1. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Application No. 63/153,347, filed February 24, 2021, and U.S. Provisional Application No. 63/008,485, filed April 10, 2020, both of which are hereby incorporated by reference in their entireties.

2. BACKGROUND

[0002] There is a critical need for therapies to manage symptoms associated with acute lung injury (ALI), in particular 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. While agents that specifically inhibit IL-6, such as tocilizumab, and agents that are more generally anti-inflammatory, such as hydroxychloroquine, are currently in clinical trials in patients with COVID-19 with ALI, there presently are no proven effective treatments for severe ALI, including that caused by coronavirus infections, especially agents that prevent the progression to intubation.

[0003] In view of the high morbidity and mortality that can follow ALI, there is an urgent need for new treatments.

3. SUMMARY

[0004] Disclosed herein are methods 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, 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.

[0005] Additionally, disclosed herein are 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. [0006] Additionally, disclosed herein are methods of treating a patient who has or is at risk for cytokine release syndrome (CRS), comprising: administering an effective amount of dociparstat sodium to a patient who has, or is at risk for, CRS.

[0007] In some embodiments, the patient has a viral infection. In some embodiments, 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.

[0008] In some embodiments, 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).

[0009] In some embodiments, the coronavirus is SARS-CoV-2 (COVID-19).

[0010] In some embodiments, 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.

[0011] In some embodiments, 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.

[0012] In some embodiments, the dociparstat sodium is administered intravenously.

[0013] In some embodiments, the dociparstat sodium is administered by inhalation.

[0014] In some embodiments, 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.

[0015] In some embodiments, 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.

[0016] In some embodiments, 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.

[0017] In some embodiments, 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.

[0018] In some embodiments, the patient is not hospitalized.

[0019] In some embodiments, the patient is hospitalized.

[0020] In some embodiments, the patient is not on a ventilator.

[0021] In some embodiments, the administration of dociparstat sodium reduces or eliminates the patient’s need for assisted ventilation.

[0022] In some embodiments, the patient has a body temperature of greater than 37.5 °C prior to first administration of dociparstat sodium. [0023] In some embodiments, 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.

[0024] In some embodiments, the method reduces the body temperature of the patient below pre treatment levels.

[0025] In some embodiments, the patient has a pre-treatment C-creative protein (CRP) level greater than 2 mg/L.

[0026] In some embodiments, 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.

[0032] In some embodiments, the post-treatment CRP level is no more than 45 mg/L.

[0033] In some embodiments, the post-treatment CRP level is no more than 40 mg/L.

[0034] In some embodiments, the post-treatment CRP level is no more than 35 mg/L.

[0035] In some embodiments, the post-treatment CRP level is no more than 30 mg/L.

[0036] In some embodiments, the post-treatment CRP level is no more than 20 mg/L.

[0037] In some embodiments, the post-treatment CRP level is no more than 10 mg/L.

[0038] In some embodiments, the post-treatment CRP level is no more than 5 mg/L.

[0039] In some embodiments, the post-treatment CRP level is no more than 1 mg/L.

[0040] In some embodiments, the method reduces the CRP level by at least 10% as compared to pre-treatment levels.

[0041] In some embodiments, the CRP level is decreased by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% as compared to pre-treatment levels.

[0042] In some embodiments, the patient has a pre-treatment free IL-6 level in serum of at least 2 pg/ml.

[0043] In some embodiments, 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.

[0044] In some embodiments, the method reduces the patient’s free IL-6 levels in serum below pre-treatment levels.

[0045] In some embodiments, 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.

[0047] In some embodiments, the patient has a pre-treatment neutrophil-to-lymphocyte ratio (NLR) greater than 2.0.

[0048] 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, 3.9, or 4.0.

[0049] In some embodiments, the patient has a pre-treatment D-Dimer level that is elevated above baseline.

[0050] In some embodiments, 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.

[0051] In some embodiments, the patient has a post-treatment NLR less than 3.18.

[0052] In some embodiments, 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. [0053] In some embodiments, the patient has a pre-treatment respiration rate on ambient air of fewer than 12 breaths or more than 20 breaths per minute.

[0054] In some embodiments, the method improves the respiration rate of the patient.

[0055] In some embodiments, the patient has a post-treatment respiration rate between 12 to 20 breaths per minute.

[0056] In some embodiments, the patient has a pre-treatment oxygen saturation level on ambient air of no more than 93%.

[0057] In some embodiments, the patient has a pre-treatment oxygen saturation level on ambient air of no more than 85%, 80%, 75%, 70%, 65% or 60%.

[0058] In some embodiments, 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.

[0059] In some embodiments, the method reduces the patient’s need for supplemental oxygen. [0060] In some embodiments, the patient is older than 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59 years of age.

[0061] In some embodiments, the patient is older than 60 years of age.

[0062] In some embodiments, the patient is younger than 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, or 50 years of age.

[0063] In some embodiments, 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. [0064] In some embodiments, the at least one second therapeutic agent is an antiviral agent. [0065] In some embodiments, the antiviral agent is favipiravir.

[0066] In some embodiments, the second therapeutic agent is remdesivir.

[0067] In some embodiments, the at least one second therapeutic agent is an antibacterial agent. [0068] In some embodiments, the antibacterial agent is selected from the group consisting of azithromycin, tobramycin, aztreonam, ciprofloxacin, meropenem, cefepime, cetadizine, imipenem, piperacillin-tazobactam, amikacin, gentamicin and levofloxacin.

[0069] In some embodiments, the antibacterial agent is azithromycin.

[0070] In some embodiments, the at least one second therapeutic agent is an ARB.

[0071] In some embodiments, the ARB is losartan.

[0072] In some embodiments, the ARB is valsartan.

[0073] In some embodiments, the at least one second therapeutic agent is an IL-6 inhibitor. [0074] In some embodiments, 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.

[0075] In some embodiments, the IL-6 inhibitor is an anti-IL-6 receptor antibody, or antigen binding fragment thereof.

[0076] In some embodiments, the anti-IL-6 receptor antibody is tocilizumab or sarilumab.

[0077] In some embodiments, the IL-6 inhibitor is an anti-IL-6 antibody, or antigen binding fragment thereof.

[0078] In some embodiments, 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). [0079] In some embodiments, the IL-6 inhibitor is a JAK/STAT inhibitor.

[0080] In some embodiments, the JAK/STAT inhibitor is selected from the group consisting of ruxolotinib, tofacitinib, and baricitinib.

[0081] In another aspect, provided herein is 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.

[0082] In some embodiments, 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.

[0083] In some embodiments, the patient has a pre-treatment neutrophil-to-lymphocyte ratio (NLR) greater than 2.0. [0084] In some embodiments, the patient has a pre-treatment D-Dimer level that is elevated above baseline.

[0085] In some embodiments, 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.

[0086] In some embodiments, the patient has a pre-treatment respiration rate on ambient air of fewer than 12 breaths or more than 20 breaths per minute.

[0087] In some embodiments, the patient has a pre-treatment oxygen saturation level on ambient air of no more than 93%.

[0088] In some embodiments, the patient is older than 50 years of age.

[0089] In some embodiments, the patient is older than 60 years of age.

[0090] In some embodiments, the patient prior to treatment is not receiving oral or intravenous anticoagulation or low molecular weight heparin (other than unfractionated heparin).

[0091] In some embodiments, 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.

[0092] In some embodiments, 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.

[0093] In some embodiments, 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.

[0094] In some embodiments, 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.

[0095] In some embodiments, 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.

[0096] In another aspect, provided herein is a kit comprising a container comprising dociparstat sodium, and instructions for using the kit.

[0097] In some embodiments, the kit further comprises a separate container comprising normal saline.

[0098] In some embodiments, the kit further comprises materials suitable for intravenous administration.

4. BRIEF DESCRIPTION OF THE DRAWINGS

[0099] These and other features, aspects, and advantages of the present invention become better understood with regard to the following description, and accompanying drawings, where: [0100] 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.

[0101] FIGURE 2 is a table showing exemplary biomarkers and levels indicating ALI.

[0102] 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.

[0103] 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). [0104] 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.

[0105] 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.

[0106] FIGURE 7 reports activated partial thromboplastin time (aPTT) over time for patients treated with dociparstat sodium (DSTAT) or placebo (PBO). “Early Tx DC (TXDC)” denotes early treatment discontinuation visit.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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. [0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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).

Patients with any invasive mechanical ventilation, ECMO, or all-cause mortality were counted as event. All other patients were censored.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] FIGURE 21 shows measured values of the biomarker HMGB1 over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).

[0121] FIGURE 22 shows measured values of the biomarker IL-6 over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).

[0122] FIGURE 23 shows measured values of the biomarker serum amyloid A (SAA) over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO). [0123] FIGURE 24 shows measured values of the biomarker antithrombin III (AT-III) over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).

[0124] FIGURE 25 shows measured values of the biomarker Ficolin-3 over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).

[0125] FIGURE 26 shows measured values of the biomarker IL-10 over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).

[0126] FIGURE 27 shows measured values of the biomarker IL-18 over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).

[0127] FIGURE 28 shows measured values of the biomarker IL-2 over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).

[0128] FIGURE 29 shows measured values of the biomarker IL-8 over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).

[0129] FIGURE 30 shows measured values of the biomarker LRG1 over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).

[0130] FIGURE 31 shows measured values of the biomarker MIP1 alpha over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).

[0131] FIGURE 32 shows measured values of the biomarker MIP-lb over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).

[0132] FIGURE 33 shows measured values of the biomarker MCP-1 over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).

[0133] FIGURE 34 shows measured values of the biomarker Nr-C AM over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).

[0134] FIGURE 35 shows measured values of the biomarker Neuropilin-1 overtime in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).

[0135] FIGURE 36 shows measured values of the biomarker NAP -2 over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).

[0136] FIGURE 37 shows measured values of the biomarker PEDF over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).

[0137] FIGURE 38 shows measured values of the biomarker RAGE over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).

[0138] FIGURE 39 shows measured values of the biomarker SHBG over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).

[0139] FIGURE 40 shows measured values of the biomarker Sortilin over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO). [0140] FIGURE 41 shows measured values of the biomarker SOD-1 over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).

[0141] FIGURE 42 shows measured values of the biomarker TAFI over time in patients treated with dociparstat sodium (DSTAT) or placebo (PBO).

[0142] FIGURE 43 reports time to hospital discharge for patients treated with dociparstat sodium (DSTAT) or placebo (PBO).

5. DETAILED DESCRIPTION

[0143] 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.

[0144] 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.

5.1. Definitions

[0145] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which the invention pertains.

[0146] As used herein, the terms “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. As such, the terms “patient” and “subject” include, but are not limited to, any non human mammal, primate and human.

[0147] 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. [0148] 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.

[0149] As used herein “preventing” a disease refers to inhibiting the full development of a disease.

[0150] As used herein, “interleukin 6 (IL-6)” or “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.

[0151] Unless otherwise specified, “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. In preferred embodiments, the IL-6 antagonist decreases IL-6 biological activity by at least about 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or even 100%. As further described below, 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.

[0152] The term “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.

[0153] The term “C-reactive protein” or “CRP” 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.

[0154] The term “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. [0155] As used herein, “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.

[0156] As used herein, “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.

[0157] Any of the biological indicators listed in Figure 2 can be utilized as biomarkers indicating a patient in need for treatment with dociparstat sodium. Additionally, any one of combination of these biomarkers can be utilized to show an improvement in patient outcome by exhibiting an improved level following treatment with dociparstat sodium. The term “biomarker” also refers to any measurable characteristic of biological processes (e.g., protein, nucleic acid).

5.2. Methods of Treating Virus-Mediated Lung Injury and Related Conditions

[0158] In an aspect, 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.

[0159] In an aspect, 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. In certain embodiments, the patient has or is at risk for ALL In certain embodiments, the patient has or is at risk of ARDS. In certain embodiments, the patient has or is at risk for ALI with concomitant pneumonia or ARDS with concomitant pneumonia.

[0160] In an aspect, 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. In various embodiments, 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. In various embodiments, the patient who has or is at risk for CRS has confirmed or suspected viral lung infection. [0161] While not wishing to be bound by theory, 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.

5.2.1. Pre-treatment symptoms and signs

5.2.1.1 Confirmed or suspected viral lung infection

[0162] In various embodiments of the methods described herein, the patient has a confirmed or suspected viral lung infection.

[0163] In some embodiments, the infection is by a virus selected from coronavirus, influenza virus, rhinovirus, respiratory syncytial virus, metapneumovirus, adenovirus, and boca virus. [0164] In some embodiments, the virus is a coronavirus. In certain embodiments, 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). In a specific embodiment, the virus is SARS-CoV-2. In particular embodiments, the patient has severe acute respiratory syndrome (SARS). In particular embodiments, the patient has middle eastern respiratory syndrome (MERS). In particular embodiments, the patient has coronavirus disease 2019 (COVID-19).

[0165] In some embodiments, the virus is an influenza virus. In particular embodiments, 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.

[0166] In various embodiments, viral infection has been or is concomitantly confirmed by detection of viral genetic material in a fluid sample from the patient. In some embodiments, 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. In particular embodiments, treatment is initiated before confirmation by detection of viral genetic material. In specific embodiments, 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.

5.2.1.2 Fever [0167] In some embodiments, the patient has fever. In some embodiments, the patient has a body temperature greater than 37.5°C. In some embodiments, 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°C or greater, 40.4°C or greater, 40.5°C or greater, 40.6°C or greater, 40.7°C or greater, 40.8°C or greater, 40.9°C or greater, 41°C or greater, or 42°C or greater. In some embodiments, 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. In typical embodiments, the body temperature is measured from clinically accessible measurement sites on the patient. In various embodiments, the measurement site is the patient’s forehead, temple, and/or other external body surfaces. In some embodiments, the measurement site is the oral cavity, rectal cavity, axilla area, or tympanic membrane.

5.2.1.3 Reduced blood oxygen saturation

[0168] In some embodiments, 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.

5.2.1.4 Pneumonia

[0169] In some embodiments, the patient has pneumonia.

5.2.1.5 Hospitalization

[0170] In some embodiments, the patient is hospitalized.

5.2.1.6 Mechanical or assisted ventilation

[0171] In some embodiments, the patient is on a ventilator. In some embodiments, the patient is not on a ventilator. 5.2.1.7 Pre-treatment d-Dimer and Sepsis-Induced Coagulopathy (SIC) Score

[0172] In certain embodiments, 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). In certain embodiments, 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.

5.2.1.8 Pre- treatment serum CRP and IL-6 levels

[0173] In some embodiments, the patient has elevated pre-treatment levels of serum C-Reactive Protein (CRP).

[0174] In some embodiments, 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. In certain embodiments, 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. In certain embodiments, 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.

[0175] In some embodiments of the methods described herein, the patient has elevated pre treatment serum levels of IL-6. In some embodiments, the patient has a pre-treatment serum IL- 6 level of at least 2 pg/ml. In various embodiments, 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. In certain embodiments, 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. In certain embodiments, 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. In certain embodiments, 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.

[0176] In some embodiments, the patient has elevated pre-treatment serum levels of CRP and elevated pre-treatment IL-6 levels. In certain embodiments, 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. In certain embodiments, 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. In certain embodiments, 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. In certain embodiments, 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. 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 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. 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 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.

[0177] In some 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. 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. 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 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. 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 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. 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 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

[0178] In some embodiments, 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.

5.2.1.10 Patient Age

[0179] In some embodiments, 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.

5.2.2. Dociparstat Sodium

[0180] In the methods described herein, the patient is administered an effective amount of dociparstat sodium (USAN).

5.2.2.1 Drug substance

[0181] 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.

[0182] Briefly, to produce dociparstat sodium, 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. 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. Thus, after manufacture from heparin sodium USP (of porcine origin), dociparstat sodium is also heterogeneous and heterodisperse. The 2-0, 3-O-desulfated repeating unit is shown below as formula (I):

4 . ►

[0183] Dociparstat sodium is an off-white to pinkish amorphous powder. It is manufactured under Good Manufacturing Practices (GMP) conditions.

5.2.2.2 Pharmaceutical compositions

[0184] In typical embodiments of the methods described herein, 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.

[0185] 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.

5.2.2.2.1 Solution for Injection

[0186] In various embodiments, dociparstat is administered as or is diluted from a pharmaceutical composition formulated as a solution for injection.

[0187] In some embodiments, sodium injection is provided as a sterile solution containing dociparstat sodium. In certain embodiments, dociparstat sodium is provided as a sterile solution containing 50 mg/mL dociparstat sodium. In typical embodiments, the solution has pH of 5.0 - 7.5. In typical embodiments, the solution is isotonic. In certain embodiments, 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.

[0188] In particular embodiments, dociparstat sodium is provided as a sterile solution containing 50 mg/mL dociparstat sodium packaged in 10 mL vials. In certain embodiments, the dociparstat sodium injection vials have the physical and chemical specifications summarized in Table 1.

*Performed only at release.

5.2.3. Dociparstat Sodium Dosage Regimens

[0189] In various embodiments of the methods described herein, 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.

[0190] In certain currently preferred intravenous embodiments, dociparstat sodium is administered by intravenous bolus infusion followed by continuous intravenous infusion.

[0191] In some embodiments, 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.

[0192] In some embodiments, the continuous intravenous infusion ranges from 1.000 mg/kg/hour to 0.375 mg/kg/hour. In certain embodiments, dociparstat sodium is administered by continuous intravenous infusion at a dose ranging from 0.250 mg/kg/hr - 0.375 mg/kg/hr. In certain embodiments, dociparstat sodium is administered by continuous intravenous infusion at a dose ranging from 0.250 mg/kg/hr- 0.325 mg/kg/hr.

[0193] In certain embodiments, 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.

[0194] In particular embodiments, dociparstat sodium is administered as a

• 4 mg/kg IV bolus followed by 0.25 mg/kg/hr continuous infusion;

• 4 mg/kg IV bolus followed by 0.325 mg/kg/hr continuous infusion; or

• 4 mg/kg IV bolus followed by 0.375 mg/kg/hr continuous infusion.

5.2.4. Additional Agents

[0195] In some embodiments, the methods of the present disclosure further comprise administering an effective amount of at least one second therapeutic agent.

[0196] In certain embodiments, one or more corticosteroids may be administered to the patient, either prior to, concurrently, or post-administration of dociparstat sodium.

[0197] In certain embodiments, 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. [0198] In certain embodiments, anticoagulants are not administered to the patient in addition to dociparstat sodium. In particular embodiments, low molecular weight heparin (LMWH) is not administered to the patient undergoing dociparstat sodium treatment. In certain embodiments, unfractionated heparin is administered to the patient undergoing dociparstat sodium treatment.

In certain embodiments, patients are provided DVT prophylaxis under certain conditions. 5.2.4.1 Anti- Viral Agents

[0199] In some embodiments, the method of the present disclosure further comprises administering an effective amount of an anti-viral agent.

[0200] In some embodiments, the anti-viral agent is selected from the group consisting of: favipiravir, remdesivir, and a combination of lopinavir and ritonavir.

[0201] In particular embodiments, the anti -viral agent is favipiravir.

[0202] In particular embodiments, the anti-viral agent is remdesivir.

[0203] In particular embodiments, the anti-viral agent is a combination of lopinavir and ritonavir.

5.2.4.2 Antibacterial Agents

[0204] In some embodiments, the method of the present disclosure further comprises administering an antibacterial agent. In some embodiments, the antibacterial agent is selected from the group consisting of azithromycin, tobramycin, aztreonam, ciprofloxacin, meropenem, cefepime, cetadizine, imipenem, piperacillin-tazobactam, amikacin, gentamicin and levofloxacin. In certain embodiments, the antibacterial agent is azithromycin.

5.2.4.3 Angiotensin Receptor Blocker (ARB)

[0205] In some embodiments, the methods herein further comprise administering an ARB.

[0206] In particular embodiments, the ARB is selected from losartan, valsartan, azilsartan, candesartan, eprosartan, irgesartan, olmesartan, and telmisartan.

5.2.4.4 IL-6 Antagonists

[0207] In certain embodiments, the patient is further administered an IL-6 antagonist. In some embodiments, 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.

5.2.4.4.1 Anti-IL-6 Receptor Antibodies

[0208] In various embodiments, the IL-6 antagonist is an anti-IL-6 receptor (anti-IL-6R) antibody or antigen-binding fragment or derivative thereof.

[0209] In typical embodiments, the anti-IL-6R reduces the biological activity of IL-6 receptor. [0210] In some embodiments, the IL-6 antagonist is an anti-IL-6R monoclonal antibody. In some embodiments, 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.

[0211] In some embodiments, 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.

[0212] In some embodiments, the anti-IL-6R antibody comprises a scaffold. In certain embodiments, the scaffold is Fc, optionally human Fc. In some embodiments, the anti-IL-6R antibody comprises a heavy chain constant region of a class selected from IgG, IgA, IgD, IgE, and IgM. In certain embodiments, 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.

[0213] In some embodiments, the IL-6 antagonist is immunoconjugate or fusion protein comprising an IL-6R antigen-binding fragment.

[0214] In some embodiments, the antibody is bispecific or multispecific, with at least one of the antigen-binding portions having specificity for IL-6 receptor.

[0215] In some embodiments, 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.

[0216] In typical embodiments, 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.

[0217] In typical embodiments, 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.

[0218] In some embodiments, 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.

Tocilizumab and Derivatives [0219] In certain embodiments, the anti-IL-6R antibody or antigen-binding portion thereof comprises all six CDRs of tocilizumab. In particular embodiments, the antibody or antigen binding portion thereof comprises the tocilizumab heavy chain V region and light chain V region. In specific embodiments, the antibody is the full-length tocilizumab antibody.

[0220] In various embodiments, the anti-IL-6R antibody is a derivative of tocilizumab.

[0221] In some embodiments, the tocilizumab derivative includes one or more amino acid substitutions in the tocilizumab heavy and/or light chain V regions.

[0222] In certain embodiments, 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.

[0223] In certain embodiments, 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.

[0224] In certain embodiments, 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.

[0225] In certain embodiments, 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).

Sarilumab and Derivatives

[0226] In certain embodiments, the anti-IL-6R antibody or antigen-binding portion thereof comprises all six CDRs of sarilumab. In particular embodiments, the antibody or antigen-binding portion thereof comprises the sarilumab heavy chain V region and light chain V region. In specific embodiments, the antibody is the full-length sarilumab antibody.

[0227] In various embodiments, the anti-IL-6R antibody is a derivative of sarilumab. [0228] In some embodiments, the sarilumab derivative includes one or more amino acid substitutions in the sarilumab heavy and/or light chain V regions.

[0229] In certain embodiments, 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.

[0230] In certain embodiments, 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.

[0231] In certain embodiments, 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.

[0232] In certain embodiments, 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).

Vobarilizumab and Derivatives

[0233] In certain embodiments, the anti-IL-6R antibody or antigen-binding portion thereof comprises all six CDRs of vobarilizumab. In particular embodiments, the antibody or antigen binding portion thereof comprises the vobarilizumab heavy chain V region and light chain V region. In specific embodiments, the antibody is the full-length vobarilizumab antibody.

[0234] In various embodiments, the anti-IL-6R antibody is a derivative of vobarilizumab.

[0235] In some embodiments, the vobarilizumab derivative includes one or more amino acid substitutions in the vobarilizumab heavy and/or light chain V regions.

[0236] In certain embodiments, 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.

[0237] In certain embodiments, 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.

[0238] In certain embodiments, 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.

[0239] In certain embodiments, 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).

Other Anti-IL-6R Antibodies and Derivatives

[0240] In certain embodiments, 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. In particular embodiments, 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. In specific embodiments, 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.

[0241] In various embodiments, 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.

Anti-IL-6:IL-6R Complex Antibodies

[0242] In various embodiments, the IL-6 antagonist is an antibody specific for the complex of IL-6 and IL-6R. In certain embodiments, 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

[0243] In various embodiments, the IL-6 antagonist is an anti-IL-6 antibody or antigen-binding fragment thereof.

[0244] In typical embodiments, the anti-IL-6 antibody or antigen-binding fragment thereof neutralizes the biological activity of human IL-6. In some embodiments, the neutralizing antibody prevents binding of IL-6 to the IL-6 receptor. In certain embodiments, the neutralizing antibody prevents binding of IL-6 to the soluble IL-6 receptor. In certain embodiments, the neutralizing antibody prevents binding of IL-6 to the membrane-bound IL-6 receptor. In certain embodiments, the neutralizing antibody prevents binding of IL-6 to both the soluble IL-6 receptor and the membrane-bound IL-6 receptor.

[0245] In some embodiments, 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.

[0246] In some embodiments, 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). In some embodiments, 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).

5.2A4.3 IL-6 Antagonist Peptides

[0247] In various embodiments, the IL-6 antagonist is an antagonist peptide.

[0248] In certain embodiments, 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). In some embodiments, the anti-IL-6 antagonist comprises soluble gpl30, FE301 (Conaris/F erring).

5.2A4.4 JAK and STAT Inhibitors

[0249] In various embodiments, the IL-6 antagonist is an inhibitor of the JAK signaling pathway. In some embodiments, the JAK inhibitor is a JAK1 -specific inhibitor. In some embodiments, the JAK inhibitor is a JAK3-specific inhibitor. In some embodiments, the JAK inhibitor is a pan- JAK inhibitor. In certain embodiments, 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.

[0250] In various embodiments, the IL-6 antagonist is a STAT3 inhibitor. In a specific embodiment, the inhibitor is AZD9150 (AstraZeneca, Isis Pharmaceuticals), a STAT3 antisense molecule.

[0251] In typical embodiments, small molecule JAK inhibitors and STAT inhibitors are administered orally.

[0252] In various embodiments, 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.

5.2.4.5 Hydroxychloroquine and Chloroquine

[0253] In some embodiments, the method further comprises administering an anti-malarial agent. In certain embodiments, the anti-malarial agent is hydroxychloroquine. In certain embodiments, the anti-malarial agent is chloroquine.

5.2.4.6 COVID-19 Immune Serum or Plasma

[0254] In some embodiments, 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.

5.2.5. Post-Treatment Reduction of IL-6 and C-Reactive protein (CRP)

[0255] In some embodiments, the administration of an effective amount of dociparstat sodium reduces the patient’s free serum IL-6 levels below pre-treatment levels. In various embodiments, the dosage regimen is adjusted to achieve a reduction in the patient’s free serum IL-6 levels below pre-treatment levels.

[0256] In some embodiments, 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. In certain embodiments, 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.

[0257] In some embodiments, the administration of an effective amount of dociparstat sodium, reduces the patient’s serum CRP levels below pre-treatment levels. In various embodiments, the dosage regimen is adjusted to achieve a reduction in the patient’s serum CRP levels below pre treatment levels.

[0258] In some embodiments, 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.

[0259] In some embodiments, 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%,

40%, 50%, 60%, 70%, 80%, or 90% as compared to pre-treatment levels. In certain embodiments, 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.

5.2.6. Other Post-Treatment Endpoints [0260] In some embodiments, administering an effective amount of dociparstat sodium to the patient prevents a hyperinflammatory response in the patient. In some embodiments, the dosage regimen is adjusted to prevent a hyperinflammatory response in the patient.

[0261] In some embodiments, administering an effective amount of dociparstat sodium to the patient results in a reduction in body temperature. In some embodiments, the patient, post treatment with an effective amount of dociparstat sodium, has a body temperature of 37.5°C or below. In some embodiments, the patient, post-treatment with an effective amount of dociparstat sodium, has a body temperature ranging from of 36 to 37.5°C.

[0262] In some embodiments, administering an effective amount of dociparstat sodium to the patient results in a reduction in the risk of respiratory morbidity and mortality. In some embodiments, the dose is adjusted to reduce the risk of respiratory morbidity and mortality.

[0263] In some embodiments, administering an effective amount of dociparstat sodium to the patient results in a reduction in the patient’s need for supplemental oxygen. In some embodiments, the dose is adjusted to reduce the patient’s need for supplemental oxygen.

[0264] In some embodiments, administering an effective amount of dociparstat sodium to the patient results in eliminating the patient’s need for assisted ventilation. In some embodiments, the dose is adjusted to eliminate the patient’s need for assisted ventilation.

[0265] Additionally, 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.

5.3. Kits

[0266] Additionally, certain components or embodiments of the compositions can be provided in a kit. For example, 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. In some embodiments, the kit may comprise ampoules, disposable syringes, capsules, vials, tubes, or the like. In some embodiments, the kit may comprise a single dose container or multiple dose containers comprising the embodiments herein. In some embodiments, each dose container may contain one or more unit doses. In some embodiments, the kit may include an applicator. In some embodiments, the kits include all components needed for the various stages of treatment. In some embodiments, the compositions may have preservatives or be preservative-free (for example, in a single-use container). In some embodiments, the kit may comprise materials for intravenous administration. In some embodiments, the kit may comprise protamine in a separate container, which can be administered to rapidly neutralize anticoagulation due to unfractionated heparin (UFH). 6. EXAMPLES

6.1. 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

6.1.1. Overall Design

[0267] A randomized, double-blind (sponsor-unblinded), placebo-controlled, Phase 1/2 study to confirm safety and therapeutic effect of dociparstat (DSTAT) in adults with severe COVID-19 who are at high risk of respiratory failure was conducted.

[0268] Eligible participants hospitalized with laboratory-confirmed SARS-CoV-2, with a resting oxygen saturation (by pulse oximetry) of <93% on ambient air were randomized 1:1 to receive dociparstat sodium (DSTAT) or placebo as an initial IV bolus dose followed by a continuous IV infusion for up to 7 days; both groups also received best supportive care (as determined by the investigator) as background therapy. Randomization was stratified by baseline NIAID score (3 or 4) and by age (<60 years or >60 years).

6.1.2. Enrollment

[0269] 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.

[0270] 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).

[0271] 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).

[0272] 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. [0273] 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.

6.1.2.1 Diagnosis and Main Criteria for Inclusion:

[0274] Study participants met all of the following criteria:

1. Hospitalized for laboratory-documented COVID-19 disease (e.g., positive for SARS- CoV-2 via nasopharyngeal swab RT-PCR or other commercial or public health assay); 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).

2. Age >18 years and <70 years.

3. Resting oxygen saturation (Sa02) of <93% while breathing ambient air.

4. Score of 3 or 4 on the NIAID ordinal scale (requires supplemental oxygen).

5. Provide informed consent to participate in the study (by participant or legally-acceptable representative).

[0275] Potential participants who met any of the following criteria were not eligible to participate in the study:

1. Currently receiving mechanical ventilation via an endotracheal tube.

2. Severe chronic respiratory disease, defined by any oxygen requirement prior to incident COVID-19.

3. Receiving any other investigational (non-approved) pharmacologic therapy (e.g., remdesivir or IL6-RA) for the treatment of COVID-19. Refer to the list of prohibited concomitant medications.

4. Receiving or anticipated to require systemic corticosteroids.

5. Receiving or anticipated to require anticoagulation for prophylaxis of deep venous thrombosis other than unfractionated heparin at a maximum dose of 5000 IU every 8 or 12 hours, or enoxaparin at a dose of 40 mg once daily, which are permitted; this criteria is also subject to further clinical review. 6. A history of congestive heart failure requiring hospitalization.

7. Active pericarditis.

8. Malignancy or other irreversible disease or condition for which 6-month mortality is estimated >50%.

9. QTc >450 msec for a male, >470 msec for a female, or >480 msec if underlying bundle branch block.

10. Calculated creatinine clearance or estimated glomerular filtration rate <30 mL/min.

11. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5x upper limit of normal (ULN).

12. Activated partial thromboplastin time (aPTT) >40 seconds.

13. Severe chronic liver disease (Child-Pugh Score of 10 to 15).

14. Received dociparstat in a different clinical study.

15. Woman of childbearing potential who is pregnant, breastfeeding, and/or not using a highly effective method of contraception (consistent with local regulations regarding the methods of contraception for those participating in clinical studies).

6.1.3. Intervention Groups and Duration

[0276] Participants received study intervention for up to 7 days and were followed for 28 days after first dose. Participants who were stabilized and eligible for hospital discharge prior to Day 7 discontinued study intervention prior to discharge.

6.1.4. Study Intervention

[0277] Subjects received blinded study intervention consisting of either dociparstat or normal saline as a placebo control for up to 7 days (starting on Day 1 and ending on Day 8 [168 hours]). Both groups also received best supportive care (as determined by the investigator).

[0278] 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.

6.1.4.1 Shipping, Storage, Handling, and Stability

[0279] Long term stability testing for API and final product (dociparstat sodium vials) in compliance with FDA requirements has been completed. Results from these stability studies indicate that dociparstat sodium API and dociparstat sodium injection 10 mL and 20 mL vials (50mg/mL) are stable for at least 48 months when stored at room temperature. A stability study of dociparstat sodium in normal saline diluted for bolus dose concentration and continuous infusion concentration (in polyethylene bags) has confirmed stability of the drug product for at least 72 hours (the maximum period tested) at 2 concentration levels (2 mg/mL and 10 mg/mL of dociparstat sodium) and at 2 temperature conditions (2-8°C and room temperature). This test covers all the ranges for dociparstat sodium concentration/dilution required when dosing for clinical trials.

[0280] 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.

6.1.4.2 Dociparstat dosing is as follows:

[0281] Phase 1, Cohort 1: 4 mg/kg IV bolus followed by continuous infusion of 0.25 mg/kg/hr. [0282] 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).

[0283] Phase 2: 4 mg/kg IV bolus followed by continuous infusion (dose determined after Phase 1). [0284] 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.

[0285] Preparation of dociparstat was performed by an unblinded pharmacist within the investigational pharmacy or other designated entity. 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.

[0286] 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.

6.1.5. Interruption of Study Intervention:

[0287] Infusion of study intervention (i.e., dociparstat sodium or placebo) was interrupted in the following situations:

[0288] 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.

[0289] 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. a. Participants in cohorts with dociparstat dosed at 0.25 mg/kg/hr: study intervention dosing was not resumed if interruption criteria were met. b. 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. [0290] 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.

[0291] QTc: Heparin is not associated with QT prolongation and no cardiac safety signal has been identified to date in preclinical and clinical dociparstat studies.

[0292] However, considering the risk of QT prolongation associated with potential concomitant medications (e.g., hydroxychloroquine), it was recommended that the investigator monitor participants in accordance with the American College of Cardiology (or equivalent) guidelines (Simpson 2020).

[0293] In the event of ventricular arrhythmia or prolonged QTc meeting the criteria below, the participant was assessed for medications that may impact QT interval, with any necessary changes (e.g., dose reduction, or discontinuation) made to concomitant medications. a. Without underlying bundle branch block: i. Interrupt for QTc >500 msec b. With underlying bundle branch block: i. If baseline QTc <450 msec, then interrupt for QTc >500 msec ii. If baseline QTc 450 to 480 msec, then interrupt for QTc >530 msec

[0294] If, by the following day, reducing the dose or discontinuing concomitant medications did not reduce QTc to <450 msec (<480 msec in participants with bundle branch block and baseline QTc 450 to 480 msec), then administration of the participant’s study intervention was discontinued.

6.1.6. Criteria for Evaluation

[0295] Efficacy was evaluated through clinical examinations, vital signs, oxygen requirements, and laboratory tests. Safety was monitored through collection of AE data and laboratory tests.

6.1.7. Results

[0296] Results of the first cohort of twelve patients randomized 1:1 for treatment with dociparstat sodium or placebo are shown in Figures 3 - 43. The results demonstrate that five patients on dociparstat sodium and four patients on placebo met the primary endpoint of survival without the need for mechanical intervention through day 28. One patient on dociparstat sodium was ventilated and recovered (Figure 3 and Figure 17). Two patients on placebo progressed to ventilation and died, one on day two and the other post day 28 (Figure 3, Figure 4, Figure 17, and Figure 18). No deaths were reported in patients treated with dociparstat sodium (Figure 18).

[0297] Administration of dociparstat sodium was effective to reduce time to at least a two- grade improvement from baseline on the NIAID ordinal scale (Figure 19). All of the patients treated with dociparstat sodium met the criteria for clinical improvement. In contrast, only two of the six patients on the placebo arm of the study met the criteria for clinical improvement (Figure 19)

[0298] Time to hospital discharge was improved for patients receiving dociparstat sodium compared to patients receiving placebo (Figure 20 and Figure 43). After 28 days, three patients on placebo remained hospitalized and one placebo patient was deceased. In contrast, only one patient treated with dociparstat sodium remained hospitalized at 28 days. Two patients treated with dociparstat sodium who were discharged were subsequently lost to follow-up.

[0299] Patients treated with dociparstat sodium did not have elevated values of D-dimer (Figure 10), IL-6 (Figure 22), or MCP-1 (Figure 33), biomarkers that have been correlated with COVID-19 disease progression and that are relevant to the proposed mechanism of action of dociparstat sodium. In contrast, two patients on placebo had substantial increases in D-dimer (Figure 10), IL-6 (Figure 22), and MCP-1 (Figure 33) by day five, reflective of the lung inflammation and thrombotic complications associated with severe COVID-19. One of the placebo patients with elevated biomarkers developed ARDS and died post day 28; the other suffered a pulmonary embolism and recovered.

[0300] Dociparstat sodium was observed to be safe and well tolerated. No patients on the dociparstat sodium treatment arm of the study discontinued treatment due to adverse events. By comparison, two patients on the placebo arm discontinued study treatment due to adverse events. [0301] As an enrollment criterion, all patients were hospitalized with confirmed COVID-19 infection and required supplemental oxygen; some patients required more intensive supplemental oxygen (noninvasive ventilation/high-flow oxygen) which is generally associated with more severe disease.

[0302] Five of the six patients on the placebo arm required noninvasive ventilation/high-flow oxygen at baseline, compared to two of the six patients treated with dociparstat sodium. The median age of patients in the first cohort was 63.0 years on the placebo arm and 50.5 on the dociparstat sodium treatment arm. The dociparstat sodium treatment arm was comprised of six males. The placebo arm was comprised of four males and two females. Being male has been associated with a higher risk of COVID-19 mortality.

7. EQUIVALENTS AND INCORPORATION BY REFERENCE [0303] All references cited herein are incorporated by reference to the same extent as if each individual publication, database entry (e.g. Genbank sequences or GenelD entries), patent application, or patent, was specifically and individually indicated incorporated by reference in its entirety, for all purposes. This statement of incorporation by reference is intended by Applicants, pursuant to 37 C.F.R. §1.57(b)(1), to relate to each and every individual publication, database entry (e.g. Genbank sequences or GenelD entries), patent application, or patent, each of which is clearly identified in compliance with 37 C.F.R. §1.57(b)(2), even if such citation is not immediately adjacent to a dedicated statement of incorporation by reference. The inclusion of dedicated statements of incorporation by reference, if any, within the specification does not in any way weaken this general statement of incorporation by reference. Citation of the references herein is not intended as an admission that the reference is pertinent prior art, nor does it constitute any admission as to the contents or date of these publications or documents.

[0304] While the invention has been particularly shown and described with reference to a preferred embodiment and various alternate embodiments, it is understood by persons skilled in the relevant art that various changes in form and details can be made therein without departing from the spirit and scope of the invention.