EOM613 for the treatment of COVID-19

Abstract

Methods of treating a subject with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with EOM613 are disclosed. In some embodiments, a subject at risk of developing severe symptoms of SARS-CoV-2 infection is selected for treatment. Also disclosed are methods in which administration of EOM613 reduces symptoms of SARS-CoV-2 infection, including symptoms of cytokine storm syndrome or multisystem inflammatory syndrome. In some embodiments, treating the subject with the therapeutically effective amount of EOM613 reduces at least one of the following symptoms of SARS-CoV-2 infection: respiratory distress, pulmonary inflammation, hypoxia, myocarditis, kidney disease, blood clotting, encephalitis, pneumonia, significant weakness, cytokine storm syndrome, and multisystem inflammatory syndrome.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 094,168, filed on October 20, 2020, and U.S. Provisional Patent Application No. 63 / 094,172, filed on October 20, 2020, both of which are incorporated herein by reference in their entirety.

[0002] Field This application relates to embodiments of methods of treating a subject having a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as well as additional conditions such as cytokine storm syndrome, multisystem inflammatory syndrome, and Kawasaki disease.

Background Art

[0003] Background In 2019, a novel coronavirus (named SARS-CoV-2 by the World Health Organization) was identified as the causative agent of coronavirus disease 2019 (COVID-19). In March 2020, the World Health Organization (WHO) declared the occurrence of COVID-19 to be a pandemic. Worldwide, SARS-CoV-2 had caused more than 35.9 million COVID-19 cases and more than 1 million deaths as of October 6, 2020.

[0004] Patients with COVID-19 have been treated with drugs such as remdesivir, hydroxychloroquine, azithromycin, dexamethasone, and interleukin-6 inhibitors, but the lung and heart complications caused by cytokine release at the site of viral infection remain the leading cause of death in COVID-19 patients. Due to its high lethality, poorly defined epidemiology, and lack of preventive or therapeutic means, there is an urgent need to develop effective treatments, especially for patients at risk of experiencing or developing cytokine storm syndrome or multisystem inflammatory syndrome secondary to SARS-CoV-2 infection.

Summary of the Invention

[0005] Abstract A method for treating a subject having severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is provided herein, the method comprising the step of administering a therapeutically effective amount of EOM613 to the subject. In some embodiments, the step of treating the subject with the therapeutically effective amount of EOM613 reduces at least one of the following symptoms of SARS-CoV-2 infection: respiratory distress, pneumonia, hypoxia, myocarditis, renal disease, blood coagulation, encephalitis, pneumonia, marked weakness, cytokine storm syndrome, and multisystem inflammatory syndrome.

[0006] In some embodiments, the subjects are selected prior to treatment by selecting, for example, subjects who have signs or symptoms of SARS-CoV-2 infection or a positive diagnosis, or subjects who are at risk of SARS-CoV-2 infection (e.g., subjects with known exposure to SARS-CoV-2 infection). In some embodiments, subjects with SARS-CoV-2 infection have or are at risk of COVID-19.

[0007] In some embodiments, the step of administering the therapeutically effective amount of EOM613 to the subject includes administering approximately 0.5 microliters to approximately 100 microliters of EOM613 per kilogram of body weight per day to the subject. In some embodiments, the step of administering the therapeutically effective amount of EOM613 to the subject includes administering approximately 1 to approximately 2 ml of EOM613 to the subject twice a day for 2 to 3 days, followed by administering approximately 1 ml of EOM613 to the subject once a day for 6 to 12 days. In some embodiments, the step of administering the therapeutically effective amount of EOM613 to the subject includes administering approximately 2 ml of EOM613 subcutaneously twice a day for 3 days, followed by administering 1 ml of EOM613 subcutaneously twice a day for 7 days. In some embodiments, the step of administering the therapeutically effective amount of EOM613 to the subject includes administering approximately 2 ml of EOM613 subcutaneously twice a day for 2 to 5 days, followed by administering 2 ml of EOM613 subcutaneously once a day for 3 to 5 days.

[0008] The aforementioned and other features and advantages of this disclosure will become apparent from the following detailed description of some embodiments, which will proceed with reference to the accompanying drawings. In embodiments of the present invention, for example, the following items are provided. (Item 1) A method for treating a subject infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the method comprising the step of administering a therapeutically effective amount of EOM613 to the subject. (Item 2) The method according to item 1, further comprising the step of selecting a subject having the SARS-CoV-2 infection for treatment. (Item 3) The subject is a person who has or is at risk of having coronavirus disease 2019 (COVID-19), according to the method of item 1 or item 2. (Item 4) The method according to any one of the above items, wherein the step of treating the subject reduces at least one of the following symptoms of SARS-CoV-2 infection: respiratory distress, pneumonia, hypoxia, myocarditis, renal disease, blood coagulation, encephalitis, pneumonia, marked weakness, lymphopenia, cytokine storm syndrome, and multisystem inflammatory syndrome. (Item 5) The method according to any one of the preceding items, comprising the step of administering to the subject an amount of EOM613 effective in inhibiting SARS-CoV-2-induced multisystem inflammatory syndrome. (Item 6) The method according to item 5, wherein the step of inhibiting SARS-CoV-2-induced multisystem inflammatory syndrome reduces organ damage to the heart, kidneys, and / or lungs. (Item 7) The subject is a child, as described in item 5 or item 6. (Item 8) The subject has one or more of the following underlying medical conditions: heart disease, cancer, chronic obstructive pulmonary disease, type 2 diabetes, type 1 diabetes, obesity, chronic kidney disease, sickle cell disease, asthma, liver disease, chronic lung disease, hypertension, or an immune system suppressed due to medical treatment, infection by a pathogen other than SARS-CoV-2, or an autoimmune disorder, as described in any one of the items above. (Item 9) The subject is a human, and the method described in any one of the items above. (Item 10) The subject is at least 75 years old, and the method described in any one of items 1-6 and 8-9. (Item 11) The method according to any one of the above items, wherein the subject has lymphopenia caused by SARS-CoV-2 infection, and the step of administering the subject a therapeutically effective amount of EOM613 increases the number of lymphocytes in the subject to a range of 20-40% of the number of white blood cells. (Item 12) The method according to any one of the preceding items, wherein the subject has elevated levels of one or more of D-dimer, troponin, C-reactive protein, procalcitonin, or cytokines, and the step of administering the subject a therapeutically effective amount of EOM613 reduces the elevated levels to undetectable or normal levels. (Item 13) The method according to item 12, wherein the subject has elevated levels of one or more of D-dimer, troponin-I, C-reactive protein, or procalcitonin. (Item 14) The method according to any one of the above items, wherein the step of administering the therapeutically effective amount of EOM613 to the subject comprises the step of administering to the subject about 0.5 microliters to about 100 microliters of EOM613 / kilogram body weight / day. (Item 15) The method according to item 14, wherein the step of administering the subject a therapeutically effective amount of EOM613 comprises administering the subject about 2.5 microliters to about 40 microliters of EOM613 per kilogram of body weight per day. (Item 16) The method according to item 14, wherein the step of administering the therapeutically effective amount of EOM613 to the subject comprises the step of administering to the subject about 10 microliters to about 25 microliters of EOM613 / kilogram body weight / day. (Item 17) The method according to any one of the above items, wherein the step of administering the therapeutically effective amount of EOM613 to the subject comprises the step of administering about 1 to about 2 ml of EOM613 to the subject twice a day. (Item 18) The method according to item 17, wherein the step of administering the therapeutically effective amount of EOM613 to the subject comprises the step of administering approximately 2 ml of EOM613 to the subject twice a day for 2 to 5 days. (Item 19) The method according to item 17 or 18, wherein the step of administering approximately 2 ml of EOM613 to the subject twice a day for 2 to 5 days is followed by the step of administering approximately 1 to approximately 2 ml of EOM613 to the subject once a day for another 2 to 5 days. (Item 20) The method according to item 17 or 18, wherein the step of administering the therapeutically effective amount of EOM613 to the subject comprises the steps of administering approximately 2 ml of EOM613 to the subject twice a day for 3 days, and then administering approximately 1 ml of EOM613 to the subject twice a day for 7 days. (Item 21) The method according to item 17, wherein the step of administering the therapeutically effective amount of EOM613 to the subject comprises the step of administering approximately 2 ml of EOM613 to the subject once a day for approximately 10 days. (Item 22) The therapeutically effective amount of EOM613 is administered parenterally, topically, by inhalation, or systemically, according to any one of the preceding items. (Item 23) The therapeutically effective amount of EOM613 is administered by inhalation using a nebulizer or inhaler, as described in item 22. (Item 24) The method according to item 22, wherein the therapeutically effective amount of EOM613 is administered parenterally by subcutaneous injection. (Item 25) The method according to any one of the preceding items, further comprising the step of administering at least one further anti-COVID-19 agent to the subject. (Item 26) The anti-COVID-19 agent is an antiviral agent, as described in item 20. (Item 27) The subject, prior to initiating treatment, has a score of 5 or higher on the World Health Organization (WHO) Clinical Improvement Order Scale, as described in any one of the above items. (Item 28) The subject, prior to initiating treatment, has a score of 6 or higher on the WHO Clinical Improvement Order Scale, as described in item 27. (Item 29) The anti-COVID-19 agent is one or more of remdesivir, hydroxychloroquine, azithromycin, dexamethasone, chloroquine phosphate, ivermectin, alpha-interferon, beta-interferon, gamma-interferon, ritonavir, or arabinol, as described in item 25. (Item 30) A method for treating a subject having lymphopenia, the method comprising the step of administering to the subject an amount of EOM613 effective for treating the lymphopenia. [Brief explanation of the drawing]

[0009] [Figure 1] Figure 1: Plasma IL-6 concentration in COVID-19 patients treated with EOM613

[0010] [Figure 2] Figure 2: Lymphocyte count (%) in COVID-19 patients treated with EOM613.

[0011] [Figure 3] Figure 3: C-reactive protein (CRP) concentrations in COVID-19 patients treated with EOM613. [Modes for carrying out the invention]

[0012] Detailed explanation I. Glossary Unless otherwise noted, technical terms are used according to their conventional usage. Definitions of common terms in molecular biology can be found in Benjamin Lewin, Genes X, published by Jones & Bartlett Publishers, 2009; and Meyers et al. (eds.), The Encyclopedia of Cell Biology and Molecular Medicine, published by Wiley-VCH in 16 volumes, 2008; and other similar references.

[0013] Where used herein, the singular forms “a,” “an,” and “the” refer to both singular and plural forms unless the context clearly indicates otherwise. For example, the term “an antigen” encompasses one or more antigens and may be considered equivalent to the phrase “at least one antigen.” Where used herein, the term “comprises” means “includes.” Any and all base sizes or amino acid sizes, as well as all molecular weight or molecular mass values, given with respect to nucleic acids or polypeptides, should be further understood to be approximations and provided for descriptive purposes unless otherwise indicated. Many methods and materials similar or equivalent to those described herein may be used, but certain suitable methods and materials are described herein. In case of any conflict, this specification prevails, including the definitions of terms. Furthermore, materials, methods, and examples are illustrative and not intended to be limiting. To facilitate the examination of various embodiments, the following glossary of terms is provided:

[0014] Approximately: Unless otherwise specified in the context, "approximately" refers to a range of ±5% of the reference value. For example, "approximately" 100 refers to a range of 95 to 105.

[0015] Administration: Introduction of the drug (e.g., EOM613) to the subject via a selected route. Administration may be topical or systemic. Exemplary routes of administration include, but are not limited to, oral, parenteral (e.g., subcutaneous, intramuscular, intradermal, intraperitoneal, and intravenous), sublingual, rectal, transdermal (e.g., topical), intranasal, vaginal, and inhalation routes.

[0016] Control: Reference standard. In some embodiments, the control is a negative control sample obtained from a healthy patient. In other embodiments, the control is a positive control sample obtained from a patient diagnosed with a disease or condition such as SARS-CoV-2 infection. In yet another embodiment, the control is a historical control or a standard reference value or range of values ​​(e.g., a previously tested control sample such as a group of patients diagnosed with a disease or condition (e.g., SARS-CoV-2 infection) with a known prognosis or outcome, or a group of samples representing baseline or normal values).

[0017] The difference between the test sample and the control may be an increase or a decrease. The difference may be a qualitative or quantitative difference, such as a statistically significant difference. In some cases, the difference is an increase or decrease of at least about 5% (e.g., at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 350%, at least about 400%, at least about 500%, or more than 500%) compared to the control.

[0018] Coronavirus: A family of positive-sense single-stranded RNA viruses known to cause severe respiratory illness. Currently known viruses that infect humans originate from the Coronavirus family, specifically from the alphacoronavirus and betacoronavirus genera.

[0019] Non-specific examples of betacoronaviruses include SARS-CoV-2, Middle East Respiratory Syndrome Coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Human Coronavirus HKU1 (HKU1-CoV), Human Coronavirus OC43 (OC43-CoV), Mouse Hepatitis Virus (MHV-CoV), Bat SARS-like Coronavirus WIV1 (WIV1-CoV), and Human Coronavirus HKU9 (HKU9-CoV). Non-specific examples of alphacoronaviruses include Human Coronavirus 229E (229E-CoV), Human Coronavirus NL63 (NL63-CoV), Porcine Epidemic Diarrhea Virus (PEDV), and Infectious Gastroenteritis Coronavirus (TGEV).

[0020] The viral genome is capped, polyadenylated, and covered with a nucleocapsid protein. Coronavirus virions contain a viral envelope that includes a type I fusion glycoprotein called the spike (S) protein. Most coronaviruses have a common genomic structure that includes a replicase gene located in the 5' portion of the genome and a structural gene located in the 3' portion of the genome.

[0021] Coronavirus Disease 2019 (COVID-19): A disease caused by SARS-CoV-2 infection. Common symptoms include fever, cough, fatigue, shortness of breath or difficulty breathing, and loss of smell and taste. The incubation period can range from 1 to 14 days. Most patients have mild symptoms, but some develop acute respiratory distress syndrome (ARDS), multiple organ failure, septic shock, and blood clots, which are likely triggered suddenly by a cytokine storm.

[0022] It is known that hosts with underlying medical conditions are at increased risk of COVID-19 and develop severe symptoms of COVID-19 after infection with SARS-CoV-2. Non-limiting examples include heart disease, cancer, chronic obstructive pulmonary disease, type 2 diabetes, type 1 diabetes, obesity, chronic kidney disease, sickle cell disease, asthma, liver disease, chronic lung disease, hypertension, or an immune system suppressed due to medical treatment, infection by pathogens other than SARS-CoV-2, or autoimmune disorders.

[0023] The World Health Organization (WHO) has published diagnostic testing guidelines for COVID-19 (see, for example, Laboratory Guidelines for the Detection and Diagnosis of COVID-19 virus infection, July 2020). The standard method for testing for SARS-CoV-2 infection is real-time reverse transcription polymerase chain reaction (rRT-PCR) on respiratory samples obtained by nasopharyngeal swabs. Standard diagnostic methods for detecting symptoms of COVID-19 are also used (e.g., pneumonia, shortness of breath, hypoxia, etc.).

[0024] Cytokine storm syndrome: A severe immune response in which the innate immune system causes an uncontrolled and excessive release of cytokines into the bloodstream. The excessive production of pro-inflammatory cytokines can further exacerbate existing respiratory distress and may lead to overwhelming systemic inflammation, hemodynamic instability, multi-organ dysfunction, and potentially death. Cytokine storm syndrome is also known as hypercytokinemia. Detection of cytokine storm syndrome in patients can be achieved using standard diagnostic methods, including but not limited to elevated plasma C-reactive protein (CRP) levels, elevated interleukin-6 (IL-6) levels, abnormal blood coagulation markers (e.g., D-dimer or fibrinogen), and elevated ferritin levels. Protocols for detecting cytokine storms in COVID-19 patients are publicly known and are described, for example, in Soy et al., Clin Rheumatol., 39(7):2085-2094, 2020. Further information on cytokine storm syndrome can be found, for example, in Ye et al., Journal of Infection, 80(6):607-613, 2020.

[0025] To detect: To identify the existence, presence, or fact of something.

[0026] Inhibiting or treating a disease or condition: for example, inhibiting the complete onset of a disease or condition in a subject at risk of developing secondary complications of a viral infection (e.g., SARS-CoV-2 infection), or in a subject at risk of or at risk of a condition such as cytokine storm syndrome or multisystem inflammatory syndrome. "Treatment" refers to a therapeutic intervention that improves the signs or symptoms of a condition after the condition has begun to develop. The term "improvement" refers to any observable beneficial effect of the above treatment in relation to a disease, syndrome, or pathological condition. Such beneficial effect may be demonstrated, for example, by a delayed onset of clinical symptoms in a susceptible subject, a reduction in the severity of some or all clinical symptoms, slower progression, a reduction in viral load, an improvement in the subject's overall health or well-being, or by other parameters specific to that particular disease, syndrome, or other pathological condition. Inhibition of disease or condition may include preventing or reducing the risk of the disease or condition described above (e.g., preventing or reducing the risk of severe symptoms resulting from a viral infection such as SARS-CoV-2 infection, e.g., cytokine storm syndrome or multisystem inflammatory syndrome). A “prophylactic” treatment is a treatment administered to a subject who shows no signs of disease or only early signs for the purpose of reducing the risk of developing the pathology. In some embodiments, the methods of this disclosure are therapeutic and not prophylactic.

[0027] Kawasaki disease is an inflammatory disease of unknown cause that primarily affects children under 5 years of age, causing fever, and is the leading cause of heart disease in children. In affected patients, blood vessels become inflamed throughout the body. The fever typically lasts for more than 5 days and is not treated with standard medication. Other common symptoms include large lymph nodes in the neck, a rash in the genital area, and conjunctivitis of the eyes, lips, palms, or soles of the feet. In some children, coronary artery aneurysms form in the heart, leading to heart disease.

[0028] The specific cause is unknown, but it is thought to result from an excessive immune response to infection in genetically predisposed children. Diagnosis is usually based on the individual's signs and symptoms. Other tests (e.g., cardiac and vascular ultrasound) may aid in the diagnosis. Detection of multisystem inflammatory syndrome in patients can be achieved using established diagnostic methods (including, but not limited to, persistent fever despite antipyretic use, tachycardia and hypotension, leukocytosis with lymphopenia, elevated C-reactive protein, elevated D-dimer and B-type natriuretic peptide). Further information on Kawasaki disease can be found, for example, in Hamden et al., British Medical Journal, 338:b1514, 1133-1138, 2009.

[0029] Pneumonia: A local defensive response induced by injury to lung tissue that works to isolate inflammatory factors. Pneumonia is characterized by the appearance or migration to the lungs of a number of such leukocytes exceeding the number of such leukocytes of any class found in such areas of tissue under normal (healthy) conditions. Detection and evaluation of pneumonia in a subject can be achieved by any appropriate means (including radiographic evaluation by X-ray).

[0030] Pneumonia can be classified as either acute or chronic. Acute pneumonia is the body's initial response to a harmful stimulus, achieved by increased migration of plasma and leukocytes from the blood to the damaged lung tissue. A cascade of biochemical events expands and matures the inflammatory response, involving the local vascular system, the immune response, and various cells within the damaged lung tissue.

[0031] Lymphocytopenia: A condition defined by an abnormally low number of lymphocytes in the blood. This condition is also called lymphocytic leukopenia or lymphopenia. Further information on lymphopenia in the context of COVID-19 can be found, for example, in Wagner et al., Int. J Lab Hematol. 10.1111 / ijlh.13288. 10 Jul. 2020, doi:10.1111 / ijlh.13288, 338:b1514, 1133-1138, 2009.

[0032] Multisystem inflammatory syndrome (MSS): A systemic disorder characterized by persistent fever and severe inflammation across multiple bodily systems, occurring in response to infection with a viral factor such as SARS-CoV-2. While MSI is most frequently observed in children under five years of age, it is also known to affect adults. Along with persistent fever, the first symptom often includes acute abdominal pain and diarrhea or vomiting. Muscle pain and general fatigue are frequent, and hypotension is also common. Other symptoms, occasionally, include conjunctivitis (pink eye), rash, lymphadenopathy, swelling of the hands and feet, and "strawberry tongue" (glossitis accompanied by enlarged fungiform papillae). Patients may develop cytokine storm syndrome. Heart failure is common, and myocardial inflammation has been reported. Clinical complications may include myocardial damage, respiratory distress, acute kidney injury, and increased blood clotting. Coronary artery abnormalities may occur (ranging from dilation to aneurysms). Detection of multisystem inflammatory syndrome in patients can be achieved using standard diagnostic methods. Further descriptions of multisystem inflammatory syndrome in children and adults can be found, for example, in Godfred-Cato et al., COVID-19-associated multisystem inflammatory syndrome in children - United States, March-July 2020. MMWR Morb Mortal Wkly Rep 2020;69:1074-80; and Morris et al., Case Series of Multisystem Inflammatory Syndrome in Adults Associated with SARS-CoV-2 Infection - United Kingdom and United States, MMWR Morb Mortal Wkly Rep 2020;69:1450-1456.

[0033] Nucleotides: Organic molecules consisting of a nucleoside and a phosphate. A nucleotide is a modified form of any of the following types: ribonucleotide, deoxynucleotide, or nucleotide. They function as monomer units in nucleic acid polymers, namely deoxyribonucleic acid and ribonucleic acid.

[0034] Nucleic acid molecule: A polymeric form of nucleotides that may include RNA, cDNA, genomic DNA, and both sense and antisense strands of synthetic and mixed polymers of the above. The term “nucleic acid molecule” is, as used herein, synonymous with “nucleic acid” and “polynucleotide.” A nucleic acid molecule is typically at least 10 nucleotides long unless otherwise specified. The term includes single-stranded and double-stranded forms of DNA. Polynucleotides may include either or both naturally occurring nucleotides and modified nucleotides linked together by naturally occurring and / or non-naturally occurring nucleotide linkages. “cDNA” means DNA that is complementary to or identical to mRNA, in either single-stranded or double-stranded form. “Encoding” refers to the essential properties of the specific sequences of nucleotides in a polynucleotide (e.g., a gene, cDNA, or mRNA) that act as a template for the synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (i.e., rRNA, tRNA, and mRNA) or a defined sequence of amino acids, as well as the biological properties arising therefrom.

[0035] Normal level: A value that falls within the “normal” reference range (“normal range”) of a population used by healthcare professionals to interpret medical tests (e.g., blood sample tests). In some embodiments, a subject has elevated levels of one or more of the following: D-dimer, troponin, C-reactive protein, procalcitonin, or cytokines, and the step of administering the subject a therapeutically effective amount of EOM613 reduces the elevated level to a normal level.

[0036] Pharmacokinetically acceptable carriers: Useful pharmacokinetically acceptable carriers remain the same as before. Remington's Pharmaceutical Sciences (EW Martin, Mack Publishing Co., Easton, PA, 19th edition, 1995) describes compositions and formulations suitable for the pharmacokinetic delivery of the disclosed immunogens.

[0037] In general, the properties of the carriers described above depend on the specific mode of administration used. For example, parenteral formulations typically include injectable fluids containing a pharmaceutically and physiologically acceptable fluid (e.g., water, saline, equilibrated salt solutions, aqueous dextrose, glycerol, etc.) as a vehicle. With respect to solid compositions (e.g., in the form of powders, pills, tablets, or capsules), conventional non-toxic solid carriers may include, for example, pharmaceutical-grade mannitol, lactose, starch, or magnesium stearate. In addition to a biologically neutral carrier, the pharmaceutical composition to be administered (e.g., an immunogenic composition) may contain trace amounts of non-toxic adjuvants (e.g., wetting or emulsifying agents, preservatives, and pH buffering agents (e.g., sodium acetate or sorbitan monolaurate)). In certain embodiments, a carrier suitable for administration to a subject may be sterile and / or suspended, or may be contained in a unit dose form containing one or more measured doses of a composition suitable for inducing a desired immune response in a different manner. It can also be achieved by pharmacotherapy in relation to its use for therapeutic purposes. The above-mentioned unit dosage form may be, for example, a sealed vial containing sterile contents, in a syringe for injection into a subject, or in solid or controlled-release dosage form, or in oral lozenge form, even if lyophilized for later solubilization and administration.

[0038] Polypeptide: Any chain of amino acids, regardless of length or post-translational modifications (e.g., glycosylation or phosphorylation). “Polypeptide” includes naturally occurring and non-naturally occurring amino acid polymers, as well as amino acid polymers in which one or more amino acid residues are non-natural amino acids (e.g., artificial chemical mimics of corresponding naturally occurring amino acids). “Residue” refers to an amino acid or amino acid mimic incorporated into the polypeptide by an amide bond or amide bond mimic. Polypeptides have an amino terminus (N-terminus) and a carboxyl terminus (C-terminus). “Polypeptide” is used interchangeably with peptide or protein and is used herein to refer to a polymer of amino acid residues.

[0039] Pulmonary function: The function of the respiratory system (which can be measured through various tests, including, but not limited to, measurements of airflow (e.g., vital capacity) or arterial blood gases (e.g., oxygen saturation level (e.g., SpO2))). Measurements of airflow included airflow rate, peak expiratory flow rate (PEFR), forced expiratory volume in the first second (FEV1), and maximal midexpiratory rate (MMEFR).

[0040] SARS-CoV-2: Also known as the Wuhan coronavirus or 2019 novel coronavirus, SARS-CoV-2 is a positive-strand single-strand RNA virus that has emerged as a highly fatal cause of severe acute respiratory infection. The viral genome is capped, polyadenylated, and covered with a nucleocapsid protein. The SARS-CoV-2 virion contains a viral envelope with a large spike glycoprotein. The SARS-CoV-2 genome, like most coronaviruses, has a typical genomic structure in which the replicase genes are contained in the 5'-side two-thirds of the genome and the structural genes are contained in the 3'-side one-third of the genome. The SARS-CoV-2 genome encodes a standard set of structural proteins, in order: 5'-spike (S)-envelope (E)-membrane (M) and nucleocapsid (N)-3'. Symptoms of SARS-CoV-2 infection include fever and respiratory illness (e.g., dry cough and shortness of breath). Severe cases of infection can progress to severe pneumonia, multiple organ failure, and death. The time from exposure to the onset of symptoms is approximately 2 to 14 days. The disease resulting from SARS-CoV-2 infection is called COVID-19.

[0041] Standard methods for detecting viral infection include, but are not limited to, assessment of the patient's symptoms and background, as well as genetic testing (e.g., reverse transcription polymerase chain reaction (rRT-PCR)), which may be used to detect SARS-CoV-2 infection. Testing may be performed on patient samples (e.g., respiratory or blood samples).

[0042] Subjects: Living multicellular vertebrates in categories including humans and non-human mammals (e.g., non-human primates, pigs, camels, bats, sheep, cattle, dogs, cats, rodents, etc.). In one example, the subject is a human. In further examples, subjects that need to inhibit SARS-CoV-2 infection are selected. For example, the above subjects are either not infected and at risk of SARS-CoV-2 infection, or infected and in need of treatment.

[0043] Therapeutic dose: A sufficient amount of a drug (e.g., a pharmaceutical composition) to prevent (including prevention), treat, reduce, and / or improve the symptoms and / or underlying causes of a disease, syndrome, or other pathological condition, for example, to prevent, inhibit, and / or treat SARS-CoV-2 infection and / or disease (e.g., COVID-19) or a secondary syndrome resulting therefrom (e.g., cytokine storm syndrome). In some embodiments, a therapeutic dose is sufficient to reduce or eliminate the symptoms of the disease. For example, this may be the amount necessary to inhibit or prevent the replication of a pathogen or to measurably alter the surface symptoms of a pathogen infection.

[0044] The World Health Organization (WHO) Ordinal Scale for Clinical Improvement is a scale developed by the World Health Organization (see Table 2) to categorize the severity of COVID-19 disease into eight ordered scores, used as a reference. The WHO Ordinal Scale for Clinical Improvement is also known as the "WHO COVID-19 Symptom Severity Scale." As used in this application, "WHO score" refers to the score on the WHO Ordinal Scale for Clinical Improvement. Further descriptions and applications of the WHO Ordinal Scale for Clinical Improvement can be found, for example, in the WHO R&D Blueprint, Novel Coronavirus, COVID-19 Therapeutic Trial Synopsis, World Health Organization, February 18, 2020 (which is incorporated herein by reference in its entirety).

[0045] It is understood that a therapeutically effective dose may include partial doses that contribute to achieving the desired response in combination with previous or subsequent administrations. For example, a therapeutically effective dose of a drug may be administered in a single dose or in several doses, for example, daily during the course of treatment. However, the therapeutically effective dose and timing of administration may depend on the subject being treated, the severity and type of the condition being treated, and the mode of administration. The therapeutically effective dose may be determined by varying the dose and measuring the resulting response (e.g., reduction of pathogen potency). The effective dose may also be determined through various in vitro, in vivo, or in situ assays. The unit dosing form of a drug may be packaged in therapeutic doses or in multiple therapeutic doses, for example, in vials (e.g., with a puncturable lid) or syringes with sterile components.

[0046] II. EOM613 EOM613, also known as Product R or AVR118, is a composition comprising nucleotides and peptides having molecular weights of 14 kDa or less, mainly 8 kDa or less. These nucleotides and peptides are degradation products of casein, peptone, RNA, and serum albumin. EOM613 and its production are described, for example, in U.S. Patents 6,528,098, 6,921,542, 7,074,767, 7,524,661, and 8,084,239 (which are incorporated herein by reference in their entirety). In these patent documents, EOM613 is referred to as Product R. A brief description of EOM613 and its production is provided herein.

[0047] Sixteen constituent compounds were identified and characterized in EOM613: three nucleosides, two nucleoside diphosphates, and eight nucleoside monophosphates, along with two peptides (one of which is a peptide-nucleic acid conjugate) and sodium chloride (derived from the neutralization of sodium hydroxide with hydrochloric acid during the manufacturing process).

[0048] The longer peptide (referred to as "peptide A") is a 31-amino acid peptide derived from bovine β-casein with a molecular weight of 3536.24 Da. The shorter peptide (referred to as "peptide B") is a peptide-oligonucleotide conjugate containing a 21-amino acid peptide linked to a diadenine (3'-5') diribonucleotide at the 18th serine residue via a diphosphodiester bond at the 3' position. This nucleopeptide conjugate has a peptide portion of MW 2215 linked to a non-peptide adduct of 740 MW, giving a total MW of 2955. Peptides A and B are present in EOM613 in approximately equal amounts (by weight). The amounts of peptides A and B in EOM613, as determined by the Lowry protein assay, are approximately 4.4–7.0 mg / mL, preferably 4.8–5.3 mg / mL.

[0049] In general, EOM613 is prepared according to the following method: Casein, beef peptone, RNA, BSA, and sodium hydroxide are suspended in a suitable volume of distilled water in the following proportions by weight: about 35-50% casein, about 15-40% beef peptone, about 10-25% RNA, about 1-10% BSA, and about 5-25% sodium hydroxide. Any RNA source can be used (e.g., plant RNA or yeast RNA). In some embodiments, yeast RNA is used as the RNA source for producing the EOM613 composition. The ratio of total protein to volume of distilled water is about 1.5-2.5 to about 100 by weight, preferably about 2.2 to about 100 by weight. Thus, 1.5-2.5 grams of total protein are suspended in about 100 milliliters of distilled water. Any suitable source can be used to obtain the starting materials. The above starting materials are commercially available or can be easily prepared by those skilled in the art.

[0050] The suspension prepared as described above is then autoclaved for approximately 2 to 10 hours, typically longer than 3 hours, at a pressure of approximately 5 to 15 pounds / square inch (e.g., 8 to 10 pounds / square inch) and a high temperature in the range of approximately 150° to 300°F (e.g., approximately 200° to 230°F). As is known to those skilled in the art, under such conditions, RNA can be completely hydrolyzed to nucleotides. After autoclaving, the solution is cooled to room temperature and then allowed to stand at a temperature of 3°C to 8°C for at least 12 hours to precipitate the insoluble elements. Alternatively, the cooled solution can be centrifuged at a temperature below 8°C to remove the insoluble elements.

[0051] Next, the obtained solution is filtered through 2-micron and 0.45-micron filters under an inert gas (e.g., nitrogen or argon) at a pressure of about 1–6 psi. In a similar manner, the solution is filtered again through an exothermic material retaining filter (e.g., an exothermic material retaining filter of about 0.2 microns). After filtration, the solution may be cooled again at 3–8°C for at least about 12 hours, if necessary, and filtered again in the same manner as described above.

[0052] Next, the obtained filtrate is assayed for total nitrogen content using any suitable method (e.g., the Kjeldahl method (see Kjeldahl, Z. Anal. Chem., Vol. 22, p366, 1883) and related methods based on the Kjeldahl method). Based on the above assay, the filtrate is then diluted with cooled distilled water to a suitable volume having a preferred total nitrogen content in the range of approximately 165 to approximately 210 mg / ml. The pH of the diluted solution is then adjusted with HCl to a physiological pH of approximately 7.3 to approximately 7.6, and the diluted solution is then filtered again through a 0.2 micron filter under an inert gas as described above. The final filtrate has an absorption spectrum with typical absorptivity of 2.0 (±10%) at 260 nm / 280 nm and 1.4 (±10%) at 260 nm / 230 nm.

[0053] The use of filtration discussed above is for removing bacteria or other particles of similar or larger size than bacteria. Any filter can be used in the production of EOM613, regardless of its manufacturer or the materials from which it is made suitable for this purpose.

[0054] Next, the final filtrate is filled into appropriate vials (e.g., 2 ml or 10 ml glass vials) under inert gas and sealed. After the filled vials are autoclaved for final sterilization, they are ready for use. Unless otherwise specified, the final filtrate is at a concentration of EOM613 suitable for administration to a subject. Thus, after following the steps outlined, the EOM613 composition is ready for administration to a subject.

[0055] III. Procedures using EOM613 A method for treating certain diseases and conditions by administering a therapeutically effective amount of EOM613 to subjects in need is provided herein.

[0056] In some embodiments, a therapeutically effective amount of EOM613 is administered to a subject to inhibit or treat SARS-CoV-2 infection in the subject. Administration of a therapeutically effective amount of EOM613 to a subject reduces and / or eliminates one or more symptoms of SARS-CoV-2 infection in the subject.

[0057] In some embodiments, subjects who have or are at risk of SARS-CoV-2 infection are selected for treatment with EOM613. In some embodiments, subjects selected for treatment have COVID-19. In some embodiments, subjects selected for treatment have SARS-CoV-2 infection and one or more of the following underlying medical conditions: heart disease, cancer, chronic obstructive pulmonary disease, type 2 diabetes, type 1 diabetes, obesity, chronic kidney disease, sickle cell disease, asthma, liver disease, chronic lung disease, hypertension, or an immune system suppressed due to medical treatment, infection by a pathogen other than SARS-CoV-2, or autoimmune disorder. The subjects may be of any age (e.g., at least 75 years).

[0058] Subjects infected with SARS-CoV-2 may exhibit symptoms ranging from mild to severe, or may be asymptomatic at all. In one example, the selected subject may not have any apparent symptoms of SARS-CoV-2 infection, and treatment with EOM613 may be prophylactic to prevent further development of the disease or symptoms. In other examples, the selected subject may have one or more symptoms of SARS-CoV-2 infection, and treatment with EOM613 may be therapeutic. Symptoms of SARS-CoV-2 infection include, but are not limited to, fever, cough, fatigue, respiratory distress, loss of taste or smell, muscle pain, chills, sore throat, runny nose, headache, chest pain, conjunctivitis, hypoxia, myocarditis, kidney disease, blood clotting, encephalitis, pneumonia, marked weakness, cytokine storm syndrome, and multisystem inflammatory syndrome. In a specific example, the selected subject has one or more of the following symptoms of SARS-CoV-2 infection: respiratory distress, hypoxia, myocarditis, renal disease, blood coagulation, encephalitis, pneumonia, marked weakness, cytokine storm syndrome, and multisystem inflammatory syndrome. In a preferred embodiment, the selected subject has cytokine storm syndrome or multisystem inflammatory syndrome.

[0059] Treatment with EOM613 reduces one or more of the symptoms of SARS-CoV-2 infection. The symptoms of SARS-CoV-2 infection do not need to be eliminated for the method to be effective. For example, the method can reduce one or more of the symptoms of SARS-CoV-2 infection by at least 10%, at least 20%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or even at least 100% (elimination of symptoms) compared to an appropriate control.

[0060] In some embodiments, the method results in a reduction of pneumonia in the subject. In some embodiments, the method results in a reduction of IL-6 levels in the subject to within the normal range. In some embodiments, the method results in an increase in lung function in the subject (e.g., an increase in airflow, maximum expiratory flow rate (PEFR), forced expiratory volume per second (FEV1), and maximum intermediate expiratory flow rate (MMEFR)). In some embodiments, the method results in an increase in blood oxygen saturation levels in the subject.

[0061] In some embodiments, the subject has elevated levels of one or more of the following: D-dimer, troponin (e.g., troponin-I, troponin-T, and troponin-C), C-reactive protein, procalcitonin, and cytokines (e.g., interleukin-6 (IL-6), interleukin-12 (IL-12), interleukin-10 (IL-10), interleukin-2 (IL-2), tumor necrosis factor α (TNF-α), or interferon-γ (INF-γ)). In some examples, the troponin is troponin-I. In some examples, the cytokine is one or more of the following: interleukin (e.g., interleukin-6 (IL-6), interleukin-12 (IL-12), interleukin-10 (IL-10), and interleukin-2 (IL-2)). In some embodiments, the above method results in a reduction of one or more elevated levels of D-dimer, troponin (e.g., troponin-I), C-reactive protein, procalcitonin, and cytokines (e.g., IL-6). D-dimer, troponin, C-reactive protein, procalcitonin, or cytokines are measured from a sample obtained from a patient (e.g., tissue or body fluid). In some examples, D-dimer, troponin, C-reactive protein, procalcitonin, or cytokines are measured from a blood sample derived from the subject. The blood sample may be whole blood or a blood derivative (e.g., plasma or serum).

[0062] In some embodiments, administration of EOM613 reduces one or more levels of D-dimer, troponins (e.g., troponin-I, troponin-T, and troponin-C), C-reactive proteins, procalcitonin, or cytokines (e.g., interleukin-6 (IL-6), interleukin-12 (IL-12), interleukin-10 (IL-10), interleukin-2 (IL-2), tumor necrosis factor α (TNF-α), or interferon-γ (INF-γ)) in the subject. For example, the above method may reduce the above levels by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or even at least 100% compared to a suitable control (e.g., pre-treatment levels). In some cases, the troponin is troponin-I. In some cases, the cytokine is one or more of the interleukins, such as interleukin-6 (IL-6), interleukin-12 (IL-12), interleukin-10 (IL-10), or interleukin-2 (IL-2). In some cases, the step of administering the therapeutically effective amount of EOM613 to the subject reduces the levels of one or more of the D-dimer, troponin, C-reactive protein, procalcitonin, or cytokine levels to undetectable or normal levels.

[0063] D-dimer, troponin (e.g., troponin-I, troponin-T, and troponin-C), C-reactive protein, procalcitonin, or cytokine (e.g., interleukin-6 (IL-6), interleukin-12 (IL-12), interleukin-10 (IL-10), interleukin-2 (IL-2), tumor necrosis factor α (TNF-α), or interferon-γ (INF-γ)) levels may be measured and / or compared periodically throughout the course of treatment, for example, daily, every other day, every three days, once a week, or once a month. In some cases, D-dimer, troponin, C-reactive protein, procalcitonin, or cytokine levels are measured before treatment and / or around day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 13, day 14, day 15, day 16, day 17, day 18, day 19, day 20, day 24, day 26, day 28, day 30, day 35, day 40, day 45, day 50, day 55, day 60, or any combination thereof. In some cases, D-dimer, troponin, C-reactive protein, procalcitonin, or cytokine levels are measured before treatment (or early in treatment, e.g., around day 1) and compared to their respective levels one day or more after EOM613 treatment, e.g., around day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 12, day 14, day 16, day 18, day 20, day 24, day 28, day 30, day 35, day 40, day 45, day 50, day 55, day 60 or later.In some cases, D-dimer, troponin, C-reactive protein, procalcitonin, or cytokine levels are measured in subjects before (or early in the treatment, e.g., around day 1) EOM613 treatment and compared to their respective levels after completion of EOM613 treatment.

[0064] In some embodiments, the method results in elevated D-dimer levels, troponin (e.g., troponin-I, troponin-T, or troponin-C) levels, C-reactive protein levels, procalcitonin, and IL-6 levels, as well as a reduction in one or more of these levels, and an increase in oxygenation levels (e.g., an increased SpO2 measurement), compared to before treatment with a therapeutically effective amount of EOM613. In some embodiments, the method results in elevated D-dimer levels, troponin levels, C-reactive protein levels, and IL-6 levels, as well as a reduction in oxygenation levels (e.g., an increased SpO2 measurement), compared to before treatment with a therapeutically effective amount of EOM613. In some embodiments, the method results in an increased lymphocyte count in the subject compared to before treatment with a therapeutically effective amount of EOM613.

[0065] In some embodiments, the subject is diagnosed with or suspected to have COVID-19. The severity of COVID-19 may be categorized using the World Health Organization (WHO) Clinical Order of Improvement Scale. In some examples, the subject has a score of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, or at least 7 on the WHO Clinical Order of Improvement Scale before initiating treatment with EOM613. In some examples, the subject has a score of approximately 1–approximately 7, approximately 1–approximately 6, approximately 1–approximately 5, approximately 1–approximately 4, approximately 1–approximately 3, approximately 1–approximately 2, approximately 2–approximately 7, approximately 3–approximately 7, approximately 4–approximately 7, approximately 5–approximately 7, approximately 6–approximately 7, approximately 2–approximately 6, approximately 2–approximately 5, approximately 2–approximately 4, approximately 2–approximately 3, approximately 3–approximately 6, approximately 3–approximately 5, approximately 3–approximately 4, approximately 4–approximately 6, approximately 4–approximately 5, or approximately 5–approximately 6 before initiating treatment with EOM613. In some cases, the subject has a score of 4 or higher on the WHO Clinical Order of Improvement Scale before initiating the treatment. In some cases, the subject has a score of 5 or higher on the WHO Clinical Order of Improvement Scale before initiating the treatment. In some cases, the subject has a score of 6 or higher on the WHO Clinical Order of Improvement Scale before initiating the treatment. In some cases, the EOM613 treatment reduces the subject's score on the WHO Clinical Order of Improvement Scale, for example, by at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, or at least 7. In some cases, the EOM613 treatment reduces the subject's score on the WHO Clinical Order of Improvement Scale to less than 4, for example, by at least 0, 1, 2, or 3.

[0066] In some embodiments, administration of EOM613 is effective in inhibiting SARS-CoV-2-induced cytokine storm syndrome. In some embodiments, the treatment reduces or maintains cytokine production or accumulation in the subject to, for example, normal levels. In some embodiments, EOM613 is administered as a prophylactic measure in an amount effective in inhibiting the development of cytokine storm syndrome induced by SARS-CoV-2 infection. Inhibiting the development of cytokine storm syndrome in the subject does not require complete inhibition, but rather may instead be a partial inhibition or reduction of the symptoms associated with cytokine storm syndrome.

[0067] In some embodiments, administration of EOM613 is effective in inhibiting SARS-CoV-2-induced multisystem inflammatory syndrome. In some such embodiments, the amount of EOM613 administered to the subject is effective in reducing organ inflammation or damage in the subject caused by multisystem inflammatory syndrome. In specific, non-limiting examples, the reduced organ damage is reduced damage to the heart, kidneys, and / or lungs. In some embodiments, the subject to be administered EOM613 in an amount effective in inhibiting SARS-CoV-2-induced multisystem inflammatory syndrome or reducing organ damage or inflammation is a child (e.g., a child aged 5 years or younger).

[0068] In some embodiments, administration of EOM613 is effective in inhibiting SARS-CoV-2 induced Kawasaki disease. In some such embodiments, the amount of EOM613 administered to the subject is effective in reducing cardiac damage in the subject caused by Kawasaki disease. In some embodiments, EOM613 is administered as a prophylactic measure in an amount effective in inhibiting the development of SARS-CoV-2 infection-induced Kawasaki disease.

[0069] In some embodiments, a therapeutically effective amount of EOM613 is administered to the subject to inhibit or treat cytokine storm syndrome in the subject. Administration of a therapeutically effective amount of EOM613 to the subject reduces and / or eliminates one or more symptoms of cytokine storm syndrome in the subject. In some embodiments, subjects who have or are at risk of cytokine storm syndrome are selected for treatment with EOM613.

[0070] Treatment with EOM613 reduces one or more of the symptoms of cytokine storm syndrome. The symptoms of cytokine storm syndrome do not need to be eliminated for the method to be effective. For example, the method may reduce one or more of the symptoms of cytokine storm syndrome by at least 10%, at least 20%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or even at least 100% (elimination of symptoms) compared to a suitable control. In some embodiments, treatment of a subject with cytokine storm syndrome with a therapeutically effective amount of EOM613 results in a reduction of one or more of elevated D-dimer levels, troponin (e.g., troponin-I, troponin-T, and troponin-C) levels, C-reactive protein levels, and IL-6 levels, as well as an increase in oxygenation levels (e.g., increased SpO2 measurements), compared to before treatment with a therapeutically effective amount of EOM613.

[0071] In some embodiments, a therapeutically effective amount of EOM613 is administered to the subject to inhibit or treat multisystem inflammatory syndrome in the subject. Administration of a therapeutically effective amount of EOM613 to the subject reduces and / or eliminates one or more symptoms of multisystem inflammatory syndrome in the subject. In some embodiments, subjects who have or are at risk of having multisystem inflammatory syndrome are selected for treatment with EOM613.

[0072] Treatment with EOM613 reduces one or more of the symptoms of multisystem inflammatory syndrome. The symptoms of multisystem inflammatory syndrome do not need to be eliminated for the above method to be effective. For example, the above method can reduce one or more of the symptoms of multisystem inflammatory syndrome by at least 10%, at least 20%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or even at least 100% (elimination of symptoms) compared to an appropriate control. In some embodiments, treatment of subjects with multisystem inflammatory syndrome with a therapeutically effective dose of EOM613 results in the resolution of leukocytosis or lymphopenia, increased band neutrophils, and a reduction in elevated plasma levels of liver enzymes (e.g., aspartate aminotransferase (AST) and alanine aminotransferase (ALT)), erythrocyte sedimentation rate (ESR), ferritin, C-reactive protein (CRP), and / or interleukin-6 (IL-6). In some embodiments, treatment of subjects with multisystem inflammatory syndrome with a therapeutically effective dose of EOM613 results in an increased lymphocyte count in the subjects compared to before treatment with a therapeutically effective dose of EOM613.

[0073] In some embodiments, a therapeutically effective amount of EOM613 is administered to the subject to inhibit or treat Kawasaki disease in the subject. Administration of a therapeutically effective amount of EOM613 to the subject reduces and / or eliminates one or more symptoms of Kawasaki disease in the subject. In some embodiments, subjects with or at risk of having multisystem inflammatory syndrome are selected for treatment with EOM613.

[0074] Treatment with EOM613 reduces one or more of the symptoms of Kawasaki disease. The symptoms of Kawasaki disease do not need to be eliminated for the method to be effective. For example, the method may reduce one or more of the symptoms of Kawasaki disease by at least 10%, at least 20%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or even at least 100% (elimination of symptoms) compared to an appropriate control. In some embodiments, treatment of subjects with Kawasaki disease with a therapeutically effective dose of EOM613 results in a reduction of rash, erythema, and lip swelling, resolution of leukocytosis or lymphopenia, an increased band of neutrophils, and a reduction in elevated plasma levels of liver enzymes (e.g., aspartate aminotransferase (AST) and alanine aminotransferase (ALT)), erythrocyte sedimentation rate (ESR), ferritin, C-reactive protein (CRP), and / or interleukin-6 (IL-6). In some embodiments, treatment of subjects with Kawasaki disease with a therapeutically effective dose of EOM613 results in an increased lymphocyte count in the subjects compared to before treatment with a therapeutically effective dose of EOM613. In some embodiments, treatment of subjects with Kawasaki disease with a therapeutically effective dose of EOM613 results in resolution of lymphopenia.

[0075] In some embodiments, a therapeutically effective amount of EOM613 is administered to the subject to inhibit or treat lymphopenia in the subject. Administration of a therapeutically effective amount of EOM613 to the subject results in an increase in lymphocyte count toward normal levels. Lymphocyte count is often measured as a percentage of white blood cells in the subject. The normal range for lymphocytes is 20-40% of white blood cells. In some embodiments, treatment of a subject with lymphopenia (e.g., a subject with a lymphocyte percentage of less than 10%) results in an increase in lymphocyte percentage toward the normal lymphocyte percentage range of 20-40%. In some embodiments, subjects with or at risk of lymphopenia are selected for treatment with EOM613.

[0076] The dose of EOM613 administered to the subject in the method provided herein may vary depending on a number of factors, including the amount and timing of administration, the subject being treated, the severity and type of the condition being treated, and the mode of administration. Generally, an appropriate dose is used that is sufficient to alleviate the symptoms of the disease without causing undesirable side effects. In some embodiments, about 0.5 microliters to about 100 microliters (e.g., about 2.5 microliters to about 40 microliters, or about 10 microliters to about 25 microliters) of EOM613 / kilogram body weight / day is administered to the subject. In some embodiments, about 1 to 2 mL (e.g., 1 mL or 2 mL) of EOM613 is administered to the subject per day. The desired dose may be administered once daily, or in two, three, or more partial doses at appropriate intervals (generally evenly distributed throughout the day in hourly increments). In some embodiments, EOM613 is administered over a period of approximately 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 14 days, 16 days, 18 days, 20 days, 22 days, 24 days, 28 days, or longer. In some embodiments, approximately 1 to 2 ml (e.g., 1 or 2 ml) of EOM613 is administered to the subject twice a day. In some embodiments, approximately 2 ml of EOM613 is administered to the subject twice a day for 2 days, followed by approximately 1 ml of EOM613 being administered to the subject twice a day for 8 days. In some embodiments, approximately 2 ml of EOM613 is administered to the subject twice a day for 3 days, followed by approximately 1 ml of EOM613 being administered to the subject twice a day for 7 days. In some embodiments, approximately 2 ml of EOM613 is administered to the subject twice a day for 2 days, followed by approximately 2 ml of EOM613 being administered once a day for 3 days. In some examples, approximately 1 to 2 ml of EOM613 is administered for 2 to 5 days, followed by approximately 1 to 2 ml of EOM613 being administered once a day for a further 2 to 5 days.In a specific, non-limiting example, 2 mL of EOM613 is administered twice daily for 5 days, followed by once daily for another 5 days. In another non-limiting example, 2 mL of EOM613 is administered once daily for 10 days.

[0077] In some embodiments, a therapeutically effective amount of EOM613 is administered orally, parenterally, topically, intranasally, by inhalation, or systemically. Parenteral administration includes techniques such as subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, intrapleural injection, intrasternal injection, or infusion. In non-limiting examples, a therapeutically effective amount of EOM613 is administered parenterally by subcutaneous injection. In some embodiments, EOM613 is administered directly to the lungs, for example, by inhalation or via an endotracheal tube. By example, one method of administration to the lungs is by inhalation via the use of a nebulizer or inhaler. For example, EOM613 may be formulated as an aerosol or particulate matter and drawn into the lungs using a standard nebulizer. The preferred route of administration may vary, for example, depending on the recipient's condition and age.

[0078] In some embodiments, including administration by inhalation, EOM613 is conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable atomizer (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas). In the case of a pressurized aerosol, the dose unit may be determined by providing a valve for delivering a measured amount. Capsules and cartridges for use in inhalers or injectors may be formulated to contain EOM613 and, if necessary, any suitable additives.

[0079] In some embodiments of the methods provided herein, at least one further therapeutic agent is administered to the subject (e.g., an antiviral agent, an antibacterial agent, an antiparasitic agent, or an anti-inflammatory agent). In non-limiting examples, the further agents are remdesivir, hydroxychloroquine, azithromycin, dexamethasone, chloroquine phosphate, ivermectin, α-interferon (e.g., interferon α2b), β-interferon, γ-interferon, λ-interferon, ritonavir, arabinol, or an antitumor necrosis factor (TNF)-α antibody (e.g., adalimumab).

[0080] In some embodiments, in addition to EOM613, oxygen is administered to the subject using a small amount of continuous positive airway pressure ("CPAP"). Furthermore, intravenous fluids may be administered to stabilize blood glucose, blood salinity, and blood pressure.

[0081] IV. Pharmaceutical preparations containing EOM613 EOM613 may be administered alone or as part of a pharmaceutical formulation. It may also be administered almost simultaneously with one or more other pharmaceuticals administered independently to the subject. When EOM613 is administered as part of a pharmaceutical formulation, the formulation of the present invention comprises at least one administered component (i.e., EOM613) together with one or more pharmaceutically acceptable carriers and, optionally, one or more further pharmaceuticals. The carriers must be pharmaceutically acceptable in the sense that they are compatible with the other components of the formulation and are not harmful to the recipient (e.g., suitable for use in vivo in the subject).

[0082] EOM613 in pharmaceutical formulations is sterile. Pharmaceutical formulations may be presented in unit dose or multi-dose containers (e.g., sealed ampoules and vials). Preferred unit-dose formulations include a daily dose or unit, a daily partial dose, or an appropriate proportion of the component to be administered.

[0083] Pharmaceutical formulations of EOM613 may be in the form of a lyophilized solid for reconstitution in saline solution, liquid, or gas (aerosol). Pharmaceutical formulations containing EOM613 may be formulated to enable EOM613 or other compounds to become bioavailable when the pharmaceutical composition is administered to a subject. Pharmaceutical formulations may take the form of one or more dose units. For example, a container of EOM613 in aerosol form may hold multiple dose units. Syringes containing unit doses of EOM613 are also provided.

[0084] With regard to oral administration, the above-mentioned pharmaceutical formulations may be in liquid form, for example, in the form of a liquid, syrup, or suspension, or may be presented as a drug product to be reconstituted with water or another suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable excipients (e.g., suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats); emulsifiers (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid). The above pharmaceutical preparations may take the form of tablets or capsules, for example, prepared by conventional means with pharmaceutically acceptable excipients (e.g., binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate)). The above tablets may be coated by methods well known in the art.

[0085] Preparations for oral administration can be appropriately formulated to provide a controlled release of the active compound. For oral administration, the above compositions may take the form of tablets or lozenges formulated in a conventional manner.

[0086] For administration by inhalation, the pharmaceutical formulation is delivered in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable atomizer (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas). In the case of pressurized aerosols, the dose unit may be determined by providing a valve for delivering a measured amount. Capsules and cartridges for use in inhalers or injectors may be formulated to include a powder mixture of EOM613 and a suitable powder base (e.g., lactose or starch).

[0087] Pharmaceutical preparations may be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Preparations for injection may be presented in unit dose forms, for example, in ampoules or in multi-dose containers (with preservatives added). The preparations may take the form of suspensions, liquids or emulsions in oily or aqueous vehicles and may contain formulation agents such as suspending agents, stabilizers and / or dispersants. Alternatively, the active ingredients may be in powder form for preparation in a suitable vehicle (e.g., sterile, pyrogen-free water) before use.

[0088] The above-mentioned pharmaceutical preparations may be formulated in the form of creams, lotions, gels, eye drops, ointments, solutions, suspensions, shampoos, or other forms known to those skilled in the art, such as those described, for example, in Remington's Pharmaceutical Sciences, 16th and 18th editions, Mack Publishing, Easton Pa. (1980 & 1990), and Introduction to Pharmaceutical Dosage Forms, 4th edition, Lea & Febiger, Philadelphia (1985). Practical methods for preparing pharmaceutical compositions are known or obvious to those skilled in the art and are described in detail, for example, in Remington's Pharmaceutical Sciences, 16th and 18th editions, Mack Publishing, Easton Pa. (1980 & 1990).

[0089] In addition to the previously described pharmaceutical formulations, EOM613 can also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. In such cases, the compound may be formulated with a suitable polymer or hydrophobic substance (e.g., as an emulsion in an acceptable oil) or an ion-exchange resin, or as a sparingly soluble derivative, for example, as a sparingly soluble salt. Liposomes and emulsions are well-known examples of delivery vehicles or carriers for hydrophilic drugs. [Examples]

[0090] Examples The following embodiments are provided to illustrate certain features of a particular embodiment, but the claims should not be limited to those illustrated features.

[0091] Example 1 Generation of EOM613 This embodiment illustrates one example of a process for producing EOM613.

[0092] In approximately 2.5 liters of sterile water for injection (USP), suspend approximately 35.0 g of casein, approximately 17.1 g of beef peptone, approximately 22.0 g of nucleic acid (yeast RNA), and approximately 3.25 g of bovine serum albumin in a suitable container at approximately 3–7°C, and gently stir until all components are properly wetted. Carefully add approximately 16.5 g of sodium hydroxide (reagent grade ACS) while stirring, and continue stirring until the sodium hydroxide is completely dissolved. Autoclave at approximately 9 lbs pressure and 200–230°F for a period of approximately 4 hours, for example, until the RNA is completely digested. At the end of this period, stop the autoclave and allow the reaction flask and its contents to cool slowly to ambient temperature. Then, cool at approximately 3–8°C for at least 6 hours.

[0093] The obtained solution is filtered at low pressure (1-6 psi) using an inert gas (e.g., nitrogen or argon) through 2 micron and 0.45 micron filters. In a similar manner, the solution is filtered again through a 0.2 micron exothermic filter. The obtained filtrate is sampled and assayed for total nitrogen. Calculations are then performed to determine the amount of cooling water for injection to be added to the filtrate to obtain a diluted filtrate with a nitrogen content between approximately 165-210 mg / 100 ml; the final volume is approximately 5 liters. The pH is then adjusted to a range of approximately 7.3-7.6 with either concentrated HCl (reagent grade ACS) or 1.0 N NaOH. The diluted solution is then filtered again at low pressure using an inert gas through a 0.2 micron filter. The final filtrate is then filled into 2 ml glass ampoules and sealed while in an inert gas atmosphere. The ampoules are collected and autoclaved for approximately 30 minutes at 240°F and 14-16 lbs pressure for final sterilization. After the sterilization cycle, the ampoules containing EOM613 are cooled and washed.

[0094] All quantities are subject to a ±15% variation in terms of pH, volume, and analytical adjustments.

[0095] Example 2 Treatment of SARS-CoV-2 infection in EOM613 This embodiment provides a treatment protocol for patients with SARS-CoV-2 infection using the EOM613 composition described in Example 1.

[0096] Patients with SARS-CoV-2 infection are selected for treatment. These patients may have active SARS-CoV-2 infection, either asymptomatic (as a prophylactic measure against the development of severe symptoms) or symptomatic, including severe symptoms (e.g., myocardial disease, renal dysfunction, coagulation disorders, encephalitis, severe fatigue, or multisystem inflammatory syndrome). These patients are administered 2 ml of EOM613 subcutaneously twice daily for 3 days, followed by 1 ml of EOM613 subcutaneously twice daily for 7 days.

[0097] Typically, patients are evaluated before and during the treatment period. Physical examination includes consciousness, orientation to time and place, body temperature, pulse, blood pressure, heart rate, EKG, respiratory rate, and chest X-ray. Clinical laboratory data to be collected include CBC, CRP, ESR, procalcitonin, SMA-18, troponin, natriuretic peptide, blood gases, and urinalysis. If the patient does not respond to the treatment protocol for the first 10 days, the treatment may be repeated.

[0098] Example 3 Management of severe SARS-CoV-2 infection in EOM613 A 91-year-old male subject with anemia tested positive for SARS-CoV-2 infection by RT-PCR. The subject presented with fever, general malaise and weakness, as well as clear clinical signs of pulmonary discomfort and pulmonary congestion. The subject was completely bedridden, emaciated, immobile, unable to move even in bed on his own, and required assistance from others. The subject had an oxygenated SpO2 percentage level in the 80 percent range and required oxygen supplementation. A lung ultrasound performed 10 days after the initial onset of symptoms revealed severe pulmonary congestion. Twelve days after the presentation of the initial signs, initial blood test data was obtained and used as a starting point for further analysis after EOM treatment. Two days after the initial blood test data, treatment with EOM613 was initiated, and the patient's progression was followed for a further 24 days following the initiation of treatment.

[0099] Regarding treatment, the subject received a 2 mL dose administered subcutaneously twice daily for the first two days, and then a 2 mL dose administered subcutaneously once daily for a further three days. The subject did not receive any antiviral agents, immunomodulators, or corticosteroid treatments simultaneously; he reduced his fever only by taking over-the-counter antipyretics.

[0100] The day after the start of EOM613 treatment, the patient opened his eyes for the first time. By the second day, he was able to turn over in bed on his own without assistance. It was also noted that the subject's pulmonary congestion had resolved. By the fourth day after the start of EOM613 treatment, the subject's pulmonary symptoms had resolved, he was able to walk, and his fever had lessened or disappeared. By the 15th day, the patient was well enough to get out of bed and walk on his own and go to the toilet independently without assistance.

[0101] The plasma IL-6 level of the subject, which rose to 216.1 ng / L on day 2 after the start of treatment, decreased to 110.3 ng / L by day 4, then to 71.3 ng / L by day 7, then to 25.7 ng / L on day 12, and further to 11 ng / L on day 24 (Figure 1). The decrease in plasma IL-6 levels observed with EOM613 treatment was consistent with and coincided with the resolution of observed inflammation and pulmonary symptoms of COVID-19 infection.

[0102] Improvement in COVID-19-related lymphopenia in the above subject was also observed with EOM613 treatment (Figure 2). Two days after the start of treatment, the subject showed a very low lymphocyte count of 7.5% in his differential blood cell count; seven days after the start of treatment, the number increased to 13.1%. By day 12, the subject's lymphocyte percentage had risen to 17.1%, and by day 24, it had rebounded further to 23.7%. Plasma C-reactive protein (CRP) levels also decreased from a high of 260.1 ng / L at day 12 after the start of treatment to 73.3 ng / L, and then further decreased to 13 ng / L at day 24 after the start of EOM613 treatment (Figure 3). The above subjects progressed from an SpO2 percentage oxygenation level of around 80% on day 1, requiring oxygen supplementation, to an SpO2 level exceeding 95% by day 24, allowing them to breathe on their own.

[0103] Example 4 Treatment of severe SARS-CoV-2 infection in obese patients with EOM613 A 31-year-old male patient with comorbid obesity was admitted to the hospital with severe symptoms of COVID-19 infection confirmed by RT-PCR testing. He presented with fever, dyspnea, respiratory distress, body aches, and recent loss of taste and smell. He was admitted to the ICU, rapidly progressed to a state requiring mechanical ventilation, and scored 6 on the WHO Clinical Order of Improvement Scale. For reference, the 8-point WHO Clinical Order of Improvement Scale is provided in Table 2 below. At this point, the patient initiated treatment with EOM613 over a 10-day period, receiving 2 mL twice daily for the first 5 days and 2 mL once daily for the remaining 5 days. Table 1 shows the patient's improvement record. [Table 1] [Table 2]

[0104] By day 2, the patient was able to be removed from mechanical ventilation, and their WHO score improved to 5, indicating the need for high-flow oxygen. At the time of evaluation, the patient showed further improvement to a WHO score of 4 on day 5, and to a score of 3 by day 11 (although hospitalized, they did not require oxygen supplementation). The patient was discharged on day 16. At follow-up on day 28, the patient was completely disease-free, assigned a WHO score of 0, and returned to normal activities.

[0105] Biochemical parameters measured on days 1, 2, 5, 8, and 11, in accordance with the progress of EOM613 treatment, showed that C-reactive protein (CRP) transiently increased to a high of 155 mg / mL on day 2, but then steadily decreased throughout the treatment period, falling to 16.8 mg / mL by day 11. Simultaneously, elevated troponin-I levels decreased from a high of 71 ng / mL on day 1 to 5 ng / mL on day 8 and 6.5 ng / mL on day 11 as the treatment progressed. Procalcitonin serum levels decreased from 0.110 ng / mL to 0.05 ng / mL on day 8 and thereafter, which was within the normal range. EOM613 also resulted in a decrease in pro-inflammatory CRP throughout the course of treatment after the initial transient increase in this patient. It also resulted in a therapeutically positive, stable decrease in procalcitonin and troponin-I (these elevations are considered prognostic biomarkers for disease progression and worsening prognostic outcomes in COVID-19 patients).

[0106] Example 5 Treatment of SARS-CoV-2 infection in asthma patients with EOM613 A 31-year-old female patient with a history of severe bronchial asthma presented with symptoms of COVID-19, including cough, fever and chills, shortness of breath, and recent loss of smell and taste. She required oxygen supplementation and was assigned a WHO Clinical Improvement Order Scale 4 upon admission (see Table 2). She presented with normal troponin-I levels but elevated D-dimer levels of 4.5 mg / mL (normal is <0.5 mg / mL). She initiated treatment with EOM613 administered subcutaneously at a dose of 2 mL once daily for 10 days. On day 2, her WHO score improved to 3, and by day 5, it had improved to 1. The patient was discharged from the hospital with a disease-free outcome and was free of activity restrictions by day 4.

[0107] The patient had elevated D-dimer levels upon admission, and this biomarker was monitored through blood tests. On day 2, her D-dimer level was read at 1.81 mg / mL, but by day 5, it had further decreased to 1.35 mg / mL.

[0108] It is clear that the exact details of the described methods or compositions may be varied or modified without departing from the spirit of the described embodiments. The inventors claim all such modifications and variations that fall within the scope and spirit of the following claims.

Claims

1. A composition for use in a method of treating a subject having a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, comprising EOM613, wherein the method comprises the step of administering the composition to the subject in a therapeutically effective amount of EOM613, the subject having a score of 5 or higher on the World Health Organization (WHO) Clinical Improvement Order Scale prior to the commencement of treatment.

2. The composition according to claim 1, wherein the method further comprises the step of selecting the subject having the SARS-CoV-2 infection for treatment.

3. The composition according to claim 1 or 2, wherein the subject has or is at risk of having coronavirus disease 2019 (COVID-19).

4. The composition according to any one of claims 1 to 3, wherein the step of treating the subject reduces at least one of the following symptoms of SARS-CoV-2 infection: respiratory distress, pneumonia, hypoxia, myocarditis, renal disease, blood coagulation, encephalitis, pneumonia, marked weakness, lymphopenia, cytokine storm syndrome, and multisystem inflammatory syndrome.

5. The composition according to any one of claims 1 to 4, wherein the method comprises the step of administering to the subject an amount of EOM613 effective in inhibiting SARS-CoV-2-induced multisystem inflammatory syndrome.

6. The composition according to claim 5, wherein the step of inhibiting SARS-CoV-2-induced multisystem inflammatory syndrome reduces organ damage to the heart, kidneys, and / or lungs.

7. The composition according to claim 5 or claim 6, wherein the subject is a child.

8. The subject has one or more of the following underlying medical conditions: heart disease, cancer, chronic obstructive pulmonary disease, type 2 diabetes, type 1 diabetes, obesity, chronic kidney disease, sickle cell disease, asthma, liver disease, chronic lung disease, hypertension, or an immune system suppressed due to medical treatment, infection by a pathogen other than SARS-CoV-2, or an autoimmune disorder, according to any one of claims 1 to 7.

9. The composition according to any one of claims 1 to 8, wherein the subject is a human.

10. The composition according to any one of claims 1 to 6 and 8 to 9, wherein the subject is at least 75 years old.

11. The composition according to any one of claims 1 to 10, wherein the subject has lymphopenia caused by SARS-CoV-2 infection, and the step of administering the composition to the subject in a therapeutically effective amount of EOM613 increases the number of lymphocytes in the subject to a range of 20 to 40% of the number of white blood cells.

12. The composition according to any one of claims 1 to 11, wherein the subject has elevated levels of one or more of D-dimer, troponin, C-reactive protein, procalcitonin, or cytokines, and the step of administering the composition to the subject in a therapeutically effective amount of EOM613 reduces the elevated levels to undetectable or normal levels.

13. The composition according to claim 12, wherein the subject has elevated levels of one or more of D-dimer, troponin-I, C-reactive protein, or procalcitonin.

14. The composition according to any one of claims 1 to 13, wherein the step of administering the composition to the subject in a therapeutically effective amount of EOM613 comprises the step of administering to the subject about 0.5 microliters to about 100 microliters of EOM613 / kilogram body weight / day.

15. The composition according to claim 14, wherein the step of administering the composition to the subject in a therapeutically effective amount of EOM613 comprises the step of administering to the subject about 2.5 microliters to about 40 microliters of EOM613 / kilogram body weight / day.

16. The composition according to claim 14, wherein the step of administering the composition to the subject in a therapeutically effective amount of EOM613 comprises the step of administering to the subject about 10 microliters to about 25 microliters of EOM613 / kilogram body weight / day.

17. The composition according to any one of claims 1 to 16, wherein the step of administering the composition to the subject in a therapeutically effective amount of EOM613 comprises the step of administering about 1 to about 2 ml of EOM613 to the subject twice a day.

18. The composition according to claim 17, wherein the step of administering the composition to the subject in a therapeutically effective amount of EOM613 comprises the step of administering about 2 ml of EOM613 to the subject twice a day for 2 to 5 days.

19. The composition according to claim 17 or 18, wherein the step of administering approximately 2 ml of EOM613 to the subject twice a day for 2 to 5 days is followed by the step of administering approximately 1 to approximately 2 ml of EOM613 to the subject once a day for a further 2 to 5 days.

20. The composition according to claim 17 or 18, wherein the step of administering the composition to the subject in a therapeutically effective amount of EOM613 comprises the steps of administering about 2 ml of EOM613 to the subject twice a day for 3 days, and then administering about 1 ml of EOM613 to the subject twice a day for 7 days.

21. The composition according to claim 17, wherein the step of administering the composition to the subject in a therapeutically effective amount of EOM613 comprises the step of administering about 2 ml of EOM613 to the subject once a day for about 10 days.

22. The composition according to any one of claims 1 to 21, characterized in that it is administered parenterally, topically, by inhalation, or systemically.

23. The composition according to claim 22, characterized in that it is administered by inhalation using a nebulizer or inhaler.

24. The composition according to claim 22, characterized in that it is administered parenterally by subcutaneous injection.

25. The composition according to any one of claims 1 to 24, characterized in that the composition is administered to the subject in combination with at least one further anti-COVID-19 agent.

26. The composition according to claim 25, wherein the anti-COVID-19 agent is an antiviral agent.

27. The composition according to any one of claims 1 to 26, wherein the subject has a score of 6 or higher on the WHO Clinical Improvement Sequence Scale before the commencement of treatment.

28. The composition according to claim 25, wherein the anti-COVID-19 agent is one or more of remdesivir, hydroxychloroquine, azithromycin, dexamethasone, chloroquine phosphate, ivermectin, α-interferon, β-interferon, γ-interferon, ritonavir, or arabinol.

29. The composition according to any one of claims 1 to 17 or 25 to 28, characterized in that approximately 1 ml to approximately 2 ml of EOM613 is administered parenterally to the subject by subcutaneous injection once or twice a day, wherein the subject has an elevated troponin level before treatment with EOM613, and the treatment with EOM613 reduces the troponin level to an undetectable level or a normal level.

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