WO2022024108A1

WO2022024108A1 - Ezrin peptide (hep-1) for use in the treatment of coronavirus disease

Info

Publication number: WO2022024108A1
Application number: PCT/IL2021/050891
Authority: WO
Inventors: Benjamin GESUNDHEIT
Original assignee: Rapo Yerape B.H. Ltd.
Priority date: 2020-07-28
Filing date: 2021-07-22
Publication date: 2022-02-03

Abstract

Disclosed are methods for treating infectious disease caused by coronavirus by using Ezrin peptides, derivatives or analogs thereof.

Description

EZRIN PEPTIDE (HEP-1) FOR USE IN THE TREATMENT OF CORONAVIRUS

DISEASE

Field of the Invention

[0001] Disclosed are methods for treating infectious diseases caused by various strains of coronavirus by using Ezrin peptides, derivatives or analogs thereof.

Background of the Invention

[0002] Coronaviruses are enveloped, positive-sense single-stranded RNA viruses having the largest genomes (26-32 kb) among known RNA viruses, and are phylogenetically divided into four genera (alpha, beta, gamma, delta), with betacoronaviruses further subdivided into four lineages (A, B, C, D). Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), where aerosol droplets is the main means of transmission.

[0003] The high hospitalization and case-fatality rate and high rate of transmissibility as well as shortage of effective prophylactic or therapeutic measures against coronaviruses, have created an urgent need for effective therapeutic agents.

[0004] Ezrin protein, also known as cytovillin or villin-2, is a protein encoded in humans by the EZR gene. Peptides derived from ezrin protein, having biological activity, are well-known. The closest analogue to the peptide used herein for treating COVID-19 is a pharmaceutical tetradecapeptide NH2-Thr-Glu-Lys-Lys-Arg-Arg-Glu-Thr-Val-Glu-Arg-Glu-Lys-Glu_COO- H (SEQ ID NO: 1), comprising 14 amino acid residues, which is known as HEP-1 peptide or human ezrin peptide one (SEQ ID NO.: 1; TEKKRRETVEREKE) and which was developed for the treatment of HIV-1 infection and, further, for the treatment of a wide range of bacterial, fungal, and viral infections.

[0005] US Patent No. 9,682,140 discloses variants of HEP-1, having the general formula XI- EKKRRETVERE- X2-X3 (SEQ ID NO.: 2), wherein each X represents a non-polar amino acid residue, and uses thereof as immunostimulatory agents, and specifically, for use in treating and preventing antiviral, antibacterial and antifungal infections, and treatment of diseases of the GI tract, in particular ulcerative disorders of the GI tract. Summary of The Invention

[0006] There are provided pharmaceutical compositions comprising Hep- 1 , derivatives or analogs thereof, for use in the treatment of infectious diseases and disorders associated with, or induced by COVID-19.

[0007] In addition, there is provided a treatment regimen for the treatment of infectious diseases and disorders associated with, or induced by, COVID-19 using Hep-1, comprising an induction phase comprising high daily doses of Hep-1 within the range of 1 to 5 mg/day, followed by a maintenance phase comprising low daily doses of Hep- 1 , wherein the low daily doses are lower by about one order of magnitude from the doses used in the preceding induction phase. The treatment regimen is concluded with a follow-up phase for monitoring patient's health for a few days.

[0008] Surprisingly, as further exemplified below, use of Hep-1 for the treatment of infectious diseases and disorders associated with, or induced by, COVID-19 is highly effective. Unexpectedly, the therapeutic effect of Hep-1 in the aforementioned treatment is expressed within 48 hours of treatment.

[0009] According to some embodiments, there is provided a method of treating infectious diseases caused by coronavirus, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising Hep- 1 and a carrier.

[0010] According to some embodiments, said administering comprises administering the pharmaceutical composition daily, for at least two days.

[0011] According to some embodiments, said administering comprises administering the pharmaceutical composition within 24 to 48 hours following diagnosis of the infectious disease.

[0012] According to some embodiments, said administering comprises administering the pharmaceutical composition to a subject having oxygen saturation levels less than 100% and more than 89%.

[0013] According to some embodiments, said infectious disease is associated with COVID-19. [0014] According to some embodiments, the daily concentration of Hep-1 is within the range of 0.05 to 5 mg.

[0015] According to some embodiments, the pharmaceutical composition is in a dosage form suitable for subcutaneous delivery. According to some embodiments, said administering comprises subcutaneous administration.

[0016] According to some embodiments, said administering comprises daily administration of the pharmaceutical composition, for at least two days, wherein each daily dose comprises Hep-1 within the range of 0.05 to 1 mg.

[0017] According to some embodiments, said administering comprises a treatment regimen comprising one or more days of induction phase comprising at least one daily administration of Hep-1 daily induction dose and one or more days of maintenance phase comprising at least one daily administration of Hep-1 daily maintenance dose, wherein the daily maintenance dose is lower than the daily induction dose and wherein the daily induction dose is within the range of 1 to 5 mg. According to some embodiments, the daily induction dose:daily maintenance dose ratio is within the range of 10:0.1 to 2:0.15.

[0018] According to some embodiments, the method further comprising a follow-up phase during which a plurality of physiological tests are carried out.

[0019] According to some embodiments, said subject in need thereof is a subject diagnosed with COVID-19.

[0020] According to some embodiments, the induction phase is at least one day shorter than the maintenance phase.

[0021] According to some embodiments, the maintenance phase initiates following attenuation in the infectious disease symptoms and/or markers.

[0022] According to some embodiments, there is provided a pharmaceutical composition comprising Hep-1 and a carrier for the treatment of infectious diseases caused by coronavirus.

[0023] According to some embodiments, the pharmaceutical composition is for daily use, for at least two days. [0024] According to some embodiments, the pharmaceutical composition is for daily use, within 24 to 48 hours following diagnosis of the infectious disease. According to some embodiments, said diagnosis comprises oxygen saturation levels <100% and >89%. According to some embodiments, said infectious disease is associated with COVID-19. According to some embodiments, the concentration of Hep-1 in the pharmaceutical composition is within the range of 0.05 to 5 mg. According to some embodiments, the pharmaceutical composition is in a dosage form suitable for subcutaneous delivery. According to some embodiments, the concentration of Hep- 1 in the pharmaceutical composition is within the range of 0.05 to 1 mg.

[0025] According to some embodiments, the pharmaceutical composition is for use in a treatment regimen comprising one or more days of induction phase comprising use of at least one Hep-1 daily induction dose, and one or more days of maintenance phase comprising at least one Hep-1 daily maintenance dose, wherein each maintenance dose is lower than the induction dose and wherein each daily induction dose is within the range of 1 to 5 mg. According to some embodiments, the induction phase is at least one day shorter than the maintenance phase. According to some embodiments, the treatment regimen further comprising a follow-up phase during which a plurality of physiological tests are carried out.

[0026] According to some embodiments, the daily induction dose: daily maintenance dose ratio is within the range of 10:0.1 to 2:0.15.

[0027] According to some embodiments, the maintenance phase initiates following attenuation in the infectious disease symptoms and/or markers.

[0028] According to some embodiments, there is provided a kit comprising a pharmaceutical composition comprising Hep-1 and a carrier for treating infectious disease caused by coronavirus. According to some embodiments, the kit further comprises instructions for use.

[0029] Other objects, features and advantages of the present invention will become clear from the following description, examples and drawings.

[0030] Certain embodiments of the present disclosure may include some, all, or none of the above advantages. One or more other technical advantages may be readily apparent to those skilled in the art from the figures, descriptions, and claims included herein. Moreover, while specific advantages have been enumerated above, various embodiments may include all, some, or none of the enumerated advantages.

Brief Description of The Drawings

[0031] Some embodiments of the disclosure are described herein with reference to the accompanying figures. The description, together with the figures, makes apparent to a person having ordinary skill in the art how some embodiments may be practiced. The figures are for the purpose of illustrative description and no attempt is made to show structural details of an embodiment in more detail than is necessary for a fundamental understanding of the disclosure. For the sake of clarity, some objects depicted in the figures are not to scale.

[0032] In the Figures:

[0033] Figure 1 presents treatment regimens, according to some embodiments.

[0034] Figure 2 presents the chronology of the disease of the first patient (initials R.P.) and treatment (Tx) time-line.

[0035] Figures 3A-3F present responses over time in terms of body temperature and clinical symptoms of COVID-19 patients untreated (3C and 3D, respectively) and treated (3A and 3B, respectively) with Ezrin and the difference between the treated and untreated groups (3E and 3F, respectively).

Detailed Description

[0036] There is provided, according to some embodiments, a method of treating COVID- 19, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising Hep-1, analogs or derivatives thereof.

[0037] The term "Hep-1" as used herein includes, but is not limited to, SEQ ID NO. 1, NH2-Thr-Glu-Lys-Lys-Arg-Arg-Glu-Thr-Val-Glu-Arg-Glu-Lys-Glu_COO-H and SEQ ID NO. 2. According to some embodiments, Hep-1 comprises SEQ ID NO:l. According to some embodiments, Hep-1 is consisting of SEQ ID NO: 1. According to some embodiments, Hep- 1 comprises analogues or derivatives of SEQ ID NO:l, as disclosed in US 9,682,140. [0038] The term "COVID-19" as used herein generally refers to coronavirus. According to certain embodiments, the coronavirus is one of SARS-CoV-2 (also termed "COVID-19"), MERS-CoV, SARS-CoV, NL63-CoV, 229E-CoV, OC43-CoV, HKUl-CoV, WIVl-CoV, MHV, HKU9-CoV, PEDV-CoV or SDCV. According to certain embodiments, the coronavirus is SARS-CoV-2, also known as COVID-19.

[0039] The term "infectious diseases and disorders associated with, or induced by, COVID-19" as used herein refers to any disease or disorder that is caused by COVID-19 or which is related to infections induced by COVID-19. The disease or disorder may include, without limitation, fatigue, pains (e.g. headaches, joint and muscle pain), low oxygen saturation (<92%), loss of taste, reduced ability to focus/concentrate, fever, coughs, and infections such as infection of the throat and tonsils and pneumonia.

[0040] the term "treatment", "treat", or "treating" refers to contacting (for example, administrating) the pharmaceutical composition disclosed herein with a subject after the onset of the disease, thereby alleviating the symptoms of the disease, compared to when the subject is not contacted with said pharmaceutical composition. The treatment as used herein does not always refer to completely suppressing the symptoms of a disease. The term "onset of a disease" refers to the appearance of the symptoms of the disease in the body.

[0041] According to some embodiments, the infectious disease is associated with COVID-19. According to some embodiments, the infectious disease is COVID-19.

[0042] According to some embodiments, said administering is performed by any suitable route of administration. According to some embodiments, said administering is performed by inhalation, via intravenous, intraarterial, subcutaneous, intramuscular, intraperitoneal, intrauterine, intrathecal or oral administration and a combination thereof. Each possibility represents a separate embodiment.

[0043] According to some embodiments, said administering is performed by subcutaneous administration. According to some embodiments, the pharmaceutical composition is administered daily at a dose ranging from 0.05 mg/day to about 5 mg/day Hep- 1. According to some embodiments, the pharmaceutical composition is administered daily at a dose ranging from 0.08 mg/day to about 4 mg/day Hep-1. [0044] As used herein, the term “about” may be used to specify a value of a quantity or parameter (e.g., dose) within a continuous range of values in the neighborhood of (and including) a given (stated) value. According to some embodiments, “about” may specify the value of a parameter to be between 80% and 120% of the given value. For example, the statement “the dose is equal to about 10 mg/day” is equivalent to the statement “the dose is between 8 mg/day and 12 mg/day”. According to some embodiments, “about” may specify the value of a parameter to be between 90% and 110% of the given value. According to some embodiments, “about” may specify the value of a parameter to be between 95% and 105% of the given value.

[0045] The term "subject" as used herein, refers to any animal, individual, or patient to which the methods described herein are performed. Generally, the subject is human, although as will be appreciated by those in the art, the subject may be an animal. Thus, other animals, including mammals such as rodents (including mice, rats, hamsters, and guinea pigs), cats, dogs, rabbits, farm animals including cows, horses, goats, sheep, pigs, etc., and non-human primates (including monkeys, chimpanzees, orangutans, and gorillas) are included within the definition of subject.

[0046] A "subject in need thereof," as used herein, refers to a subject afflicted with, or at risk of developing, a disease, specifically coronavirus disease. The subject in need thereof may be a subject being hospitalized with symptoms of coronavirus disease, a subject having symptoms of coronavirus diseases and is under ambulatory setting or at home, or a subject having asymptomatic coronavirus disease and is under ambulatory setting or at home.

[0047] According to some embodiments, the subject in need thereof is having mild coronavirus illness. Symptoms associated with mild coronavirus illness (disease) include, but are not limited to, fever of about 38°C or higher, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, and loss of taste and smell. Typically, subjects with mild coronavirus do not have shortness of breath, dyspnea on exertion, or abnormal chest imaging. Most of the mildly ill subjects can be managed in an ambulatory setting or at home through telemedicine or telephone visits. Treatment of a mildly ill subject does not usually require imaging or specific laboratory evaluations. Elderly subjects and subjects with underlying comorbidities are at higher risk of disease progression and hence may require continuous monitoring by health care providers until clinical recovery is achieved. [0048] It should be noted that any shortness of breath combined with the aforementioned mild symptoms may indicate the presence of moderate to severe, or severe disease and should be checked. Mild coronavirus infection may include a mild form of pneumonia and moderate coronavirus infection may include moderate form of pneumonia. Despite having only mild to moderate symptoms, mild, moderate, or mild to moderate forms of pneumonia may require hospitalization and antibiotics, along with supplemental oxygen. According to the World Health Organization (WHO) a mild to moderate case of COVID-19 will typically run its course in about two weeks. In addition, 80% of laboratory confirmed cases of COVID-19 cases exhibited mild to moderate symptoms according to data from WHO.

[0049] According to some embodiments, said administering comprises administering the pharmaceutical composition daily, for at least two days. According to some embodiments, said administering comprises administering the pharmaceutical composition daily, for at least three days. According to some embodiments, said administering comprises administering the pharmaceutical composition daily, for at least four days. According to some embodiments, said administering comprises administering the pharmaceutical composition daily, for at least seven days. According to some embodiments, said administering comprises administering the pharmaceutical composition daily, for at least ten days.

[0050] According to some embodiments, said administering comprises administering the pharmaceutical composition within 24 to 48 hours following diagnosis of the infectious disease. According to some embodiments, said administering comprises administering the pharmaceutical composition within 24 following diagnosis of the infectious disease. According to some embodiments, said administering comprises administering the pharmaceutical composition within 36 hours following diagnosis of the infectious disease. According to some embodiments, said administering comprises administering the pharmaceutical composition within 48 hours following diagnosis of the infectious disease. According to some embodiments, said administering comprises administering the pharmaceutical composition within 72 hours following diagnosis of the infectious disease. According to some embodiments, said administering comprises administering the pharmaceutical composition within 96 hours following diagnosis of the infectious disease.

[0051] The term "diagnosis" as used herein refers to any clinically acceptable diagnosis of infectious disease caused by coronavirus, including, but not limited to, polymerase chain reaction (PCR) and antibody testing. PCR and antibody testing are the dominant ways that global healthcare systems use for COVID-19 testing. However, as these techniques have their caveats, alternative ways to screen for the deadly disease are being searched for, such as lateral flow tests which are designed to identify the presence of a specific biological marker.

[0052] Markers for identifying infectious disease caused by coronavirus include, but are not limited to, oxygen saturation levels <92%, P/F ratio, namely, the arterial oxygen partial pressure (“P” or "pCk") divided by the fraction of inspired oxygen that the patient is receiving, (“F” or "FIC ") where a P/F ratio <300 indicates acute respiratory failure, and SOFA scores which stands for sequential organ failure assessment score (previously known as sepsis- related organ failure assessment score), and is used for monitoring patients' status at an intensive care unit in order to determine the extent of the organ function or rate of failure.

[0053] According to some embodiments, a subject in need thereof is a subject having oxygen saturation levels <98%. According to some embodiments, a subject in need thereof is a subject having oxygen saturation levels <95%. According to some embodiments, a subject in need thereof is a subject having oxygen saturation levels <92%. According to some embodiments, a subject in need thereof is a subject having oxygen saturation levels <90%. According to some embodiments, a subject in need thereof is a subject having oxygen saturation levels <89%. According to some embodiments, a subject in need thereof is a subject having oxygen saturation levels <87%. According to some embodiments, a subject in need thereof is a subject having oxygen saturation levels <85%.

[0054] According to some embodiments, the daily concentration of Hep-1 is within the range of 0.05 to 5 mg/day. According to some embodiments, the daily concentration of Hep- 1 is within the range of 0.08 to 4 mg/day. According to some embodiments, the daily concentration of Hep-1 is within the range of 0.1 to 3 mg/day. According to some embodiments, the daily concentration of Hep- 1 is within the range of 1 to 3 mg/day. According to some embodiments, the daily concentration of Hep- 1 is within the range of 0.1 to 2 mg/day. According to some embodiments, the daily concentration of Hep- 1 is within the range of 0.2 to 2 mg/day. According to some embodiments, the daily concentration of Hep-1 is within the range of 0.2 to 1.5 mg/day. According to some embodiments, the daily concentration of Hep- 1 is within the range of 0.1 to 1.5 mg/day.

[0055] The daily concentration of Hep-1 refers to the daily dose of Hep-1. According to some embodiments, the daily dose is provided in one administration. According to some embodiments, the daily dose is provided via a plurality of administrations. For example, a portion of the daily dose may be administered in the morning, and another portion may be administered later during the day (noon time, afternoon, evening, or night) such that the two portions together constitute the daily dose. Alternatively, the daily dose may be distributed into more than two portions (e.g., three, four, five etc.) which can be administered daily every few hours, such that at the end of the day all administered portions add up to the daily dose of Hep-1.

[0056] The term "plurality", as used herein, may refer to more than one (e.g., 2, 3, 4, 5 or more).

[0057] According to some embodiments, said administering comprises a treatment regimen comprising one or more days of induction phase comprising at least one daily administration of Hep-1 daily induction dose and one or more days of maintenance phase comprising at least one daily administration of Hep-1 daily maintenance dose, wherein the daily maintenance dose is lower than the daily induction dose and wherein the daily induction dose is within the range of 1 to 5 mg.

[0058] According to some embodiments, the induction phase comprises a plurality of daily administrations of Hep-1 daily induction dose. According to some embodiments, the induction phase comprises two daily administrations of Hep-1 daily induction dose. According to some embodiments, the induction phase comprises three daily administrations of Hep- 1 daily induction dose.

[0059] The term "induction phase" as used herein refers to an initial treatment phase comprising administration of high daily doses of Hep- 1, relative to the daily dose administered during the maintenance phase. In this respect, the "maintenance phase" refers to the phase following the induction phase, during which the daily doses of Hep- 1 are lower than the doses administered during the induction phase.

[0060] According to some embodiments, the treatment regimen further comprises a follow-up phase, during which Hep-1 is not administered. The follow-up phase is a phase intended for monitoring the health of the patient who was treated during the induction and the maintenance phases. The follow-up phase may include subjecting the patient to physiological test, including, but not limited to, pulmonary function tests (PFTs) such as tests that measure lung volume, lung capacity, rates of flow, and gas exchange. [0061] According to some embodiments, the follow-up phase includes testing the subject in need thereof for COVID-19.

[0062] According to some embodiments, the daily induction dose: daily maintenance dose ratio is within the range of 10:0.1 to 2:0.15.

[0063] According to some embodiments, there is provided a kit comprising a pharmaceutical composition comprising Hep-1 and a carrier for treating infectious disease caused by coronavirus. According to some embodiments, the kit further comprises instructions for use of the pharmaceutical composition for the treatment of infectious disease caused by coronavirus. The instructions can be presented in the form of a data sheet, a manual, in a piece of paper, printed on one or more containers or devices of the kit. Alternatively, the instructions can be provided in electronic form, for instance, available in a disc or online with a weblink available from the kit.

[0064] The kit can comprise, in addition to Hep- 1 and the carrier, a buffer, a solution for dilution, instructions, and the like.

[0065] According to some embodiments, the kit comprises at least one container enclosing therein the pharmaceutical composition.

[0066] According to some embodiments, the kit comprises a plurality of containers, each enclosing therein the pharmaceutical composition.

[0067] According to some embodiments, each container of the plurality of containers contains a unit dosage form of the pharmaceutical composition for a single administration.

[0068] According to some embodiments, each container of the plurality of containers contains a unit dosage form of the pharmaceutical composition for a single use.

[0069] According to some embodiments, the kits include separate containers/receptacles for containing the pharmaceutical composition as described herein. According to some embodiments, the kits include a device suitable for subcutaneous administration of the pharmaceutical composition. According to some embodiments, the kit includes an aerosolization device for forming an aerosol of the pharmaceutical compositions. According to some embodiments, the kits include nasal spray device. According to some embodiments, the pharmaceutical composition is present in aerosol form in the kit. [0070] The carrier is a pharmaceutically acceptable carrier, such as an excipient, an extending agent, a binder, and a lubricant, and a known additive (including a buffering agent, a tonicity agent, a chelating agent, a colorant, a preservative, an aroma chemical, a flavoring agent, a sweetening agent and the like), for example.

[0071] Reference is now made to Figure 1, which schematically depicts an exemplary treatment regimen, according to some embodiments. Figure 1 shows two treatment regimens, one for rapid responders and another one for slow responders. Prior to each of the two treatment regimens an immune profile (Fig. 1 , triangle) and biochemistry and/or hematology assessments (Fig. 1, circle) are performed. The treatment regimen for the rapid responders includes an induction phase that lasts two days (D1 and D2) during which two daily doses of 2 mg Hep-1 are administered, one in the morning and one in the afternoon/evening of each day. On each day of the induction phase, biochemistry and/or hematology assessments are carried out. After the two days of the induction phase, a maintenance phase is carried out for 8 days (days 3 to 10; D3 - D10) during which a daily dose of 0.2 mg Hep-1 is administered. At the first day of the maintenance phase, immune profile and biochemistry and/or hematology assessments are carried out. Furthermore, during the maintenance phase (e.g., on day 8), a PCR test for COVID-19 is performed. On the last day of the maintenance phase (D10), biochemistry and/or hematology assessments are performed. One day after completing the maintenance phase, namely at day 11, a follow up phase initiates, which is carried out for seven days. On the first day of the follow-up phase, an immune profile assessment is performed. During the follow-up phase, e.g., on the second day of the follow up phase, an additional PCR test for COVID-19 is performed. Based on the results of the PCR (indicating whether or not the patient is healthy, i.e., free of COVID-19), a decision is made regarding continuation (or not) of the treatment disclosed herein or any other treatment, including a combination of the treatment disclosed herein with one or more additional treatments/drugs. The treatment regimen for the slow responders includes an induction phase which lasts four days (D1 - D4), wherein on each day two daily doses of 2 mg Hep-1 are administered, one in the morning and one in the afternoon/evening. On each day of the induction phase, biochemistry and/or hematology assessments are carried out. After the four days of the induction phase, a maintenance phase is carried out, for 8 days (days 5 to 12; D5 - D12) during which a daily dose of 0.2 mg Hep-1 is administered. At the first day of the maintenance phase, immune profile and biochemistry and/or hematology assessments are carried out. Furthermore, during the maintenance phase (e.g. on day 10) a PCR test for COVID-19 is performed. On the last day of the maintenance phase (D12), biochemistry and/or hematology assessments are performed. A day after completing the maintenance phase, namely at day 11 , a follow-up phase is initiated, which is carried out for seven days. On the first day of the follow-up phase, an immune profile assessment is performed. During the follow up phase, e.g., on the second day of the follow up phase, an additional PCR test for COVID-19 is performed.

[0072] According to some embodiments, Hep-1 as disclosed herein can be applied in combination with another pharmaceutically active agent, including, but not limited to, antiviral agents, antibiotics, steroids and any active agent(s) suitable for treatment of lung diseases, such as, pneumonia and cystic fibrosis.

[0073] It can be expected that combined administration of the pharmaceutical composition of the present invention and at least one of antiviral/anti-inflammatory agents exert more advantageous effects than an independent use thereof. Such advantageous effects include an effect alleviating adverse effects more than conventional therapies while maintaining the therapeutic effects.

[0074] According to some embodiments, the immune profile assessment includes assessing the presence and/or level of one or more immune markers, including, but not limited to, pro- and anti-inflammatory markers.

[0075] According to some embodiments, the immune markers are selected from the group consisting of: colony stimulating factors (CSF), the chemokine family, growth factors (GF), and others.

[0076] According to some embodiments, the pro-inflammatory markers comprise any one or more of IL-Ib, IL-6, IL-12, TNF, and IFN-g.

[0077] According to some embodiments, the anti-inflammatory markers comprise any one or more of IL-4, IL-10, IL-13, and TGF-b.

[0078] It is to be understood that the cytokine storm is a crucial cause of Acute respiratory distress syndrome (ARDS), a systemic inflammatory response, and multiple organ failure. Moreover, viruses can invade lung epithelial cells and alveolar macrophages to produce viral nucleic acid, which stimulates the infected cells to release cytokines and chemokines, activating macrophages, dendritic cells, and others. Chemokines and cytokines are increasingly released from these cells to attract more inflammatory cells to migrate to the site of inflammation from the blood vessels, thereby cascading the amplification of the inflammatory response. Acute lung injury (ALI) is a common consequence of cytokine storm in lung tissue and systemic circulation. The pulmonary pathology of SARS-CoV-2 infection showed that the major changes in the lung tissue is diffuse alveolar damage, alveolar edema and proteinaceous exudates, thickening of alveolar walls, evident desquamation of pneumocytes and hyaline membrane formation, indicative of ARDS. Multinucleated giant cells in the alveolar cavity and inflammatory infiltration of the lymphocytes in the pulmonary mesenchyme have been demonstrated. In addition, the pathological results have confirmed that the number of CD4⁺ T and CD8⁺ T cells in the peripheral blood is reduced but that these cells are overactivated. CCR4⁺/ CCR6⁺ Thl7 cells have been found to increase and can have high proinflammatory effects, and CD8⁺ T cells contain high concentrations of cytotoxic granules, mainly perforin and granulysin, which cause severe immune damage in patients. Thus, evaluation of cytokines, chemokines and other immune markers is informative, and may be used to monitor and optimize the treatment regimen disclosed herein.

[0079] The principles, uses and implementations of the teachings herein may be better understood with reference to the accompanying description and figures. Upon perusal of the description and figures present herein, one skilled in the art will be able to implement the teachings herein without undue effort or experimentation. In the figures, same reference numerals refer to same parts throughout. In the figures, same reference numerals refer to same parts throughout.

[0080] In the description and claims of the application, the words “include” and “have”, and forms thereof, are not limited to members in a list with which the words may be associated.

[0081] One skilled in the art readily appreciates that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The examples provided herein are representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. Examples

[0082] Example 1 : Clinical results

[0083] Patients who participated in the study were subjects who were tested and found positive (PCR-positive) for COVID-19.

[0084] Patient No. 1. The first patient was a 69-y.o. male (initials: P.R.), with no background diseases. Four days prior to being diagnosed with COVID-19, the patient suffered from headaches, coughs, fatigue, weakness, loss of appetite and had a fever (38.3°C). One day after being diagnosed with COVID-19, the patient started receiving HEP-1 (Fig. 2, under 'Lab and Tx' section, where Tx stands for 'treatment(s)'). Treatment regimen included daily subcutaneous administrations of HEP1, 0.2 mg in 1 ml NS (saline containing 0.90% by w/v of NaCl or 9.0 gr/liter solution) for a week (7 consecutive days).

[0085] After the second administration of HEP1, the patient reported improvement in all of the symptoms from which he suffered prior to being diagnosed with COVID-19. Surprisingly, after the fourth administration of HEP1 the patient was completely recovered. A PCR test performed at the fifth day from the initiation of HEP-1 treatment indicated that the patient was negative for COVID-19.

[0086] The chronology of the disease of the first patient is illustrated in Fig. 2.

[0087] Patient No. 2. The second patient was a 58-y.o. male, who was healthy for years prior to being infected with COVID-19. This patient had asthma in childhood, and for more than 10 years prior to being infected with COVID-19, the patient used to suffer from influenza with coughs in winter with no fever. Patient received influenza vaccines yearly for over 10 years.

[0088] The patient received two COVID-19 vaccinations, three weeks apart from one another. After receiving the first vaccine, and five days prior to receiving the second vaccine, and throughout the week after receiving the second vaccine, patient was exposed to subjects infected with COVID-19.

[0089] Nine days after receiving the second vaccine dose, patient felt influenza-like symptoms with coughs, weakness, headache, and joint and muscle pains. A day after, namely ten days after receiving the second COVID-19 vaccine dose, symptoms got worse and the patient felt fatigue, joints and muscles pain, headache, could not concentrate, sensations in the throat, slept almost around the clock, diarrhea, chills with no temperature. However, he did not lose taste and his oxygen saturation was 91-92%. On that day, the patient was found to be positive for COVID-19 (PCR test).

[0090] On the third day after being diagnosed with COVID-19, the patient started receiving HEP-1. Treatment regimen included daily subcutaneous administrations of HEP1, 2 mg in 1 ml NS for four days followed by daily subcutaneous administrations of HEP1, 0.2 mg in 1 ml NS for a week (7 consecutive days).

[0091] Unexpectedly, patient felt improvements, namely, less fatigue, less headache and better ability to concentrate already at the second day of treatment with Hepl (2mg/day). A more significant improvement was observed on the third day of treatment with Hepl (2mg/day) - patient felt more energetic, could concentrate, practiced on treadmill for more than 20 min, had minimal joint and muscle pains, was active for 16 hours without the need to rest, had no sensation in throat, and had an oxygen saturation of 95%. On the fourth day of treatment with Hep 1 (2mg/day) patient slept for only 4.5 hours and woke up fully energetic, gained back his ability to highly concentrate, and did not feel tired during the entire day.

[0092] On the fifth day of treatment onwards (days 5 - 11), patient received a lower dose of Hepl (0.2 mg/day) and continued to be highly energetic, and was able to fully concentrate with no headaches nor joint and muscle pains.

Example 2. Hep-1 treatment regimen

[0093] After providing an informed consent, patients are treated with an induction dosage of HEP-1 within the range of 1 to 5 mg/day for at least two days, and up to 4 days. The extension of the induction phase is based on patient's reaction: in case improvement is observed within the first two days, the induction phase ends after two days. However, if improvement is not satisfactory, the induction phase is extended by another day or two, thereby up to a total of 3 to 4 days.

[0094] After completion of the 2 to 4 days of induction phase, treatment proceed with additional 8 -day maintenance dose with lower concentrations of HEP- 1, ranging from about 0.05 mg/day to about 1 mg/day. [0095] After termination of the aforementioned induction and maintenance phases, the treatment regimen concludes with a follow-up phase of 1 to 7 days.

[0096] To summarize, the induction dose serves as a high-dose priming phase which rapidly initiates the immunological response to the virus, as can be seen in Patient No. 2. The following maintenance dose, which is lower by about one order of magnitude from the induction dose, is used until a full response is obtained - namely, until the treated subject is feeling healthy again, by regaining his/her usual/normal activities. Typically, the maintenance phase lasts for up to seven days. However, in the event that the rate of improvement is slow and by the seventh day of the maintenance phase patient has not yet gained sufficient energy which enables going back to patient's normal activities, the maintenance phase is extended until reaching significant improvement. The advantage of the treatment regimen disclosed herein is that it does not require use of high doses of Hep 1 until healing is achieved, but rather requires a short term (2 to 4 days) of high doses and then continues with much lower doses (namely, maintenance phase), while not compromising on the healing process.

Example 3. Clinical study

[0097] In this study, up to 40 COVID-19 patients receive standard of care (SOC) therapy with add-on HEP-1 treatment according to the treatment protocols exhibited in Fig. 1. The study population contains 4 cohorts:

Cohort A (10 adult human patients): Compassionate treatment - Intubated patients with a positive SARS-CoV-2 PCR result hospitalized in the intensive care coronavirus unit.

Cohort B (10 adult human patients): Patients hospitalized in the coronavirus ward with a positive SARS-CoV-2 PCR result and on high-flow nasal oxygen therapy who might need intubation and mechanical ventilation.

Cohort C (10 adult human patients): hospitalized in the coronavirus ward with a positive SARS-CoV-2 PCR result and presenting with one or more clinical symptoms of COVID-19 disease: temperature (>38°C), headache, loss of taste, loss of smell, joint pain, respiratory symptoms. Cohort D (10 patients): Patients with a positive SARS-CoV-2 PCR result, treated in the community.

[0098] After providing informed consent, patients are treated with an induction dosage of HEP-1 for 2 days, which is extended to 4 days if improvement is not satisfactory, followed by an 8-day maintenance dose treatment with HEP-1. After completion of therapy, patients are followed up to 7 days.

[0099] Dosage: 2 mg Ezrin peptide 1 , dissolved in normal saline, separated into 10 single doses, 1 single dose per subcutaneous administration twice a day during the induction phase. For the maintenance phase, the dose is diluted to 0.2 mg per each administration.

[00100] The graphs shown in Figs. 3A - 3D represent anticipated responses in terms of body temperature and total symptoms over time of COVID-19 patients untreated (Figs. 3C and 3D, respectively) compared to patients treated with HEP-1 (Figs. 3A and 3B, respectively). The evaluation of total symptoms is expressed in arbitrary units (a.u) as it is based on accumulation of data, such as, body temperature and respiratory symptoms (oxygen saturation and/or listening with a statoscope) and on information obtained from the patients regarding pain (e.g. joints, head) and loss of taste/smell. Figs. 3E and 3F present the differences between the data shown in Figs. 3A - 3D, namely, the results in terms of body temperature and total clinical symptoms of the two populations - treated and untreated, respectively, indicating shortening of clinical course of newly diagnosed and admitted patients, as presented by the profile of temperature and clinical symptoms reduction over time.

[00101] While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

[00102] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In case of conflict, the patent specification, including definitions, governs. As used herein, the indefinite articles “a” and “an” mean “at least one” or “one or more” unless the context clearly dictates otherwise. [00103] Embodiments of the present disclosure may include apparatuses for performing the operations described herein. The apparatuses may be specially constructed for the desired purposes or may include a general-purpose computer(s) selectively activated or reconfigured by a computer program stored in the computer for docketing patient's status, and PCR data, throughout treatment regimen. The apparatuses may be specifically constructed to perform analytic processes, and statistics, as required. Such a computer program may be stored in a computer readable storage medium, such as, but not limited to, any type of disk, or any other type of media suitable for storing electronic instructions, and capable of being coupled to a computer system bus.

[00104] However, the aforementioned operations are not inherently related to any particular computer or other apparatus. Various general-purpose systems may be used with programs as may be required, or it may prove convenient to construct a more specialized apparatus to perform the desired method(s).

Claims

1. A method of treating infectious diseases caused by coronavirus, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising Hep-1 and a carrier.

2. The method of claim 1, wherein said administering comprises administering the pharmaceutical composition daily, for at least two days.

3. The method of claim 1, wherein said administering comprises administering the pharmaceutical composition within 24 to 48 hours following diagnosis of the infectious disease.

4. The method of claim 1, wherein said administering comprises administering the pharmaceutical composition to a subject having oxygen saturation levels less than 100% and more than 89%.

5. The method of claim 3, wherein said infectious disease is associated with COVID- 19.

6. The method of claim 2, wherein the daily concentration of Hep- 1 is within the range of 0.05 to 5 mg.

7. The method of claim 1 , wherein the pharmaceutical composition is in a dosage form suitable for subcutaneous delivery.

8. The method of claim 7, wherein said administering comprises subcutaneous administration.

9. The method of claim 6, wherein said administering comprises daily administration of the pharmaceutical composition, for at least two days, wherein each daily dose comprises Hep- 1 within the range of 0.05 to 1 mg.

10. The method of claim 6, wherein said administering comprises a treatment regimen comprising one or more days of induction phase comprising at least one daily administration of Hep- 1 daily induction dose and one or more days of maintenance phase comprising at least one daily administration of Hep-1 daily maintenance dose, wherein the daily maintenance dose is lower than the daily induction dose and wherein the daily induction dose is within the range of 1 to 5 mg.

11. The method of claim 10, wherein the daily induction dose:daily maintenance dose ratio is within the range of 10:0.1 to 2:0.15.

12. The method of claim 10, further comprising a follow-up phase during which a plurality of physiological tests are carried out.

13. The method of claim 1, wherein said subject in need thereof is a subject diagnosed with COVID-19.

14. The method of claim 10, wherein the induction phase is at least one day shorter than the maintenance phase.

15. The method of claim 10, wherein the maintenance phase initiates following attenuation in the infectious disease symptoms and/or markers.

16. A pharmaceutical composition comprising Hep-1 and a carrier for the treatment of infectious diseases caused by coronavirus.

17. The pharmaceutical composition of claim 16, for daily use, for at least two days.

18. The pharmaceutical composition of claim 16, for daily use, within 24 to 48 hours following diagnosis of the infectious disease.

19. The pharmaceutical composition of claim 18, wherein said diagnosis comprises oxygen saturation levels <100% and >89%.

20. The pharmaceutical composition of claim 16, wherein said infectious disease is associated with COVID-19.

21. The pharmaceutical composition of claim 17, wherein the concentration of Hep-1 in the pharmaceutical composition is within the range of 0.05 to 5 mg.

22. The pharmaceutical composition of claim 16, in a dosage form suitable for subcutaneous delivery.

23. The pharmaceutical composition of claim 21, wherein the concentration of Hep-1 in the pharmaceutical composition is within the range of 0.05 to 1 mg.

24. The pharmaceutical composition of claim 16, for use in a treatment regimen comprising one or more days of induction phase comprising use of at least one Hep- 1 daily induction dose, and one or more days of maintenance phase comprising at least one Hep-1 daily maintenance dose, wherein each maintenance dose is lower than the induction dose and wherein each daily induction dose is within the range of 1 to 5 mg.

25. The pharmaceutical composition of claim 24, wherein the daily induction dose:daily maintenance dose ratio is within the range of 10:0.1 to 2:0.15.

26. The pharmaceutical composition of claim 24, wherein the treatment regimen further comprising a follow-up phase during which a plurality of physiological tests are carried out.

27. The pharmaceutical composition of claim 24, wherein the induction phase is at least one day shorter than the maintenance phase.

28. The pharmaceutical composition of claim 24, wherein the maintenance phase initiates following attenuation in the infectious disease symptoms and/or markers.

29. A kit comprising a pharmaceutical composition comprising Hep-1 and a carrier for treating infectious disease caused by coronavirus.