CORONA VIRUS INFECTIONS

BACKGROUND

[0001] Coronaviruses are a group of RNA viruses that recognize and bind to Angiotensin converting enzyme 2 (ACE2) as an important step in the viral infection process.

Coronaviruses have surface glycoproteins (“spike proteins”) that bind to ACE2, thereby facilitating viral entry into target cells. Coronaviruses include the SARS (Severe Acute Respiratory Syndrome) and MERS (Middle East Respiratory Syndrome) viruses. A new member of this group was identified in 2019: this novel human respiratory coronavirus is variously known as: SARS-CoV-2, COVID-2019, or 2019-nCoV, and the disease caused by this virus as “Coronavirus Disease 2019” or COVID-19. GenBank terms the virus “Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)” and reports its linear RNA genome at NCBI Reference Sequence C_045512.2. The disease due to this virus will be referred to as “COVID-19” hereafter. Symptoms of COVID-19, which may appear about two to fourteen days after exposure to the virus, include fever, cough, shortness of breath, sometimes headache or other bodily ache. Corona viral infections, including COVID-19 due to SARS-CoV-2 infection, can lead to serious and fatal illness, particularly in the old, the immunocompromised, or other susceptible group (e.g., people suffering from diabetes, people suffering from hypertension, and others). These viruses are often highly communicable, so that large fractions of the population, whether particularly vulnerable or not, are infected, leading to significant morbidity and mortality numbers. Reducing the risk of infection (e.g., by social distancing) and reducing the duration and severity of the infection (possibly by administration of convalescent plasma, monoclonal antibodies, chloroquine, hydroxychloroquine, remdesivir, or other agents) are important goals in combatting viral diseases such as COVD-19 or other diseases caused by coronaviruses.

[0002] Although it is possible to develop and manufacture vaccines to reduce the numbers of infected patients, and to reduce or prevent the spread of coronavirus diseases, vaccines take time to develop, test, validate, manufacture, and deliver. However, for novel viruses such as SARS-CoV-2, the spread of the infection may outpace the timetable for development and deployment of a vaccine. [0003] Accordingly, methods of reducing the risk of coronavirus infection, of reducing the severity of an infection when contracted, and of reducing the duration of the infection are needed.

SUMMARY

[0004] Prior methods of treating viral infections, and coronaviruses in particular, fall short of reducing risk of infection or of reducing severity or duration of coronavirus infection, as is tragically shown by the present COVID-19 pandemic. There is great need for treatment methods to aid those presently suffering from infectious diseases such as COVID-19 due to SARS-CoV-2 virus infection, and to reduce the numbers of people who would otherwise suffer from such infections by reducing the risk of contracting a viral infection, e.g., a coronavirus infection such as a SARS-CoV-2 infection.

[0005] Administration of glucocorticoid receptor modulators (GRMs) affects the immune system, and affects other systems, and may affect gene expression and protein levels in animal cells and organs. Administration of glucocorticoid agonists, such as dexamethasone, is often effective to inhibit the immune system. Administration of glucocorticoid receptor antagonists (GRAs) stimulates the immune system and enhances immune response in subjects, including in patients suffering from disease.

[0006] Infection due to many viruses may be related to, or aided by, glucocorticoid- modulated host receptor proteins. In some cases, as with many coronaviruses, viruses bind to glucocorticoid-modulated host receptor proteins, which binding is important (and may be crucial) for viral entry into the cell and for viral infection of the cell to which the virus binds. For example, coronaviruses such as SARS-CoV-2 and others bind to angiotensin-converting enzyme 2 (ACE2) and thereby gain entry into the cell leading to infection. For example, coronaviruses such as SARS-CoV-2 and others interact with transmembrane serine protease 2 (TMPRSS2) and thereby gain entry into the cell leading to infection. In embodiments, Applicant discloses novel methods for treating viral infections or for reducing the risk of viral infections.

[0007] Applicant discloses herein methods suitable for treating patients suffering from a viral infection, such as a coronavirus infection, e.g., a SARS-CoV-2 infection (COVID-19 disease), and suitable for reducing the risk of contracting a viral infection, such as a SARS- CoV-2 or other coronavirus infection. The treatments for coronavirus infections, including SARS-CoV-2 infections, comprise administering a GRA effective to reduce angiotensin- converting enzyme 2 (ACE2) levels in the patient, to reduce transmembrane serine protease 2 (TMPRSS2) levels in the patient, to reduce the risk of developing a coronavirus infection, to reduce the severity of a coronavirus infection, to reduce the duration of a coronavirus infection, to enhance the immune response in the patient, or combinations thereof. The dose amount of GRA administered may be reduced, or the treatment may be stopped, if the patient develops signs of inflammation, increased C-Reactive protein (CRP) levels, signs of respiratory distress, or of excess cytokine activity (e.g., signs of a “cytokine storm”), or other indications of an excessive immune response to the viral infection.

[0008] Methods disclosed herein include administering a GRA to a patient who does not exhibit symptoms of a coronavirus infection (e.g., a SARS-CoV-2 infection), i.e., is considered asymptomatic of a coronavirus infection (e.g., a SARS-CoV-2 infection), but has been exposed to a coronavirus (e.g., SARS-Cov-2 virus or a person having COVID-19), or is considered at risk of developing such an infection, or is suspected of having such an infection despite not exhibiting symptoms of that infection. Such a person may be a carrier of a coronavirus (e.g., a SARS-CoV-2 virus) despite not exhibiting symptoms of a viral infection. A person may be considered at risk of developing a coronavirus infection if, for example, they have been exposed to a coronavirus (e.g., has been in contact with, or near to, a person with a coronavirus infection, or in an environment suspected of harboring a coronavirus), or may have a risk factor for such an infection, or may be considered to be at risk of developing a coronavirus infection for other reasons. In embodiments of the methods of administering a GRA to a patient not exhibiting symptoms of a viral infection, the GRA administration may continue for several days (e.g., 3, 4, 5, or 6 days), or a week, or weeks (e.g., 2, 3, 4, or more weeks), or until the subject appears to suffer from an immune-system response indicative of an excessive immune response to the viral infection (e.g., if the patient exhibits signs of inflammation, increased CRP levels, respiratory distress, or of suffering from a “cytokine storm”, or when the patient may otherwise be a candidate for treatment with dexamethasone, or other glucocorticoid (GC)), at which time the GRA administration may be reduced in dosage, or may be stopped. The treatment may be stopped in a patient who initially tested negative for the presence of a coronavirus (e.g., SARS-CoV-2 virus), or was exposed to, or otherwise considered at risk of developing a coronavirus infection (e.g., a SARS-CoV-2 infection), if the patient again tests negative for the presence of the coronavirus (e.g., SARS- CoV-2 virus) after 3 to 4 weeks of treatment. Where the patient has been receiving GRA administration prior to testing positively for a coronavirus infection (e.g., where the patient suffers from excess cortisol levels (e.g., has Cushing’s syndrome or Cushing’s Disease)), the patient’s GRA dose may be increased following receipt of the positive coronavirus test results. In general, GRA administration should be reduced or discontinued when the patient’s condition indicates the administration of a GC such as dexamethasone, e.g., if the patient exhibits signs of excessive immune response, inflammation, respiratory distress, increased CRP levels, signs of a cytokine storm, or is considered at risk of suffering from a cytokine storm, or is otherwise indicative of GC administration.

[0009] Methods disclosed herein include administering a GRA to a patient who has tested positively for a coronavirus infection (e.g., a SARS-CoV-2 infection), but has not yet exhibited symptoms of the infection. In embodiments of the methods of administering a GRA to a patient not exhibiting symptoms of a viral infection, the GRA administration may continue for several days (e.g., 3, 4, 5, or 6 days), or a week, or weeks (e.g., 2, 3, 4, or more weeks), or until the subject appears to suffer from an immune-system response indicative of an excessive immune response to the viral infection (e.g., when the patient may be a candidate for treatment with dexamethasone, or other GC), at which time the GRA administration may be reduced in dosage, or may be stopped. Where the patient has been receiving GRA administration prior to testing positively for a coronavirus infection (e.g., where the patient suffers from excess cortisol levels (e.g., has Cushing’s syndrome or Cushing’s Disease)), the patient’s GRA dose may be increased following receipt of the positive coronavirus test results. In general, GRA administration should be reduced or discontinued when the patient’s condition indicates the administration of a GC such as dexamethasone. The treatment may be stopped in a patient who initially tested positive for the presence of a coronavirus (e.g., SARS-CoV-2 virus), if the patient tests negative for the presence of the coronavirus (e.g., SARS-CoV-2 virus) after 3 to 4 weeks of treatment.

[0010] Methods disclosed herein include administering a GRA to a patient who exhibits symptoms of a coronavirus infection (e.g., a SARS-CoV-2 infection). Such symptoms of a coronavirus infection may be mild symptoms (including, e.g., fever, chills, shortness of breath, headache, fatigue, sore throat, runny nose, loss of smell, diarrhea, and other symptoms). Such symptoms of a coronavirus infection may be serious symptoms (in addition to symptoms seen in mild cases, serious symptoms may include, e.g., high fever, extreme difficulty breathing, low blood oxygen levels, confusion, extreme fatigue, difficulty waking or remaining awake, blue-tinted lips or nail beds, and other symptoms). In embodiments of the methods of administering a GRA to a patient exhibiting symptoms of such a viral infection, the GRA administration may continue for several days (e.g., 3, 4, 5, or 6 days), or a week, or weeks (e.g., 2, 3, 4, or more weeks), or until the patient appears to suffer from an immune-system response indicative of an excessive immune response to the viral infection (e.g., when the patient may be a candidate for treatment with dexamethasone, or other GC), at which time the GRA administration may be reduced in dosage, or may be stopped. Where the patient has been receiving GRA administration prior to exhibiting symptoms of a coronavirus infection (e.g., where the patient suffers from excess cortisol levels (e.g., has Cushing’s syndrome or Cushing’s Disease)), the patient’s GRA dose may be increased following identification of coronavirus symptoms. In general, GRA administration should be reduced or discontinued when the patient’s condition indicates the administration of a GC such as dexamethasone. The treatment may be stopped in a patient who exhibited symptoms of a coronavirus infection (e.g., a SARS-Cov-2 infection), if the patient tests negative for the presence of the coronavirus (e.g., the SARS-CoV-2 virus) after 3 to 4 weeks of treatment.

[0011] Disclosed herein are novel methods for treating viral infections; for reducing the risk of viral infections; for reducing the severity of viral infections; for reducing the duration of viral infections; for reducing the expression of, or numbers of, host receptor proteins involved in viral binding to, or entry into, cells of a patient, and other methods useful for treating patients having viral infections or at risk of having a viral infection. Infection due to many viruses may be related to, or aided by, glucocorticoid-modulated host receptor proteins. Applicant discloses herein methods to modulate the expression of, or numbers of, glucocorticoid-modulated host receptor proteins effective to reduce viral binding to such host receptor proteins, and effective to reduce viral infection, reduce the severity of viral infections, reduce the duration of viral infections, and otherwise prevent or treat viral infections. The methods disclosed herein include methods of reducing the numbers of, or expression of, host receptor proteins effective to reduce viral infection. For example, the methods disclosed herein include methods of administering GRMs effective to modulate the expression of, numbers of, or both, of glucocorticoid-modulated host receptor proteins thereby modulating the ability of viruses to infect cells in a patient. An example, among many host receptor proteins suitable for modulation by the methods disclosed herein, is angiotensin-converting enzyme 2 (ACE2), which is a glucocorticoid-modulated host receptor protein (for, e.g., coronaviruses); a further example is transmembrane serine protease 2 (TMPRSS2). Both ACE2 and TMPRSS2 are involved in SARS-CoV-2 entry into cells, and are involved with SARS-CoV-2 infections. In preferred embodiments, such modulation of host receptor proteins reduces the expression of, numbers of, or both, of glucocorticoid- modulated host receptor proteins thereby reducing the ability of viruses to infect cells in a patient. Where, for example, the glucocorticoid-modulated host receptor protein is the ACE2 protein or the TMPRSS2 protein, such reductions may include, e.g., reducing ACE2 or TMPRSS2 expression; reducing the amount of ACE2 or TMPRSS2 molecules in the patient; reducing the numbers of ACE2 or TMPRSS2 molecules in the patient; reducing the numbers of ACE2 or TMPRSS2 molecules on patient cells; reducing the number of ACE2 or TMPRSS2 molecules in the patient; reducing the activity of ACE2 or TMPRSS2 molecules in the patient, and on patient cells; and other reductions.

[0012] Such reduction of viral ability to infect cells is effective to treat viral infections, reduce the severity of viral infections, reduce the duration of viral infections, reduce viral binding to patient cells, reduce viral entry into patient cells, and otherwise improve treatments of viral infections and reduce the risk of having a viral infection in a patient.

[0013] In particular embodiments, Applicant discloses novel methods for treating coronavirus infections, for reducing the risk of, reducing the severity of, and for reducing the duration of coronavirus infections, including infections due to novel human respiratory coronavirus SARS-CoV-2 (which causes COVID-19). Thus, the novel methods disclosed herein include novel methods for treating or reducing SARS-CoV-2 infections. The methods disclosed herein include methods of reducing the numbers of, or expression of, ACE2 or TMPRSS2 molecules effective to reduce viral infection. For example, the methods disclosed herein include methods of administering glucocorticoid receptor antagonists (GRAs) effective to modulate the expression of, numbers of, or both, of ACE2 or TMPRSS2 molecules thereby reducing the ability of coronaviruses to infect cells in a patient. Reducing the ability of coronaviruses, including SARS-CoV-2, reduces the risk, severity, and duration, of coronavirus infection, including of SARS-CoV-2 infection.

[0014] Prior methods of treating coronaviruses fall short of reducing risk of infection or of reducing severity or duration of coronavirus infection, as is tragically shown by the present COVID-19 pandemic caused by the SARS-CoV-2 virus. The methods disclosed herein provide advantages and improvements in the treatment, and reduction in the risk of COVID- 19 and other viral infectious diseases. Accordingly, the present methods provide needed treatments and methods previously lacking in the art. BRIEF DESCRIPTION OF THE DRAWING

[0015] FIGURE 1 shows C-Reactive protein levels over time in patients with Cushing’s syndrome treated with relacorilant. C-reactive protein (CRP) levels increase upon inflammation; thus, increased CRP levels indicate an enhanced immune response. C-Reactive protein levels initially rise somewhat (at four weeks), and then return towards baseline levels after some months of relacorilant treatment.

DETAILED DESCRIPTION

INTRODUCTION

[0016] The methods disclosed herein can be used to treat a patient suffering from a viral infection by administering an effective amount of a glucocorticoid receptor antagonist (GRA), preferably a selective glucocorticoid receptor antagonist (SGRA), effective to treat the viral infection by reducing the expression of, or levels of, glucocorticoid-modulated receptor proteins associated with viral infection (e.g., by viral binding to such receptor proteins). Such a viral infection may be a coronavirus infection, and may be a SARS-CoV-2 infection. In embodiments, the expression, or levels, or both, of the glucocorticoid-modulated receptor proteins may be increased by glucocorticoids (GCs) such as, e.g., cortisol (hydrocortisone), dexamethasone, prednisone, prednisolone, or other GCs. In embodiments, the expression, or levels, or both, of the glucocorticoid-modulated receptor proteins may be reduced by administration of GRAs, including, e.g., SGRAs. In embodiments, the activity of the glucocorticoid-modulated receptor proteins may be reduced by administration of GRAs, including, e.g., SGRAs. Angiotensin-converting enzyme 2 (ACE2) is glucocorticoid- modulated receptor protein important to the binding of coronaviruses to cells or to the entry of coronaviruses into cells, and so is crucial to coronavirus infection. Other proteins may also serve coronaviruses as glucocorticoid-modulated receptor proteins important to the binding of coronaviruses to cells or to the entry of coronaviruses into cells; for example, transmembrane serine protease 2 (TMPRSS2) is a glucocorticoid-modulated receptor protein for involved in coronavirus entry into, and infection of, cells.

[0017] The methods disclosed herein can be used to treat a patient suffering from a viral infection, e.g., a coronavirus infection, by administering an effective amount of a glucocorticoid receptor antagonist (GRA), preferably a selective glucocorticoid receptor antagonist (SGRA), effective to treat the coronavirus infection. In embodiments, the coronavirus is a virus that causes severe acute respiratory syndrome (SARS), or a virus that causes Middle East Respiratory Syndrome (MERS), or, in particular embodiments, a virus that causes the novel human respiratory coronavirus variously known as SARS-CoV-2, COVID-2019, and 2019-nCoV. In particular embodiments, the virus is SARS-CoV-2, the virus that causes COVID-19. Coronaviruses, including SARS-CoV-2, utilize the ACE2, TMPRSS2, and other molecules to enter cells and infect them; the virus binds to ACE2, so that the presence and numbers of ACE2 macromolecules present on or in the cells of a subject at risk of infection, or suffering from an infection, play crucial roles in the risk of infection, in the infection process, and in recovery from infection. Similarly, TMPRSS2 plays an important role in viral infection, so that the presence and numbers of TMPRSS2 macromolecules present on or in the cells of a subject at risk of infection, or suffering from an infection, play crucial roles in the risk of infection, in the infection process, and in recovery from infection. Thus, reducing the presence and numbers of ACE2 or TMPRSS2 macromolecules on or in a patient’s cells reduces the risk of infection, reduces the duration and severity of an infection, improves recovery from such infections, and is thereby beneficial to the patient.

[0018] In addition, coronaviruses such as SARS-CoV2 require functional ACE2 enzymes, and not inactive forms, to bind to and infect cells. Coronaviruses such as SARS-CoV2 also appear to require functional TMPRSS2 enzymes to infect cells. (Among other enzymes, metalloproteinase 17 (“AD AMI 7”) aids in activating ACE2.) Thus, since active forms of ACE2 and TMPRSS2 are required for infection, reducing ACE2 activity and TMPRSS2 activity is important in reducing the risk of infection, in inhibiting the infection process, and in promoting recovery from infection. Reducing ACE2 activity and TMPRSS2 activity reduces the risk of infection, reduces the duration and severity of an infection, improves recovery from such infections, and is thereby beneficial to the patient. The methods disclosed herein can be used to treat a patient suffering from a viral infection, e.g., a coronavirus infection, by administering an effective amount of a glucocorticoid receptor antagonist (GRA), preferably a selective glucocorticoid receptor antagonist (SGRA), effective to reduce ACE2 activity, TMPRSS2 activity, or both.

[0019] In addition to the administration of a GRA, the present methods may further comprise administration of a therapeutic agent selected from hydroxychloroquine, chloroquine, mefloquine, and colchicine. Studies have shown that infection of a cell by a coronavirus induces endoplasmic reticulum stress (ER stress) due to increased synthesis of proteins necessary for the replication of the virus. Agents such as hydroxychloroquine, chloroquine, mefloquine, and colchicine are lysosome inhibitors, acting to inhibit lysosomal activities and functions, which activities and functions are essential for processing of proteins and degradation of unfolded proteins in a cell. Thus, the negative effects of those drugs on lysosomal activities and functions leads to further increase in ER stress, inhibition of the synthesis of viral proteins essential for viral replication, and death of the affected cells. One effect of GRA administration is also to increase ER stress, an effect that can potentiate the effect of lysosome inhibitors. Without being limited to any one theory, combined administration of a GRA with one or more of hydroxychloroquine, chloroquine, mefloquine, and colchicine is believed to synergistically increase ER stress, thereby fighting viral infection by synergistically reducing the production and processing of viral proteins.

[0020] Further embodiments may also, or alternatively, (in addition to the administration of a GRA, or a GRA and one or more of hydroxychloroquine, chloroquine, mefloquine, and colchicine) comprise administration of an antiviral agent selected from remdesivir, ritonavir, saquinavir, nelfmavir, indinavir, boceprevir, lopinavir, telaprevir, tipranavir, paritaprevir, oseltamivir, zanamivir, and peramivir. Further embodiments may also, or alternatively, further comprise administration of convalescent plasma (i.e., plasma derived from a person who has antibodies to a corona virus such as SARS-CoV-2, typically due to that person having suffered from, and recovered from, e.g., a SARS-CoV-2 infection); or administration of one or more monoclonal antibodies directed to a coronavirus, such as SARS-CoV-2 virus (such monoclonal antibodies include, for example, bamlanivimab (YL-CoV555), etesevimab (LY-C0VOI6), and combinations of these, casirivimab, imdevimab, and combinations of these; and other monoclonal antibody compositions. Yet further embodiments may also, or alternatively, comprise administration of a therapy selected administration of oxygen, administration of respiratory support comprising use of a ventilator, positioning of the patient in a prone (face-down) position, administration of muscle relaxants or neuromuscular blocking agents, administration of nitric oxide, administration of aerosolized prostacyclin, and combinations thereof.

[0021] Administration of a GRA is effective to stimulate the immune system, or otherwise enhance the immune response, of a subject. C-reactive protein (CRP) levels increase upon inflammation; thus, increased CRP levels indicate an enhanced immune response. For example, immune response enhancement was demonstrated in a phase 2 study of patients with Cushing’s syndrome administered daily doses of relacorilant (a heteroaryl -ketone fused azadecalin GRA) as shown in the Figure. The Figure shows rapid development of an enhanced immune response in patients with Cushing’s syndrome treated with relacorilant; this enhancement was evident even with small doses (e.g., 100 milligrams (mg) or 200 mg per day). Relacorilant was administered to two groups of patients with Cushing’s syndrome once per day for four months. Group 1 received 100 milligrams per day (mg/day) which, if tolerated, was raised to 200 mg/day after four weeks at the lower dose during their 16 weeks under study. Group 2 received relacorilant doses according to the following schedule: the starting doses were 250 milligrams (mg) per day of relacorilant for four weeks, followed by 300 mg/day relacorilant for the next four weeks, followed by 350 mg/day relacorilant for a further four weeks, and then 400 mg relacorilant for another four weeks. (Some patients did not tolerate the higher doses, and remained on a lower dose for the duration of the study, or ended the study prior to 16 weeks.)

[0022] Consistent with the results obtained from patients with Cushing’s syndrome, healthy subjects administered high doses of relacorilant in a phase 1 study experienced symptoms of inflammation in areas of previous injuries, consistent with an immune system enhancement by GR antagonism. Enhancement of the immune system is believed to be important in the reducing risk of suffering from an infection, in reducing the severity of an infection, in reducing the duration of an infection, and otherwise to improve a patient’s response to an infection. Thus, GRA administration effective to upregulate the immune response, even in an otherwise healthy subject, can be protective against viral infection, including being effective as prophylactic treatment for coronavirus infection, such as COVID-19, reducing the risk of contracting such an infection. GRA administration effective to upregulate the immune response in patients suffering from coronavirus infection, such as COVID-19, can thus be useful to reduce the severity of, and the duration of, a viral infection, including a coronavirus infection, such as COVID-19.

[0023] The Figure shows C-Reactive protein (CRP) levels over time in patients with Cushing’s syndrome treated with relacorilant. CRP level is correlated with the level of inflammation in a patient. CRP levels initially rise somewhat (at four weeks), and then return towards baseline levels after some months of relacorilant treatment. These changes in CRP are correlated with immune function, and indicate that relacorilant treatment is effective to stimulate the immune response at least during the first 4 or more weeks of treatment.

[0024] Eosinophil count is a marker of inflammation. Eosinophil counts are reported as numbers of cells per liter. Normal ranges of eosinophils are about 0.05 - 0.55 thousands per pL = 0.05 - 0.55 10 ⁹ /L (or, as percent - eosinophils: 0 - 7% of white blood cells). Lymphocyte counts also increased in patients receiving high doses of relacorilant. As shown in the Table, relacorilant treatment of patients with Cushing’s syndrome increased eosinophil counts (indicative of inflammation) and lymphocyte counts consistent with enhanced immune response in these patients. This is consistent with the finding that both adult and pediatric patients with endogenous Cushing’s syndrome characteristically have suppressed immune systems, and are at risk of suffering autoimmune disease following surgical treatment to resolve the syndrome (Tatsi, 2018; de Mota, 2011). The observed GRA-induced enhancement of immune system function indicated by the Table is consistent with the observed rebound enhancement of the immune system found following treatment of Cushing’s syndrome.

Table: Relacorilant Treatment Leads to Improved Immune Response

(See also U.S. Patent Publication 20200268723 (U.S. Application 16/797,421), filed February 21, 2020, and U.S. Patent Publication 20200197411 (U.S. Application 16/723,626), filed December 20, 2019, the entire contents of both of which applications are hereby incorporated by reference in their entireties.)

[0025] Administration of a GRA thus has at least two, synergistic beneficial effects: i) GRA administration reduces the ACE2 levels, reducing the ability of coronavirus to infect cells; and ii) GRA administration increases immune response, enhancing the ability to combat a coronavirus (or other) infection. Thus decreasing the levels of ACE2 and stimulating the immune response in someone who has been exposed to the coronavirus will decrease the infectivity and the transmission of the virus.

[0026] Similarly, administration of a GRA thus has at least two, synergistic beneficial effects: i) GRA administration reduces the TMPRSS2 levels, reducing the ability of coronavirus to infect cells; and ii) GRA administration increases immune response, enhancing the ability to combat a coronavirus (or other) infection. Thus decreasing the levels of TMPRSS2 and stimulating the immune response in someone who has been exposed to the coronavirus will decrease the infectivity and the transmission of the virus.

[0027] Such enhancement of immune response is believed to be effective in treating a coronavirus or other infection, including in treating infections due to SARS-CoV-2 virus. It is believed that reducing ACE2 or TMPRSS2 activity in a patient, and in a patient’s cells, reduces risk of infection by a coronavirus such as SARS-CoV-2 virus, and reduces the duration and severity of such an infection. Combined with the effect of reducing ACE2 or TMPRSS2 expression, these GRA effects would act synergistically to reduce risk of coronavirus infection, and to improve patient response to a coronavirus infection. Such enhancement of immune response, combined with the GRA-induced reduction of ACE2 or TMPRSS2 expression, and/or combined with the GRA-induced reduction of ACE2 or TMPRSS2 activity, is thus believed to be effective to reduce the severity of a coronavirus or other infection, including aiding in reducing the severity of an infection due to SARS-CoV-2 virus. Such enhancement of immune response, combined with the GRA-induced reduction of ACE2 or TMPRSS2 expression and/or activity, is thus believed to be effective to reduce the duration of a coronavirus or other infection, including aiding in reducing the duration of an infection due to SARS-CoV-2 virus. Such enhancement of immune response, combined with the GRA-induced reduction of ACE2 or TMPRSS2 expression and/or activity, is thus believed to be effective to reduce the risk of contracting a coronavirus or other infection, including reducing the risk of contracting an infection due to SARS-CoV-2 virus. Such enhancement of immune response, combined with the GRA-induced reduction of ACE2 or TMPRSS2 expression and/or activity, is effective to provide other improvements in fighting infection, decreasing risk of infection, and improving patient health.

[0028] The treatments disclosed herein may be administered to a subject who has been exposed to a coronavirus (e.g., has been exposed to SARS-CoV-2); may be administered to subjects interacting with carriers or family members of carriers of SARS-CoV-2, or to people suspected of having COVID-19; may be administered to a patient who presents with early symptoms of COVID-19; may be administered to a patient who presents with established symptoms of COVID-19; may be administered to a patient who has COVID-19 which appears to be resolving, in order to reduce the risk of recurrence or sudden or unexpected worsening of symptoms (as sometimes happens); may be administered to a patient whose COVID-19 symptoms have resolved and is thought to be cured, in order to reduce the risk of recurrence. The treatments may be administered prophylactically to subjects interacting with carriers (people infected with a coronavirus, such as SARS-CoV-2) or family members of carriers.

[0029] Accordingly, in particular embodiments, Applicant discloses novel methods for reducing the risk of developing a coronavirus (including SARS-CoV-2) infection, comprising administering a glucocorticoid receptor antagonist, effective to reduce ACE2 or TMPRSS2 expression in the patient (e.g., in susceptible cells of the patient), and to reduce ACE2 or TMPRSS2 levels in susceptible cells of the patient (where a susceptible cell is a cell often infected by a coronavirus, such as SARS-CoV-2, in a coronavirus infection). Susceptible cells often express host receptor proteins; cells expressing or having receptor proteins are susceptible cells. The novel methods include, for example, methods for reducing the severity of a coronavirus (including SARS-CoV-2) infection, comprising administering a glucocorticoid receptor antagonist, effective to reduce ACE2 or TMPRSS2 expression in the patient (e.g., in susceptible cells of the patient), and to reduce ACE2 or TMPRSS2 levels in susceptible cells of the patient. The novel methods include, for example, methods for reducing the duration of a coronavirus (including SARS-CoV-2) infection, comprising administering a glucocorticoid receptor antagonist, effective to reduce ACE2 or TMPRSS2 expression in the patient (e.g., in susceptible cells of the patient), and to reduce ACE2 or TMPRSS2 levels in susceptible cells of the patient. The novel methods include, for example, methods for reducing ACE2 or TMPRSS2 expression in a patient, comprising administering a glucocorticoid receptor antagonist, effective to reduce ACE2 or TMPRSS2 expression in the patient (e.g., in susceptible cells of the patient), and to reduce ACE2 or TMPRSS2 levels in susceptible cells of the patient. The novel methods include, for example, methods for reducing the amount, or numbers of, ACE2 or TMPRSS2 in or on susceptible cells of a patient, comprising administering a glucocorticoid receptor antagonist, effective to reduce ACE2 or TMPRSS2 expression in the patient (e.g., in susceptible cells of the patient), and to reduce ACE2 or TMPRSS2 levels in susceptible cells of the patient. The novel methods include, for example, methods for reducing coronavirus binding to cells in a patient, comprising administering a glucocorticoid receptor antagonist, effective to reduce ACE2 or TMPRSS2 expression in the patient, and to reduce ACE2 or TMPRSS2 levels in or on cells of the patient. Such cells may be susceptible cells. The novel methods include, for example, methods for reducing coronavirus binding to cells in a patient, comprising administering a glucocorticoid receptor antagonist, effective to reduce ACE2 or TMPRSS2 expression in or on susceptible cells of the patient, and to reduce ACE2 or TMPRSS2 levels in or on susceptible cells of the patient. The novel methods include, for example, methods for reducing coronavirus infection of cells in a patient, comprising administering a glucocorticoid receptor antagonist, effective to reduce ACE2 or TMPRSS2 expression in the patient, and to reduce ACE2 or TMPRSS2 levels in or on cells of the patient. Such cells may be susceptible cells. The novel methods include, for example, methods for reducing coronavirus infection of cells in a patient, comprising administering a glucocorticoid receptor antagonist, effective to reduce ACE2 or TMPRSS2 expression in or on susceptible cells of the patient, and to reduce ACE2 levels in or on susceptible cells of the patient. The novel methods include, for example, methods for reducing coronavirus infection of cells in a patient, comprising administering a glucocorticoid receptor antagonist, effective to reduce ACE2 or TMPRSS2 activity in the patient, and to reduce ACE2 or TMPRSS2 activity in cells of the patient.

[0030] In embodiments, in addition to the administration of a GRA in any of the methods disclosed herein, these methods may further comprise administration of a therapeutic agent selected from hydroxychloroquine, chloroquine, mefloquine, and colchicine. In embodiments, in addition to the administration of a GRA in any of the methods disclosed herein, including methods comprising administration of a therapeutic agent selected from hydroxychloroquine, chloroquine, mefloquine, and colchicine, the methods may further comprise administration of an antiviral agent selected from remdesivir, ritonavir, saquinavir, ne!fmavir, indinavir, boceprevir, lopinavir, telaprevir, tipranavir, paritaprevir, oseltamivir, zanamivir, and peramivir. In embodiments, in addition to the administration of a GRA and including any of the methods disclosed in this paragraph, the methods may further comprise administration of convalescent plasma, administration of monoclonal antibodies, administration of a therapy selected administration of oxygen, administration of respiratory support comprising use of a ventilator, positioning of the patient in a prone (face-down) position, administration of muscle relaxants or neuromuscular blocking agents, administration of nitric oxide, administration of aerosolized prostacyclin, and combinations thereof.

[0031] In embodiments, the methods disclosed herein include steps of: a) Measuring ACE2 or TMPRSS2 expression and coronavirus RNA or protein in a sample obtained from a patient (e.g. measuring ACE2 or TMPRSS2 expression and coronavirus RNA or protein in epithelial cells obtained with a nasal or throat swab from the patient); b) Administering at least one dose of a GRA (e.g., a non-steroidal, or a steroidal GRA) to the patient; c) Measuring ACE2 or TMPRSS2 expression and coronavirus RNA or protein in a patient (e.g., measuring ACE2 or TMPRSS2 expression and coronavirus RNA or protein in a sample (e.g., of epithelial cells obtained with a nasal or throat swab) obtained from the patient after the GRA administration; whereby the ACE 2 or TMPRSS2 levels in the patient are decreased. In embodiments, the methods are effective to decrease ACE 2 or TMPRSS2 levels in the patient by at least about 10%, or about 20%, or about 30%, or about 40%, or about 50% after GRA administration as compared with ACE 2 or TMPRSS2 levels in the patient prior to GRA administration. ACE2 or TMPRSS2 levels may be measured by levels of expression of message encoding ACE2 or TMPRSS2; may be measured by numbers of ACE2 or TMPRSS2 proteins; or by other measures indicative of the amounts of ACE2 or TMPRSS2 proteins in the patient. Coronavirus RNA or protein levels may be measured by levels of expression of coronavirus message or protein in the patient. In embodiments, ACE2 or TMPRSS2 and coronavirus RNA or protein levels may be determined for nasal, throat, or buccal cells; for lung epithelial cells; for kidney epithelial cells; for intestinal epithelial cells; for blood vessel epithelial cells; in the blood; or for other cells or in other bodily fluids (e.g., urine).

[0032] In embodiments, the treatment is effective to reduce the severity of a coronavirus infection; to reduce the duration of a coronavirus infection; to reduce or block the spread to the lower respiratory track upon exposure to a coronavirus. In embodiments, the treatment is effective to reduce the risk of the patient contracting a coronavirus infection. In embodiments, the treatment is effective to prevent the patient from contracting a coronavirus infection.

[0033] In embodiments, the methods disclosed herein include steps of: a) Measuring ACE2 or TMPRSS2 expression and SARS-CoV-2 RNA in a patient (e.g. measuring ACE2 or TMPRSS2 expression and SARS-CoV-2 RNA in epithelial cells obtained with a nasal or throat swab from the patient); b) Administering at least one dose of a GRA (e.g., a non-steroidal, or a steroidal GRA); c) Measuring ACE2 or TMPRSS2 expression and SARS-CoV-2 RNA in a patient (e.g., measuring ACE2 or TMPRSS2 expression and SARS-CoV-2 RNA in epithelial cells obtained with a nasal or throat swab after the GRA administration; whereby the ACE 2 levels or TMPRSS2 levels in the patient are decreased. In embodiments, the methods are effective to decrease ACE 2 levels or TMPRSS2 levels in the patient by at least about 10%, or about 20%, or about 30%, or about 40%, or about 50% after GRA administration as compared with ACE 2 or TMPRSS2 levels in the patient prior to GRA administration. ACE2 or TMPRSS2 levels may be measured by levels of expression of message encoding ACE2 or TMPRSS2; may be measured by numbers of ACE2 or TMPRSS2 proteins; or by other measures indicative of the amounts of ACE2 or TMPRSS2 proteins in the patient. SARS-CoV-2 levels may be measured by levels of expression of SARS-CoV-2 message in the patient. In embodiments, these methods are effective to reduce ACE2 or TMPRSS2 activity in the patient and in patient cells; such reductions in ACE2 or TMPRSS2 activity may include, for example, reductions of about 10% to about 50% in ACE2 or TMPRSS2 activity. In embodiments, ACE2 or TMPRSS2 and SARS-CoV-2 RNA levels may be determined for nasal, throat, or buccal cells; for lung epithelial cells; for kidney epithelial cells; for intestinal epithelial cells; for blood vessel epithelial cells; in the blood; or for other cells or in other bodily fluids (e.g., urine).

[0034] Methods disclosed herein include administering a GRA to a patient who does not exhibit symptoms of a coronavirus infection (e.g., a SARS-CoV-2 infection). Such a patient may be asymptomatic, or a carrier of, but considered at risk of developing such an infection. Such a patient may be suspected of having such an infection despite not exhibiting symptoms of that infection. Such a person may be a carrier of a coronavirus (e.g., a SARS-CoV-2 virus) despite not exhibiting symptoms of a viral infection. In embodiments, such a patient may continue to receive GRA administration for several days (e.g., 3, 4, 5, or 6 days), or a week, or weeks (e.g., 2, 3, 4, or more weeks), or longer. If such a patient has been previously been receiving GRA administration (e.g., where the patient suffers from excess cortisol levels (e.g., has Cushing’s syndrome or Cushing’s Disease)), the patient’s GRA dose may be increased following receipt of positive coronavirus test results.

[0035] Such methods include administering a GRA to a patient who has tested positively for a coronavirus infection (e.g., a SARS-CoV-2 infection), but has not yet exhibited symptoms of the infection. In such a patient, GRA administration may continue for several days (e.g., 3, 4, 5, or 6 days), or a week, or weeks (e.g., 2, 3, 4, or more weeks), or longer.

[0036] Methods disclosed herein include administering a GRA to a patient who exhibits symptoms of a coronavirus infection (e.g., a SARS-CoV-2 infection). Such symptoms of a coronavirus infection may be mild symptoms (including, e.g., fever, chills, shortness of breath, headache, fatigue, sore throat, runny nose, loss of smell, diarrhea, and other symptoms). Such symptoms of a coronavirus infection may be serious symptoms (in addition to symptoms seen in mild cases, serious symptoms may include, e.g., high fever, extreme difficulty breathing, low blood oxygen levels, confusion, extreme fatigue, difficulty waking or remaining awake, blue-tinted lips or nail beds, and other symptoms). In embodiments of the methods of administering a GRA to a patient exhibiting symptoms of such a viral infection, the GRA administration may continue for several days (e.g., 3, 4, 5, or 6 days), or a week, or weeks (e.g., 2, 3, 4, or more weeks), or longer.

[0037] In general, for any patient, whether initially not testing positive, or initially asymptomatic, or initially symptomatic for a viral infection such as a coronavirus infection e.g., a SARS-CoV-2 infection), GRA administration should be reduced or discontinued when the patient’s condition indicates the administration of a GC such as dexamethasone, e.g., if the patient exhibits signs of a cytokine storm, or is considered at risk of suffering from a cytokine storm, or if the patient’s condition otherwise indicates the advisability of GC administration.

DEFINITIONS

[0038] As used herein, the term “patient” refers to a human that is or will be receiving, or has received, medical care for a disease or condition. A healthy person may be termed a patient where that healthy person is treated, e.g., prophylactically, in order to reduce the risk of contracting a viral infection.

[0039] As used herein, the terms and phrases “test positive”, patient tests positive”, “positive test”, and the like, including grammatical variants thereof, refer to the determination or discovery of the presence of markers of corona virus infection in a sample obtained from a patient. For example, a patient tests positively for a coronavirus infection (e.g., a SARS-CoV- 2 infection) where a nasal swab, throat swab, nasal aspirate, tracheal aspirate, sputum sample, blood sample, or other sample, obtained from the subject is found to have viral proteins or viral genetic message, or other indicator of the presence of the virus in the sample. In some cases, an asymptomatic person presenting with an abnormal chest X-ray or other image of the chest or lungs may be determined to suffer from a coronavirus infection.

[0040] As referred to herein, a patient is considered at risk of developing an infection due to an infectious disease (e.g., a coronavirus infection such as a SARS-CoV-2 infection) if the subject or patient has been exposed to a virus that causes the infectious disease, or has been near to, or in contact with, a person or persons (or animal or contaminated food) having the infectious disease, or has been present in a location (e.g., a room, car, bus, or other enclosed location) suspected of harboring a coronavirus, or has otherwise possibly come into contact with the virus or a person, animal, location, or contaminated food suspected of harboring the virus. In addition, a patient may be considered at risk of developing a coronavirus infection (e.g., a SARS-Cov-2 infection) if, for example, the patient is immunocompromised, elderly, obese, has diabetes, has a respiratory condition or disorder (e.g., asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, etc.), has hypertension, cardiovascular disease, cerebrovascular disease, or other risk factor associated with developing a coronavirus disease such as COVID-19.

[0041] As referred to herein, a patient is suspected of having an infection (e.g., a coronavirus infection such as a SARS-CoV-2 infection) despite not exhibiting symptoms of that infection if, for example, a chest image (e.g., a chest X-ray, computerized tomography (CT) or magnetic resonance image (MRI)) of the subject or patient shows a “ground glass pattern” or “ground glass opacities”, or exhibits “crazy paving” in the lungs, as these terms are used in the art; if the subject or patient exhibits signs of pneumonia, particularly if the subject or patient has been near or in contact with a person, animal, or contaminated food suspected of harboring a virus that causes the infection. Such suspicion is strengthened if these findings are observed in both the right and left lungs, or in more than one lobe; if such “ground glass opacities” in the lungs are observed in areas also exhibiting vascular dilatation (blood vessel widening) or exhibiting traction bronchiectasis or exhibiting distortion of subpleural bands, as these terms are used in the art.

[0042] As referred to herein, a patient’s condition indicates the administration of a GC such as dexamethasone when the patient develops signs of inflammation, increased C-Reactive protein (CRP) levels, signs of respiratory distress, or of excess cytokine activity (e.g., signs of a “cytokine storm”), or other indications of an excessive immune response to the viral infection.

[0043] As used herein, the term “susceptible cell” refers to a cell that is often infected by a virus. Susceptible cells often express host receptor proteins; cells expressing or having receptor proteins are susceptible cells. For example, susceptible cells that are susceptible to coronavirus infection (e.g., susceptible to SARS-CoV-2 infection) often express the receptor protein angiotensin-converting enzyme 2 (ACE2) to which coronaviruses bind, aiding viral infection, and often express transmembrane serine protease 2 (TMPRSS2). Thus, a cell that expresses ACE2 or TMPRSS2, or has ACE2 or TMPRSS2 proteins (e.g., on its surface) is a susceptible cell, and at risk of coronavirus (e.g., SARS-CoV-2) infection. Susceptible cells include, without limitation, epithelial cells of the lung, kidney, intestine, and blood vessels.

[0044] Immunocompromised patients may be at greater risk of severe or fatal SARS-CoV- 2 infection than patients with healthy immune systems. Patients suffering from diabetes, hypertension, cardiovascular disease, or cerebrovascular disease are believed to be at greater risk of severe or fatal SARS-CoV-2 infection than patients without such conditions. ACE2 levels are increased above normal in patients with diabetes or hypertension (treatment with ACE inhibitors or angiotensin blockers is believed to increase ACE levels) (Fang et ah, Lancet Respir Med 2020 (https://doi.org/10.1016/PII)). A patient having high ACE2 levels, such as a diabetic or hypertensive patient, may have higher than normal numbers of susceptible cells susceptible to coronaviruses such as SARS-CoV-2 (e.g., cells expressing ACE2); and, such susceptible cells may be more susceptible to coronavirus infection, due to increased expression or levels of ACE2, as compared to normal patients.

[0045] As used herein, the term “coronavirus” refers to a class of single-stranded RNA viruses. Coronavirus infection is typically mediated by contact with host receptor proteins, such as angiotensin-converting enzyme 2 (ACE2). Coronaviruses include, for example, the SARS (Severe Acute Respiratory Syndrome) virus, the MERS (Middle East Respiratory Syndrome) virus, and the recently identified novel human respiratory coronavirus variously known as: SARS-CoV-2, COVID-2019, and 2019-nCoV. Information regarding the SARS- CoV-2 virus may be found, for example, on GenBank, which reports its linear RNA genome at NCBI Reference Sequence NC 045512.2. Symptoms of coronavirus infections may include respiratory congestion, cough, fever, fatigue, and bodily ache.

[0046] The disease caused by a SARS-CoV-2 viral infection may be termed COVID-19 (the phrases “COVID-19 infection” or “COVID-19 disease” may also refer to this disease). Symptoms of COVID-19, which may appear about two to fourteen days after exposure to the SARS-CoV-2 virus, typically include fever, cough, shortness of breath (respiratory congestion), and often also fatigue, runny nose, sore throat, headache, or other bodily ache. Corona viral infections, including SARS-CoV-2 infections, can lead to serious and fatal illness, particularly in the old, the immunocompromised, or other susceptible group (e.g., people suffering from diabetes, people suffering from hypertension, and others).

[0047] As used herein, the term “host receptor protein” refers to a protein expressed by the host (e.g., the patient) to which a virus binds, or which is otherwise used by the virus to infect a host cell. Viral infection, and viral transmission (e.g., from one host to another, such as from one patient to another patient) for many viruses, such as coronaviruses, may be mediated by, or enhanced by, viral binding to host receptor proteins. For example, the host receptor protein utilized by many coronaviruses, including SARS-CoV-2, is ACE2. Coronavirus (e.g., SARS-CoV-2) entry into cells may also be facilitated by TMPRSS2, which also serves as a host protein; it is believed that TMPRSS2 facilitates infection by promoting fusion of viral membrane with cell membranes.

[0048] As used herein, the term “glucocorticoid-modulated host receptor protein” refers to a host receptor protein the expression of which, or levels of which, is modulated by glucocorticoids such as cortisol or others. For example, angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are host receptor proteins for coronaviruses. A coronavirus host receptor protein may serve as a factor or as an element in the process of coronavirus infection. Levels or expression of coronavirus host receptor proteins may be modulated by GCs. Cortisol is the endogenous glucocorticoid in humans. For example, the levels of angiotensin-converting enzyme 2 (ACE2) are increased by GCs (e.g., cortisol (hydrocortisone), dexamethasone, prednisone, and prednisolone: (Fishel et al., Hypertension 25(3):343-349 (1995)). TMPRSS2 level or expression may be modulated by GCs and androgens (Ragia et al., Eur J. Clin Pharmacol, 76:1623-1630(2020)), and by interleukins (e.g., IL-13; Kimura et al., J Allergy Clin Immunol 146(l):80-88 (2020)). Such glucocorticoid-modulated host receptor proteins are important to the binding of coronaviruses to cells, and so are crucial to coronavirus infection. Other proteins may also serve coronaviruses as glucocorticoid-modulated host receptor proteins.

[0049] As used herein, the terms “angiotensin-converting enzyme 2” and “ACE2” (also known as angiotensin I converting enzyme 2) refer to the protein of that name that acts to convert angiotensin to angiotensinogen, and also serves as a target for coronaviruses, aiding their entry and infection of cells. Expression of ACE2 refers to the production of such proteins, or to the production of message which encodes for such proteins. The human gene encoding ACE2 has gene ID number 59272 (location: Xp22.2, Exon count 21). ACE2 is a membrane bound protein, although it (or portions of it) may be found free in blood or other bodily fluids (e.g., urine). ACE2 levels may be measured, for example, by enzyme-linked immunoassay (ELISA) (to determine protein levels; e.g., by an Abeam Human ACE2 ELISA kit available from Abeam, Cambridge, U.K.). ACE2 levels may be measured, for example, by polymerase chain reaction methods (PCR, including reverse transcription PCR (rtPCR)) (to measure nucleic acid message encoding ACE2 protein).

[0050] As used herein, the terms “transmembrane serine protease 2” and “TMPRSS2” refer to the protein of that name that acts to convert angiotensin to angiotensinogen, and also serves as a target for coronaviruses, aiding their entry and infection of cells. Expression of TMPRSS2 refers to the production of such proteins, or to the production of message which encodes for such proteins. TMPRSS2, also known as PRSS10, is a membrane bound protein with an extracellular portion. The human gene encoding TMPRSS2 has gene ID number 7113 (location: chromosome 21, NC_000021.9 (41464305..41508158, complement)). TMPRSS2 levels may be measured, for example, by enzyme-linked immunoassay (ELISA) (to determine protein levels. TMPRSS2 levels may be measured, for example, by polymerase chain reaction methods (PCR, including reverse transcription PCR (rtPCR)) (to measure nucleic acid message encoding ACE2 protein). A TMPRSS2 assay is described by Shrimp et al., ACS Pharmacol Transl Sci. 2020 Oct 9; 3(5): 997-1007.

[0051] As used herein, the term “antiviral agent” refers to a therapeutic compound or composition that is used to treat viral infections. Antiviral agents include, without limitation, remdesivir, ritonavir, saquinavir, nelfmavir, indinavir, boceprevir, lopinavir, telaprevir, tipranavir, paritaprevir, oseltamivir (Tamiflu), zanamivir (Relenza) and peramivir (Rapivab). Also included as antiviral agents are convalescent plasma compositions, which include antibodies active against coronavirus (including, e.g., SARS-CoV-2) infections. Also included as antiviral agents are monoclonal antibodies, and compositions including monoclonal antibodies, such as, e.g., IgGl monoclonal antibodies directed to the “spike protein” of SARS-CoV-2 vims, such as bamianivimab (YL-CoV555), etesevimab (LY- CoVOlo), and combinations of these, casirivimab, imdevi ab, and combinations of these; and other monoclonal antibody compositions. Such monoclonal antibody compositions may be directed against SARS-CoV-2 vims antigens (e.g., an epitope of a SARS-CoV-2 spike protein), and may be directed against other coronavirus antigens. Such monoclonal antibody compositions may be directed against cellular targets of SARS-CoV-2 vims (e.g., ACE2 or TMPRS82), and may be directed against cellular targets of other coronavirus antigens.

[0052] As used herein, the terms “muscle relaxant” and “neuromuscular blocking agent” refer to therapeutic compounds or compositions that may be used to reduce muscle activity, tension, and even to induce therapeutic paralysis. Such agents include, without limitation, cisatracurium, cisatracurium besylate, rocuronium, suxamethonium, atracurium, vecuronium, pancuronium, tizanidine, baclofen, carisoprodol, and others. These agents are used in treating patients suffering from respiratory distress, particularly if the patients require external respiratory support (e.g., by use of a ventilator). Patients suffering from coronavirus infections, including infections due to SARS-CoV-2 virus, may suffer from respiratory distress and may require external respiratory support.

[0053] As used herein, the terms “administer,” “administering,” “administered” or “administration” refer to providing a compound or a composition (e.g., one described herein), to a patient. Administration may be by oral administration (i.e., the subject receives the compound or composition via the mouth, as a pill, capsule, liquid, or in other form suitable for administration via the mouth). Oral administration may be buccal (where the compound or composition is held in the mouth, e.g., under the tongue, and absorbed there). Administration may be by injection, i.e., delivery of the compound or composition via a needle, microneedle, pressure injector, or other means of puncturing the skin or forcefully passing the compound or composition through the skin of the subject. Injection may be intravenous (i.e., into a vein); intraarterial (i.e., into an artery); intraperitoneal (i.e., into the peritoneum); intramuscular (i.e., into a muscle); or by other route of injection. Routes of administration may also include rectal, vaginal, transdermal, via the lungs (e.g., by inhalation), subcutaneous (e.g., by absorption into the skin from an implant containing the compound or composition), or by other route.

[0054] As used herein, the term “effective amount” or “therapeutic amount” refers to an amount of a pharmacological agent effective to treat, eliminate, or mitigate at least one symptom of the disease being treated. In some cases, “therapeutically effective amount” or “effective amount” can refer to an amount of a functional agent or of a pharmaceutical composition useful for exhibiting a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The effective amount can be an amount effective to treat a viral infection, or to reduce the risk of contracting a viral infection.

[0055] As used herein, the term “combination therapy” refers to the administration of at least two pharmaceutical agents to a subject to treat a disease or condition. The two agents may be administered simultaneously, or sequentially in any order during the entire or portions of the treatment period. The at least two agents may be administered following the same or different dosing regimens. Such agents may include, for example, e.g., a GRA, GRM, SGRA, or SGRM, and an antiviral agent, or an agent useful in treating a symptom that accompanies a viral infection (e.g., an antihistamine, or an agent for reducing headache or body aches (e.g., aspirin, acetaminophen, ibuprofen, or other agent)). In some cases, one agent is administered following a scheduled regimen while the other agent is administered intermittently. In some cases, both agents are administered intermittently. In some embodiments, the one pharmaceutical agent may be administered daily, and the other pharmaceutical agent may be administered every two, three, or four days.

[0056] As used herein, the term "compound" is used to denote a molecular moiety of unique, identifiable chemical structure. A molecular moiety ("compound") may exist in a free species form, in which it is not associated with other molecules. A compound may also exist as part of a larger aggregate, in which it is associated with other molecule(s), but nevertheless retains its chemical identity. A solvate, in which the molecular moiety of defined chemical structure ("compound") is associated with a molecule(s) of a solvent, is an example of such an associated form. A hydrate is a solvate in which the associated solvent is water. The recitation of a "compound" refers to the molecular moiety itself (of the recited structure), regardless of whether it exists in a free form or an associated form.

[0057] As used herein, the term "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0058] As used herein with reference to proteins and genetic message (e.g., ribonucleic acid (RNA) or deoxyribonucleic acid (DNA)), encoding proteins, including regarding host receptor proteins, the terms “amount” and “level” refer to the copy number, or level of expression, or other measure of the numbers of copies of genetic message encoding the protein; and refer to the numbers of proteins, or the weight or concentration of such proteins, or the activity of such proteins.

[0059] The term “measuring the level,” in the context of a protein, or genetic message (e.g., ribonucleic acid (RNA) or deoxyribonucleic acid (DNA)), or an analyte such as, e.g., cortisol, refers to determining, detecting, or quantitating the amount, level, or concentration of, that compound in a sample obtained from a subject. The sample may be, e.g., a blood sample, a saliva sample, a urine sample, a sputum sample, a throat swab, a nasal swab, or other sample obtained from the patient or a bodily fluid obtained from the patient. A level may be measured from a fraction of a sample. For example, a level (e.g., cortisol) may be measured in the plasma fraction of a blood sample; may be measured in a serum fraction of a blood sample; or, in embodiments, may be measured in whole blood. A level may be measured from cells obtained in a sample.

[0060] The terms “reduce ACE2 expression”, “reduce ACE2 level”, “reduce the level of ACE2 expression”, “reduce ACE2 numbers”, “reduce the amount of ACE2 expression”, “reduce ACE2 activity”, and plural and grammatical variants thereof, refer to decreasing the amount of ACE2 genetic message and to decreasing the amount or activity of ACE2 protein.

[0061] The terms “reduce TMPRSS2 expression”, “reduce TMPRSS2 level”, “reduce the level of TMPRSS2 expression”, “reduce TMPRSS2 numbers”, “reduce the amount of TMPRSS2 expression”, “reduce TMPRSS2 activity”, and plural and grammatical variants thereof, refer to decreasing the amount of TMPRSS2 genetic message and to decreasing the amount or activity of TMPRSS2 protein.

[0062] The term “cortisol” refers to the naturally occurring glucocorticoid hormone (also known as hydrocortisone) that is produced by the zona fasciculata of the adrenal gland. Cortisol has the structure:

The term “total cortisol” refers to cortisol that is bound to cortisol-binding globulin (CBG or transcortin) and free cortisol (cortisol that is not bound to CBG). The term “free cortisol” refers to cortisol that is not bound to cortisol-binding globulin (CBG or transcortin). As used herein, the term “cortisol” refers to total cortisol, free cortisol, and/or cortisol bound of CBG.

[0063] As used herein, the term “glucocorticoid receptor” (“GR”) refers to the type II GR, a family of intracellular receptors which specifically bind to cortisol and/or cortisol analogs such as dexamethasone (See, e.g., Turner & Muller, J. Mol. Endocrinol. October 1, 2005 35 283-292). The glucocorticoid receptor is also referred to as the cortisol receptor. The term includes isoforms of GR, recombinant GR and mutated GR.

[0064] The term “glucocorticosteroid” or “glucocorticoid” (“GC”) refers to a steroid hormone or analog that acts as a glucocorticoid receptor agonist (i.e., activates the GR, or enhances the activity of the GR). GCs include for example, dexamethasone, prednisone, hydrocortisone (cortisol), and prednisolone. GCs are typically characterized by having 21 carbon atoms, an a,b-unsaturated ketone in ring A, and an a-ketol group attached to ring D. They may differ in the extent of oxygenation or hydroxylation at C-l 1, C-17, and C-19; see Rawn, “Biosynthesis and Transport of Membrane Lipids and Formation of Cholesterol Derivatives,” in Biochemistry, Daisy etal. (eds.), 1989, pg. 567.

[0065] As referred to herein, a patient’s condition may “indicate the administration of a glucocorticoid” if, for example, the patient exhibits inflammation, skin reddening, edema, respiratory distress, increased CRP levels, or other signs of excessive immune response. A patient’s condition may “indicate the administration of a glucocorticoid” when the patient is determined to be at elevated risk of suffering from a cytokine storm, or exhibits signs of a cytokine storm. A patient’s condition may “indicate the administration of a glucocorticoid” if the patient has been suffering from a coronavirus infection (e.g., from SARS-Cov-2) for a long-enough time that the patient is at elevated risk of suffering from a cytokine storm.

[0066] As used herein, the term “cytokine storm”, also referred to as “cytokine release syndrome”, or as “hypercytokinemia”, refers to a condition in which a patient exhibits a severe reaction to a viral infection (e.g., to a coronavirus infection, such as from SARS-Cov- 2). Such a severe reaction includes symptoms of inflammation and includes excess levels of one or more cytokines, including interleukins and other cytokines. A “cytokine storm” thus comprises elevated levels of cytokines and other inflammatory molecules; the presence of such excess levels of cytokines and inflammatory molecules in a patient, or patient sample, are signs of a cytokine storm in a patient. Signs of a cytokine storm include, e.g., elevated interleukin levels (including, e.g., elevated interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6) levels, interleukin-7 (IL-7), or interleukin 10 (IL-10) levels; or elevated interferon-gamma (IFN-g) levels; or elevated tumor necrosis factor alpha (TNF-a) levels; elevated granulocyte-colony-stimulating factor (GCSF) levels; elevated monocyte chemoattractant protein-1 (MCP-1) levels; elevated macrophage inflammatory protein 1-A (MIP-1 A) levels; or other symptoms of a cytokine storm. Other signs and symptoms may include high fever, fatigue, nausea, swelling or edema, skin redness, and other symptoms. [0067] The term “glucocorticoid receptor modulator” (GRM) refers to any compound which modulates GC binding to GR, or which modulates any biological response due to such binding. For example, a GRM that acts as an agonist, such as dexamethasone, increases the activity of tyrosine aminotransferase (TAT) in HepG2 cells (a human liver hepatocellular carcinoma cell line; ECACC, UK). A GRM that acts as an antagonist, such as mifepristone, decreases the activity of tyrosine aminotransferase (TAT) in HepG2 cells. TAT activity can be measured as outlined in the literature by A. Ali etal. , J. Med. Chem., 2004, 47, 2441- 52.

[0068] As used herein, the term “selective glucocorticoid receptor modulator” (SGRM) refers to any composition or compound which modulates GC binding to GR, or modulates any biological response due to such binding. By “selective,” the drug preferentially binds to the GR rather than other nuclear receptors, such as the progesterone receptor (PR), the mineralocorticoid receptor (MR) or the androgen receptor (AR). It is preferred that the selective glucocorticoid receptor modulator bind GR with an affinity that is lOx greater (1/10 ^th the Kd value) than its affinity to the MR, AR, or PR, both the MR and PR, both the MR and AR, both the AR and PR, or to the MR, AR, and PR. In a more preferred embodiment, the selective glucocorticoid receptor modulator binds GR with an affinity that is lOOx greater (l/lOO ¹¹¹ the K _d value) than its affinity to the MR, AR, or PR, both the MR and PR, both the MR and AR, both the AR and PR, or to the MR, AR, and PR. In another embodiment, the selective glucocorticoid receptor modulator binds GR with an affinity that is lOOOx greater (l/lOOO ¹¹¹ the K _d value) than its affinity to the MR, AR, or PR, both the MR and PR, both the MR and AR, both the AR and PR, or to the MR, AR, and PR. Relacorilant is a SGRM.

[0069] “Glucocorticoid receptor antagonist” (GRA) refers to any compound which inhibits GC binding to GR, or which inhibits any biological response due to such binding. Accordingly, GR antagonists can be identified by measuring the ability of a compound to inhibit the effect of dexamethasone. TAT activity can be measured as outlined in the literature by A. Ali et al ., J. Med. Chem., 2004, 47, 2441-2452. A GRA is a compound with an IC50 (half maximal inhibition concentration) of less than 10 micromolar. See Example 1 of U.S. Patent 8,859,774, the entire contents of which is hereby incorporated by reference in its entirety.

[0070] As used herein, the term “selective glucocorticoid receptor antagonist” (SGRA) refers to any composition or compound which inhibits GC binding to GR, or which inhibits any biological response due to such binding (where inhibition is determined with respect to the response in the absence of the compound). By “selective,” the drug preferentially binds to the GR rather than other nuclear receptors, such as the progesterone receptor (PR), the mineralocorticoid receptor (MR) or the androgen receptor (AR). It is preferred that the selective glucocorticoid receptor antagonist bind GR with an affinity that is lOx greater (1/10 ^th the Kd value) than its affinity to the MR, AR, or PR, both the MR and PR, both the MR and AR, both the AR and PR, or to the MR, AR, and PR. In a more preferred embodiment, the selective glucocorticoid receptor antagonist binds GR with an affinity that is lOOx greater (l/lOO ¹¹¹ the K _d value) than its affinity to the MR, AR, or PR, both the MR and PR, both the MR and AR, both the AR and PR, or to the MR, AR, and PR. In another embodiment, the selective glucocorticoid receptor antagonist binds GR with an affinity that is lOOOx greater (l/lOOO ¹¹¹ the K _d value) than its affinity to the MR, AR, or PR, both the MR and PR, both the MR and AR, both the AR and PR, or to the MR, AR, and PR. Relacorilant is a SGRA.

[0071] Non-steroidal GRA, SGRA, GRM, and SGRM compounds include compounds comprising a fused azadecalin structure (which may also be termed a fused azadecalin backbone), compounds comprising a heteroaryl -ketone fused azadecalin structure (which may also be termed a heteroaryl -ketone fused azadecalin backbone), compounds comprising an octahydro fused azadecalin structure (which may also be termed an octahydro fused azadecalin backbone), and compounds comprising a pyrimidine cyclohexyl backbone.

[0072] Exemplary non-steroidal GRA, SGRA, GRM, and SGRM compounds comprising a fused azadecalin structure include those described in U.S. Patent Nos. 7,928,237 and 8,461,172. Exemplary non-steroidal GRA, SGRA, GRM, and SGRM compounds comprising a heteroaryl -ketone fused azadecalin structure include those described in U.S. Patent 8,859,774. Exemplary non-steroidal GRA, SGRA, GRM, and SGRM compounds comprising an octahydro fused azadecalin structure include those described in U.S. Patent 10,047,082. Exemplary non-steroidal GRA, SGRA, GRM, and SGRM compounds comprising a pyrimidine cyclohexyl backbone include compounds disclosed in U.S. Patent 8,685,973. All patents, patent publications, and patent applications disclosed herein, both supra and infra , are hereby incorporated by reference in their entireties.

[0073] Exemplary glucocorticoid receptor antagonists comprising a cyclohexyl pyrimidine structure include those described in U.S. Patent No. 8,685,973; in U.S. Patent No. 8,906,917; and in U.S. Patent No. 9,321,736. In embodiments, the cyclohexyl pyrimidine GRA is the compound (E)-6-(4-Phenylcyclohexyl)-5-(3-trifluoromethylbenzyl)-lH-py rimidine-2,4-dione (termed “miricorilant” and “CORT118335”), which has the structure:

[0074] Exemplary glucocorticoid receptor antagonists comprising a fused azadecalin structure include those described in U.S. Patent No. 7,928,237; and U.S. Patent No. 8,461,172. In embodiments, the fused azadecalin GRA is the compound (R)-4-a- ethoxymethyl-l-(4-fluoro-phenyl)-6-(4-trifluoromethyl-benzen esulfonyl)-4,4a,5,6,7,8- hexahydro-lH,l,2,6-triaza-cyclopenta[b]naphthalene (“CORT 108297”), which has the structure:

[0075] Exemplary heteroaryl -ketone fused azadecalin compounds are described in U.S. Patent 8,859,774; in U.S. Patent 9,273,047; in U.S. Patent 9,707,223; and in U.S. Patent 9,956,216, all of which patents are hereby incorporated by reference in their entireties. In embodiments, the heteroaryl -ketone fused azadecalin GRA is the compound (R)-(l-(4- fluorophenyl)-6-((l-methyl-lH-pyrazol-4-yl)sulfonyl)-4, 4a, 5,6,7, 8-hexahydro-lH- pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin -2-yl)methanone (Example 18 of U.S. 8,859,774), also known as “relacorilant” and as “CORT125134”, which has the following structure:

[0076] In embodiments, the heteroaryl -ketone fused azadecalin GRA is the compound (R)- (l-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl) sulfonyl)-4, 4a, 5,6,7,8-hexahydro-l-H- pyrazolo P,4-g]isoquinolin-4a-yl) (pyridin-2-yl)methanone (termed “CORT113176”), which has the following structure:

[0077] Exemplary glucocorticoid receptor antagonists comprising an octohydro fused azadecalin structure include those described in U.S. Patent No. 10,047,082. In embodiments, the octahydro fused azadecalin compound is the compound ((4aR,8aS)-l-(4-fluorophenyl)-6- ((2-methyl-2H-l,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9 -octahydro-lH-pyrazolo[3,4- g]isoquinolin-4a-yl)(4-

(trifluoromethyl)pyridin-2-yl)methanone (termed “exicorilant” and “CORT125281”) which has the structure:

[0078] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients such as the said compounds, their tautomeric forms, their derivatives, their analogues, their stereoisomers, their polymorphs, their deuterated species, their pharmaceutically acceptable salts, esters, ethers, metabolites, mixtures of isomers, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions in specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term in relation to a pharmaceutical composition is intended to encompass a product comprising the active ingredient (s), and the inert ingredient (s) that make up the carrier, as well as any product which results, directly or indirectly, in combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention are meant to encompass any composition made by admixing compounds of the present invention and their pharmaceutically acceptable carriers.

[0079] In some embodiments, the term “consisting essentially of’ refers to a composition in a formulation whose only active ingredient is the indicated active ingredient, however, other compounds may be included which are for stabilizing, preserving, etc. the formulation, but are not involved directly in the therapeutic effect of the indicated active ingredient. In some embodiments, the term “consisting essentially of’ can refer to compositions which contain the active ingredient and components which facilitate the release of the active ingredient. For example, the composition can contain one or more components that provide extended release of the active ingredient over time to the subject. In some embodiments, the term “consisting” refers to a composition, which contains the active ingredient and a pharmaceutically acceptable carrier or excipient.

[0080] As used herein, the phrase “non-steroidal backbone” in the context of SGRMs refers to SGRMs that do not share structural homology to, or are not modifications of, cortisol with its steroid backbone containing seventeen carbon atoms, bonded in four fused rings.

[0081] Non-steroidal GRA, SGRA, GRM, and SGRM compounds include compounds comprising a fused azadecalin structure (which may also be termed a fused azadecalin backbone), compounds comprising a heteroaryl -ketone fused azadecalin structure (which may also be termed a heteroaryl -ketone fused azadecalin backbone), compounds comprising an octahydro fused azadecalin structure (which may also be termed an octahydro fused azadecalin backbone), and compounds comprising a pyrimidine cyclohexyl backbone. Exemplary non-steroidal GRA, SGRA, GRM, and SGRM compounds comprising a fused azadecalin structure include those described in U.S. Patent Nos. 7,928,237 and 8,461,172. Exemplary non-steroidal GRA, SGRA, GRM, and SGRM compounds comprising a heteroaryl -ketone fused azadecalin structure include those described in U.S. Patent 8,859,774. Exemplary non-steroidal GRA, SGRA, GRM, and SGRM compounds comprising an octahydro fused azadecalin structure include those described in U.S. Patent 10,047,082. Exemplary non-steroidal GRA, SGRA, GRM, and SGRM compounds comprising a pyrimidine cyclohexyl backbone include compounds disclosed in U.S. Patent 8,685,973. All patents, patent publications, and patent applications disclosed herein are hereby incorporated by reference in their entireties.

[0082] “Salt” refers to acid or base salts of the compounds used in the methods of the present invention. Illustrative examples of pharmaceutically-acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, and the like) salts, and quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the pharmaceutically-acceptable salts are non-toxic. Additional information on suitable pharmaceutically-acceptable salts can be found in Remington's Pharmaceutical Sciences,

17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0083] “Isomers” refers to compounds with the same chemical formula but which are structurally distinguishable.

[0084] “Tautomer” refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one form to another.

[0085] “Pharmaceutically-acceptable excipient” and “pharmaceutically-acceptable carrier” refer to a substance that aids the administration of an active agent to - and absorption by - a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. As used herein, these terms are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, antioxidant agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Non-limiting examples of pharmaceutically- acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, encapsulating agents, plasticizers, lubricants, coatings, sweeteners, flavors and colors, and the like. One of ordinary skill in the art will recognize that other pharmaceutical excipients are useful in the present invention. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions. One of ordinary skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.

TREATMENT METHODS

[0086] In embodiments, Applicant discloses methods to modulate (including to reduce) the expression of, or numbers of, glucocorticoid-modulated host receptor proteins effective to reduce viral binding to such host receptor proteins, and effective to reduce viral infection, reduce the severity of viral infections, reduce the duration of viral infections, and otherwise prevent or treat viral infections. The methods disclosed herein include methods of reducing the numbers of, or expression of, host receptor proteins effective to reduce viral infection. For example, the methods disclosed herein include methods of administering glucocorticoid receptor antagonists (GRAs) effective to reduce the expression of, numbers of, or both, of glucocorticoid-modulated host receptor proteins thereby reducing the ability of viruses to infect cells in a patient.

[0087] In particular embodiments, Applicant discloses novel methods for treating infections or reducing levels of proteins involved in viral binding to, or entry into, cells of a patient, and wherein said glucocorticoid-modulated host receptor proteins are proteins for which the expression of genetic message encoding them, or the levels of which proteins in or on cells of a patient, are modulated by glucocorticoids,

Comprising administration of a glucocorticoid receptor antagonist, effective to reduce the expression of, or level of, said glucocorticoid-modulated host receptor proteins,

Whereby the risk of developing a viral infection in the patient is reduced in comparison to the risk of developing a viral infection in a subject whose expression of glucocorticoid-regulated host receptor proteins has not been reduced.

[0088] In an embodiment, Applicant discloses methods of reducing the risk of developing a coronavirus infection in a patient, comprising:

Administering an amount of a glucocorticoid receptor antagonist (GRA) effective to reduce ACE2 or TMPRSS2 expression in the patient, Whereby the risk of developing a coronavirus infection is reduced in comparison to the risk of developing a coronavirus infection in a subject whose ACE2 or TMPRSS2 expression has not been reduced.

[0089] In an embodiment, Applicant discloses a method of reducing the severity of a coronavirus infection in a patient having a coronavirus infection, comprising:

Administering an amount of a glucocorticoid receptor antagonist (GRA) effective to reduce ACE2 or TMPRSS2 expression in the patient,

Whereby the severity of said coronavirus infection is reduced in comparison to the severity of such a coronavirus infection in a subject whose ACE2 or TMPRSS2 expression has not been reduced.

[0090] In an embodiment, Applicant discloses a method to reduce the duration of a coronavirus infection in a patient, comprising:

Administering an amount of a glucocorticoid receptor antagonist (GRA) effective to reduce ACE2 or TMPRSS2 expression in the patient,

Whereby the duration of said coronavirus infection is reduced in comparison to the duration of such a coronavirus infection in a subject whose ACE2 or TMPRSS2 expression has not been reduced.

[0091] In an embodiment, Applicant discloses a method to reduce angiotensin-converting enzyme 2 (ACE2) or transmembrane serine protease 2 (TMPRSS2) expression in a patient, comprising:

Administering an amount of a glucocorticoid receptor antagonist (GRA) effective to reduce ACE2 or TMPRSS2 expression in the patient,

Whereby the level of ACE2 or TMPRSS2 expression is reduced in said patient as compared to the level of ACE2 or TMPRSS2 expression in a subject whose ACE2 or TMPRSS2 expression has not been reduced.

[0092] In an embodiment, Applicant discloses a method to reduce the amount of angiotensin-converting enzyme 2 (ACE2) or transmembrane serine protease 2 (TMPRSS2) macromolecules on the surface of cells in a patient, comprising:

Administering an amount of a glucocorticoid receptor antagonist (GRA) effective to reduce ACE2 or TMPRSS2 expression in the patient, Whereby the amount of ACE2 or TMPRSS2 macromolecules on the surface of cells in said patient is reduced as compared to the amount of ACE2 or TMPRSS2 macromolecules on the surface of cells in a subject whose ACE2 or TMPRSS2 expression has not been reduced.

[0093] In an embodiment, Applicant discloses a method to reduce coronavirus binding to cells susceptible to coronavirus infection, comprising:

Administering an amount of a glucocorticoid receptor antagonist (GRA) effective to reduce ACE2 or TMPRSS2 expression in the patient,

Whereby the coronavirus binding sites on cells susceptible to coronavirus infection in said patient is reduced as compared to coronavirus binding sites in cells susceptible to coronavirus infection in a subject whose ACE2 or TMPRSS2 expression has not been reduced, effective to reduce coronavirus binding to cells susceptible to coronavirus infection in the patient.

[0094] In an embodiment, Applicant discloses a method to reduce the activity of angiotensin-converting enzyme 2 (ACE2) or transmembrane serine protease 2 (TMPRSS2) in a patient, including in cells of a patient, comprising:

Administering an amount of a glucocorticoid receptor antagonist (GRA) effective to reduce ACE2 or TMPRSS2 activity in the patient and in patient cells,

Whereby the ACE2 or TMPRSS2 activity in said patient and in patient cells, is reduced as compared to the amount of ACE2 or TMPRSS2 activity in a subject and in the subject’s cells whose ACE2 or TMPRSS2 activity has not been reduced.

[0095] In embodiments, the coronavirus is selected from SARS-CoV-2, SARS, and MERS viruses. In an embodiment, the virus is SARS-CoV-2.

[0096] In embodiments, the methods are suitable for use with, and may be applied to the treatment of, a patient who has high cortisol levels as compared to normal cortisol levels for a subject of that age or condition. In embodiments, the methods are suitable for use with, and may be applied to the treatment of, a patient who has high cortisol levels as compared to average cortisol levels for a subject of that age or condition.

[0097] In embodiments, the patient suffers from a disease or condition characterized by high cortisol levels as compared to cortisol levels in normal subjects not suffering from said disease or condition. In embodiments, the patient suffers from a disease or condition selected from Cushing’s syndrome, depression, an anxiety disorder, post-traumatic stress disorder, and alcohol dependence. In embodiments, the patient suffers from a disease or condition selected from Cushing’s syndrome, depression, an anxiety disorder, post-traumatic stress disorder, and alcohol dependence, and has been receiving GRA administration prior to becoming at risk for a coronavirus infection, or prior to testing positively for a coronavirus infection, or prior to exhibiting symptoms of a coronavirus infection. In embodiments, the patient suffers from hypertension, diabetes, or cancer. In embodiments, the patient has been administered an ACE inhibitor. In embodiments, the patient has been administered an ACE inhibitor in an amount or for a duration effective to increase ACE2 expression in cells of that patient to higher than normal levels. In embodiments, the patient has been administered an angiotensin receptor blocker. In embodiments, the patient has been administered an angiotensin receptor blocker in an amount or for a duration effective to increase ACE2 expression in cells of the patient to higher than normal levels.

[0098] In further embodiments, the patient has normal, or average, cortisol levels for a patient of that age or condition. In embodiments, the patient is a healthy patient.

[0099] In any of the embodiments disclosed herein, the duration of GRA administration may be, e.g., 3 weeks, or 4 weeks, and may be stopped after a test of a sample obtained from the patient indicates that the patient does not harbor the SARS-CoV-2 virus. In embodiments, GRA administration may be stopped after the patient exhibits one or more of signs of excess immune response, inflammation, increased C-Reactive Protein levels, and respiratory distress. In embodiments, GRA administration may be stopped after the patient exhibits signs indicating that the patient is a candidate for treatment by a glucocorticoid. In embodiments, GRA administration may be stopped after the patient exhibits a sign of suffering from a cytokine storm. Examples of signs of suffering from a cytokine storm include, e.g., an elevated level of one or more of an interleukin, interferon-gamma (IFN-g), tumor necrosis factor alpha (TNF-a), granulocyte-colony-stimulating factor (GCSF), monocyte chemoattractant protein- 1 (MCP-1), and macrophage inflammatory protein 1-A (MIP-IA). Interleukins which may be signs of a cytokine storm include, e.g., interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6) levels, interleukin-7 (IL-7), and interleukin 10 (IL- 10).

[0100] In embodiments disclosed herein in which the patient, prior to being exposed to SARS-CoV-2, or prior to exhibiting symptoms of a SARS-CoV-2 infection, had been receiving prior GRA treatment comprising administration of a prior GRA dose, the patient may continue to receive administration of the prior GRA dose for at least 3 weeks, or at least 4 weeks, following said exposure to SARS-CoV-2 or following exhibiting symptoms of a SARS-CoV-2 infection. In embodiments disclosed herein in which the patient, prior to being exposed to SARS-CoV-2, or prior to exhibiting symptoms of a SARS-CoV-2 infection, had been receiving prior GRA treatment comprising administration of a prior GRA dose, the patient may receive administration of a dose of GRA that is a higher GRA dose than the prior GRA dose, for at least 3 weeks or at least 4 weeks after being exposed to SARS-CoV-2, or after exhibiting symptoms of a SARS-CoV-2 infection. In embodiments in which the patient, prior to being exposed to SARS-CoV-2, or prior to exhibiting symptoms of a SARS-CoV-2 infection, had been receiving GRA treatment comprising administration of a prior GRA dose, the patient may continue to receive administration of said prior GRA dose, or said higher GAR dose, until the patient exhibits signs indicating that the patient is a candidate for treatment by a glucocorticoid, and then administration of said GRA dose is stopped.

[0101] The GRA may be a SGRA. In embodiments of the methods disclosed herein, the GRA or SGRA is a steroidal GRA or SGRA. In embodiments, the steroidal GRA or SGRA has an aryl substituent at the 11 -position of the steroid backbone. In embodiments, the steroidal GRA is mifepristone.

[0102] In embodiments of the methods disclosed herein, the GRA or SGRA is a non steroidal GRA or SGRA. In embodiments, the non-steroidal GRA or SGRA is a compound comprising a cyclohexyl pyrimidine structure; or a fused azadecalin structure; or a heteroaryl- ketone fused azadecalin structure; or an octahydro fused azadecalin structure. Non-steroidal compounds comprising a fused azadecalin structure are described and disclosed in U.S.

Patent 7,928,237 and in U.S. Patent 8,461,172, the entire contents of both of which patents are hereby incorporated by reference in their entireties. Non-steroidal compounds comprising a heteroaryl -ketone fused azadecalin structure are described and disclosed in U.S. Patent 8,859,774, the entire contents of which is hereby incorporated by reference in its entirety. Non-steroidal compounds comprising an octahydro fused azadecalin structure are described and disclosed in U.S. Patent 10,047,082, the entire contents of which is hereby incorporated by reference in its entirety. Non-steroidal compounds comprising a pyrimidine cyclohexyl structure are described and disclosed in U.S. Patent 8,685,973, the entire contents of which is hereby incorporated by reference in its entirety.

[0103] In embodiments, the methods comprise administration of the compound comprising a cyclohexyl pyrimidine structure that is (E)-6-(4-Phenylcyclohexyl)-5-(3- trifluoromethylbenzyl)-lH-pyrimidine-2,4-dione (termed “miricorilant” or “CORT118335”), having the formula:

[0104] In embodiments, the methods comprise administration of the compound comprising a fused azadecalin structure that is (R)-4-a-ethoxymethyl-l-(4-fluoro-phenyl)-6-(4- trifluoromethyl-benzenesulfonyl)-4, 4a, 5,6,7, 8-hexahydro-lH, 1,2, 6-triaza- cyclopenta[b]naphthalene (“CORT108297”), having the formula:

[0105] In embodiments, the methods comprise administration of the compound comprising a heteroaryl -ketone fused azadecalin structure that is (R)-(l-(4-fluorophenyl)-6-((l-methyl-lH- pyrazol-4-yl)sulfonyl)-4, 4a, 5,6,7, 8-hexahydro-lH-pyrazolo[3, 4-g]isoquinolin-4a-yl)(4- (trifluoromethyl)pyridin-2-yl)methanone (termed “relacorilant” or“CORT125134”), having the formula:

[0106] In embodiments, the compound comprising a heteroaryl -ketone fused azadecalin structure is (R)-(l-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl) sulfonyl)-4, 4a, 5, 6,7,8- hexahydro-l-H-pyrazolo P,4-g]isoquinolin-4a-yl) (pyridin-2-yl)methanone (termed “CORT113176”), having the formula:

[0107] In embodiments, the methods comprise administration of the compound comprising an octahydro fused azadecalin structure that is ((4aR,8aS)-l-(4-fluorophenyl)-6-((2-methyl- 2H-l,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro- lH-pyrazolo[3,4-g]isoquinolin- 4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (termed “exicorilant”, or “CORT125281”), having the formula:

[0108] In embodiments, Applicant discloses methods of reducing a patient’s risk of developing a viral infection in a patient, said viral infection due to a virus whose binding to, or entry into, patient cells is related to glucocorticoid-modulated host receptor proteins, the method comprising:

Administering an amount of a glucocorticoid receptor antagonist (GRA) effective to reduce the expression or levels in said patient of said glucocorticoid-modulated host receptor proteins, wherein said glucocorticoid-modulated host receptor proteins are involved in viral binding to, or entry into, cells of a patient, and wherein said glucocorticoid-modulated host receptor proteins are proteins for which the expression of genetic message encoding them, or the levels of which proteins in or on cells of a patient, are modulated by glucocorticoids,

Whereby the risk of developing a viral infection in the patient is reduced in comparison to the risk of developing a viral infection in a subject whose expression of glucocorticoid-regulated host receptor proteins has not been reduced. [0109] In embodiments, Applicant discloses methods of reducing the severity of a viral infection in a patient having an infection due to a virus whose binding to, or entry into, patient cells is related to glucocorticoid-modulated host receptor proteins, comprising:

Administering an amount of a glucocorticoid receptor antagonist (GRA) effective to reduce the expression or levels in said patient of said glucocorticoid-modulated host receptor proteins, wherein said glucocorticoid-modulated host receptor proteins are involved in viral binding to, or entry into, cells of a patient, and wherein said glucocorticoid-modulated host receptor proteins are proteins for which the expression of genetic message encoding them, or the levels of which proteins in or on cells of a patient, are modulated by glucocorticoids,

Whereby the severity of said viral infection in the patient is reduced in comparison to the severity of a viral infection due to the same virus in a subject whose expression of glucocorticoid-regulated host receptor proteins has not been reduced.

[0110] In embodiments, Applicant discloses methods to reduce the duration of a viral infection in a patient having an infection due to a virus whose binding to, or entry into, patient cells is related to glucocorticoid-modulated host receptor proteins, comprising:

Administering an amount of a glucocorticoid receptor antagonist (GRA) effective to reduce the expression or levels in said patient of said glucocorticoid-modulated host receptor proteins, wherein said glucocorticoid-modulated host receptor proteins are involved in viral binding to, or entry into, cells of a patient, and wherein said glucocorticoid-modulated host receptor proteins are proteins for which the expression of genetic message encoding them, or the levels of which proteins in or on cells of a patient, are modulated by glucocorticoids,

Whereby the duration of said viral infection in the patient is reduced in comparison to the duration of a viral infection due to the same virus in a subject whose expression of glucocorticoid-regulated host receptor proteins has not been reduced.

[0111] In embodiments, Applicant discloses methods to reduce the expression of, or numbers of, glucocorticoid-modulated host receptor proteins in a patient, comprising:

Administering an amount of a glucocorticoid receptor antagonist (GRA) effective to reduce the expression or levels in said patient of said glucocorticoid-modulated host receptor proteins, wherein said glucocorticoid-modulated host receptor proteins are proteins for which the expression of genetic message encoding them, or the levels of which proteins in or on cells of a patient, are modulated by glucocorticoids,

Whereby the expression of, or numbers of, said glucocorticoid-modulated host receptor proteins in the patient is reduced in comparison to the expression of, or numbers of, said glucocorticoid-modulated host receptor proteins in a subject whose expression of glucocorticoid-regulated host receptor proteins has not been reduced.

[0112] In embodiments, Applicant discloses methods to reduce viral binding to cells in a patient, wherein said cells are susceptible to viral infection, wherein said viral binding is mediated, at least in part, by glucocorticoid-modulated host receptor proteins in a patient, the method comprising:

Administering an amount of a glucocorticoid receptor antagonist (GRA) effective to reduce the expression or levels in said patient of said glucocorticoid-modulated host receptor proteins, wherein said glucocorticoid-modulated host receptor proteins are proteins for which the expression of genetic message encoding them, or the levels of which proteins in or on cells of a patient, are modulated by glucocorticoids,

Whereby the expression of, or numbers of, said glucocorticoid-modulated host receptor proteins in the patient is reduced in comparison to the expression of, or numbers of, said glucocorticoid-modulated host receptor proteins in a subject whose expression of glucocorticoid-regulated host receptor proteins has not been reduced.

[0113] Accordingly, in embodiments of the methods disclosed herein, said glucocorticoid- modulated host receptor proteins are negatively modulated by administration of a glucocorticoid receptor antagonist (GRA), effective to decrease the expression of genetic message encoding glucocorticoid-modulated host receptor proteins, leading to a decrease in the levels of glucocorticoid-modulated host receptor proteins in or on cells of a patient as compared to the levels of said expression or of said proteins in the absence of GRAs.

[0114] In embodiments, Applicant discloses methods of administering a GRA to reduce viral binding to cells in a patient, wherein said cells are susceptible to viral infection, wherein said viral binding is mediated, at least in part, by glucocorticoid-modulated host receptor proteins in a patient, wherein the patient is a healthy patient. In embodiments of any and all of the methods disclosed herein, these methods are effective to reduce the risk of subsequently contracting a viral infection when administered to a healthy patient prior to their contracting a viral infection. In embodiments, these methods are effective to reduce the severity of, and to reduce the duration of, a subsequent viral infection when administered to a healthy patient prior to their contracting a viral infection. Such methods of administered to a healthy patient prior to their contracting a viral infection are prophylactic methods. Such prophylactic methods may be effective to reduce the spread of a viral infection in a population when administered to multiple healthy patients in the population, or to reduce the duration of the epidemic or pandemic due to the virus, or to reduce the severity of symptoms in patients in a population when administered to multiple healthy patients in the population.

[0115] The present methods are believed to be suitable for treatment not only of many viruses, including known coronaviruses such as SARS-CoV-2, SARS, and MERS, but to be also suitable for treatment, including prophylactic treatments, for viruses related to, but different from (e.g., mutated versions) of viruses known today, such as the coronaviruses listed here. In particular, the present methods are believed to be also suitable for treatment not only of known viruses, but also or viruses related to, but different from (e.g., mutated versions) of viruses known today, where such viruses bind to host receptor proteins. For example, the present methods are believed to be also effective to reduce viral binding to cells in a patient, wherein said cells are susceptible to viral infection, wherein said viral binding is mediated, at least in part, by glucocorticoid-modulated host receptor proteins in a patient, where the viruses are related to, but different from (e.g., mutated versions) of viruses known today. Such methods may be applied to a patient suffering from a viral infection, and may be applied to a healthy patient.

[0116] The present methods are suitable for use in treating (prophylactically prior to infection, or treating after infection) any viral infection that is mediated by, or enhanced by, viral binding to host receptor proteins, and such host receptor proteins are regulated by glucocorticoids. Thus, any and all methods disclosed herein are suitable for use in treating an infection due to any virus whose transmission is mediated by a glucocorticoid-modulated host receptor protein.

GLUCOCORTICOID RECEPTOR MODULATORS (GRMl

[0117] Generally, Applicant discloses herein that treatment of infection by a virus whose transmission is mediated by a glucocorticoid-modulated host receptor protein may be treated by administration of a glucocorticoid receptor antagonist (GRA). Such treatments include administration of an effective amount of a GRA effective to reduce the amount of, or expression of, the glucocorticoid-modulated host receptor proteins utilized by the virus for viral transmission, or to otherwise reduce viral transmission mediated by viral recognition of or binding to the glucocorticoid-modulated host receptor protein. In embodiments, the GRA is mifepristone. In embodiments, the GRA is a selective GRA (SGRA). In embodiments, treatment of c can be provided by administering an effective amount of a SGRA. In preferred embodiments, treatment of viral infection can be provided by administering an effective amount of a non-steroidal GRA or SGRA. Provided herein are classes of exemplary GRAs, and in particular, exemplary non-steroidal SGRAs, and specific members of such classes. However, one of skill in the art will readily recognize other related or unrelated GRAs that can be employed in the treatment methods described herein.

[0118] In some embodiments, treating a viral infection involves a GRA comprising a fused azadecalin structure; a GRA comprising a heteroaryl -ketone fused azadecalin structure; a GRA comprising an octahydro fused azadecalin structure; or a GRA comprising a pyrimidine cyclohexyl structure. Exemplary GRAs comprising a fused azadecalin structure include those described in U.S. Patent Nos. 7,928,237; and 8,461,172 and can be prepared as disclosed therein. Exemplary GRAs comprising a heteroaryl -ketone fused azadecalin structure include those described in U.S. 8,859,774, which can be prepared as disclosed therein. Exemplary GRMs comprising an octahydro fused azadecalin structure include those described in U.S. 10,047,082 and can be prepared as described therein. Exemplary GRAs comprising a pyrimidine cyclohexyl structure include those described and disclosed in U.S. Patent 8,685,973. The entire contents of all patents cited herein are hereby incorporated by reference in their entireties.

PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATION

[0119] In embodiments, the present methods may utilize a pharmaceutical composition including a pharmaceutically acceptable excipient and a GRA or SGRA.

[0120] As used herein, the terms “excipient”, “pharmaceutically acceptable excipient”, and “pharmaceutically acceptable carrier” are used interchangeably to refer to any compound or material which is included in a formulation or in a pharmaceutical composition other than the active ingredient (or active ingredients where more than one compound may have the desired pharmaceutical activity). An excipient may serve as, e.g., a solvent, solubilizer or solubility enhancer; an emulsifier; a bulking agent; a stabilizer; a diluent; a surfactant; a preservative; a colorant; a flavor; a filler; a lubricant; or other agent which may serve other functions. Non limiting examples of excipients include water, sodium chloride (NaCl), normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors, and the like. Excipients used in formulations as disclosed herein may include various cyclodextrins such as, e.g., a- cyclodextrin, b-cyclodextrin, hydroxypropyl-P-cyclodextrin, sulfobutylether-P-cyclodextrin, and others. Cyclodextrins may be used, e.g., as emulsifiers, solubilizers, and for other purposes. As used herein, these terms are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Additional information on suitable pharmaceutically acceptable excipients, and also on techniques for formulation and administration can be found in Remington: The Science and Practice of Pharmacy, 22nd ed., Pharmaceutical Press and Philadelphia College of Pharmacy, 2012, which is incorporated herein by reference.

[0121] Formulations comprising a GRA may contain, in addition to the GRA, one or more pharmaceutically acceptable excipients, including, e.g., a solubilizer, a surfactant, a disintegrant, a lubricant, a glidant, an antioxidant, a filler, or one or more other excipient.

[0122] Solubilizers (also termed solvents or solubility enhancers) may include, e.g., ethanol, glycerin, A ^f -methyl -2-pyrrol idone, dimethylacetamide, dimethylsulfoxide, glycerols including glycerol caprylates, polyethylene glycols (PEG), propylene glycols (including, e.g., a propylene glycol or propylene glycol ester, such as, e.g., a propylene glycol caprylate (e.g., a propylene glycol monocaprylate), glycerols, polypropylene glycerols, glycerin, A ^f - ethy 1-2- pyrrol idone, dimethylacetamide, dimethylsulfoxide, other water-soluble organic solvents, and other solubilizers known in the art. In embodiments, a solubilizer may be,

[0123] As used herein, the term “surfactant” refers to, without limitation, polyethoxylated castor oil and other oils; polysorbate (polyoxyethylene sorbitan monolaureate) surfactants and detergents (such as, e.g., Tween ^® 20, Tween ^® 80, and others); polyoxyl glycerides, e.g., lauryl polyoxyl glycerides and other polyoxyl glycerides; and include ionic and non-ionic surfactants. Non-ionic surfactants include sorbitan surfactants such as sorbitan monooleate; polysorbates (of many sizes, including e.g., polysorbate 20, polysorbate 80, also known as Tween ^® 20 and Tween ^® 80 as discussed above); and other non-ionic surfactants. Polysorbate surfactants and detergents aid in the emulsification and/or solubilization of active compounds in addition to their actions as surfactants. Ionic surfactants include, e.g., sodium lauryl sulfate (SLS).

[0124] Disintegrants include, without limitation, agar, alginic acid, calcium carbonate, methyl cellulose, microcrystalline cellulose, croscarmellose sodium, crospovidone (cross- linked polyvinyl pyrrolidone), croscarmellose sodium, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof. [0125] Lubricants include, without limitation, magnesium stearate, calcium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.

[0126] Glidants include, without limitation, talc, corn starch, silicon dioxide, sodium lauryl sulfate, magnesium stearate, calcium stearate, sodium stearate, stearic acid, sodium stearyl fumarate, hydrogenated cotton seed oil, talc, waxes, cetyl alcohol, glyceryl stearate, glyceryl palmitate, glyceryl behenate, hydrogenated vegetable oils, and stearyl alcohol.

[0127] Antioxidants may include, e.g., butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tert-butyl hydroquinone (TBHQ), a gallate such as propyl gallate, a tocopherol such as alpha tocopherol, and other antioxidants.

[0128] Excipients used in formulations as disclosed herein may include lipids and phospholipids, including naturally occurring lipid compositions such as, e.g., castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil and palm seed oil). Excipients used in formulations as disclosed herein may also include phospholipids such as, e.g., phosphatidylcholine, distearoylphosphatidylglycerol L-a- dimyristoylphosphatidylcholine, L-a-dimyristoylphosphatidylglycerol, and other phospholipids. Lipids and phospholipids may be used, e.g., as emulsifiers, bulking agents, fillers, lubricants, and for other purposes.

[0129] In embodiments, formulations as disclosed herein containing a GRM may include triglycerides, including medium chain triglycerides. Medium chain triglycerides are triglycerides with fatty acid chain lengths of between about 6 to about 12 carbons long. Triglycerides may include, e.g., 1,2,3-triacetoxypropane (also known as triacetin or as glycerin triacetate). Triglyceride excipients such as, e.g., triacetin, may serve, e.g., as solvents, as plasticizers, and as hu ectants.

[0130] Formulations including a GRA, such as a GRA formulation for oral administration, may include solid amorphous granules produced from a spray-dried dispersion (SDD) which include that GRA. Such granules may also contain excipients, such as, e.g., eudragit (poly(m ethyl methacrylate-co-(methacrylic acid)) (PMMAMA), polymers (e.g., hydroxypropyl methyicelluiose acetate succinate (HPMCAS)), and other excipients such as, e.g., surfactants, disintegrants, lubricants, glidants, and other excipients.

[0131] The GRA or SGRA can be prepared and administered in a wide variety of oral, parenteral and topical dosage forms. In some cases, the GRA or SGRA may be orally administered. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. GRAs and SGRAs can also be administered by injection, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally; by infusion; by transdermal application; by a nebulized suspension; by an aerosol spray; or by inhalation, for example, intranasally. In embodiments, the GRA or SGRA may be administered by inhalation, for example, intranasally.

[0132] In some cases, the effective amount of the GRA or SGRA is a daily dose of between 1 and 100 mg/kg/day, wherein the GRA or SGRA. In some embodiments, the daily dose of the GRA or SGRA is 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 30, 40, 5060, 70, 80, 90 or 100 mg/kg/day. In some cases, the GRA or SGRA is administrated for at least 1, 2, 3, 4, 5, 6, 7, or more days; or for 1, 2, 3, 4, or more weeks.

[0133] For preparing pharmaceutical compositions from GRAs or SGRAs, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

[0134] In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component, a GRA or SGRA. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0135] The powders and tablets preferably contain from about 5% or 10% to about 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyicelluiose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0136] Suitable solid excipients are carbohydrate or protein fillers including, but are not limited to sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl- cellulose, or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins such as gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.

[0137] Dragee cores are provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound (i.e., dosage). Pharmaceutical preparations of the invention can also be used orally using, for example, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules can contain GR modulator mixed with a filler or binders such as lactose or starches, lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the GR modulator compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers.

[0138] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0139] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide ( e.g ., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol ( e.g ., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g, polyoxyethylene sorbitan mono-oleate). The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. Formulations can be adjusted for osmolarity.

[0140] Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0141] Oil suspensions can be formulated by suspending a GRA or SGRA in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical formulations of the invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono- oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.

[0142] The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component, a GRA or SGRA. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0143] The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to 6000 mg, most typically 50 mg to 500 mg. Suitable dosages also include about 1 mg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90,

100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600,

1700, 1800, 1900, or 2000 mg, according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.

[0144] In some embodiments, the GRA or SGRA is administered in one dose, e.g., a single once-daily dose. In other embodiments, the GRA or SGRA is administered in more than one dose, e.g., 2 doses, 3 doses, 4 doses, 5 doses, 6 doses, 7 doses, or more. In some cases, the doses are of an equivalent amount. In other cases, the doses are of different amounts. The doses can increase or taper over the duration of administration. The amount will vary according to, for example, the GRA or SGRA properties and patient characteristics.

[0145] Any suitable GRA or SGRA dose may be used in the methods disclosed herein. The dose of GRA or SGRA that is administered can be at least about 300 milligrams (mg) per day, or about 600 mg/ day, e.g, about 600 mg/day, about 700 mg/day, about 800 mg/day, about 900 mg/day, about 1000 mg/day, about 1100 mg/day, about 1200 mg/day, or more. For example, where the GRA is mifepristone, the dose may be, e.g., 300 mg/day, or 600 mil day, or 900 mg/day, or 1200 mg/day of mifepristone. In embodiments, the GRA or SGRA is administered orally.

[0146] Single or multiple administrations of formulations can be administered depending on the dosage and frequency as required and tolerated by the patient. The formulations should provide a sufficient quantity of active agent to effectively treat the disease state.

Thus, in one embodiment, the pharmaceutical formulation for oral administration of a GRA or SGRA is in a daily amount of between about 0.01 to about 150 mg per kilogram of body weight per day (mg/kg/day). In some embodiments, the daily amount is from about 1.0 to 100 mg/kg/day, 5 to 50 mg/kg/day, 10 to 30 mg/kg/day, and 10 to 20 mg/kg/day. Lower dosages can be used, particularly when the drug is administered to an anatomically secluded site, such as the cerebral spinal fluid (CSF) space, in contrast to administration orally, into the blood stream, into a body cavity or into a lumen of an organ. Substantially higher dosages can be used in topical administration. Actual methods for preparing parenterally administrable formulations will be known or apparent to those skilled in the art and are described in more detail in such publications as Remington's, supra. See also Nieman, In "Receptor Mediated Antisteroid Action," Agarwal, et al., eds., De Gruyter, New York (1987).

[0147] The duration of treatment with a GRA or SGRA to treat a viral infection can vary according to the severity of the condition in a subject and the subject's response to the GRA or SGRA. In some embodiments, GRA or SGRAs can be administered for a period of less than about 1 week to about 20 weeks, more typically about 1 week to 10 weeks, most typically about 1 to about 3 or 4 weeks. Suitable periods of administration also include about 1 day to about 3 or 4 days; about 1 day to about 7 days; about 1 week to about 2 weeks; about 1 week to about 3 weeks; about 1 week to about 4 weeks; about 1 week to about 5 weeks; about 1 week to about 6 weeks, or more. Suitable periods of administration also include 1, 2, 3, 4, 5, 6, or 7 days; and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 weeks. Generally administration of a GRA or SGRA should be continued until clinically significant reduction or amelioration is observed.

[0148] In some embodiments, administration of a GRA or SGRA is not continuous and can be stopped for one or more periods of time, followed by one or more periods of time where administration resumes. Suitable periods where administration stops include about 1 day to 2 days; about 1 day to about 3 or 4 days; about 1 day to about 7 days; about 1 week to about 2 weeks; about 1 week to about 3 weeks; and about 1 week to about 4 weeks.

[0149] GRAs and SGRAs can be used in combination with other active agents known to be useful in modulating a glucocorticoid receptor, or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent. In embodiments, the combination provides synergistic effects greater than the sum of the individual effects expected from the GRA and the one or more agent individually.

[0150] In some embodiments, co-administration includes administering one active agent, a GRA or SGRA, within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co-administration includes administering two active agents simultaneously, approximately simultaneously ( e.g ., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active and/or adjunctive agents may be linked or conjugated to one another.

[0151] After a pharmaceutical composition including a GR modulator of the invention has been formulated in an acceptable carrier, it can be placed in an appropriate container and labeled for treatment of an indicated condition. For administration of a GRA or SGRA, such labeling would include, e.g ., instructions concerning the amount, frequency and method of administration.

[0152] Where applicable, pharmaceutical compositions comprising a GRA can be provided as a salt and can be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protic solvents that are the corresponding free base forms. In other cases, the preparation may be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%- 7% mannitol at a pH range of 4.5 to 5.5, that is combined with buffer prior to use.

[0153] In another embodiment, the compositions disclosed herein may be useful for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or lumen of an organ. The formulations for administration will commonly comprise a solution of the compositions of the present invention dissolved in a pharmaceutically acceptable carrier. Among the acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter. These formulations may be sterilized by conventional, well known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g. , sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of the compositions of the present invention in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs. For IV administration, the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, such as a solution of 1,3-butanediol.

COMBINATION THERAPIES

[0154] Various combinations with a GRA or SGRA and an antiviral, or other agent (or a combination of other medicinal agents and compounds) may be employed to treat the patient. By “combination therapy” or “in combination with”, it is not intended to imply that the therapeutic agents must be administered at the same time and/or formulated for delivery together, although these methods of delivery are within the scope described herein. The GRA or SGRA and the other medicinal agent can be administered following the same or different dosing regimen. In some embodiments, the GRA or SGRA and the other medicinal agent are administered sequentially in any order during the entire or portions of the treatment period. In some embodiments, the GRA or SGRA and the other medicinal agent are administered simultaneously or approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other). Non-limiting examples of combination therapies are as follows, with administration of the GRA or SGRA and the other medicinal agent for example, GRA or SGRA is “A” and the other medicinal agent is "B":

[0155] A/B/AB/A/BB/B/AA/A/BA/B/BB/A/AA/B/B/B B/A/B/B

[0156] B/B/B/A B/B/A/B A/A/B/B A/B/A/B A/B/B/A B/B/A/A

[0157] B/A/B/A B/A/A/B A/A/A/B B/A/A/A A/B/A/A A/A/B/A

[0158] Administration of the therapeutic compounds or agents to a patient will follow general protocols for the administration of such compounds, taking into account the toxicity, if any, of the therapy. Surgical intervention may also be applied in combination with the descirbed therapy if indicated. The present methods can be combined with any other means of treatment as indicated.

EXAMPLES

[0159] The following examples are provided by way of illustration only and not by way of limitation. Those of skill will readily recognize a variety of noncritical parameters which could be changed or modified to yield essentially similar results. [0160] In the following Examples, the GRA relacorilant is used in exemplary descriptions of ways in which the methods disclosed herein may be used to treat patients. It will be understood that the methods disclosed herein may be practiced with any of the GRAs disclosed herein, at any suitable dose, for any suitable duration of treatment, according to the present disclosure, including without limitation relacorilant, miricorilant, exicorilant, and any other fused azadecalin, heteroaryl -ketone fused azadecalin, octahydro fused azadecalin, and cyclohexyl pyrimidine GRA disclosed herein.

EXAMPLE 1 Relacorilant Treatment of a Coronavirus Infection

[0161] In a cruise ship 5 members of the crew develop symptoms of a viral infection and are diagnosed with COVID-19. Others on the ship are at risk of developing CoVID-19. A nasal swab is obtained from each of forty passengers with close contact with infected crew members; each swab is tested for SARS-CoV-2 RNA and also for ACE2 expression. SARS- CoV-2 RNA is found in the swabs of 20 of the 40 passengers. 10 passengers positive for the virus as indicated by the presence of SARS-CoV-2 RNA in their swabs receive daily administration of 400 milligrams (mg) of the glucocorticoid receptor antagonist (GRA) relacorilant.10 passengers negative for the virus (as indicated by the absence of SARS-CoV-2 RNA in their swabs) also receive daily administration of 400 mg relacorilant.

[0162] The result of 14 days of relacorilant administration is that no SARS-CoV-2 positive patient receiving relacorilant has severe COVID-19 disease (i.e., infection by the SARS- CoV-2 virus), while several SARS-CoV-2 positive patients not receiving relacorilant have severe COVID-19 disease. The result of 14 days of relacorilant administration is that no SARS-CoV-2 negative passenger receiving relacorilant has COVID-19 disease. These SARS- CoV-2 negative passengers not having COVID-19 disease and receiving relacorilant remain negative for SARS-CoV-2 RNA as indicated by testing a nasal swab obtained from these passengers. Patients receiving relacorilant have significantly lower ACE2 levels compared those not receiving relacorilant.

[0163] In contrast, 2 SARS-CoV-2 positive patients not receiving relacorilant develop severe COVID-19 disease and receive intubation. Half (5) of the SARS-CoV-2 negative passengers not receiving relacorilant test positive for SARS-CoV-2 RNA in a second test 14 days after the first test. EXAMPLE 2. Relacorilant Treatment of a Coronavirus Infection

[0164] In a cruise ship 5 members of the crew develop symptoms of a viral infection and are diagnosed with COVID-19. Others on the ship are at risk of developing CoVID-19. A nasal swab is obtained from each of forty passengers with close contact with infected crew members; each swab is tested for SARS-CoV-2 RNA and also for TMPRSS2 expression. SARS-CoV-2 RNA is found in the swabs of 20 of the 40 passengers. 10 passengers positive for the virus as indicated by the presence of SARS-CoV-2 RNA in their swabs receive daily administration of 400 milligrams (mg) of the glucocorticoid receptor antagonist (GRA) relacorilant.10 passengers negative for the virus (as indicated by the absence of SARS-CoV-2 RNA in their swabs) also receive daily administration of 400 mg relacorilant.

[0165] The result of 14 days of relacorilant administration is that no SARS-CoV-2 positive patient receiving relacorilant has severe COVID-19 disease (i.e., infection by the SARS- CoV-2 virus), while several SARS-CoV-2 positive patients not receiving relacorilant have severe COVID-19 disease. The result of 14 days of relacorilant administration is that no SARS-CoV-2 negative passenger receiving relacorilant has COVID-19 disease. These SARS- CoV-2 negative passengers not having COVID-19 disease and receiving relacorilant remain negative for SARS-CoV-2 RNA as indicated by testing a nasal swab obtained from these passengers. Patients receiving relacorilant have significantly lower TMPRSS2 levels compared those not receiving relacorilant.

[0166] In contrast, 2 SARS-CoV-2 positive patients not receiving relacorilant develop severe COVID-19 disease and receive intubation. Half (5) of the SARS-CoV-2 negative passengers not receiving relacorilant test positive for SARS-CoV-2 RNA in a second test 14 days after the first test.

EXAMPLE 3 Relacorilant Treatment Reduces Duration of a Coronavirus Infection [0167] A patient suffering from one or more symptoms of a viral infection is determined to suffer a viral infection due to the novel human respiratory coronavirus known as SARS-CoV- 2

[0168] The patient is orally administered 400 mg relacorilant per day with a meal.

[0169] Although such a viral infection typically lasts for about two weeks, the symptoms abate and the infection is resolved within about one week of the daily treatment. EXAMPLE 4. Relacorilant Treatment Reduces Coronavirus Infection Duration and Severity

[0170] A patient suffering from one or more symptoms of a viral infection is determined to suffer a viral infection due to the novel human respiratory coronavirus known as SARS-CoV- 2

[0171] The patient is orally administered 400 mg relacorilant per day with a meal.

[0172] The symptoms of the infection are less severe for the patient than the severity of symptoms generally experienced by the average patient suffering from a SARS-CoV-2 infection (COVID-19 disease). Although such a viral infection typically lasts for about two weeks, the symptoms for this patient abate and the infection is resolved within about one week of the daily treatment.

[0173] The treatment is continued for a week after the symptoms have abated. The patient does not suffer a return of symptoms, and does not relapse.

EXAMPLE 5 Relacorilant Treatment Reduces ACE2 Levels and Coronavirus Infection Severity

[0174] A patient suffering from one or more symptoms of a viral infection is determined to suffer a viral infection due to the novel human respiratory coronavirus known as SARS-CoV- 2. The patient has a normal level of angiotensin-converting enzyme 2 (ACE2) expression.

[0175] The patient is orally administered 400 mg relacorilant per day with a meal for a period of two weeks. Within three days of initiation of relacorilant administration, ACE2 expression in the patient is reduced in the patient as compared to the levels prior to initiation of relacorilant treatment. Since the patient’s ACE2 expression levels are normal prior to relacorilant treatment, the patient’s ACE2 expression level is reduced as compared to normal ACE2 expression levels.

[0176] The severity of the SARS-CoV-2 infection is reduced as compared to the severity of such infections generally observed in other COVID-19 patients whose ACE2 expression has not been reduced.

EXAMPLE 6 Relacorilant Treatment Reduces TMPRSS2 Levels and Coronavirus Infection Severity

[0177] A patient suffering from one or more symptoms of a viral infection is determined to suffer a viral infection due to the novel human respiratory coronavirus known as SARS-CoV- 2. The patient has a normal level of TMPRSS2 expression. [0178] The patient is orally administered 400 mg relacorilant per day with a meal for a period of two weeks. Within three days of initiation of relacorilant administration, ACE2 expression in the patient is reduced in the patient as compared to the levels prior to initiation of relacorilant treatment. Since the patient’s TMPRSS2 expression levels are normal prior to relacorilant treatment, the patient’s TMPRSS2 expression level is reduced as compared to normal TMPRSS2 expression levels.

[0179] The severity of the SARS-CoV-2 infection is reduced as compared to the severity of such infections generally observed in other COVID-19 patients whose TMPRSS2 expression has not been reduced.

EXAMPLE 7 Relacorilant Treatment Reduces Risk of Coronavirus Infection [0180] A healthy patient, at risk of developing a viral infection due to the novel human respiratory coronavirus known as SARS-CoV-2 due to prevalence of the novel human respiratory coronavirus known as SARS-CoV-2 in the region where the patient lives and works, is prophylactically treated with daily oral administration of 400 mg relacorilant, taken with a meal. The treatment is continued for several weeks.

[0181] The dose of relacorilant is effective to reduce the patient’s risk of developing a coronavirus infection, where such risk is in comparison reduced in comparison to the risk of developing a coronavirus infection in a subject who has not received such relacorilant treatment.

[0182] The patient does not suffer from a SARS-CoV-2 infection.

EXAMPLE 8 Relacorilant Treatment Reduces ACE2 Levels and Risk of Coronavirus Infection

[0183] A healthy patient, at risk of developing a viral infection due to the novel human respiratory coronavirus known as SARS-CoV-2, said risk due to prevalence of the novel human respiratory coronavirus known as SARS-CoV-2 in the region where the patient lives and works, is prophylactically treated with daily oral administration of 400 mg relacorilant, taken with a meal. The treatment is continued for several weeks.

[0184] The dose of relacorilant is effective to reduce angiotensin-converting enzyme 2 (ACE2) expression in the patient. The patient’s risk of developing a coronavirus infection in a patient is reduced in comparison to the risk of developing a coronavirus infection in a subject whose ACE2 expression has not been reduced.

[0185] The patient does not suffer from a SARS-CoV-2 infection. EXAMPLE 9. Relacorilant Treatment Reduces TMPRSS2 Levels and Risk of Coronavirus

Infection

[0186] A healthy patient, at risk of developing a viral infection due to the novel human respiratory coronavirus known as SARS-CoV-2, said risk due to prevalence of the novel human respiratory coronavirus known as SARS-CoV-2 in the region where the patient lives and works, is prophylactically treated with daily oral administration of 400 mg relacorilant, taken with a meal. The treatment is continued for several weeks.

[0187] The dose of relacorilant is effective to reduce TMPRSS2 expression in the patient.

The patient’s risk of developing a coronavirus infection in a patient is reduced in comparison to the risk of developing a coronavirus infection in a subject whose TMPRSS2 expression has not been reduced.

[0188] The patient does not suffer from a SARS-CoV-2 infection.

EXAMPLE 10 Relacorilant Treatment Reduces Coronavirus Infection Duration and Severity in Diabetics

[0189] A diabetes patient suffering from one or more symptoms of a viral infection is determined to suffer a viral infection due to the novel human respiratory coronavirus known as SARS-CoV-2.

[0190] The patient is orally administered 400 mg relacorilant per day with a meal. The treatment is continued for three weeks.

[0191] Although such a viral infection typically lasts for about two weeks, the symptoms abate and the infection is resolved with about one week of the daily treatment. The patient suffers an infection that is less severe than generally experienced by diabetes patients who contract an infection due to SARS-CoV-2 (COVID-19 disease). The relacorilant treatment is continued after symptoms abate as a precaution against relapse.

Example 11. Relacorilant Treatment Reduces Coronavirus Infection Duration and Severity in Hypertensive Patients Taking ACE Inhibitors

[0192] A patient suffering from hypertension who has been taking the angiotensin-converting enzyme inhibitor benazepril, and having increased levels of angiotensin-converting enzyme 2 (ACE2) as compared to ACE2 levels in the general population, also suffers from one or more symptoms of a viral infection. The hypertension patient is determined to suffer a viral infection due to the novel human respiratory coronavirus known as SARS-CoV-2. [0193] The patient is treated for two weeks with daily oral administration of 400 mg relacorilant, taken with a meal. The patient continues to take benazepril without change in dose or frequency of benazepril administration.

[0194] Such a viral infection typically lasts for about two weeks. The hypertension patient’s viral infection symptoms abate and the infection is resolved with about one week of the daily relacorilant treatment. The patient suffers an infection that is less severe than generally experienced by hypertension patients who contract a SARS-CoV-2 infection (COVID-19 disease). The relacorilant treatment is continued for one week after symptoms abate as a precaution against relapse.

EXAMPLE 11 Relacorilant Treatment Reduces Coronavirus Infection Duration and Severity in Hypertensive Patients Taking Angiotensin Receptor Blockers

[0195] A patient suffering from hypertension who has been taking the angiotensin II receptor blocker losartan, and having increased levels of angiotensin-converting enzyme 2 (ACE2) as compared to ACE2 levels in the general population, also suffers from one or more symptoms of a viral infection. The hypertension patient is determined to suffer a viral infection due to the novel human respiratory coronavirus known as SARS-CoV-2.

[0196] The patient is treated for two weeks with daily oral administration of 400 mg relacorilant, taken with a meal. The patient continues to take losartan without change in losartan dose or frequency of administration.

[0197] Such a viral infection typically lasts for about two weeks. The hypertension patient’s viral infection symptoms abate and the infection is resolved with about one week of the daily treatment. The patient suffers an infection that is less severe than generally experienced by hypertension patients who contract SARS-CoV-2 infection (COVID-19 disease). The relacorilant treatment is continued for one week after symptoms abate as a precaution against relapse.

EXAMPLE 12 Relacorilant Treatment Reduces Risk of Coronavirus Infection in Diabetic Patients

[0198] A patient suffering from diabetes and at risk of developing a viral infection (due to prevalence of the novel human respiratory coronavirus known as SARS-CoV-2 in the region where the patient lives and works) is prophylactically treated with daily oral administration of 400 mg relacorilant, taken with a meal. The relacorilant treatment is continued for several weeks. [0199] The patient does not suffer from a SARS-CoV-2 infection. The lack of contracting a SARS-CoV-2 infection indicates that the patient’s risk of developing a SARS-CoV-2 infection is reduced.

EXAMPLE 13 Relacorilant Treatment Reduces Risk of Coronavirus Infection in Hypertensive Patients Taking ACE Inhibitors

[0200] A patient suffering from hypertension who has been taking the angiotensin-converting enzyme inhibitor benazepril, and having increased levels of angiotensin-converting enzyme 2 (ACE2) as compared to ACE2 levels in the general population, is at risk of developing a viral infection due to prevalence of the novel human respiratory coronavirus known as SARS- CoV-2 in the region where the patient lives and works. The patient is prophylactically treated with daily oral administration of 400 mg relacorilant, taken with a meal. The relacorilant treatment is continued for several weeks.

[0201] The patient does not suffer from a SARS-CoV-2 infection. The lack of contracting a SARS-CoV-2 infection indicates that the patient’s risk of developing a SARS-CoV-2 infection is reduced.

EXAMPLE 14 Relacorilant Treatment Reduces Risk of Coronavirus Infection in Hypertensive Patients Taking Angiotensin Receptor Blockers

[0202] A patient suffering from hypertension who has been taking the angiotensin II receptor blocker losartan, and having increased levels of angiotensin-converting enzyme 2 (ACE2) as compared to ACE2 levels in the general population, is at risk of developing a viral infection due to prevalence of the novel human respiratory coronavirus known as SARS-CoV-2 in the region where the patient lives and works. The patient is prophylactically treated with daily oral administration of 400 mg relacorilant, taken with a meal. The relacorilant treatment is continued for several weeks.

[0203] The patient does not suffer from a SARS-CoV-2 infection. The lack of contracting a SARS-CoV-2 infection indicates that the patient’s risk of developing a SARS-CoV-2 infection is reduced.

EXAMPLE 15 Relacorilant Treatment Reduces ACE2 Levels and Coronavirus Infection Severity

[0204] A patient suffering from one or more symptoms of a viral infection is determined to suffer a viral infection due to the novel human respiratory coronavirus known as SARS-CoV- 2. The numbers of angiotensin-converting enzyme 2 (ACE2) proteins on lung epithelial cells of the patient are normal.

[0205] The patient is orally administered 400 mg relacorilant per day with a meal for a period of two weeks. Within three days of initiation of relacorilant administration, number of ACE2 proteins on the patient’s lung epithelial cells is reduced in the patient as compared to the number prior to initiation of relacorilant treatment. Since the number of ACE2 proteins is normal prior to relacorilant treatment, the number of ACE2 proteins is reduced as compared to the patient’s prior (normal) number of ACE2 proteins.

[0206] The severity of the SARS-CoV-2 infection (COVID-19 disease) is reduced as compared to the severity of such infections generally observed in other COVID-19 patients whose ACE2 expression has not been reduced.

EXAMPLE 16 Relacorilant Treatment Reduces TRPMSS2 Levels and Coronavirus Infection Severity

[0207] A patient suffering from one or more symptoms of a viral infection is determined to suffer a viral infection due to the novel human respiratory coronavirus known as SARS-CoV- 2. The numbers of TRPMSS2 proteins on lung epithelial cells of the patient are normal.

[0208] The patient is orally administered 400 mg relacorilant per day with a meal for a period of two weeks. Within three days of initiation of relacorilant administration, number of TRPMSS2 proteins on the patient’s lung epithelial cells is reduced in the patient as compared to the number prior to initiation of relacorilant treatment. Since the number of TRPMSS2 proteins is normal prior to relacorilant treatment, the number of TRPMSS2 proteins is reduced as compared to the patient’s prior (normal) number of TRPMSS2 proteins.

[0209] The severity of the SARS-CoV-2 infection (COVID-19 disease) is reduced as compared to the severity of such infections generally observed in other COVID-19 patients whose TRPMSS2 expression has not been reduced.

EXAMPLE 17 Relacorilant Treatment Reduces ACE2 Expression and Coronavirus Binding in Coronavirus Infection

[0210] A patient suffering from one or more symptoms of a viral infection is determined to suffer a viral infection due to the novel human respiratory coronavirus known as SARS-CoV- 2 [0211] The patient is orally administered 400 mg relacorilant per day with a meal for a period of two weeks. The relacorilant administration is effective to reduce ACE2 expression in the patient. Within three days of initiation of relacorilant administration, the number of coronavirus binding sites on cells susceptible to coronavirus infection in the patient is reduced (as compared to coronavirus binding sites in cells susceptible to coronavirus infection in the subject prior to infection, and as compared to the average number of coronavirus binding sites on susceptible cells in a subject whose ACE2 expression has not been reduced). Cells susceptible to coronavirus infection include lung, kidney, intestine, and blood vessel epithelial cells.

[0212] The treatment is effective to reduce coronavirus binding to cells susceptible to coronavirus infection in the patient.

EXAMPLE 18 Relacorilant Treatment Reduces TMPRSS2 Expression and Coronavirus Binding in Coronavirus Infection

[0213] A patient suffering from one or more symptoms of a viral infection is determined to suffer a viral infection due to the novel human respiratory coronavirus known as SARS-CoV- 2

[0214] The patient is orally administered 400 mg relacorilant per day with a meal for a period of two weeks. The relacorilant administration is effective to reduce TMPRSS2 expression in the patient. Within three days of initiation of relacorilant administration, the number of coronavirus binding sites on cells susceptible to coronavirus infection in the patient is reduced (as compared to coronavirus binding sites in cells susceptible to coronavirus infection in the subject prior to infection, and as compared to the average number of coronavirus binding sites on susceptible cells in a subject whose TMPRSS2 expression has not been reduced). Cells susceptible to coronavirus infection include lung, kidney, intestine, and blood vessel epithelial cells.

[0215] The treatment is effective to reduce coronavirus binding to cells susceptible to coronavirus infection in the patient.

[0216] All patents, patent applications, patent publications, and publications cited in this application are hereby incorporated by reference herein in their entireties as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. [0217] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.