  • the patient has a pre-treatment serum IL-6 level of at least 4 pg/ml and a pre treatment CRP level of at least 10 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 5 pg/ml and a pre-treatment CRP level of at least 2 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 5 pg/ml and a pre- treatment CRP level of at least 2.5 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 5 pg/ml and a pre-treatment CRP level of at least 5 mg/L.
  • the patient has a pre-treatment serum IL-6 level of at least 5 pg/ml and a pre treatment CRP level of at least 10 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 10 pg/ml and a pre-treatment CRP level of at least 2 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 10 pg/ml and a pre treatment CRP level of at least 2.5 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 10 pg/ml and a pre-treatment CRP level of at least 5 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 10 pg/ml and a pre treatment CRP level of at least 10 mg/L.
  • the patient has a pre-treatment serum IL-6 level of at least 10 pg/ml and a pre-treatment CRP level of at least 10 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 10 pg/ml and a pre-treatment CRP level of at least 20 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 10 pg/ml and a pre-treatment CRP level of at least 30 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 10 pg/ml and a pre-treatment CRP level of at least 40 mg/L.
  • the patient has a pre-treatment serum IL-6 level of at least 20 pg/ml and a pre-treatment CRP level of at least 10 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 20 pg/ml and a pre-treatment CRP level of at least 20 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 20 pg/ml and a pre-treatment CRP level of at least 30 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 20 pg/ml and a pre-treatment CRP level of at least 40 mg/L.
  • the patient has a pre-treatment serum IL-6 level of at least 30 pg/ml and a pre-treatment CRP level of at least 10 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 30 pg/ml and a pre-treatment CRP level of at least 20 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 30 pg/ml and a pre-treatment CRP level of at least 30 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 30 pg/ml and a pre-treatment CRP level of at least 40 mg/L.
  • the patient has a pre-treatment serum IL-6 level of at least 40 pg/ml and a pre-treatment CRP level of at least 10 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 40 pg/ml and a pre-treatment CRP level of at least 20 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 40 pg/ml and a pre-treatment CRP level of at least 30 mg/L. In certain embodiments, the patient has a pre-treatment serum IL-6 level of at least 40 pg/ml and a pre-treatment CRP level of at least 40 mg/L. 5.2.1.9 Pre-Treatment Neutrophil-To-Lymphocyte Ratio
  • the patient has a pre-treatment neutrophil-to-lymphocyte ratio (NLR) greater than 2.0. In some embodiments, the patient has a pre-treatment NLR greater than 3.0. In some embodiments, the patient has a pre-treatment NLR greater than 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, or 3.9. In some embodiment, the patient has a pre-treatment NLR greater than 4.0.
  • NLR neutrophil-to-lymphocyte ratio
  • the patient is older than 60 years old. In some embodiments, the patient is older than 50 years old. In some embodiments, the patient is older than 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 years old. In some embodiments, the patient is younger than 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, or 50 years old. In some embodiments the patient is a young adult between the age of 20-35. In some embodiments, the patient is middle aged, between the age of 35-50. In some embodiments, the patient is a teenager between the age of 13-19. In some embodiments, the patient is a child between the age of 5-12. In alternative embodiments, the patient is a toddler between the age of 1-4. In further embodiments, the patient is an infant between the age of newborn to one year old.
  • the patient is administered an effective amount of dociparstat sodium (USAN).
  • dociparstat sodium USAN
  • Dociparstat sodium is a glycosaminoglycan agent derived from porcine heparin that retains the poly anionic and anti-inflammatory properties of unfractionated heparin but has significantly reduced anticoagulant activity.
  • Dociparstat sodium and its synthesis are described in US Patent Nos. 5,707,974; 5,668,118; 8,734,804; 9,271,999; and 10,052,346, the disclosures of which are incorporated herein by reference in their entireties.
  • heparin sodium USP is chemically modified to remove the 2-sulfate from the oxygen of IdoA 2-sulfate and the 3-sulfate from the oxygen of GlcNSO 3,6-disulfate to form 2-0, 3-0 desulfated heparin.
  • This is performed by lyophilizing unfractionated heparin at a pH of greater than 13.0, with the addition of sodium borohydride (NaBH4) and sodium hydroxide (NaOH). Thereafter, the solution undergoes ultrafiltration and re-lyophilization. This produces a modified polysaccharide with an average molecular weight ranging from 8,000 to 14,000 Daltons.
  • heparin sodium USP The starting material, heparin sodium USP, is structurally heterogeneous because of incomplete biosynthetic modifications of its precursors and uneven distribution of heterogeneous regions in different heparin chains.
  • dociparstat sodium is also heterogeneous and heterodisperse.
  • the 2-0, 3-O-desulfated repeating unit is shown below as formula (I):
  • Dociparstat sodium is an off-white to pinkish amorphous powder. It is manufactured under Good Manufacturing Practices (GMP) conditions.
  • dociparstat sodium is administered as or is diluted from a pharmaceutical composition.
  • the pharmaceutical composition comprises dociparstat sodium and at least one diluent or excipient.
  • Any suitable pharmaceutical excipient may be used, and one of ordinary skill in the art is capable of selecting suitable pharmaceutical excipients. Accordingly, the pharmaceutical excipients provided below are intended to be illustrative, and not limiting. Additional pharmaceutical excipients include, for example, those described in the Handbook of Pharmaceutical Excipients, 8th revised ed. (2017), incorporated herein by reference in its entirety.
  • Dociparstat sodium can be formulated in any appropriate pharmaceutical composition for administration by any suitable route of administration.
  • Suitable routes of administration include, but are not limited to, intravenous, subcutaneous, pulmonary (including pulmonary administration by oral inhalation), and intranasal.
  • a particularly preferred route of administration for use in the methods described herein is intravenous administration.
  • dociparstat is administered as or is diluted from a pharmaceutical composition formulated as a solution for injection.
  • sodium injection is provided as a sterile solution containing dociparstat sodium.
  • dociparstat sodium is provided as a sterile solution containing 50 mg/mL dociparstat sodium.
  • the solution has pH of 5.0 - 7.5.
  • the solution is isotonic.
  • the sterile solution for injection is manufactured with Sterile Water for Injection (USP), Sodium Chloride (USP), and 2-0, 3-0 desulfated heparin. Hydrochloric acid and sodium hydroxide are used to adjust pH.
  • dociparstat sodium is provided as a sterile solution containing 50 mg/mL dociparstat sodium packaged in 10 mL vials.
  • the dociparstat sodium injection vials have the physical and chemical specifications summarized in Table 1.
  • dociparstat sodium is administered by a route selected from intravenous, subcutaneous, pulmonary (including but not limited to pulmonary administration by oral inhalation), and intranasal administration.
  • a particularly preferred route of administration for use in the methods described herein is intravenous administration.
  • dociparstat sodium is administered by intravenous bolus infusion followed by continuous intravenous infusion.
  • the bolus dose ranges from 2-10 mg/kg. In certain embodiments, the bolus dose is 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg or 10 mg/kg. In particular embodiments, the bolus dose is 4 mg/kg.
  • the continuous intravenous infusion ranges from 1.000 mg/kg/hour to 0.375 mg/kg/hour.
  • dociparstat sodium is administered by continuous intravenous infusion at a dose ranging from 0.250 mg/kg/hr - 0.375 mg/kg/hr.
  • dociparstat sodium is administered by continuous intravenous infusion at a dose ranging from 0.250 mg/kg/hr- 0.325 mg/kg/hr.
  • the continuous intravenous infusion is administered for 2-14 days. In various embodiments, the continuous intravenous infusion is administered for 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, or longer.
  • dociparstat sodium is administered as a
  • the methods of the present disclosure further comprise administering an effective amount of at least one second therapeutic agent.
  • one or more corticosteroids may be administered to the patient, either prior to, concurrently, or post-administration of dociparstat sodium.
  • the second therapeutic agent is selected from the group consisting of an antiviral agent, an antibacterial agent, an angiotensin receptor blocker (ARB), an IL-6 inhibitor, hydroxychloroquine, chloroquine, and COVID-19 immune serum or plasma.
  • anticoagulants are not administered to the patient in addition to dociparstat sodium.
  • low molecular weight heparin (LMWH) is not administered to the patient undergoing dociparstat sodium treatment.
  • unfractionated heparin is administered to the patient undergoing dociparstat sodium treatment.
  • patients are provided DVT prophylaxis under certain conditions.
  • DVT prophylaxis under certain conditions.
  • the method of the present disclosure further comprises administering an effective amount of an anti-viral agent.
  • the anti-viral agent is selected from the group consisting of: favipiravir, remdesivir, and a combination of lopinavir and ritonavir.
  • the anti -viral agent is favipiravir.
  • the anti-viral agent is remdesivir.
  • the anti-viral agent is a combination of lopinavir and ritonavir.
  • the method of the present disclosure further comprises administering an antibacterial agent.
  • the antibacterial agent is selected from the group consisting of azithromycin, tobramycin, aztreonam, ciprofloxacin, meropenem, cefepime, cetadizine, imipenem, piperacillin-tazobactam, amikacin, gentamicin and levofloxacin.
  • the antibacterial agent is azithromycin.
  • the methods herein further comprise administering an ARB.
  • the ARB is selected from losartan, valsartan, azilsartan, candesartan, eprosartan, irgesartan, olmesartan, and telmisartan.
  • the patient is further administered an IL-6 antagonist.
  • the IL-6 inhibitor or antagonist is selected from the group consisting of: an anti- IL-6 receptor antibody or an antigen binding fragment thereof; an anti-IL-6 antibody or an antigen binding fragment thereof; and a JAK/STAT inhibitor.
  • the IL-6 antagonist is an anti-IL-6 receptor (anti-IL-6R) antibody or antigen-binding fragment or derivative thereof.
  • the anti-IL-6R reduces the biological activity of IL-6 receptor.
  • the IL-6 antagonist is an anti-IL-6R monoclonal antibody.
  • the IL-6 antagonist is a polyclonal composition comprising a plurality of species of anti-IL-6R antibodies, each of the plurality having unique CDRs.
  • the anti-IL-6R antibody is a Fab, Fab', F(ab')2 , Fv, scFv, (scFv)2, single chain antibody molecule, dual variable domain antibody, single variable domain antibody, linear antibody, or V domain antibody.
  • the anti-IL-6R antibody comprises a scaffold.
  • the scaffold is Fc, optionally human Fc.
  • the anti-IL-6R antibody comprises a heavy chain constant region of a class selected from IgG, IgA, IgD, IgE, and IgM.
  • the anti-IL-6R antibody comprises a heavy chain constant region of the class IgG and a subclass selected from IgGl, IgG2, IgG3, and IgG4.
  • the IL-6 antagonist is immunoconjugate or fusion protein comprising an IL-6R antigen-binding fragment.
  • the antibody is bispecific or multispecific, with at least one of the antigen-binding portions having specificity for IL-6 receptor.
  • the antibody is fully human. In some embodiments, the antibody is humanized. In some embodiments, the antibody is chimeric and has non-human V regions and human C region domains. In some embodiments, the antibody is murine.
  • the anti-IL-6R antibody has a KD for binding human IL-6 receptor of less than 100 nM. In some embodiments, the anti-IL-6R antibody has a KD for binding human IL-6 receptor of less than 75 nM, 50 nM, 25 nM, 20 nM, 15 nM, or 10 nM. In particular embodiments, the anti-IL-6R antibody has a KD for binding human IL-6 receptor of less than 5 nM, 4 nM, 3 nM, or 2 nM. In selected embodiments, the anti-IL-6R antibody has a KD for binding human IL-6 receptor of less than 1 nM, 750 pM, or 500 pM. In specific embodiments, the anti-IL-6R antibody has a KD for binding human IL-6 receptor of no more than 500 pM, 400 pM, 300 pM, 200 pM, or 100 pM.
  • the anti-IL-6R antibody has an elimination half-life following intravenous administration of at least 7 days. In certain embodiments, the anti-IL-6R antibody has an elimination half-life of at least 14 days, at least 21 days, or at least 30 days.
  • the anti-IL-6R antibody has a human IgG constant region with at least one amino acid substitution that extends serum half-life as compared to the unsubstituted human IgG constant domain.
  • the anti-IL-6R antibody or antigen-binding portion thereof comprises all six CDRs of tocilizumab.
  • the antibody or antigen binding portion thereof comprises the tocilizumab heavy chain V region and light chain V region.
  • the antibody is the full-length tocilizumab antibody.
  • the anti-IL-6R antibody is a derivative of tocilizumab.
  • the tocilizumab derivative includes one or more amino acid substitutions in the tocilizumab heavy and/or light chain V regions.
  • the tocilizumab derivative comprises fewer than 25 amino acid substitutions, fewer than 20 amino acid substitutions, fewer than 15 amino acid substitutions, fewer than 10 amino acid substitutions, fewer than 5 amino acid substitutions, fewer than 4 amino acid substitutions, fewer than 3 amino acid substitutions, fewer than 2 amino acid substitutions, or 1 amino acid substitution relative to the original VH and/or VL of the tocilizumab anti-IL-6R antibody, while retaining specificity for human IL-6 receptor.
  • the tocilizumab derivative comprises an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the VH and VL domain of tocilizumab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the tocilizumab derivative comprises an amino acid sequence in which the CDRs comprise an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the respective CDRs of tocilizumab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the VH and/or VL CDR derivatives comprise conservative amino acid substitutions at one or more predicted nonessential amino acid residues (i.e., amino acid residues which are not critical for the antibody to specifically bind to human IL 6 receptor).
  • the anti-IL-6R antibody or antigen-binding portion thereof comprises all six CDRs of sarilumab.
  • the antibody or antigen-binding portion thereof comprises the sarilumab heavy chain V region and light chain V region.
  • the antibody is the full-length sarilumab antibody.
  • the anti-IL-6R antibody is a derivative of sarilumab.
  • the sarilumab derivative includes one or more amino acid substitutions in the sarilumab heavy and/or light chain V regions.
  • the sarilumab derivative comprises fewer than 25 amino acid substitutions, fewer than 20 amino acid substitutions, fewer than 15 amino acid substitutions, fewer than 10 amino acid substitutions, fewer than 5 amino acid substitutions, fewer than 4 amino acid substitutions, fewer than 3 amino acid substitutions, fewer than 2 amino acid substitutions, or 1 amino acid substitution relative to the original VH and/or VL of the sarilumab anti-IL-6R antibody, while retaining specificity for human IL-6 receptor.
  • the sarilumab derivative comprises an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the VH and VL domain of sarilumab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the sarilumab derivative comprises an amino acid sequence in which the CDRs comprise an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the respective CDRs of sarilumab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the VH and/or VL CDR derivatives comprise conservative amino acid substitutions at one or more predicted nonessential amino acid residues (i.e., amino acid residues which are not critical for the antibody to specifically bind to human IL 6 receptor).
  • the anti-IL-6R antibody or antigen-binding portion thereof comprises all six CDRs of vobarilizumab.
  • the antibody or antigen binding portion thereof comprises the vobarilizumab heavy chain V region and light chain V region.
  • the antibody is the full-length vobarilizumab antibody.
  • the anti-IL-6R antibody is a derivative of vobarilizumab.
  • the vobarilizumab derivative includes one or more amino acid substitutions in the vobarilizumab heavy and/or light chain V regions.
  • the vobarilizumab derivative comprises fewer than 25 amino acid substitutions, fewer than 20 amino acid substitutions, fewer than 15 amino acid substitutions, fewer than 10 amino acid substitutions, fewer than 5 amino acid substitutions, fewer than 4 amino acid substitutions, fewer than 3 amino acid substitutions, fewer than 2 amino acid substitutions, or 1 amino acid substitution relative to the original VH and/or VL of the vobarilizumab anti-IL-6R antibody, while retaining specificity for human IL-6 receptor.
  • the vobarilizumab derivative comprises an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the VH and VL domain of vobarilizumab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the vobarilizumab derivative comprises an amino acid sequence in which the CDRs comprise an amino acid sequence that is at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to the amino acid sequence of the respective CDRs of vobarilizumab.
  • the percent sequence identity is determined using BLAST algorithms using default parameters.
  • the VH and/or VL CDR derivatives comprise conservative amino acid substitutions at one or more predicted nonessential amino acid residues (i.e., amino acid residues which are not critical for the antibody to specifically bind to human IL 6 receptor).
  • the anti-IL-6R antibody or antigen-binding portion thereof comprises all six CDRs of an antibody selected from the group consisting of: SA237 (Roche), NI-1201 (Novlmmune), and an antibody described in US 2012/0225060.
  • the antibody or antigen-binding portion thereof comprises the heavy chain V region and light chain V region of an antibody selected from the group consisting of: SA237 (Roche), NI-1201 (Novlmmune), and an antibody described in US 2012/0225060.
  • the antibody is a full-length selected from the group consisting of: SA237 (Roche), NI-1201 (Novlmmune), and an antibody described in US 2012/0225060.
  • the anti-IL-6R antibody is a derivative of an antibody selected from the group consisting of: SA237 (Roche), NI-1201 (Novlmmune), or an antibody described in US 2012/0225060.
  • the IL-6 antagonist is an antibody specific for the complex of IL-6 and IL-6R.
  • the antibody has the six CDRs of an antibody selected from those described in US 2011/0002936, which is incorporated herein by reference in its entirety. 5.2A4.2 Anti-IL-6 Antibodies
  • the IL-6 antagonist is an anti-IL-6 antibody or antigen-binding fragment thereof.
  • the anti-IL-6 antibody or antigen-binding fragment thereof neutralizes the biological activity of human IL-6.
  • the neutralizing antibody prevents binding of IL-6 to the IL-6 receptor.
  • the neutralizing antibody prevents binding of IL-6 to the soluble IL-6 receptor.
  • the neutralizing antibody prevents binding of IL-6 to the membrane-bound IL-6 receptor.
  • the neutralizing antibody prevents binding of IL-6 to both the soluble IL-6 receptor and the membrane-bound IL-6 receptor.
  • the IL-6 antagonist is an anti-IL-6 monoclonal antibody. In some embodiments, the IL-6 antagonist is a polyclonal composition comprising a plurality of species of anti-IL-6 antibodies, each of the plurality having unique CDRs.
  • the anti-IL-6 antibody is selected from the group consisting of: ziltivekimab, siltuximab, gerilimzumab, sirukumab, clazakizumab, olokizumab, VX30 (VOP- R003; Vaccinex), EB-007 (EBI-029; Eleven Bio), and FM101 (Femta Pharmaceuticals, Lonza).
  • the antigen-binding fragment is a fragment of an antibody selected from the group consisting of: ziltivekimab, siltuximab, gerilimzumab, sirukumab, clazakizumab, olokizumab, VX30 (VOP-R003; Vaccinex), EB-007 (EBI-029; Eleven Bio), and FM101 (Femta Pharmaceuticals, Lonza).
  • the IL-6 antagonist is an antagonist peptide.
  • the IL-6 antagonist is C326 (an IL-6 inhibitor by Avidia, also known as AMG220), or FE301, a recombinant protein inhibitor of IL-6 (F erring International Center S.A., Conaris Research Institute AG).
  • the anti-IL-6 antagonist comprises soluble gpl30, FE301 (Conaris/F erring).
  • the IL-6 antagonist is an inhibitor of the JAK signaling pathway.
  • the JAK inhibitor is a JAK1 -specific inhibitor.
  • the JAK inhibitor is a JAK3-specific inhibitor.
  • the JAK inhibitor is a pan- JAK inhibitor.
  • the JAK inhibitor is selected from the group consisting of tofacitinib (Xeljanz), decemotinib, ruxolitinib, upadacitinib, baricitinib, filgotinib, lestaurtinib, pacritinib, peficitinib, momelotinib, INCB-039110, ABT-494, INCB-047986 and AC-410.
  • the IL-6 antagonist is a STAT3 inhibitor.
  • the inhibitor is AZD9150 (AstraZeneca, Isis Pharmaceuticals), a STAT3 antisense molecule.
  • small molecule JAK inhibitors and STAT inhibitors are administered orally.
  • the inhibitor is administered once or twice a day at an oral dose of 0.1 - 1 mg, 1 - 10 mg, 10 - 20 mg, 20 - 30 mg, 30 - 40 mg, or 40 - 50 mg. In some embodiments, the inhibitor is administered once or twice a day at a dose of 50 - 60 mg, 60 - 70 mg, 70 - 80 mg, 80 - 90 mg, or 90 - 100 mg. In some embodiments, the inhibitor is administered at a dose of 0.1, 0.5, 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg PO once or twice a day. In some embodiments, the inhibitor is administered at a dose of 75 mg or 100 mg PO once or twice a day.
  • the method further comprises administering an anti-malarial agent.
  • the anti-malarial agent is hydroxychloroquine. In certain embodiments, the anti-malarial agent is chloroquine.
  • the method further comprises administering a COVID-19 immune serum or plasma, or a composition comprising isolated or recombinantly expressed anti-SARS- CoV-2 antibodies having sequences derived from COVID-19 immune serum or plasma.
  • the administration of an effective amount of dociparstat sodium reduces the patient’s free serum IL-6 levels below pre-treatment levels.
  • the dosage regimen is adjusted to achieve a reduction in the patient’s free serum IL-6 levels below pre-treatment levels.
  • the free serum IL-6 level is decreased by at least 10% as compared to pre-treatment levels. In various embodiments, the free serum IL-6 level is decreased by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% as compared to pre-treatment levels. In certain embodiments, the free serum IL-6 level is decreased by at least 20% as compared to pre-treatment levels. In certain embodiments, the free serum IL-6 level is decreased by at least 30% as compared to pre-treatment levels. In certain embodiments, the free serum IL-6 level is decreased by at least 40% as compared to pre-treatment levels. In certain embodiments, the free serum IL-6 level is decreased by at least 50% as compared to pre-treatment levels.
  • the free serum IL-6 level is decreased by at least 60% as compared to pre treatment levels. In certain embodiments, the free serum IL-6 level is decreased by at least 70% as compared to pre-treatment levels. In certain embodiments, the free serum IL-6 level is decreased by at least 80% as compared to pre-treatment levels. In certain embodiments, the free serum IL-6 level is decreased by at least 90% as compared to pre-treatment levels.
  • the administration of an effective amount of dociparstat sodium reduces the patient’s serum CRP levels below pre-treatment levels.
  • the dosage regimen is adjusted to achieve a reduction in the patient’s serum CRP levels below pre treatment levels.
  • the post-treatment CRP level is no more than 45 mg/L. In certain embodiments, the post-treatment CRP level is no more than 40 mg/L. In certain embodiments, the post-treatment CRP level is no more than 30 mg/L. In certain embodiments, the post treatment CRP level is no more than 20 mg/L. In certain embodiments, the post-treatment CRP level is no more than 10 mg/L. In certain embodiments, the post-treatment CRP level is no more than 5 mg/L. In certain embodiments, the post-treatment CRP level is no more than 2.5 mg/L. In certain embodiments, the post-treatment CRP level is no more than 2 mg/L. In certain embodiments, the post-treatment CRP level is no more than 1 mg/L.
  • the CRP level is decreased by at least 10% as compared to pre treatment levels. In various embodiments, the CRP level is decreased by at least 20%, 30%,
  • the CRP level is decreased by at least 20% as compared to pre-treatment levels. In certain embodiments, the CRP level is decreased by at least 30% as compared to pre-treatment levels. In certain embodiments, the CRP level is decreased by at least 40% as compared to pre treatment levels. In certain embodiments, the CRP level is decreased by at least 50% as compared to pre-treatment levels. In certain embodiments, the CRP level is decreased by at least 60% as compared to pre-treatment levels. In certain embodiments, the CRP level is decreased by at least 70% as compared to pre-treatment levels. In certain embodiments, the CRP level is decreased by at least 80% as compared to pre-treatment levels. In certain embodiments, the CRP level is decreased by at least 90% as compared to pre-treatment levels.
  • administering an effective amount of dociparstat sodium to the patient prevents a hyperinflammatory response in the patient.
  • the dosage regimen is adjusted to prevent a hyperinflammatory response in the patient.
  • administering an effective amount of dociparstat sodium to the patient results in a reduction in body temperature.
  • the patient, post treatment with an effective amount of dociparstat sodium has a body temperature of 37.5°C or below.
  • the patient, post-treatment with an effective amount of dociparstat sodium has a body temperature ranging from of 36 to 37.5°C.
  • administering an effective amount of dociparstat sodium to the patient results in a reduction in the risk of respiratory morbidity and mortality.
  • the dose is adjusted to reduce the risk of respiratory morbidity and mortality.
  • administering an effective amount of dociparstat sodium to the patient results in a reduction in the patient’s need for supplemental oxygen.
  • the dose is adjusted to reduce the patient’s need for supplemental oxygen.
  • administering an effective amount of dociparstat sodium to the patient results in eliminating the patient’s need for assisted ventilation.
  • the dose is adjusted to eliminate the patient’s need for assisted ventilation.
  • any of the primary and/or secondary endpoints listed in Figure 2 can be met by administering an effective amount of dociparstat sodium as described herein.
  • kits certain components or embodiments of the compositions can be provided in a kit.
  • the dociparstat sodium composition, as well as the related buffers or other components related to administration can be provided in separate containers and packaged as a kit, alone or along with separate containers of any of the other agents from any pre-conditioning or post-conditioning steps, and optional instructions for use.
  • the kit may comprise ampoules, disposable syringes, capsules, vials, tubes, or the like.
  • the kit may comprise a single dose container or multiple dose containers comprising the embodiments herein.
  • each dose container may contain one or more unit doses.
  • the kit may include an applicator.
  • kits include all components needed for the various stages of treatment.
  • the compositions may have preservatives or be preservative-free (for example, in a single-use container).
  • the kit may comprise materials for intravenous administration.
  • the kit may comprise protamine in a separate container, which can be administered to rapidly neutralize anticoagulation due to unfractionated heparin (UFH). 6.
  • UHF unfractionated heparin
  • Example 1 Phase 1/2 Pilot Study to Confirm the Safety and Therapeutic Effect of Dociparstat Sodium for the Treatment of Severe COVID-19 in Subjects at High Risk of Respiratory Failure
  • Phase 1 Cohort 1: 6 subjects were randomized to dociparstat sodium, 6 randomized to placebo. Dociparstat sodium is dosed as 4 mg/kg IV bolus followed by continuous infusion of 0.25 mg/kg/hr.
  • Phase 1 Cohort 2: 6 subjects randomized to dociparstat sodium, 6 randomized to placebo.
  • Dociparstat sodium is dosed as 4 mg/kg IV bolus followed by continuous infusion at a dose of 0.325 or 0.375 mg/kg/hr (dose determined after review of data from Cohort 1).
  • Phase 2 21 subjects randomized to dociparstat sodium, 21 randomized to placebo.
  • Dociparstat sodium is dosed as 4 mg/kg IV bolus followed by continuous infusion at a dose of 0.25, 0.325, or 0.375 mg/kg/hr (dose determined after review of data from Phase 1).
  • the primary efficacy endpoint is the time to clinical improvement, defined as time to at least a 2-grade improvement from baseline on the NIAID ordinal scale.
  • the ordinal scale is an assessment of the clinical status of the subject. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 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 requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities.
  • ECMO extracorporeal membrane oxygenation
  • Secondary endpoints include clinical status assessed by the NIAID ordinal scale at fixed time points, time to hospital discharge or National Early Warning Score (NEWS) of ⁇ 2 maintained for 24 hours, time to resolution of fever for 48 hours without antipyretics, number of ventilator-free days, all-cause mortality, and changes in CRP, d-dimer, serum ferritin, LDH, HMGB1, IL-6, TNFa, PF4, and SAA levels. Safety, including the incidence of AEs, severe AEs, and SAEs, was assessed throughout the study.
  • NEWS National Early Warning Score
  • test must have been performed less than 72 hours prior to randomization (Note: 72 hours is not necessarily time from initial diagnosis. If >72 hours since positive PCR, the PCR may be repeated to assess eligibility).
  • Severe chronic respiratory disease defined by any oxygen requirement prior to incident COVID-19.
  • QTc >450 msec for a male, >470 msec for a female, or >480 msec if underlying bundle branch block.
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • UPN upper limit of normal
  • Activated partial thromboplastin time >40 seconds.
  • Dociparstat sodium was provided as a sterile solution containing 50 mg/mL dociparstat sodium packaged in 10 mL vials.
  • the dociparstat sodium inj ection vials had the physical and chemical specifications summarized in Table 2.
  • dociparstat sodium vials Room temperature is recommended for the shipping and storage of dociparstat sodium vials, preferably between 5 and 25°C (41-77°F). Based on the results from a photostability study conducted with dociparstat sodium vials, dociparstat sodium in vials is photostable and thus there is no need to protect from direct or indirect light.
  • Phase 1 Cohort 1: 4 mg/kg IV bolus followed by continuous infusion of 0.25 mg/kg/hr.
  • Phase 1 Cohort 2: 4 mg/kg IV bolus followed by continuous infusion at a dose of 0.325 or 0.375 mg/kg/hr (dose confirmed after review of data from Cohort 1).
  • Phase 2 4 mg/kg IV bolus followed by continuous infusion (dose determined after Phase 1).
  • Dociparstat sodium solution for injection 50 mg/mL was provided by the sponsor in 10-mL vials. Each vial was labeled in accordance with applicable regulatory requirements. Normal saline was sourced and provided by the study center.
  • Dociparstat was initially administered as an IV bolus dose over 5 minutes, followed by a continuous maintenance infusion of dociparstat administered 24 hours daily for up to 7 days.
  • the unblinded pharmacist prepared each study intervention to the appropriate dose based on the individual participant’s body weight. Normal saline was used to dilute the IV bolus dose and continuous maintenance infusion of dociparstat treatment. The dociparstat IV bolus dose was diluted to a total infusion volume of 30 mL. The 24-hour continuous infusion had the appropriate volume of dociparstat added to approximately 250 mL or 500 mL of 0.9% normal saline.
  • aPTT Participants with aPTT >50 seconds had repeat testing performed as soon as practicable. If aPTT was confirmed >50 seconds (or unable to confirm with a retest within same day), the study intervention infusion was interrupted. aPTT samples were not obtained from the same line as the study intervention infusion (e.g., collected samples via peripheral venipuncture). a. Participants in cohorts with dociparstat dosed at 0.25 mg/kg/hr: study intervention dosing was not resumed if interruption criteria was met. b.
  • Participants in cohorts with dociparstat dosed at 0.325 or 0.375 mg/kg/hr To minimize time that the participant is off therapy, perform repeat testing for aPTT approximately 2 to 6 hours after interruption (as practicable). When aPTT is ⁇ 40 seconds, the infusion may be resumed at a reduced dose of 0.25 mg/kg/hr.
  • Grade 3 or higher hemorrhagic AEs Study intervention infusion was interrupted for Grade 3 or higher hemorrhagic AEs in the setting of aPTT >45 seconds, or Grade 3 or higher hemorrhagic AEs that were deemed related to study intervention, regardless of aPTT.
  • Participants in cohorts with dociparstat dosed at 0.325 or 0.375 mg/kg/hr When the participant is determined stable and the aPTT is ⁇ 40 seconds, the infusion may be resumed at a reduced dose of 0.25 mg/kg/hr.
  • Renal function If the calculated creatinine clearance or estimated glomerular filtration rate (eGFR) dropped below 30 mL/min prior to or during dosing with study intervention, the infusion was held until the creatinine clearance or eGFR rose to >30 mL/min.
  • eGFR estimated glomerular filtration rate
  • QTc Heparin is not associated with QT prolongation and no cardiac safety signal has been identified to date in preclinical and clinical dociparstat studies.

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Abstract

L'invention concerne des procédés et des compositions associés à l'utilisation de l'héparine 2-O, 3-O désulfatée (ODSH, dociparstat sodium, [DSTAT]) pour le traitement d'infections pulmonaires aiguës et d'états ou de maladies associés. Dans certains modes de réalisation, les procédés concernent le traitement de lésions pulmonaires médiées par coronavirus.
PCT/US2021/026713 2020-04-10 2021-04-09 Traitement d'une lésion pulmonaire aiguë WO2021207697A1 (fr)

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