WO2022197626A1

WO2022197626A1 - Combination therapy for treating covid-19

Info

Publication number: WO2022197626A1
Application number: PCT/US2022/020228
Authority: WO
Inventors: Dayu Teng
Original assignee: Drugarray, Inc.
Priority date: 2021-03-15
Filing date: 2022-03-14
Publication date: 2022-09-22

Abstract

The present disclosure provides methods of treating coronavirus-associated diseases in an individual comprising administering to the individual an effective amount of cidofovir and a second antiviral agent. Also provided are formulations and methods of delivering the formulations to an individual.

Description

COMBINATION THERAPY FOR TREATING COVID-19

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application 63/161,372, filed March 15, 2021, the contents of which are incorporated herein by reference in its entirety.

TECHNICAU FIEUD

[0002] The present disclosure is directed to methods of treating coronavirus-associated diseases in an individual comprising administering to the individual an effective amount of cidofovir and a second antiviral agent. Also provided are compositions of cidofovir and a second antiviral agent, and methods and dosing of delivering the combination compositions to an individual.

BACKGROUND

[0003] Coronaviruses are known to cause deadly diseases. For example, Coronavirus Disease-2019 (COVID-19), which is caused by SARS-CoV-2 (also known as 2019-nCov; a member of the coronavirus family), may lead to rapid onset of Acute Respiratory Distress Syndrome (ARDS) in addition to causing cardio-pulmonary distress. COVID-19 has a high fatality rate (about 3+%). The unique and devastating characteristics of COVID-19 are attributable to the high transmissibility of SARS-CoV-2, which is akin to the common cold. SARS-CoV-2, and the spread of COVID-19, is nearly impossible to contain due to the high transmissibility and the lengthy, and often asymptomatic, incubation period (on average about 7-14 days, and up to 20+ days in certain cases). Additionally, much like influenza, coronaviruses are RNA viruses and are prone to mutation. It has already been reported that several unique strains of SARS-CoV-2 exist. Vaccine -based approaches for mitigating the spread of COVID-19 may have very limited success due the continual mutation of the virus. Such a strategy will be in a “continuous” catch-up cycle. Other means for preventing and treating coronavirus-associated diseases are desperately needed.

BRIEF SUMMARY

[0004] In some aspects, provided herein is a method of treating an infectious disease in an individual comprising administering to an individual a) an effective amount of cidofovir and b) an effective amount of at least one other antiviral agent, wherein the other antiviral agent is selected from the group consisting of a reverse transcriptase inhibitor and a viral DNA polymerase inhibitor.

[0005] In some embodiments, the infectious disease is a coronavirus-associated disease. In some embodiments, the coronavirus-associated disease is Severe Acute Respiratory Syndrome Coronavirus 2 (COVID-19), an Angiotensin-Converting Enzyme 2 (ACE2)- associated disease, Acute Respiratory Distress Syndrome (ARDS), Severe Acute Respiratory Syndrome (SARS), or Middle East Respiratory Syndrome (MERS).

[0006] In some embodiments, the other antiviral agent is a reverse transcriptase inhibitor. In some embodiments, the reverse transcriptase inhibitor is a nucleoside analog reverse transcriptase inhibitor. In some embodiments, the nucleoside analog reverse transcriptase inhibitor is zidovudine. In other embodiments, the nucleoside analog reverse transcriptase inhibitor is stavudine.

[0007] In some embodiments, the other antiviral agent is a viral DNA polymerase inhibitor. In some embodiments, the viral DNA polymerase inhibitor is valacyclovir.

[0008] In some embodiments, the cidofovir is administered orally. In other embodiments, the cidofovir is administered intramuscularly. In other embodiments, the cidofovir is administered intravenously. In some embodiments, the other antiviral agent is administered orally. In other embodiments, the other antiviral agent is administered intramuscularly. In other embodiments, the other antiviral agent is administered intravenously.

[0009] In some embodiments, the cidofovir is administered as a one-time dose. In some embodiments, the zidovudine is administered orally once daily. In some embodiments, the stavudine is administered orally every 12 hours. In some embodiments, the valacyclovir is administered orally twice daily for 10 days.

[0010] In some embodiments, the cidofovir and the other antiviral agent are administered simultaneously. In some embodiments, the cidofovir and the other antiviral agent are administered as a single composition.

[0011] In some embodiments, the cidofovir and the other antiviral agent are administered sequentially. In some embodiments, the cidofovir is administered prior to administration of the other antiviral agent. In other embodiments, the cidofovir is administered following administration of the other antiviral agent.

[0012] In some embodiments, the individual is a human. In some embodiments, the individual suffers from a pre-existing health condition correlated with poor prognosis following SARS-CoV-2 disease. In some embodiments, the pre-existing health condition is selected from the group consisting of cancer, chronic kidney disease, chronic obstructive pulmonary disease, Down Syndrome, heart conditions, heart failure, coronary artery disease, cardiomyopathy, immunocompromised states, obesity, pregnancy, sickle cell disease, smoking, Type I diabetes mellitus, Type 2 diabetes mellitus, asthma, cerebrovascular· disease, cystic fibrosis, hypertension, neurologic conditions, liver disease, pulmonary fibrosis, thalassemia, and 65 year's or greater of age.

[0013] In some embodiments, a second therapy is administered to the individual. In some embodiments, the second therapy comprises remdesivir, monoclonal antibodies, mechanical ventilation, or combinations thereof. In some embodiments, the second therapy comprises administration of an effective amount of remdesivir. In some embodiments, the second therapy comprises administration of an effective amount of monoclonal antibody targeting against SARS-CoV-2. In some embodiments, the second therapy comprises administration of casirivimab and imdevimab intravenously. In some embodiments, the second therapy is mechanical ventilation.

[0014] In some aspects, herein provided is a pharmaceutical composition comprising a) cidofovir and b) at least one other antiviral agent, wherein the other antiviral agent is selected from the group consisting of a reverse transcriptase inhibitor and a viral DNA polymerase inhibitor.

[0015] In some embodiments, the other antiviral agent is a reverse transcriptase inhibitor. In some embodiments, the reverse transcriptase inhibitor is a nucleoside analog reverse transcriptase inhibitor. In some embodiments, the nucleoside analog reverse transcriptase inhibitor is zidovudine. In other embodiments, the nucleoside analog reverse transcriptase inhibitor is stavudine.

[0016] In some embodiments, the other antiviral agent is a viral DNA polymerase inhibitor. In some embodiments, the viral DNA polymerase inhibitor is valacyclovir.

[0017] In some embodiments, the pharmaceutical composition is a tablet. In some embodiments, the pharmaceutical composition is a capsule. In some embodiments, the pharmaceutical composition is a caplet. In some embodiments, the pharmaceutical composition is in a vial.

[0018] In some embodiments, the weight ratio of the cidofovir and the other antiviral in the composition is about 25:1 to about 1:5.

[0019] In some embodiments, the pharmaceutical composition contains about 25-1000 mg cidofovir. In some embodiments, the pharmaceutical composition contains about 100-1000 mg zidovudine. In some embodiments, the pharmaceutical composition contains about 1- 1000 mg stavudine. In some embodiments, the pharmaceutical composition contains about 0.25 to 5 grams valacyclovir.

[0020] In some aspects, there is provided a pharmaceutical composition according to any one of the pharmaceutical compositions described herein (e.g., including any of the combinations disclosed in FIG. 3 and FIG. 4), for use in the manufacture of a medicament for treating or preventing an infectious disease in a subject in thereof.

[0021] In some aspects, there is provided a pharmaceutical composition according to any one of the pharmaceutical compositions provided herein (e.g., including any of the combinations disclosed in FIG. 3 and FIG. 4), for use in treating or preventing an infectious disease in a subject in thereof.

[0022] In some aspects, there is provided use of any one of the pharmaceutical described herein (e.g., including any of the combinations disclosed in FIG. 3 and FIG. 4) for use in treating or preventing an infectious disease in a subject in thereof.

[0023] In some aspects, provided herein is a kit comprising agents described herein (e.g., including agents in any of the combinations disclosed in FIG. 3 and FIG. 4). In some embodiments, the agents in the kit are in separate compositions. In some aspects, provided herein is a kit, comprising: a) cidofovir; b) at least one other antiviral agent, wherein the other antiviral agent is selected from the group consisting of a reverse transcriptase inhibitor, a protease inhibitor, an integrase inhibitor, and a viral DNA polymerase inhibitor; and optionally c) instructions for using a) and b) in combination for treating or preventing an infectious disease in a subject in thereof. In some embodiments, a) and b) in the kit are in separate compositions.

[0024] In some embodiments, the infectious disease is a coronavirus-associated disease. In some embodiments, the coronavirus-associated disease is Severe Acute Respiratory Syndrome Coronavirus 2 (COVID-19), an Angiotensin-Converting Enzyme 2 (ACE2)- associated disease, Acute Respiratory Distress Syndrome (ARDS), Severe Acute Respiratory Syndrome (SARS), or Middle East Respiratory Syndrome (MERS).

DESCRIPTION OF THE DRAWINGS

[0025] The drawings illustrate certain features and advantages of this disclosure. These embodiments are not intended to limit the scope of the appended claims in any manner.

[0026] FIG. 1 shows the effect of various antiviral agents on the growth and proliferation of SARS-CoV-2 in Vero cell culture. FIG. 1A shows antiviral agents and combinations of antiviral agents that result in a low SARS-CoV-2 density per cell from Plate 1. FIG. IB shows antiviral agents and combinations of antiviral agents that result in a low SARS-CoV-2 density per cell from Plate 2.

[0027] FIG. 2 shows the effect of various antiviral agents on the growth and proliferation of SARS-CoV-2 in Vero cell culture. FIG. 2A shows antiviral agents and combinations of antiviral agents that result in a high SARS-CoV-2 density per cell from Plate 1. FIG. 2B shows antiviral agents and combinations of antiviral agents that have a high SARS-CoV-2 density per cell from Plate 2.

[0028] FIG. 3 shows the quantified average intensity of SARS-CoV-2 per cell for each antiviral combination tested. FIG. 3 A shows the results for Plate 1. FIG. 3B shows the results for Plate 2.

[0029] FIG. 4 shows the quantified intensity per cell for each antiviral combination for Plates 1 and 2.

DETAILED DESCRIPTION

[0030] All publications, comprising patent documents, scientific articles and databases, referred to in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were individually incorporated by reference. If a definition set forth herein is contrary to or otherwise inconsistent with a definition set forth in the patents, applications, published applications and other publications that are herein incorporated by reference, the definition set forth herein prevails over the definition that is incorporated herein by reference.

[0031] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0032] Provided herein, in some aspects, is a method of treating a coronavirus-associated disease in an individual, the method comprising administering to the individual an effective amount of cidofovir and a second antiviral agent. The present disclosure is based on the surprising finding that certain combinations of cidofovir with a second antiviral agent can be useful for treating a coronavirus-associated disease by reducing the replication and proliferation of SARS-CoV-2. The present application thus in one aspect provides a method of treating a coronavirus-associated disease in an individual comprising administering to an individual an effective amount of cidofovir, and an effective amount of at least one other antiviral agent, wherein the other antiviral agent is selected from the group consisting of a reverse transcriptase inhibitor and a viral DNA polymerase inhibitor. In another aspect, there is provided a pharmaceutical composition comprising cidofovir and at least one other antiviral agent, wherein the other antiviral agent is selected from the group consisting of a reverse transcriptase inhibitor and a viral DNA polymerase inhibitor.

Definitions

[0033] For purpose of interpreting this specification, the following definitions will apply and, whenever appropriate, terms used in the singular will also include the plural and vice versa. In the event that any definition set forth below conflicts with any document incorporated herein by reference, the definition set forth shall control.

[0034] “Antiviral” or “antiviral agent” refers to a category of antimicrobial drugs that are used specifically for treating viral infections by inhibiting the development of the viral pathogen inside the host cell. “Antivirals” and “antiviral agents” described herein include, but are not limited to, several categories based on their target, including: 1) entry blockers, which interfere with the attachment and penetration of the virus into the host cell; 2) nucleoside/nucleotide analogues and nonnucleoside analogues, which interfere with nucleic acid synthesis by blocking viral polymerases; this class includes viral DNA polymerase inhibitors and reverse transcriptase inhibitors.; 3) protein synthesis inhibitors, which interfere with viral replication; 4) protease inhibitors, which interfere with the maturation of the virus and its infectivity; and 5) integrase inhibitors. (DeClercq, Antiviral drugs in current clinical use , J. Clin. Virol., 30, 115-33, 2004).

[0035] “Viral DNA polymerase inhibitor” is an antiviral agent that inhibits the function of a viral DNA polymerase required for viral replication.

[0036] “Reverse transcriptase inhibitor” is an antiviral agent that inhibits the function of a reverse transcriptase enzyme required for viral replication.

[0037] “Treating” a disease or disorder with the compounds and methods discussed herein is defined as administering one or more of the compounds discussed herein, with or without additional therapeutic agents, in order to reduce or eliminate either the disease or disorder or one or more symptoms of the disease or disorder, or to retard the progression of the disease or disorder or of one or more symptoms of the disease or disorder, or to reduce the severity of the disease or disorder or of one or more symptoms of the disease or disorder.

[0038] The term “effective amount,” as used herein, refers to an amount of a compound or composition sufficient to treat a specified disorder, condition, or disease such as ameliorate, palliate, lessen, and/or delay one or more of its symptoms. As is understood in the art, an “effective amount” may be in one or more doses, e.g., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and combinations may be considered to be given in an effective amount if a desirable or beneficial result may be or is achieved. The components (e.g., the first and second therapies) in a combination treatment described in the present application may be administered sequentially, simultaneously, or concurrently using the same or different routes of administration for each component. Thus, an effective amount of a combination therapy includes an amount of the first therapy and an amount of the second therapy that when administered sequentially, simultaneously, or concurrently produces a desired outcome.

[0039] “In conjunction with” or “in combination with” refers to administration of one treatment modality in addition to another treatment modality. As such, “in conjunction with” or “in combination with” refers to administration of one treatment modality before, during or after delivery of the other treatment modality to the individual.

[0040] The term “simultaneous administration,” as used herein, means that a first agent and second agent in a combination therapy are administered with a time separation of no more than about 15 minutes, such as no more than about any of 10, 5, or 1 minutes. When the first and second agents are administered simultaneously, the first and second gents may be contained in the same composition (e.g., a composition comprising both a first and second agent) or in separate compositions (e.g., a first agent is contained in one composition and a second agent is contained in another composition).

[0041] As used herein, the term “sequential administration” means that the first agent and second agent in a combination therapy are administered with a time separation of more than about 15 minutes, such as more than about any of 20, 30, 40, 50, 60, or more minutes. Either the first agent or the second agent may be administered first. The first and second agents are contained in separate compositions, which may be contained in the same or different packages or kits.

[0042] A “subject,” “individual,” or “patient” is a vertebrate. In some embodiments, the vertebrate is a mammal. In other embodiments, the subject, individual, or patient is a food animal, such as a chicken, turkey, duck, goose, cow, lamb, sheep, pig, or goat. In other embodiments, the subject, individual, or patient is a domestic animal, such as a cat, dog, bird, rabbit, or guinea pig. The compounds, compositions, and methods disclosed herein can be used in human medicine and in veterinary medicine. In some embodiments, the individual is a human.

[0043] The term “pharmaceutically acceptable,” as used herein, is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers, excipients, or salts have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.

[0044] The terms “comprising,” “having,” “containing,” and “including,” and other similar forms, and grammatical equivalents thereof, as used herein, are intended to be equivalent in meaning and to be open ended in that an item or items following any one of these words is not meant to be an exhaustive listing of such item or items, or meant to be limited to only the listed item or items. For example, an article “comprising” components A, B, and C can consist of (i.e., contain only) components A, B, and C, or can contain not only components A, B, and C but also one or more other components. As such, it is intended and understood that “comprises” and similar forms thereof, and grammatical equivalents thereof, include disclosure of embodiments of “consisting essentially of’ or “consisting of.”

[0045] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0046] Reference to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X.” In some embodiments, numerical designations are provided herein for ease of understanding the scope of the present disclosure, wherein the numerical designations are calculated from experimental values and may include approximations, e.g., rounded weight percentages calculated from an amount of a starting material. In some embodiments, numerical designations provided herein, e.g., weight percentages, may vary (±) by increments of 0.1 to 0.5.

[0047] Reference to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X.”

[0048] The term “about X-Y” used herein has the same meaning as “about X to about Y.” [0049] As used herein, including in the appended claims, the singular forms “a,” “or,” and “the” include plural referents unless the context clearly dictates otherwise.

Methods

[0050] Provided herein are methods for treating and/or preventing coronavirus-associated infection in an individual comprising administering to the individual an effective amount of cidofovir and a second antiviral agent. In some embodiments, the second antiviral agent is a reverse transcriptase inhibitor. In other embodiments, the other antiviral agent is a viral DNA polymerase inhibitor.

[0051] Certain aspects of the present disclosure relate to viral infections. In some embodiments, the virus is an enveloped virus. Examples of enveloped viruses are well known in the art and include, without limitation, the virus families of Arenavirus, Arterivirus, Asfarvirus, Baculovirus, Bunyavirus, Coronavirus, Cystovirus, Deltavirus, Filovirus, Flavivirus, Fusellovirus, Hepadnavirus, Herpesvirus, Iridovirus, Lipothrixivirus, Orthomyxovirus, Paramyxovirus, Plasmavirus, Polydnavirus, Poxvirus, Retrovirus, Rhabdovirus, and Togavirus. In some embodiments, the virus is a Coronavirus, e.g., severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or Middle East respiratory syndrome-related coronavirus (MERS-CoV). In some embodiments, the virus is an Orthomyxovirus, e.g., influenza virus A, B, or C. In some embodiments, the virus is an Orthopneumovirus, e.g., respiratory syncytial virus (RSV).

[0052] In some embodiments, an individual has been diagnosed with a coronavirus- associated disease. In some embodiments, an individual has been diagnosed with Severe Acute Respiratory Syndrome Coronavirus 2 (COVID-19). In some embodiments, an individual has or has been diagnosed with acute respiratory distress syndrome (ARDS), e.g., prior to treatment with the combination therapy. Methods for diagnosis of ARDS include, without limitation, chest X-ray, CT scanning, and/or measurement of oxygen levels. In some embodiments, an individual has been diagnosed with an Angiotensin-Converting Enzyme 2 (ACE2)-associated disease. In some embodiments, an individual has been diagnosed with Severe Acute Respiratory Syndrome (SARS). In some embodiments, an individual has been diagnosed with Middle East Respiratory Syndrome (MERS).

[0053] In some embodiments, an individual is treated with a combination of cidofovir and another antiviral agent. In some embodiments, the other antiviral agent is a reverse transcriptase inhibitor. In some embodiments, the reverse transcriptase inhibitor is a nucleoside analog reverse transcriptase inhibitor. In some embodiments the nucleoside analog reverse transcriptase inhibitor is zidovudine. In some embodiments, the nucleoside analog reverse transcriptase inhibitor is stavudine.

[0054] In some embodiments, the other antiviral agent is a DNA polymerase inhibitor. In some embodiments, the DNA polymerase inhibitor is valacyclovir.

[0055] In some embodiments, the other antiviral agent is administered orally. In some embodiments, the other antiviral agent is administered intramuscularly. In other embodiments, the other antiviral agent is administered intravenously. In some embodiments, the cidofovir and the other antiviral agent are administered simultaneously.

[0056] In some embodiments, the cidofovir and other antiviral agent are administered in a single composition. In some embodiments, the single composition is administered orally. In some embodiments, the single composition is administered intravenously. In some embodiments, the single composition is administered intramuscularly.

[0057] The composition comprising cidofovir and the other antiviral agent can be administered simultaneously (i.e., simultaneous administration and/or sequentially (i.e., sequential administration)).

[0058] In some embodiments, the cidofovir and the other antiviral agent are administered simultaneously. The term “simultaneous administration,” as used herein, means that the cidofovir and the other antiviral agent are administered with a time separation no more than about 15 minutes(s), such as no more than about any of 10, 5, or 1 minutes. When the drugs are administered simultaneously, the cidofovir and the other antiviral compound may be contained in the same composition (e.g., a composition comprising the cidofovir and the other antiviral agent) or in separate compositions (e.g., the cidofovir is contained in one composition and the other antiviral agent is contained in another composition).

[0059] In some embodiments, the cidofovir and the other antiviral agent are administered sequentially. The term “sequential administration” as used herein means that the cidofovir and the other antiviral agent are administered with a time separation of more than about 15 minutes, such as more than any of 20, 30, 40, 50, or more minutes. Either the cidofovir or the other antiviral agent may be administered first. In some embodiments, the cidofovir is administered prior to administration of the other antiviral agent. In some embodiments, the cidofovir is administered following administration of the other antiviral agent. The cidofovir and the other antiviral agent are contained in separate compositions, which may be contained in the same or different packages. [0060] In some embodiments, the individual is a human. In some embodiments, the individual suffers from a pre-existing health condition correlated with poor prognosis following SARS-CoV2- disease. In some embodiments, the pre-existing health condition is cancer. In some embodiments, the pre-existing health condition is chronic kidney disease. In some embodiments, the pre-existing health condition is chronic obstructive pulmonary disease. In some embodiments, the pre-existing health condition is Down Syndrome. In some embodiments, the pre-existing health condition is a heart condition. In some embodiments, the pre-existing health condition is heart failure. In some embodiments, the pre-existing health condition is coronary artery disease. In some embodiments, the pre-existing health condition is cardiomyopathy. In some embodiments, the pre-existing health condition is an immunocompromised state. In some embodiments, the pre-existing health condition is obesity. In some embodiments, the pre-existing health condition is pregnancy. In some embodiments, the pre-existing health condition is sickle cell disease. In some embodiments, the pre-existing health condition is smoking. In some embodiments, the pre-existing health condition is Type I diabetes mellitus. In some embodiments, the pre-existing health condition is Type 2 diabetes mellitus. In some embodiments, the pre-existing health condition is asthma. In some embodiments, the pre-existing health condition is cerebrovascular disease. In some embodiments, the pre-existing health condition is cystic fibrosis. In some embodiments, the pre-existing health condition is hypertension. In some embodiments, the pre-existing health condition is a neurologic condition. In some embodiments, the pre-existing health condition is liver disease. In some embodiments, the pre-existing health condition is pulmonary fibrosis. In some embodiments, the pre-existing health condition is thalassemia. In some embodiments, the pre-existing health condition is 65 years or greater of age.

[0061] In some embodiments, the cidofovir and other antiviral is accompanied by a second therapy administered to the individual. In some embodiments, the second therapy is remdesivir. In some embodiments, the second therapy is monoclonal antibody. In some embodiments, the monoclonal antibody is targeted against SARS-CoV-2. In some embodiments, the second therapy is casirivimab and imdevimab. In some embodiments, the second therapy is administered intravenously. In some embodiments, the second therapy is mechanical ventilation. Cidofovir

Cidofovir

[0062] Cidofovir is an antiviral compound that belongs to the class of nucleoside analogues. Nucleoside analogs are first converted into an active compound through intracellular phosphorylation. The phosphorylated form competes with cellular nucleotides and inhibits viral replication enzymes by introducing a chain terminator into the growing DNA strand during transcription.

[0063] Cidofovir is injectable and has been approved for the treatment of cytomegalovirus (CMV) retinitis in people with AIDS. In some embodiments, the cidofovir is administered intravenously. In other embodiments, the cidofovir is administered intramuscularly. In other embodiments, the cidofovir is administered orally. In some embodiments, the individual is administered a one-time dose. In some embodiments, the individual is administered more than one dose. In some embodiments, the individual is administered about 5 mg per kg body weight cidofovir. In some embodiments, the cidofovir is administered at a constant rate over one hour. In some embodiments, the cidofovir is administered once per week for two weeks. In some embodiments, the individual is administered 300 mg cidofovir. In other embodiments, the individual is administered about 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg cidofovir. In some embodiments the individual is administered about 1500-2500 mg cidofovir or more.

Reverse transcriptase inhibitors

[0064] Reverse transcriptase inhibitors are a class of anti-viral drug. In particular, the class is used to treat HIV/AIDS. Reverse transcriptase inhibitors inhibit the activity of reverse transcriptase, an enzyme required for the replication of retroviruses.

[0065] Suitable reverse transcriptase inhibitors described herein include, for example, 1) nucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs); 2) non-nucleoside reverse-transcriptase inhibitors (NNRTIs); 3) nucleoside reverse transcriptase translocation inhibitors (NNRTIs); and 4) Portmanteau inhibitors.

[0066] In some embodiments, the other antiviral agent is a reverse transcriptase inhibitor. In some embodiments, the reverse transcriptase inhibitor is a nucleoside analog reverse transcriptase inhibitor. Nucleoside analog reverse transcriptase inhibitors are first converted into an active compound through intracellular phosphorylation to a triphosphate form. The triphosphate form of the nucleoside analog inhibitor competes with cellular nucleotides and inhibits the reverse transcriptase enzyme by introducing a chain terminator into the growing DNA strand during reverse transcription. In some embodiments, the other antiviral is a nucleoside analog reverse transcriptase inhibitor. In some embodiments, the nucleoside analog reverse transcriptase inhibitor is zidovudine. In some embodiments, the nucleoside reverse transcriptase inhibitor is stavudine.

[0067] In some embodiments, the nucleoside analog reverse transcriptase inhibitor is a thymidine analogue. In some embodiments, the thymidine analogue is zidovudine. In some embodiments, the thymidine analogue is stavudine. In some embodiments, the nucleoside analogue reverse transcriptase inhibitor is a cytidine analogue. In some embodiments, the nucleoside analogue reverse transcriptase inhibitor is a guanosine analogue. In some embodiments, the nucleoside analog reverse transcriptase inhibitor is an adenosine analogue.

Zidovudine Stavudine

[0068] In some embodiments, the other antiviral agent is a viral DNA polymerase inhibitor. Viral DNA polymerases function through inhibition of the viral DNA polymerase, which prevents viral genome replication and transcription. In some embodiments, the viral DNA polymerase inhibitor is valacyclovir.

Exemplary embodiments for combination therapy of cidofovir with other antiviral agent

[0069] In some embodiments, there is provided a method of treating an infectious disease in an individual comprising administering to an individual: a) an effective amount of cidofovir, and b) an effective amount of zidovudine. In some embodiments, the individual is administered zidovudine orally. In some embodiments, the individual is administered about 600 mg zidovudine once daily. In some embodiments, the individual is administered about 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg zidovudine. In other embodiments, the individual is administered about 1000-2000 mg zidovudine or more. In some embodiments, the cidofovir is administered intravenously. In other embodiments, the cidofovir is administered intramuscularly. In other embodiments, the cidofovir is administered orally. In some embodiments, the individual is administered a one-time dose. In some embodiments, the individual is administered more than one dose. In some embodiments, the individual is administered about 5 mg per kg body weight cidofovir. In some embodiments, the cidofovir is administered at a constant rate over one hour. In some embodiments, the cidofovir is administered once per week for two weeks. In some embodiments, the individual is administered 300 mg cidofovir. In other embodiments, the individual is administered about 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg cidofovir. In some embodiments the individual is administered about 1500-2500 mg cidofovir or more.

[0070] In some embodiments, there is provided a method of treating an infectious disease in an individual comprising administering to an individual: a) an effective amount of cidofovir, and b) an effective amount of stavudine. In some embodiments, the stavudine is administered orally. In some embodiments, the individual is administered less than 30 mg/60kg body weight. In some embodiments, the individual is administered stavudine every 12 hours. In some embodiments, the individual is administered at least 40 mg/60 kg body weight. In some embodiments, the individual is administered stavudine every 12 hours. In some embodiments, the individual is administered about 5, 10, 15, 20, or 25 mg stavudine per 60 kg body weight. In other embodiments, the individual is administered about 35 mg stavudine per 60 kg body weight. In other embodiments, the individual is administered about 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg stavudine per 60 kg body weight. In other embodiments, the individual is administered about 150 to about 500 mg stavudine per kg body weight. In some embodiments, the individual is administered less than about 20 -40 mg stavudine. In other embodiments, the individual is administered more than about 40-60 mg stavudine. In some embodiments, the cidofovir is administered intravenously. In other embodiments, the cidofovir is administered intramuscularly. In other embodiments, the cidofovir is administered orally. In some embodiments, the individual is administered a one - time dose. In some embodiments, the individual is administered more than one dose. In some embodiments, the individual is administered about 5 mg per kg body weight cidofovir. In some embodiments, the cidofovir is administered at a constant rate over one hour. In some embodiments, the cidofovir is administered once per week for two weeks. In some embodiments, the individual is administered 300 mg cidofovir. In other embodiments, the individual is administered about 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550,

600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg cidofovir. In some embodiments the individual is administered about 1500-2500 mg cidofovir or more.

[0071] In some embodiments, there is provided a method of treating an infectious disease in an individual comprising administering to an individual: a) an effective amount of cidofovir, and b) an effective amount of valacyclovir. In some embodiments, the valacyclovir is administered orally. In some embodiments, the valacyclovir is administered 1 gram twice daily for 10 days. In some embodiments, the individual is administered about 0.25, 0.5, 0.75, 1, 2, 3, 4, or 5 grams valacyclovir. In other embodiments, the individual is administered 5-8 grams valacyclovir or more. In some embodiments, the cidofovir is administered intravenously. In other embodiments, the cidofovir is administered intramuscularly. In other embodiments, the cidofovir is administered orally. In some embodiments, the individual is administered a one-time dose. In some embodiments, the individual is administered more than one dose. In some embodiments, the individual is administered about 5 mg per kg body weight cidofovir. In some embodiments, the cidofovir is administered at a constant rate over one hour. In some embodiments, the cidofovir is administered once per week for two weeks. In some embodiments, the individual is administered 300 mg cidofovir. In other embodiments, the individual is administered about 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg cidofovir. In some embodiments the individual is administered about 1500-2500 mg cidofovir or more.

[0072] In some embodiments, there is a pharmaceutical composition comprising cidofovir and at least one other antiviral agent. In some embodiments, the other antiviral agent is a reverse transcriptase inhibitor. In some embodiments, the reverse transcriptase inhibitor is a nucleoside analog reverse transcriptase inhibitor. In some embodiments, the nucleoside analog reverse transcriptase inhibitor is zidovudine. In other embodiments, the nucleoside analog reverse transcriptase inhibitor is stavudine.

[0073] In some embodiments, the nucleoside analog reverse transcriptase inhibitor is a thymidine analogue. In some embodiments, the thymidine analogue is stavudine. In other embodiments, the thymidine analogue is zidovudine. In some embodiments, the nucleoside analogue reverse transcriptase inhibitor is a cytidine analogue. In some embodiments, the nucleoside analogue reverse transcriptase inhibitor is a guanosine analogue. In some embodiments, the nucleoside analog reverse transcriptase inhibitor is an adenosine analogue. [0074] In some embodiments, the other antiviral agent is a viral DNA polymerase inhibitor. Viral DNA polymerases function through inhibition of the viral DNA polymerase, which prevents viral genome replication and transcription. In some embodiments, the viral DNA polymerase inhibitor is valacyclovir.

Pharmaceutical Compositions

[0075] Also provided are pharmaceutical compositions comprising cidofovir and other antiviral agents. Pharmaceutical compositions containing the compounds of the present disclosure may be in any form suitable for the intended method of administration. In some embodiments, the pharmaceutical composition is suitable for oral administration. Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice, (b) capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as solids or granules, (c) suspensions in an appropriate liquid, and (d) suitable emulsions. Tablet forms can include one or more of lactose, mannitol, com starch, potato starch, microcrystalline cellulose, acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible excipients. Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such excipients as are known in the art.

[0076] Examples of suitable carriers, excipients, and diluents include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, saline solution, syrup, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, and mineral oil. The formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents.

[0077] Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.

[0078] Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents.

[0079] In some embodiments, the formulation is suitable for intravenous administration. In other embodiments, the formulation is suitable for intramuscular administration.

Formulations suitable for intravenous and intramuscular administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation compatible with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described. [0080] In some embodiments, the ratio by weight of the cidofovir and the other antiviral agent in the pharmaceutical composition is about 1 to 1. In some embodiments, the weight ratio may be between about 0.001 to about 1 and about 1000 to about 1, or between about 0.01 to about 1 and 100 to about 1. In some embodiments, the ratio by weight of the cidofovir and the other antiviral is less than any of about 1000:1, 900:1, 800:1, 700:1, 600:1, 500:1, 400:1, 300:1, 200:1, 100:1, 50:1, 30:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, and 1:1. In some embodiments, the ratio by weight of the cidofovir and the other antiviral is more than any of about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 30:1, 50:1, 75:1, 100:1, 200:1, 300:1, 400:1, 500:1, 600:1, 700:1, 800:1, 900:1, and 1000:1. In some embodiments, the ratio by weight of the cidofovir and the other antiviral is less than any of about 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:30, 1:50, 1:100, 1:200, 1:300, 1:400, 1:500, 1:600, 1:700,

1:800, 1:900, and 1:1000. In other embodiments, the ratio by weight of the cidofovir and the other antiviral is more than any of about 1:1000, 1:900, 1:800, 1:700, 1:600, 1:500, 1:400, 1:300, 1:200, 1:100, 1:50, 1:30, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, and 1:1. Other ratios are contemplated.

[0081] In some embodiments, there is provided a pharmaceutical composition comprising: a) cidofovir, and b) zidovudine. In some embodiments, the composition is suitable for intravenous administration. In other embodiments, the composition is suitable for oral administration. In other embodiments, the composition is suitable for intramuscular administration. In some embodiments, the weight ratio of the cidofovir to zidovudine in the pharmaceutical composition is about any of 10:1, 9:2, 8:1, 7:1, 6:1, 5:1. 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.

[0082] In some embodiments, there is provided a pharmaceutical composition comprising: a) cidofovir, and b) stavudine. In some embodiments, the composition is suitable for intravenous administration. In other embodiments, the composition is suitable for oral administration. In other embodiments, the composition is suitable for intramuscular administration. In some embodiments, the weight ratio of the cidofovir to stavudine in the pharmaceutical composition is about any of 10:1, 9:2, 8:1, 7:1, 6:1, 5:1. 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.

[0083] In some embodiments, there is provided a pharmaceutical composition comprising: a) cidofovir, and b) valacyclovir. In some embodiments, the composition is suitable for intravenous administration. In other embodiments, the composition is suitable for oral administration. In other embodiments, the composition is suitable for intramuscular administration. In some embodiments, the weight ratio of the cidofovir to valganciclovir in the pharmaceutical composition is about any of 10:1, 9:2, 8:1, 7:1, 6:1, 5:1. 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.

[0084] Also within the scope of the present disclosure is a kit comprising a combination therapy described herein. The kit can include one or more other elements including: instructions for use; devices or other materials for preparing the compositions for administration; pharmaceutically acceptable carriers; and devices or other materials for administration to a subject.

[0085] The combination therapies disclosed herein have in vitro and in vivo therapeutic and/or prophylactic utilities. For example, the compositions disclosed herein can be administered to cells in culture, in vitro or ex vivo , or to a subject, e.g., a human subject, to treat, prevent, and/or diagnose a variety of disorders, such as viral infection, e.g., SARS- CoV-2 infection.

Patient Population

[0086] In some embodiments, the individual is a human. In some embodiments, the individual is a male. In some embodiments, the individual is a female. In some embodiments, the individual is at least about any of 12, 24, 36, 48, 50, 55, 60, 65, 70, 75, or 80 years old, or older. In some embodiments, the individual is no more than about 60, 50, 40, 30, 20, or 10 years old, or younger. In some embodiments, the individual is clinically obese. In some embodiments, the individual is overweight. In other embodiments, the individual is normal weight. In other embodiments, the individual is underweight. In some embodiments, the individual has a body mass index (BMI) of about >30. In other embodiments, the individual has a BMI between about 25 and 30. In other embodiments, the individual has a BMI between bout 18.5 and 25. In other embodiments, the individual has a BMI under about 18.5. [0087] In some embodiments, the individual suffers from a pre-existing health condition correlated with poor prognosis following SARS-CoV2- disease. In some embodiments, the pre-existing health condition is cancer. In some embodiments, the pre-existing health condition is chronic kidney disease. In some embodiments, the pre-existing health condition is chronic obstructive pulmonary disease. In some embodiments, the pre-existing health condition is Down Syndrome. In some embodiments, the pre-existing health condition is a heart condition. In some embodiments, the pre-existing health condition is heart failure. In some embodiments, the pre-existing health condition is coronary artery disease. In some embodiments, the pre-existing health condition is cardiomyopathy. In some embodiments, the pre-existing health condition is an immunocompromised state. In some embodiments, the pre-existing health condition is obesity. In some embodiments, the pre-existing health condition is pregnancy. In some embodiments, the pre-existing health condition is sickle cell disease. In some embodiments, the pre-existing health condition is smoking. In some embodiments, the pre-existing health condition is Type I diabetes mellitus. In some embodiments, the pre-existing health condition is Type 2 diabetes mellitus. In some embodiments, the pre-existing health condition is asthma. In some embodiments, the pre- existing health condition is cerebrovascular disease. In some embodiments, the pre-existing health condition is cystic fibrosis. In some embodiments, the pre-existing health condition is hypertension. In some embodiments, the pre-existing health condition is a neurologic condition. In some embodiments, the pre-existing health condition is liver disease. In some embodiments, the pre-existing health condition is pulmonary fibrosis. In some embodiments, the pre-existing health condition is thalassemia. In some embodiments, the pre-existing health condition is 65 years or greater of age.

EXAMPLES

[0088] The following example is provided to illustrate, but not limit, the present disclosure.

Example 1

In vitro Screening of Combined Antiviral Activity: Screen Studies in an In Vitro Model of Inhibiting SARS-CoV-2 Growth and Proliferation

[0089] Combinations of antiviral agents were shown to inhibit the growth of SARS-CoV-2 in vitro. Two 96-well plates were seeded with Vero (African green monkey kidney epithelial) cells. The cells were then infected with SARS-CoV-2 virus and treated with 192 different antiviral agent combinations. The antiviral agent combinations were introduced to the 96- well plate cell cultures using pin-array technology.

[0090] The individual wells of each plate were then analyzed using florescence microscopy to measure inhibition of growth and proliferation of the SARS-CoV-2 virus in vitro. Both the nucleus of the Vero cells and the SARS-CoV-2 nucleocapsid protein were imaged. The average intensity of the nucleocapsid protein per cell was measured and quantified for each antiviral agent combination.

[0091] The disclosures of all publications, patents, patent applications and published patent applications referred to herein by an identifying citation are hereby incorporated herein by reference in their entirety. [0092] The present disclosure is not intended to be limited in scope to the particular disclosed embodiments, which are provided, for example, to illustrate various aspects of the present disclosure. Various modifications to the compositions and methods described will become apparent from the description and teachings herein. Such variations may be practiced without departing from the true scope and spirit of the disclosure and are intended to fall within the scope of the present disclosure.

Claims

1. A method of treating an infectious disease in an individual comprising administering to an individual: a) an effective amount of cidofovir, and b) an effective amount of at least one other antiviral agent, wherein the other antiviral agent is selected from the group consisting of a reverse transcriptase inhibitor and a viral DNA polymerase inhibitor.

2. The method of claim 1, wherein the infectious disease is a coronavirus-associated disease.

3. The method of claim 2, wherein the coronavirus-associated disease is Severe Acute Respiratory Syndrome Coronavirus 2 (COVID-19), an Angiotensin-Converting Enzyme 2 (ACE2)-associated disease. Acute Respiratory Distress Syndrome (ARDS), Severe Acute Respiratory Syndrome (SARS), or Middle East Respiratory Syndrome (MERS).

4. The method according to any one of claims 1-3, wherein the other antiviral agent is a reverse transcriptase inhibitor.

5. The method according to claim 4, wherein the reverse transcriptase inhibitor is a nucleoside analog reverse transcriptase inhibitor.

6. The method according to claim 5, wherein the nucleoside analog reverse transcriptase inhibitor is zidovudine or stavudine.

7. The method according to any one of claims 1-3, wherein the other antiviral agent is a viral DNA polymerase inhibitor.

8. The method according to claim 7, wherein the viral DNA polymerase inhibitor is valacyclovir,

9. The method according to any one of claims 1-8, wherein the cidofovir is administered orally.

10. The method according to any one of claims 1-8, wherein the cidofovir is administered intramuscularly.

11. The method according to any one of claims 1-8, wherein the cidofovir is administered intravenously.

12. The method according to any one of claims 1-8, wherein the other antiviral agent is administered orally.

13. The method according to any one of claims 1-8, wherein the other antiviral agent is administered intramuscularly.

14. The method according to any one of claims 1-8, wherein the other antiviral agent is administered intravenously.

15. The method according to any one of claims 1-14, wherein the cidofovir is administered in a one-time dose.

16. The method according to claim 5, wherein the nucleoside analogue reverse transcriptase inhibitor is zidovudine, and wherein the zidovudine is administered orally once daily.

17. The method according to claim 5, wherein the nucleoside analogue reverse transcriptase inhibitor is stavudine, and wherein the stavudine is administered orally every 12 hours.

18. The method according to claim 8, wherein the valacyclovir is administered orally twice daily for 10 days.

19. The method according to any one of claims 1-18, wherein the cidofovir and the other antiviral agent are administered simultaneously.

20. The method according to claim 19, wherein the cidofovir and the other antiviral agent are administered in a single composition.

21. The method according to any one of claims 1-18, wherein the cidofovir and the other antiviral agent are administered sequentially.

22. The method according to claim 21, wherein the cidofovir is administered prior to administration of the other antiviral agent.

23. The method according to claim 21 , wherein the cidofovir is administered following administration of the other antiviral agent.

24. The method according to any one of claims 1-23, wherein the individual is a human.

25. The method according to any one of claims 1-23, wherein the individual suffers from a pre-existing health condition correlated with poor prognosis following SARS-CoV-2 disease.

26. The method according to claim 25, wherein the pre-existing health condition is selected from the group consisting of cancer, chronic kidney disease, chronic obstructive pulmonary disease, Down Syndrome, heart conditions, heart failure, coronary artery disease, cardiomyopathy, immunocompromised states, obesity, pregnancy, sickle cell disease, smoking, Type I diabetes mellitus, Type 2 diabetes mellitus, asthma, cerebrovascular disease, cystic fibrosis, hypertension, neurologic conditions, liver disease, pulmonary fibrosis, thalassemia, and 65 years or greater of age.

27. The method according to any one of claims 1-26, further comprising administering a second therapy to the individual.

28. The method according to claim 27 wherein the second therapy comprises remdesivir, monoclonal antibodies, mechanical ventilation, or combinations thereof.

29. The method according to claim 27, wherein the second therapy comprises administration of an effective amount of remdesivir.

30. The method according to claim 27, wherein the second therapy comprises administration of an effective amount of a monoclonal antibody targeting against SARS-CoV-2.

31. The method according to claim 30, wherein the second therapy comprises administration of casirivimab and imdevimab intravenously.

32. The method according to claim 27, wherein the second therapy is mechanical ventilation.

33. A pharmaceutical composition comprising: a) cidofovir; and b) at least one other antiviral agent, wherein the other antiviral agent is selected from the group consisting of a reverse transcriptase inhibitor and a viral DNA polymerase inhibitor.

34. The pharmaceutical composition according to claim 33, wherein the other antiviral agent is a reverse transcriptase inhibitor.

35. The pharmaceutical composition according to claim 34, wherein the other reverse transcriptase inhibitor is a nucleoside analog reverse transcriptase inhibitor.

36. The pharmaceutical composition according to claim 35, wherein the other nucleoside analog reverse transcriptase inhibitor is zidovudine or stavudine.

37. The pharmaceutical composition according to claim 33, wherein the other antiviral agent is a viral DNA polymerase inhibitor.

38. The pharmaceutical composition according to claim 37, wherein the viral DNA polymerase inhibitor is val acyclovir.

39. The pharmaceutical composition of any one of claims 33-38, wherein the pharmaceutical composition is a tablet, capsule, or caplet.

40. The pharmaceutical composition of any one of claims 33-39 wherein the pharmaceutical composition is in a vial.

41. The pharmaceutical composition of any one of claims 33-38, wherein the weight ratio of the cidofovir and the other antiviral in the composition is about 25:1 to about 1:5.

42. The pharmaceutical composition of any one of claims 33-41 , wherein the composition contains about 25·· 1000 mg cidofovir.

43. The pharmaceutical composition of claim 35, wherein nucleoside analogue reverse transcriptase inhibitor is zidovudine, and wherein the composition contains about 100-1000 mg zidovudine.

44. The pharmaceutical composition of claim 35, wherein the nucleoside analog reverse transcriptase inhibitor is stavudine, and wherein the composition contains about 1-1000 mg stavudine.

45. The pharmaceutical composition of claim 38, wherein the composition contains about 0.25 to 5 grams valacyclovir.

46. The pharmaceutical composition of any one of claims 33-45 for use in the manufacture of a medicament for treating or preventing an infectious disease in a subject in thereof.

47. The pharmaceutical composition of any one of claims 33-46 for use in treating or preventing an infectious disease in a subject in thereof.

48. Use of the pharmaceutical composition of any one of claims 33-47 for treating or preventing an infectious disease in a subject in thereof.

49. A kit, comprising: a) cidofovir; b) at least one other antiviral agent, wherein the other antiviral agent is selected from the group consisting of a reverse transcriptase inhibitor, a protease inhibitor, an integrase inhibitor, and a viral DNA polymerase inhibitor; and optionally c) instructions for using a) and b) in combination for treating or preventing an infectious disease in a subject in thereof.

50. The kit of claim 49, wherein a) and b) are in separate compositions.

51. The pharmaceutical composition of claim 46 or 47, the use in claim 48, or the kit of claim 49 or 50, wherein the infectious disease is a coronavirus-associated disease.

52. The pharmaceutical composition, use, or kit of claim 51, wherein the coronavirus- associated disease is Severe Acute Respiratory Syndrome Coronavirus 2 (COVID-19), an Angiotensin-Converting Enzyme 2 (ACE2)-associated disease, Acute Respiratory Distress Syndrome (ARDS), Severe Acute Respiratory Syndrome (SARS), or Middle East Respiratory Syndrome (MERS).