WO2024097908A1

WO2024097908A1 - Combination therapy for covid19 disease: inhibiting pyrimidine biosynthesis

Info

Publication number: WO2024097908A1
Application number: PCT/US2023/078560
Authority: WO
Inventors: Charles David Pauza; Nikolay Savchuk
Original assignee: Viriom, Inc.
Priority date: 2022-11-04
Filing date: 2023-11-02
Publication date: 2024-05-10

Abstract

The present invention is generally directed to a potent therapy for SARS-CoV-2 (CoV2) disease which involve combinations of agents. Here we describe combinations of 2 drugs wherein the combination inhibits CoV2 replication through one or more mechanisms of action and increases potency of nucleoside and nucleotide analog drugs through inhibition of cellular enzymes involved in purine nucleotide biosynthesis. The combinations may be delivered as individual doses, concurrent dosing, or co-formulation of 2 or more agents. The invention provides of a defined combination of one or more drugs targeting viral components plus one or more drugs targeting cellular enzymes, in a fixed ratio with a specified therapeutic regimen.

Description

Combination Therapy for COVID19 Disease: Inhibiting Pyrimidine Biosynthesis

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and benefit of U.S. Provisional Patent Application Serial No. 63/422,559 filed November 4, 2022, entitled “Combination Therapy for COVID19 Disease: Inhibiting Pyrimidine Biosynthesis’’ the disclosure of which are incorporated by reference in its entirety for all purposes.

FIELD OF INVENTION

[0002] The invention relates to the field of antiviral therapy and, in particular, to drug combinations useful for treatment and prevention of SARS-CoV-2 virus infection. The invention provides novel drug combinations for treatment or prophylaxis of SARS-CoV-2 mediated diseases including COVID 19, its prodrome, and the long COVID syndrome. The invention is concerned with combination product and pharmaceutical composition that improve potency of each component while also increasing safety margins.

BACKGROUND

[0003] The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 within the city of Wuhan, China, as an outbreak of severe respiratory disease. This highly infectious agent spread rapidly and caused a global pandemic with many deaths and hardships. Since January 2020, there have been approximately 500,000,000 confirmed cases of COVID- 19 and more than 6,000,000 deaths reported to the World Health Organization (WHO). More than 78,000,000 confirmed cases of COVID- 19 and nearly 1,000,000 deaths were reported in the United States (US). Multiple vaccine development and distribution programs collectively administered > 10,000,000,000 vaccine doses as of March 2022 and as of February 25, 2022, more than 500,000,000 vaccine doses were administered in the US alone (https://covidl9.who.int/ accessed on March 8, 2022).

[0004] Despite efforts to roll out vaccine programs, the COVID-19 pandemic has not been contained and there is an urgent need to supplement vaccination efforts with antiviral drug therapy. Oral antiviral drugs are particularly valuable options for COVID-19 especially if used early to slow or prevent disease progression. Several antiviral compounds have already been approved for COVID- 19 on an emergency use basis in the US, European Union (EU), United Kingdom, China, Russia, and India with a number of other countries accelerating reviews for emergency use approval.

[0005] Three oral antiviral compounds for treating of COVID-19 in hospital, outpatient and community settings include Favipiravir (also known as AVIFAVIR, AVIGAN, FABIFLU), Molnupiravir (also known as Lagevrio), and the combination of Nirmatrelvir/Ritonavir (also known as Paxlovid). The three treatments were developed originally for a viral disease other than COVID-19 before being repurposed as SARS-CoV-2 antiviral agents. Because of prior experience with these drugs, it was possible to develop and provide treatments expeditiously as part of the emergency pandemic response.

[0006] Experimental testing identified the active [pharmaceutical ingredient favipiravir, as a substance capable of inhibiting CoV2 replication in vitro. Subsequent clinical studies validated the utility of favipiravir for CoV2 therapy. Chromis, a sister company to Viriom, Inc. developed a new, oral formulation of favipiravir known as Avifavir. In vitro studies verified the potency of Avifavir for CoV2 inhibition and subsequent clinical testing confirmed drug potency for reducing morbidity and mortality after CoV2 infection (Fujii, Ibe et al. 2021, Ivashchenko, Dmitriev et al. 2021, Korman 2021). Avifavir treatment was effective for decreasing time to negative tests for CoV2 in patients with recurrent viremia after discharge from hospital (Zhao, Zhang et al. 2021).

[0007] Favipiravir demonstrates two mechanisms of action for inhibiting the replication of RNA viruses. First, the drug acts as a chain terminator to block elongation of nascent RNA. In the specific example of SARS-CoV-2 replication, the chain termination function is less effective compared to other RNA viruses due, in part, to the RNA-dependent RNA polymerase complex of SARS-CoV-2 having one subunit function as an editing exonuclease to improve replication fidelity. Second, Favipiravir acts as a lethal mutagen to reduce viral fitness through incorporation of non-natural nucleotides causing G to A or C to U nucleotide transitions. The editing function mentioned above, permits Favipiravir incorporation into growing RNA chains and mis-reading results in fixing these mutations in the viral genome. Lethal mutagenesis through incorporation of non-natural nucleotides is a potent mechanism for virus eradication and is highly resistant to the develop of drug-resistance mutations [0008] The main obstacle to routine use of Favipiravir for COVID 19 is the high pill burden required to achieve active drug levels. Consequently, medical professionals are seeking new drug combinations including Favipiravir to improve potency and possibly reduce the pill burden.

[0009] Drugs capable of altering pyrimidine biosynthesis may disturb cellular nucleotide or nucleoside pools and improve potency of nucleoside analog drugs including favipiravir. Three categories of cellular targets are incorporated into this invention. Inhibiting the production of pyrimidines nucleosides will disturb the normal regulation of pyrimidine nucleotide pools and favor the incorporation of Favipiravir with consequent lethal mutagenesis, as a mechanism for inhibiting SARS-CoV-2 replication. The cellular enzyme Dihydroorotase dehydrogenase (DHODH) represents a key step in pyrimidine biosynthesis and has been targeted by several drugs including Leflunomide (Hoffmann, Kunz et al. 2011), Teriflunomide (tradename Aubagio), Brequinar and Atovaquone (Hansen, Le Nours et al. 2004), Atovaquone, and a number of experimental DHODH are being developed. Because the favipiravir drug has structural features resembling both pyrimidine nucleosides, it is important to recognize the potential for DHODH inhibitors to decrease pyrimidine pools and increase ribosylation and phosphorylation of favipiravir.

[0010] Inhibitors of cellular enzyme activity may be small molecule pharmaceuticals or nucleic acid drugs. Nucleic acid drugs are primarily RNA inhibitors of protein synthesis including short-interfering RNA (siRNA), short hairpin RNA (shRNA), micro RNA (miRNA), antisense oligonucleotides, hammerhead ribozymes and other targeted nucleotide inhibitors of purine biosynthesis composed of naturally occurring or synthetic nucleotides and provided to host cells as nanoparticles or encoded in viral vectors including DNA plasmids, lentivirus vectors, adeno-associated viral vectors, Adenovirus vectors or any of the range of vector delivery systems available to those skilled in the art.

[0011] The instant invention provides combinations of Favipiravir and inhibitors of pyrimidine biosynthesis with increased potency and better safety margins and defines these combinations in terms of precise molar ratios most suitable for SARS-CoV-2 therapy.

[0012] COVID 19 disease is a consequence of infection by the SARS-CoV-2 virus (CoV2) including all known variant strains. Efficient and potent antiviral therapies are needed to slow or prevent disease progression to reduce morbidity and mortality among infected individuals. Effective therapy may also be used for CoV2 prophylaxis among otherwise healthy individuals, especially if they have or are suspected of having or endure as an occupational hazard the exposure to infected individuals.

SUMMARY

[0013] A first aspect of the invention relates to a combination product of (i) inhibitor viral RNA replication and (ii) Dihydroorotase dehydrogenase (DHODH) inhibitor.

[0014] The present invention describes novel combinations of (i) inhibitor of viral RNA replication, and (ii) DHODH inhibitors and their use in therapy, in particular in the treatment of infections caused by RNA viruses.

[0015] More specifically the present invention describes novel combination products of (i) favipiravir, and (ii) DHODH inhibitors and their use in therapy, in particular in the treatment of infections caused by RNA viruses.

[0016] According one embodiments combination product is a mixture of (i) inhibitor of viral RNA replication and (ii) DHODH inhibitor, or a mixture of pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0017] More specifically combination product is a mixture of (i) favipiravir and (ii) DHODH inhibitor described herein, or a mixture of pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0018] In some aspects the combination product is a kit of parts comprising components (i) and (ii), for sequential, separate, or simultaneous use.

[0019] In some aspects the combination product is a composition comprising components (i) and (ii) and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0020] Another aspect of the invention relates to a method of treatment a disease or disorder associated with RNA virus. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with RNA virus infection an effective amount of a combination product or a pharmaceutical composition described herein.

[0021] Another aspect of the invention relates to a method of treating a disease or disorder associated with SARS-CoV-2 virus. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with SARS-CoV-2 virus an effective amount of a combination product or pharmaceutical composition described herein. [0022] Another aspect of the invention is directed to a method of inhibiting RNA virus replication by inhibiting orotate biosynthesis. The method involves administering to a patient in need thereof an effective amount of a combination product or a pharmaceutical composition described herein.

[0023] Another aspect of the invention is directed to a method of inhibiting SARS-CoV-2 virus replication coupled with inhibiting orotate biosynthesis. The method involves administering to a patient in need thereof an effective amount of a combination product or a pharmaceutical composition described herein.

[0024] Another aspect of the present invention relates to a combination product of favipiravir and Dihydroorotase dehydrogenase (DHODH) inhibitor, for use in the manufacture of a medicament for inhibiting of RNA virus replication.

[0025] Another aspect of the present invention relates to a combination product of favipiravir and Dihydroorotase dehydrogenase (DHODH) inhibitor, for use in the manufacture of a medicament for inhibiting of SARS-CoV-2 virus replication.

[0026] In a particular embodiment, the combination product of the invention further comprises at least one other therapeutically active agent such as an antifibrotic agent, an antiinflammatory agent or an immunosuppressive agent.

[0027] Another aspect of the present invention relates to a combination product, or a pharmaceutical composition described herein, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0028] Another aspect of the present invention relates to a combination product, or a pharmaceutical composition described herein, for use in the manufacture of a medicament for treating or preventing a viral infection disclosed herein.

[0029] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a combination product or a pharmaceutical composition disclosed herein.

[0030] Another aspect of the present invention relates to a use of a combination product or a pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein. [0031] The present invention further provides methods of treating a disease or disorder associated with RNA viral infection, comprising administering to a patient suffering from at least one of said RNA viral infection a combination product or a pharmaceutical composition thereof.

[0032] The present invention provides a combination product which acts as inhibitor of RNA virus replication and orotate biosynthesis that are therapeutic agents in the treatment of diseases and disorders.

[0033] The present invention further provides a combination product and a pharmaceutical composition with an improved efficacy and safety profile relative to known inhibitors of RNA virus replication.

[0034] The present invention further provides methods of treating a disease or disorder associated with viral infection, comprising administering to a patient suffering from at least one of said viral infection a combination product or pharmaceutical composition thereof.

[0035] The present invention provides combined inhibitors of viral RNA replication and orotate biosynthesis that are therapeutic agents in the treatment of viral infections associated with RNA viruses.

[0036] The present invention provides combined inhibitors of viral RNA replication and orotate biosynthesis that are therapeutic agents in the treatment of viral infections.

[0037] The present invention further provides a combination product or a pharmaceutical composition with an improved efficacy and safety profile relative to known viral RNA replication inhibitors. The present disclosure also provides agents with novel mechanisms of action toward viral RNA replication in the treatment of various types of viral infections, including SARS-CoV-2 infection.

[0038] Another aspect of the invention relates to lowering the normal dose of favipiravir needed for effective antiviral therapy.

[0039] Another aspect of the invention relates to lowering the normal dose of favipiravir needed for effective SARS-CoV-2 therapy.

[0040] Another aspect of the invention relates to lowering the dose of Dihydroorotase dehydrogenase (DHODH) inhibitor needed to increase inhibition of viral RNA replication. [0041] Another aspect of the invention relates to lowering the dose of Dihydroorotase dehydrogenase (DHODH) inhibitor needed to increase inhibition of SARS-CoV-2 virus replication.

[0042] Another aspect of the invention relates to lowering the dose of farudodstat needed to increase inhibition of viral RNA replication.

[0043] Another aspect of the invention relates to lowering the dose of farudodstat needed to increase inhibition of SARS-CoV-2 virus replication.

[0044] The present invention further provides methods of preventing, treating, or ameliorating a viral infection caused by virus selected from Measles, Mumps, Respiratory Syncytial Virus, Metapneumovirus, Poliovirus, Enterovirus, Chikungunya virus, Hepatitis A virus, Hepatitis C virus, Hepatitis E virus, West Nile virus, Zika virus, Dengue virus, Lassa Fever virus, Junin South American hemorrhagic fever virus, Marburg virus, Ebola virus, Norovirus (human caliciviruses) infections including the Norwalk agent, Rift Valley Fever virus, Nipah virus, Hendra virus, HIV-1, HTLV-1, HTLV-2, rotavirus, seasonal and pandemic coronaviruses, Picobirnaviruses, Toroviruses, Astroviruses, and Herpesviruses.

[0045] The present invention further provides methods of treating, or ameliorating a viral infection caused by virus selected from Measles, Mumps, Respiratory Syncytial Virus, Metapneumovirus, Poliovirus, Enterovirus, Chikungunya virus, Hepatitis A virus, Hepatitis C virus, Hepatitis E virus, West Nile virus, Zika virus, Dengue virus, Lassa Fever virus, Junin South American hemorrhagic fever virus, Marburg virus, Ebola virus, Norovirus (human caliciviruses) infections including the Norwalk agent, Rift Valley Fever virus, Nipah virus, Hendra virus, HIV-1, HTLV-1, HTLV-2, rotavirus, seasonal and pandemic coronaviruses, Picobirnaviruses, Toroviruses, Astroviruses, and Herpesviruses comprising administering to a patient suffering from at least one of said viral infections a combination product or pharmaceutical composition thereof.

[0046] In some aspects, the present disclosure provides a method of manufacturing of a combination product or a pharmaceutical composition of the present disclosure.

[0047] In some aspects, the present disclosure provides a method of preparing combination product of the present disclosure, comprising one or more steps described herein.

[0048] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting.

[0049] Other features and advantages of the disclosure will be apparent from the following detailed description and claims

BRIEF DESCRIPTION OF THE DRAWINGS

[0050] FIG. 1: Concentration-effect relationship for the inhibition (%) of influenza virus cytopathic activity for Favipiravir and Farudodstat. MDCK cells were infected with influenza at m.o.i. 0.01 for 1 hour. After removing the virus inoculum, the cells were treated with twofold serial dilutions of Favipiravir or Farudodstat. The cells were further maintained in the medium containing drugs for two days. For each compound, activity was expressed relative to uninfected/untreated controls (100% inhibition of viral cytopathic activity) and infected/untreated controls (0% inhibition of viral activity). For Favipiravir, activity was assessed at concentrations range from 100 pM to 0.78 pM with two-fold serial dilutions in triplicate. For Farudodstat, activity was assessed at concentrations range from 50 pM to 0.39 pM with two-fold serial dilutions in triplicate. IC50 for each compound was calculated using a four-parameter logistic nonlinear regression model by GraphPad Prism and is indicated. Cell viability at each level relative to control is shown (triangles).

[0051] FIG. 2 and FIG. 3: Concentration-effect relationship for the inhibition (%) of influenza virus cytopathic activity for Favipiravir and Farudodstat combination. MDCK cells were infected with influenza at m.o.i. 0.01 for 1 hour. After removing the virus inoculum, the cells were treated for with two-fold serial dilutions of Favipiravir in the presence of different fixed concentrations of Viramidine. The cells were further maintained in the medium containing drugs for two days. For each drug combination, activity was expressed relative to uninfected/untreated controls (100% inhibition of viral cytopathic activity) and infected/untreated controls (0% inhibition of viral activity). IC50 for each drug combination was calculated using a four-parameter logistic nonlinear regression model by GraphPad Prism and is indicated.

[0052] FIG. 4, FIG. 5, and FIG. 6: Favipiravir and Farudodstat display synergistic interaction at specific concentrations. The SynergyFinder2.0 was used to calculate the highest single agent (HSA) synergy score of two-drug combinations from different pairwise combinations. The dose-response matrix (FIG. 4) and the synergy map of two-drug combinations treatment (FIG. 5 and FIG. 6) are shown. Based on the “Most synergistic area score” (FIG. 5 and FIG. 6), the combination of Favipiravir at concentrations range from 6.2 pM to 25 pM and Farudodstat at concentrations range from 3.1 pM to 12.5 pM might display best synergistic interaction (FIG. 5 and FIG. 6). Areas with synergy score less than -10: the interaction between two drugs is likely to be antagonistic; from -10 to 10: the interaction between two drugs is likely to be additive; larger than 10: the interaction between two drugs is likely to be synergistic.

DETAILED DESCRIPTION

[0053] The present disclosure provides methods of treating, preventing, or ameliorating a disease or disorder associated with RNA virus infection by administering to a subject in need thereof a therapeutically effective amount of a combination product as disclosed herein.

[0054] The present invention provides a combination of an inhibitor viral RNA replication with DHODH inhibitors with improved activity profile and lower dose of each compound and lower toxicity.

[0055] The inventors found that favipiravir in combination with DHODH inhibitors show therapeutic activities that are useful in therapy, in particular for the treatment of infections caused by RNA viruses.

[0056] The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties.

Definitions

[0057] The articles "a" and "an" are used in this disclosure to refer to one or more than one (z.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0058] The term "and/or" is used in this disclosure to mean either "and" or "or" unless indicated otherwise.

[0059] The term “combination” and/or “combination product” refers to a product composed of any combination of a drug. Each drug included in a combination product is referred to as a “constituent part” of the combination product. The combination product is a kit of parts comprising components i) and ii), for sequential, separate, or simultaneous use or a composition (a mixture) of two components i) and ii).

[0060] The term “pharmaceutical composition” refers to admixture of different chemical substances, including the active drug (or number of active drugs), are combined to produce a final medicinal product.

[0061] A “viral disease” (or “viral infection”, abbreviated vid or VID) occurs when an organism's body is invaded by pathogenic viruses, and infectious virus particles (virions) attach to and enter susceptible cells.

[0062] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0063] “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.

[0064] “Viral DNA polymerase inhibitor” is an antiviral agent that inhibits the function of a viral DNA polymerase required for viral replication.

[0065] 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.

[0066] A "patient" or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus.

[0067] An "effective amount" when used in connection with a compound is an amount effective for treating or preventing a disease in a subject as described herein.

[0068] The term "carrier", as used in this disclosure, encompasses carriers, excipients, and diluents, and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.

[0069] The term "treating" with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder. “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. [0070] The term "administer", "administering", or "administration" as used in this disclosure refers to either directly administering a disclosed combination product or a composition to a subject, or administering a prodrug derivative or analog of the compounds of combination product or composition to the subject, which can form an equivalent amount of active compound within the subject's body.

[0071] The term "prodrug", as used in this disclosure, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound.

[0072] The term “salt’ refers to pharmaceutically acceptable salts.

[0073] “Inhibitors RNA virus replication” as used herein refer to combination product and/or compositions comprising a combination product which inhibit of viral RNA replication.

[0074] “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.

[0075] 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).

[0076] 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.

[0077] The amount of combination product or composition described herein needed for achieving a therapeutic effect may be determined empirically in accordance with conventional procedures for the particular purpose. Generally, for administering therapeutic agents (e.g. combination products or compositions (and/or additional agents) described herein) for therapeutic purposes, the therapeutic agents are given at a pharmacologically effective dose.

[0078] A “pharmacologically effective amount”, “pharmacologically effective dose”, “therapeutically effective amount”, or “effective amount” refers to an amount sufficient to produce the desired physiological effect or amount capable of achieving the desired result, particularly for treating the disorder or disease. An effective amount as used herein would include an amount sufficient to, for example, delay the development of a symptom of the disorder or disease, alter the course of a symptom of the disorder or disease (e.g., slow the progression of a symptom of the disease), reduce or eliminate one or more symptoms or manifestations of the disorder or disease, and reverse a symptom of a disorder or disease. For example, administration of therapeutic agents to a subject suffering from SARS-CoV-2 infection provides a therapeutic benefit not only when the underlying condition is eradicated or ameliorated, but also when the subject reports a decrease in the severity or duration of the symptoms associated with the disease, e.g., a decrease in viral burden, a decrease in circulating of SARS-CoV-2 viruses, an increase in progression free survival. Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is realized.

Combination product of the Present Disclosure

[0079] A first aspect of the invention relates to a combination product of (i) inhibitor viral RNA replication and (ii) inhibitor of dihydroorotate dehydrogenase (DHODH).

[0080] More specifically, the present disclosure provides a combination therapy for RNA viral infection treatment by administering of favipiravir and farudodstat.

[0081] In some embodiments, the combination product comprises favipiravir (i) as a nucleoside base (favipiravir), favipiravir ribonucleotide or favipiravir nucleotide triphosphate (favipiravir-NTP), prodrugs of Favipiravir,

Favipiravir-NTP or a pharmaceutically acceptable salt, solvate, or tautomer thereof.

[0082] Favipiravir, a purine nucleoside analogue capable of causing lethal mutagenesis during RNA virus replication.

[0083] Farudodstat is an oral inhibitor of dihydroorotate dehydrogenase (DHODH) and is currently in development for autoimmune disease. Farudodstat is a highly selective and potent inhibitor of DHODH (IC50 = 35 nM) and has been shown to be more than 30 times more potent at inhibiting the DHODH enzyme in assays than the first-generation inhibitor teriflunomide. Existing DHODH inhibitors have associated toxicities requiring safety monitoring that make them less suited as long term treatment options. New data from a study conducted by the University of Liverpool, UK, published in the Toxicology in Vitro Journal in 2021, demonstrated that, out of a panel of six DHODH inhibitors tested, farudodstat has the lowest potential for hepatotoxicity despite being one of the most potent inhibitors of DHODH.

[0084] The mechanism of action of DHODH inhibitor presented at the scheme below:

inhibitor

[0085] In some embodiments, DHODH inhibitor (ii) is selected from: merimepodib, brequinavir, leflunomide, teriflunomide, EICAR, atovaquone and farudodstat or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

[0086] In some embodiments, DHODH inhibitor (ii) is farudodstat

or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

[0087] In some embodiments, a combination product comprises (i) favipiravir and (ii) farudodstat.

[0088] In some embodiments, the combination product is selected from the combinations described in Table 1.

[0089] Table 1. Examples of composition of combination product.

[0090] In some embodiments, compounds formed combination product described herein are pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers of these compounds.

[0091] A suitable pharmaceutically acceptable salt of a compound of the combination is, for example, an acid-addition salt of a compound of the disclosure, which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the disclosure which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or //7.s-(2-hydroxyethyl)amine.

[0092] It would be understood that the compounds of any one of the combination products disclosed herein and any pharmaceutically acceptable salts thereof, comprise stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of said compounds. [0093] In some embodiments, combination product is selected from the compositions presented in the Table 1 or pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof.

[0094] In some embodiments, the compounds of the combination product are selected from the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0095] In some embodiments, the compounds of the combination product are selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0096] In some embodiments, the compounds of the combination product are selected from the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0097] In some embodiments, the compounds of the combination product are selected from the compounds described in Table 1.

[0098] In some embodiments, the compound of the combination product is a pharmaceutically acceptable salt of any one of the compounds described in Table 1.

[0099] In some embodiments, the compound of the combination product is a lithium salt, sodium salt, potassium salt, calcium salt, or magnesium salt of any one of the compounds described in Table 1.

[0100] In some embodiments, the compound of the combination product is a sodium salt or potassium salt of any one of the compounds described in Table 1.

[0101] In some embodiments, the compound of the combination product is a salt of any acid described in the Table 2 and any one of the compounds described in Table 1.

[0102] Table 2. Pharmaceutical acceptable acid forming salts with the compounds of the combination product.

[0103] In some aspects, the present disclosure provides a compound of the combination product being an isotopic derivative (e.g., isotopically labeled compound) of any one of the compounds disclosed herein.

[0104] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof. [0105] In some embodiments, at least one compound of combination product is an isotopic derivative of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0106] In some embodiments, at least one compound of combination product is an isotopic derivative of any one of prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0107] In some embodiments, at least one compound of combination product is an isotopic derivative of any one of the compounds described in Table 1.

[0108] In some embodiments, the isotopic derivative is a deuterium labeled compound.

[0109] The term “isotopic derivative”, as used herein, refers to a derivative of a compound in which one or more atoms are isotopically enriched or labelled. For example, an isotopic derivative of a compound of Formula (I) is isotopically enriched with regard to, or labelled with, one or more isotopes as compared to the corresponding compound of Formula (I). In some embodiments, the isotopic derivative is enriched with regard to, or labelled with, one or more atoms selected from ²H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸0, ²⁹Si, ³¹P, and ³⁴S. In some embodiments, the isotopic derivative is a deuterium labeled compound (i.e., being enriched with ²H with regard to one or more atoms thereof).

[0110] In some embodiments, at least one compound of combination product is a deuterium labeled compound of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[OlH] In some embodiments, at least one compound of combination product is a deuterium labeled compound of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0112] In some embodiments, at least one compound of combination product is a deuterium labeled compound of any one of the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0113] In some embodiments, at least one compound of combination product is a deuterium labeled compound of any one of the compounds described in Table 1.

[0114] It is understood that the deuterium labeled compound comprises a deuterium atom having an abundance of deuterium that is substantially greater than the natural abundance of deuterium, which is 0.015%.

[0115] In some embodiments, the deuterium labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). As used herein, the term “deuterium enrichment factor” means the ratio between the deuterium abundance and the natural abundance of a deuterium.

[0116] In some embodiments, at least one compound of combination product is a ¹⁸F labeled compound. [0117] In some embodiments, at least one compound of combination product is a ³³S labeled compound, a ³⁴S labeled compound, a ³⁵S labeled compound, a ³⁶S labeled compound, or any combination thereof.

[0118] As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.

[0119] It is to be understood that the compounds of combination product of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others.

[0120] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterised by the absolute configuration of its asymmetric centre and is described by the R- and -sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0121] The compounds of combination product of this disclosure may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (5)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the disclosure may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present disclosure encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess inflammasome inhibitory activity.

[0122] It is also to be understood that certain compounds of any one of combination product disclosed herein may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. A suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate. It is to be understood that the disclosure encompasses all such solvated forms that possess inflammasome inhibitory activity.

[0123] It is also to be understood that certain compounds of any one of the combination products disclosed herein may exhibit polymorphism, and that the disclosure encompasses all such forms, or mixtures thereof, which possess inflammasome inhibitory activity. It is generally known that crystalline materials may be analysed using conventional techniques such as X-Ray Powder Diffraction analysis, Differential Scanning Calorimetry, Thermal Gravimetric Analysis, Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and/or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials may be determined by Karl Fischer analysis.

[0124] Compounds of any one of the combination products disclosed herein may exist in a number of different tautomeric forms and references to compound of Formula (I) include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula (I). Examples of tautomeric forms include keto-, enol-, and enolate- forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci -nitro.

keto enol enolate

[0125] The compounds of any one of the combination products disclosed herein may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure. A prodrug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the disclosure. A prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the ester or amide group in any one of the compounds of combination products disclosed herein.

[0126] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity. Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1- 38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h)E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergam on Press, 1987. [0127] A suitable pharmaceutically acceptable prodrug of a compound of any one of the combination products disclosed herein that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of any one of the Formulae disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include C1-C10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1-C10 alkoxycarbonyl groups such as ethoxycarbonyl, A,A-(Ci-Ce alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2- carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, A-alkylaminomethyl, A,A-dialkylaminomethyl, morpholinomethyl, piperazin- 1-ylmethyl and 4-(CI-C4 alkyl)piperazin-l-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include oc-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0128] A suitable pharmaceutically acceptable prodrug of a compound of any one of the combination products disclosed herein that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a Ci-4alkylamine such as methylamine, a (C1-C4 alkyl)2amine such as dimethylamine, N- ethyl-A-methyl amine or di ethylamine, a C1-C4 alkoxy-C2-C4 alkylamine such as 2-methoxy ethylamine, a phenyl-Ci-C4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0129] A suitable pharmaceutically acceptable prodrug of a compound of any one of the combination products disclosed herein that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-C10 alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminom ethyl, N, A-dialkylaminom ethyl, morpholinomethyl, piperazin- 1-ylmethyl and 4- (C1-C4 alkyl)piperazin- 1-ylmethyl. [0130] In some embodiments, the combination product is a combination of a pharmaceutical composition of component (i) and a pharmaceutical composition of component (ii).

[0131] In some embodiments, the combination product is a combination of pharmaceutical composition of favipiravir (i) and a pharmaceutical composition of DHODH inhibitor (ii).

[0132] In some embodiments, the combination product is a kit of parts comprising components (i) and (ii), for sequential, separate, or simultaneous use.

[0133] In some embodiments, the combination product is a kit of parts comprising components (i) and (ii) for sequential use.

[0134] In some embodiments, the combination product is a kit of parts comprising components (i) and (ii) for separate use.

[0135] In some embodiments, the combination product is a kit of parts comprising components (i) and (ii) for simultaneous use.

[0136] In some embodiments, the combination product is a composition comprising components (i) and (ii) and a pharmaceutically acceptable carrier.

[0137] The in vivo effects of a compound of any one of the combination products disclosed herein may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of any one of the combination products disclosed herein. As stated hereinbefore, the in vivo effects of a compound of any one of the combination products disclosed herein may also be exerted by way of metabolism of a precursor compound (a prodrug).

Pharmaceutical Compositions

[0138] In some aspects, the present disclosure provides a pharmaceutical composition comprising the compounds of the combination product as active ingredients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one inhibitor of viral RNA replication (i) and at least one DHODH inhibitor (ii), or their pharmaceutically acceptable salt or solvate, and one or more pharmaceutically acceptable carriers or excipients.

[0139] In some embodiments, the present disclosure provides a pharmaceutical composition comprising (i) Favipiravir or pharmaceutically acceptable salt, solvate, or tautomer thereof; (ii) DHODH inhibitor or pharmaceutically acceptable salt, solvate, or tautomer thereof and a pharmaceutically acceptable carrier.

[0140] In some embodiments, the present disclosure provides a pharmaceutical composition comprising inhibitor of viral RNA replication and at least one DHODH inhibitor (ii) selected from: merimepodib, leflunomide, EICAR, atovaquone and farudodstat or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

[0141] In some embodiments, a pharmaceutical composition comprising (i) favipiravir or pharmaceutically acceptable salt, solvate, or tautomer thereof; (ii) farudodstat or pharmaceutically acceptable salt, solvate, or tautomer thereof and a pharmaceutically acceptable carrier.

[0142] As used herein, the term “pharmaceutical composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0143] In some embodiments, the ratio by weight of the favipiravir and the DHODH inhibitor 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.

[0144] The pharmaceutical composition of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.

[0145] In some embodiments, a pharmaceutical composition of present disclosure can be formulated for oral administration in form of tablets.

[0146] In some embodiments, a pharmaceutical composition of present disclosure can be formulated for oral administration in form of capsules (each of which includes sustained release or timed-release formulations).

[0147] In some embodiments, a pharmaceutical composition of present disclosure can be formulated for oral administration in form of pills.

[0148] In some embodiments, a pharmaceutical composition of present disclosure can be formulated for oral administration in form of powders.

[0149] In some embodiments, a pharmaceutical composition of present disclosure can be formulated for oral administration in form of granules.

[0150] In some embodiments, a pharmaceutical composition of present disclosure can be formulated for oral administration in form of elixirs.

[0151] In some embodiments, a pharmaceutical composition of present disclosure can be formulated for oral administration in form of tinctures.

[0152] In some embodiments, a pharmaceutical composition of present disclosure can be formulated for oral administration in form of suspensions.

[0153] In some embodiments, a pharmaceutical composition of present disclosure can be formulated for oral administration in form of syrups.

[0154] In some embodiments, a pharmaceutical composition of present disclosure can be formulated for oral administration in form of emulsions.

[0155] The pharmaceutical composition of present disclosure can also be formulated for intravenous (bolus or in-fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0156] In some embodiments, a pharmaceutical composition is in the form of liposomal formulations.

[0157] In some embodiments, a pharmaceutical composition is in the form of liposomal formulations for inhalation delivery. [0158] The formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity/suspending agent, buffer, and pH modifying agent, and a mixture thereof.

[0159] Any suitable solubility enhancing agent can be used. Examples of a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl-P-cyclodextrin, methyl-P-cyclodextrin, randomly methylated-P-cyclodextrin, ethylated-P-cyclodextrin, triacetyl-|3-cyclodextrin, peracetylated-P-cyclodextrin, carboxymethyl-P-cyclodextrin, hydroxy ethyl-P-cyclodextrin, 2-hydroxy-3- (trimethylammonio)propyl-P-cyclodextrin, glucosyl-P-cyclodextrin, sulfated P-cyclodextrin (S-P-CD), maltosyl-P-cyclodextrin, P-cyclodextrin sulfobutyl ether, branched-P- cyclodextrin, hydroxypropyl-y-cyclodextrin, randomly methylated-y-cyclodextrin, and trimethyl-y-cyclodextrin, and mixtures thereof.

[0160] Any suitable chelating agent can be used. Examples of a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, di sodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0161] Any suitable preservative can be used. Examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl- -hydroxybenzoate. and sorbic acid, and mixtures thereof.

[0162] In some embodiments, examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p- hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0163] The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof. In some embodiments, the tonicity agent is selected from the group consisting of a glycol (such as propylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof.

[0164] The aqueous vehicle may also contain a viscosity/suspending agent. Suitable viscosity/suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof.

[0165] In order to adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH modifying agent. The pH modifying agent is typically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and/or hydrochloric acid. These acidic and/or basic pH modifying agents are added to adjust the formulation to the target acceptable pH range. Hence it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range.

[0166] The aqueous vehicle may also contain a buffering agent to stabilize the pH. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and s-aminocaproic acid, and mixtures thereof.

[0167] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylenepolyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.

[0168] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0169] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises compounds (i) and (ii) of a combination product of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0170] In some embodiments, a pharmaceutical composition described herein may further comprise one or more additional pharmaceutically active agents.

[0171] The compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0172] The pharmaceutical compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.

[0173] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent a viral infection referred to herein, slow its progression and/or reduce the symptoms associated with the condition.

[0174] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat a viral infection related condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.

[0175] The size of the dose for therapeutic or prophylactic purposes of a combination product will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or subject and the route of administration, according to well-known principles of medicine.

[0176] In some embodiments, there is provided a pharmaceutical composition comprising: (i) favipiravir, and (ii) farudodstat. 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 favipiravir to farudodstat 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.

[0177] 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. [0178] 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.

Biological Assays

[0179] Combination product designed, selected and/or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity.

[0180] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the combination products described herein for activity, using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.

[0181] Various in vitro or in vivo biological assays may be suitable for detecting the effect of the combination products of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

Methods of Use

[0182] In some aspects, the present disclosure provides a method of inhibition of replication of RNA virus (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a combination product of the present disclosure.

[0183] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0184] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0185] In some embodiments, the disease or disorder is an RNA viral infection.

[0186] In some embodiments, the disease or disorder is a disease or disorder in which RNA viral infection is implicated.

[0187] The combination product of the invention is an antiviral agent.

[0188] The pharmaceutical composition of the invention is an antiviral agent.

[0189] In some embodiments, the combination product, pharmaceutical compositions, and methods disclosed herein are used in the prevention or treatment of a viral infection. Exemplary viral infection includes but are not limited to SARS-CoV-2 viral infection.

[0190] The combination product of the invention is also useful in treating viral infections caused by RNA viruses. For example, viral infections treatable according to the methods of the invention caused by seasonal, pandemic or drug-resistant influenza virus disease, Measles, Mumps, Respiratory Syncytial Virus, SARS-CoV-2, Metapneumovirus, Poliovirus, Chikungunya virus, Hepatitis A virus, Hepatitis C virus, Hepatitis E virus, West Nile virus, Zika virus, Dengue virus, Lassa Fever virus, lunin South American hemorrhagic fever virus, Marburg virus, Ebola virus, Norovirus (human caliciviruses) infections including the Norwalk agent, Rift Valley Fever virus, Nipah virus, Hendra virus, HIV-1, HTLV-1, HTLV- 2, rotavirus, seasonal and pandemic coronaviruses, Picobimaviruses, Toroviruses, and Astroviruses.

[0191] In some embodiments, the viral infection is seasonal, pandemic or drug-resistant influenza virus disease.

[0192] In some embodiments, the viral infection is SARS-CoV-2 viral infection.

[0193] In some embodiments, the viral infection is Measles viral infection.

[0194] In some embodiments, the viral infection is Mumps viral infection.

[0195] In some embodiments, the viral infection is Respiratory Syncytial Virus infection. [0196] In some embodiments, the viral infection is Metapneumovirus infection. [0197] In some embodiments, the viral infection is Poliovirus infection.

[0198] In some embodiments, the viral infection is Enterovirus infection

[0199] In some embodiments, the viral infection is Chikungunya virus infection.

[0200] In some embodiments, the viral infection is Hepatitis A virus infection.

[0201] In some embodiments, the viral infection is Hepatitis C virus infection.

[0202] In some embodiments, the viral infection is Hepatitis E virus infection.

[0203] In some embodiments, the viral infection is West Nile virus infection.

[0204] In some embodiments, the viral infection is Zika virus infection.

[0205] In some embodiments, the viral infection is Dengue virus infection.

[0206] In some embodiments, the viral infection is Lassa Fever virus infection.

[0207] In some embodiments, the viral infection is Junin South American hemorrhagic fever virus infection.

[0208] In some embodiments, the viral infection is Marburg virus infection.

[0209] In some embodiments, the viral infection is Ebola virus infection.

[0210] In some embodiments, the viral infection is Norovirus (human caliciviruses) infections including the Norwalk agent virus infection.

[0211] In some embodiments, the viral infection is Rift Valley Fever virus infection.

[0212] In some embodiments, the viral infection is Nipah virus infection.

[0213] In some embodiments, the viral infection is Hendra virus infection.

[0214] In some embodiments, the viral infection is HIV-1 infection.

[0215] In some embodiments, the viral infection is HTLV-1 infection.

[0216] In some embodiments, the viral infection is HTLV-2 infection.

[0217] In some embodiments, the viral infection is rotavirus infection.

[0218] In some embodiments, the viral infection is seasonal coronaviruses infection.

[0219] In some embodiments, the viral infection is pandemic coronaviruses infection.

[0220] In some embodiments, the viral infection is Picobirnaviruses infection.

[0221] In some embodiments, the viral infection is Toroviruses infection.

[0222] In some embodiments, the viral infection is Astroviruses infection.

[0223] In some embodiments, the viral infection is Herpesvirus infection.

[0224] In some aspects, the present disclosure provides a method of treating or preventing a SARS-CoV-2 viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0225] In some aspects, the present disclosure provides a method of treating or preventing a is seasonal, pandemic or drug-resistant influenza virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure. [0226] In some aspects, the present disclosure provides a method of treating or preventing a Measles viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0227] In some aspects, the present disclosure provides a method of treating or preventing a Mumps viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0228] In some aspects, the present disclosure provides a method of treating or preventing a Respiratory Syncytial Virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0229] In some aspects, the present disclosure provides a method of treating or preventing a Metapneumovirus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0230] In some aspects, the present disclosure provides a method of treating or preventing a Poliovirus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0231] In some aspects, the present disclosure provides a method of treating or preventing a Chikungunya virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure. [0232] In some aspects, the present disclosure provides a method of treating or preventing a Hepatitis A virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0233] In some aspects, the present disclosure provides a method of treating or preventing a Hepatitis C virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0234] In some aspects, the present disclosure provides a method of treating or preventing a Hepatitis E virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0235] In some aspects, the present disclosure provides a method of treating or preventing a West Nile virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0236] In some aspects, the present disclosure provides a method of treating or preventing a Zika virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0237] In some aspects, the present disclosure provides a method of treating or preventing a Dengue virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0238] In some aspects, the present disclosure provides a method of treating or preventing a Lassa Fever virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0239] In some aspects, the present disclosure provides a method of treating or preventing a Junin South American hemorrhagic fever virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure. [0240] In some aspects, the present disclosure provides a method of treating or preventing a Marburg virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0241] In some aspects, the present disclosure provides a method of treating or preventing a Ebola virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0242] In some aspects, the present disclosure provides a method of treating or preventing a Norovirus (human caliciviruses) infections including the Norwalk agent virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0243] In some aspects, the present disclosure provides a method of treating or preventing a Rift Valley Fever virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0244] In some aspects, the present disclosure provides a method of treating or preventing a Nipah virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0245] In some aspects, the present disclosure provides a method of treating or preventing a Hendra virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0246] In some aspects, the present disclosure provides a method of treating or preventing a HIV-1 infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure. [0247] In some aspects, the present disclosure provides a method of treating or preventing a HTLV-1 infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0248] In some aspects, the present disclosure provides a method of treating or preventing a HTLV-2 infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0249] In some aspects, the present disclosure provides a method of treating or preventing a rotavirus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0250] In some aspects, the present disclosure provides a method of treating or preventing a seasonal coronaviruses infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0251] In some aspects, the present disclosure provides a method of treating or preventing a pandemic coronaviruses infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0252] In some aspects, the present disclosure provides a method of treating or preventing a Picobimaviruses infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0253] In some aspects, the present disclosure provides a method of treating or preventing a Toroviruses infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0254] In some aspects, the present disclosure provides a method of treating or preventing a Astroviruses infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0255] In some aspects, the present disclosure provides a method of treating a seasonal, pandemic or drug-resistant influenza virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0256] In some aspects, the present disclosure provides a method of treating a SARS-CoV-2 viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0257] In some aspects, the present disclosure provides a method of treating a Measles viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0258] In some aspects, the present disclosure provides a method of treating a Mumps viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0259] In some aspects, the present disclosure provides a method of treating a Respiratory Syncytial Virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0260] In some aspects, the present disclosure provides a method of treating a Metapneumovirus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0261] In some aspects, the present disclosure provides a method of treating a Poliovirus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure. [0262] In some aspects, the present disclosure provides a method of treating a Chikungunya virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0263] In some aspects, the present disclosure provides a method of treating a Hepatitis A virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0264] In some aspects, the present disclosure provides a method of treating a Hepatitis C virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0265] In some aspects, the present disclosure provides a method of treating a Hepatitis E virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0266] In some aspects, the present disclosure provides a method of treating a West Nile virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0267] In some aspects, the present disclosure provides a method of treating a Zika virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0268] In some aspects, the present disclosure provides a method of treating a Dengue virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0269] In some aspects, the present disclosure provides a method of treating a Lassa Fever virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0270] In some aspects, the present disclosure provides a method of treating a Junin South American hemorrhagic fever virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0271] In some aspects, the present disclosure provides a method of treating a Marburg virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0272] In some aspects, the present disclosure provides a method of treating an Ebola virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0273] In some aspects, the present disclosure provides a method of treating a Norovirus (human caliciviruses) infections including the Norwalk agent virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0274] In some aspects, the present disclosure provides a method of treating a Rift Valley Fever virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0275] In some aspects, the present disclosure provides a method of treating a Nipah virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0276] In some aspects, the present disclosure provides a method of treating a Hendra virus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure. [0277] In some aspects, the present disclosure provides a method of treating a HIV-1 infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0278] In some aspects, the present disclosure provides a method of treating a HTLV-1 infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0279] In some aspects, the present disclosure provides a method of treating a HTLV-2 infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0280] In some aspects, the present disclosure provides a method of treating a rotavirus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0281] In some aspects, the present disclosure provides a method of treating a seasonal coronaviruses infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0282] In some aspects, the present disclosure provides a method of treating a pandemic coronaviruses infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0283] In some aspects, the present disclosure provides a method of treating a Picobimaviruses infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0284] In some aspects, the present disclosure provides a method of treating a Toroviruses infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0285] In some aspects, the present disclosure provides a method of treating a Astroviruses infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination product of the present disclosure or a pharmaceutical composition of the present disclosure.

[0286] In some aspects, the present disclosure provides a combination product of the present disclosure for use in inhibiting of virus RNA replication (e.g., in vitro or in vivo).

[0287] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a disease or disorder disclosed herein.

[0288] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a viral infection disclosed herein.

[0289] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a disease or disorder disclosed herein.

[0290] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a viral infection disclosed herein.

[0291] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a seasonal, pandemic or drug-resistant influenza viral infection in a subject in need thereof.

[0292] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a SARS-CoV-2 viral infection in a subject in need thereof.

[0293] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a Measles viral infection in a subject in need thereof.

[0294] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a Mumps viral infection in a subject in need thereof.

[0295] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a Respiratory Syncytial Virus infection in a subject in need thereof. [0296] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a Metapneumovirus infection in a subject in need thereof.

[0297] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a Poliovirus infection in a subject in need thereof. [0298] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a Chikungunya virus infection in a subject in need thereof.

[0299] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a Hepatitis A virus infection in a subject in need thereof.

[0300] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a Hepatitis C virus infection in a subject in need thereof.

[0301] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a Hepatitis E virus infection in a subject in need thereof.

[0302] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a West Nile virus infection in a subject in need thereof.

[0303] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a Zika virus infection in a subject in need thereof. [0304] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a Dengue virus infection in a subject in need thereof.

[0305] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a Lassa Fever virus infection in a subject in need thereof.

[0306] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a Junin South American hemorrhagic fever virus infection in a subject in need thereof. [0307] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a Marburg virus infection in a subject in need thereof.

[0308] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing an Ebola virus infection in a subject in need thereof.

[0309] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a Norovirus (human caliciviruses) infections including the Norwalk agent virus infection in a subject in need thereof.

[0310] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a Rift Valley Fever virus infection in a subject in need thereof.

[0311] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a Nipah virus infection in a subj ect in need thereof. [0312] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a Hendra virus infection in a subject in need thereof.

[0313] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a HIV-1 infection in a subject in need thereof.

[0314] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a HTLV-1 infection in a subject in need thereof. [0315] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a HTLV-2 infection in a subject in need thereof.

[0316] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a rotavirus infection in a subject in need thereof. [0317] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a seasonal coronaviruses infection in a subject in need thereof.

[0318] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a pandemic coronaviruses infection in a subject in need thereof. [0319] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a Picobimaviruses infection in a subject in need thereof.

[0320] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a Toroviruses infection in a subj ect in need thereof. [0321] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating or preventing a Astroviruses infection in a subject in need thereof.

[0322] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a seasonal, pandemic or drug-resistant influenza viral infection in a subject in need thereof.

[0323] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a SARS-CoV-2 viral infection in a subject in need thereof.

[0324] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a Measles viral infection in a subject in need thereof.

[0325] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a Mumps viral infection in a subject in need thereof.

[0326] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a Respiratory Syncytial Virus infection in a subject in need thereof.

[0327] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a Metapneumovirus infection in a subject in need thereof.

[0328] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a Poliovirus infection in a subject in need thereof.

[0329] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a Chikungunya virus infection in a subject in need thereof.

[0330] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a Hepatitis A virus infection in a subject in need thereof.

[0331] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a Hepatitis C virus infection in a subject in need thereof. [0332] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a Hepatitis E virus infection in a subject in need thereof

[0333] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a West Nile virus infection in a subject in need thereof.

[0334] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a Zika virus infection in a subject in need thereof.

[0335] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a Dengue virus infection in a subject in need thereof.

[0336] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a Lassa Fever virus infection in a subject in need thereof.

[0337] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a Junin South American hemorrhagic fever virus infection in a subject in need thereof.

[0338] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a Marburg virus infection in a subject in need thereof.

[0339] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating an Ebola virus infection in a subject in need thereof.

[0340] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a Norovirus (human caliciviruses) infections including the Norwalk agent virus infection in a subject in need thereof.

[0341] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a Rift Valley Fever virus infection in a subject in need thereof.

[0342] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a Nipah virus infection in a subject in need thereof.

[0343] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a Hendra virus infection in a subject in need thereof.

[0344] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a HIV-1 infection in a subject in need thereof.

[0345] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a HTLV-1 infection in a subject in need thereof. [0346] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a HTLV-2 infection in a subject in need thereof.

[0347] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a rotavirus infection in a subject in need thereof.

[0348] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a seasonal coronaviruses infection in a subject in need thereof. [0349] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a pandemic coronaviruses infection in a subject in need thereof. [0350] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a Picobirnaviruses infection in a subject in need thereof.

[0351] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a Toroviruses infection in a subject in need thereof.

[0352] In some aspects, the present disclosure provides a combination product of the present disclosure for use in treating a Astroviruses infection in a subject in need thereof.

[0353] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for inhibiting viral RNA replication (e.g., in vitro or in vivo).

[0354] In some aspects, the present disclosure provides use of a combination product of the present disclosure or a pharmaceutical composition thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0355] In some aspects, the present disclosure provides use of a pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0356] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a viral infection disclosed herein.

[0357] In some aspects, the present disclosure provides use of a combination product of the present disclosure or a pharmaceutical composition thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein. [0358] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating a viral infection disclosed herein.

[0359] In some aspects, the present disclosure provides use of a pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating a viral infection disclosed herein.

[0360] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a seasonal, pandemic or drug-resistant influenza viral infection in a subject in need thereof.

[0361] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a SARS- CoV-2 viral infection in a subject in need thereof.

[0362] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a Measles viral infection in a subject in need thereof.

[0363] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a Mumps viral infection in a subject in need thereof.

[0364] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a Respiratory Syncytial Virus infection in a subject in need thereof.

[0365] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a Metapneumovirus infection in a subject in need thereof.

[0366] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a Poliovirus infection in a subject in need thereof.

[0367] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a Chikungunya virus infection in a subject in need thereof. [0368] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a Hepatitis A virus infection in a subject in need thereof.

[0369] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a Hepatitis C virus infection in a subject in need thereof.

[0370] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a Hepatitis E virus infection in a subject in need thereof.

[0371] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a West Nile virus infection in a subject in need thereof.

[0372] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a Zika virus infection in a subject in need thereof.

[0373] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a Dengue virus infection in a subject in need thereof.

[0374] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a Lassa Fever virus infection in a subject in need thereof.

[0375] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a lunin South American hemorrhagic fever virus infection in a subject in need thereof.

[0376] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a Marburg virus infection in a subject in need thereof.

[0377] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing an Ebola virus infection in a subject in need thereof. [0378] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a Norovirus (human caliciviruses) infections including the Norwalk agent virus infection in a subject in need thereof.

[0379] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a Rift Valley Fever virus infection in a subject in need thereof.

[0380] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a Nipah virus infection in a subject in need thereof.

[0381] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a Hendra virus infection in a subject in need thereof.

[0382] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a HIV-1 infection in a subject in need thereof.

[0383] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a HTLV-1 infection in a subject in need thereof.

[0384] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a HTLV-2 infection in a subject in need thereof.

[0385] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a rotavirus infection in a subject in need thereof.

[0386] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a seasonal coronaviruses infection in a subject in need thereof.

[0387] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a pandemic coronaviruses infection in a subject in need thereof. [0388] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a Picobimaviruses infection in a subject in need thereof

[0389] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a Toroviruses infection in a subject in need thereof.

[0390] In some aspects, the present disclosure provides use of a combination product of the present disclosure in the manufacture of a medicament for treating or preventing a Astroviruses infection in a subject in need thereof.

[0391] The present disclosure provides combination products and pharmaceutical compositions that function as inhibitors of viral RNA replication (e.g., in vitro or in vivo).

[0392] The present disclosure therefore provides a method of inhibiting of viral RNA replication in vitro or in vivo, said method comprising contacting a cell with a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein.

[0393] In some embodiments, the inhibitor of viral RNA replication is a combination product of the present disclosure.

[0394] In some embodiments, the inhibitor of viral RNA replication is a pharmaceutical composition of the present disclosure.

[0395] Industry-accepted assays/disease models can determine effectiveness of combination products of the disclosure according to standard practices of elucidating the same as described in the art and are found in the current general knowledge.

[0396] The present disclosure also provides a method of treating a viral infection in a subject in need of such treatment, said method comprising administering to said subject a therapeutically effective amount of a combination product or a pharmaceutical composition as defined herein.

[0397] Another aspect of the invention relates to lowering the dose of (i) favipiravir needed to increase inhibition of SARS-CoV-2 virus replication.

[0398] Another aspect of the invention relates to lowering the dose of (ii) DHODH inhibitor needed to increase inhibition of SARS-CoV-2 virus replication. [0399] Another aspect of the invention relates to lowering the dose of (ii) farudodstat needed to increase inhibition of SARS-CoV-2 virus replication.

[0400] Another aspect of the invention relates to lowering the dose of (ii) merimepodib needed to increase inhibition of SARS-CoV-2 virus replication.

[0401] Another aspect of the invention relates to use of combination of (i) favipiravir and (ii) DHODH inhibitor, for treating seasonal, pandemic and drug -resistant influenza virus disease. [0402] Another aspect of the invention relates to use of combination of (i) favipiravir and (ii) farudodstat, for treating seasonal, pandemic and drug-resistant influenza virus disease.

[0403] Another aspect of the invention relates to use of combination of (i) favipiravir and (ii) merimepodib, for treating seasonal, pandemic and drug-resistant influenza virus disease.

[0404] Another aspect of the invention relates to use of combination of (i) favipiravir and (ii) Dihydroorotase dehydrogenase (DHODH) inhibitor for treating diseases caused by RNA virus infection including seasonal, pandemic and drug-resistant influenza virus disease, Measles, Mumps, Respiratory Syncytial Virus, Metapneumovirus, Poliovirus, Chikungunya virus, Hepatitis A virus, Hepatitis C virus, Hepatitis E virus, West Nile virus, Zika virus, Dengue virus, Lassa Fever virus, Junin South American hemorrhagic fever virus, Marburg virus, Ebola virus, Norovirus (human caliciviruses) infections including the Norwalk agent, Rift Valley Fever virus, Nipah virus, Hendra virus, HIV-1, HTLV-1, HTLV-2, rotavirus, seasonal and pandemic coronaviruses, Picobirnaviruses, Toroviruses, and Astroviruses.

[0405] Another aspect of the invention relates to use of combination of (i) favipiravir and (ii) farudodstat for treating diseases caused by RNA virus infection including seasonal, pandemic and drug-resistant influenza virus disease, Measles, Mumps, Respiratory Syncytial Virus, Metapneumovirus, Poliovirus, Chikungunya virus, Hepatitis A virus, Hepatitis C virus, Hepatitis E virus, West Nile virus, Zika virus, Dengue virus, Lassa Fever virus, Junin South American hemorrhagic fever virus, Marburg virus, Ebola virus, Norovirus (human caliciviruses) infections including the Norwalk agent, Rift Valley Fever virus, Nipah virus, Hendra virus, HIV-1, HTLV-1, HTLV-2, rotavirus, seasonal and pandemic coronaviruses, Picobirnaviruses, Toroviruses, and Astroviruses.

[0406] Another aspect of the invention relates to use of combination of (i) favipiravir-NTP and (ii) farudodstat for treating diseases caused by RNA virus infection including seasonal, pandemic and drug-resistant influenza virus disease, Measles, Mumps, Respiratory Syncytial Virus, Metapneumovirus, Poliovirus, Chikungunya virus, Hepatitis A virus, Hepatitis C virus, Hepatitis E virus, West Nile virus, Zika virus, Dengue virus, Lassa Fever virus, Junin South American hemorrhagic fever virus, Marburg virus, Ebola virus, Norovirus (human caliciviruses) infections including the Norwalk agent, Rift Valley Fever virus, Nipah virus, Hendra virus, HIV-1, HTLV-1, HTLV-2, rotavirus, seasonal and pandemic coronaviruses, Picobimaviruses, Toroviruses, and Astroviruses.

[0407] In some embodiments, the subject is avian.

[0408] In some embodiments, the subject is a mammal.

[0409] In some embodiments, the subject is a human.

Routes of Administration

[0410] The combination products of the disclosure or pharmaceutical compositions comprising these combination products may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action).

[0411] Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrastemal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.

[0412] In some embodiments, the combination product administers by inhalation.

[0413] In some embodiments, the combination product administers by inhalation of liposomal formulations of the combination product.

[0414] In pulmonary drug delivery, there are three main barriers against the deposition of the aerosol in the deep lung (i.e. respiratory bronchioles and the alveolar region), and these are: (a) the anatomic barrier - the tracheobronchial tree structure of the pulmonary system is the main protection mechanism against the deposition of deleterious particles and pollutants; (b) the pathological barrier - the disease status may affect the viscoelastic properties of the mucous covering the respiratory tract epithelium, hence affecting the clearance of deposited material and absorption profile, and (c) the immunological barrier - alveolar macrophages are involved in the defense mechanism and hence particles depositing in the alveolar region might be engulfed and transported to the upper respiratory tract where the mucociliary escalator can eradicate the particles because there is always competition between clearance and absorption.

[0415] Liposome formulations is aerosolized into particles that have a high fine particle fraction, and these liposomes should encapsulate a therapeutically feasible concentration of the drug which can then exhibit prolonged release from the liposome vesicles to the desired target within the lung. Aerodynamic size of inhaled particles should be smaller than 5 or 6 pm, with particles smaller than 2 pm being the most suitable for deposition in the alveolar region.

EXAMPLES OF COMBINATION PRODUCTS

[0416] In the Table 3 presented certain non-limiting examples of the combination products.

[0417] Table 3 Selected examples of the combination products

EXAMPLES OF PHARMACEUTICAL COMPOSITIONS

[0418] Certain non-limiting examples of the pharmaceutical compositions of the combination products described here..

[0419] The pharmaceutical composition according to disclosure comprises combination product and auxiliary compounds.

[0420] The examples of combination products according to invention presented in the Table 3.

[0421] According to an embodiment of the present invention, the pharmaceutical composition may be in the form of tablets, capsules, tablets fdled in capsule, minitablets filled in capsule, sachets containing powder or granules, pellets, and the like. The pharmaceutical composition is meant for once daily or twice daily administration.

[0422] The preparation of film coated tablets having some of the auxiliary ingredients as listed below which can either include or exclude when prepared using conventional techniques:

• Sodium lauryl sulfate

• Microcrystalline cellulose

• Lactose monohydrate

• Lactose 200 mesh

• Croscarmellose sodium

• Hydroxypropyl methyl cellulose (Hypromellose)

• Sodium carboxymethylcellulose

• Talc

• Magnesium stearate

• Lactose DC • Maize starch

• Pregelatinized starch

• Colloidal silicon dioxide

• Polyethylene glycol 6000 (macrogol)

• Basic calcium phosphate

• Menitol

• Ethyl cellulose

• Hydroxypropyl methylcellulose klOO

• Light magnesium oxide

• Magnesium hydroxide

• Calcium CMC

• Hydrogenated castor oil

• Sodium starch glycolate

• Sodium benzoate

• Sodium methyl parabe sodium propyl paraben

• PVP k30

• PVP k90

• FILM COAT

• Titanium dioxide

• Polyethylene glycol 6000 (macrogol).

Biological Assays

Example A. Inhibition test for flu virus (and other respiratory viruses).

[0423] MDCK cell expansion: Mardin-Darbin canine kidney cells were maintained in modified Eagle’s medium (MEM) containing 10% of fetal bovine serum (FBS). When the confluent monolayer reached 80 to 90%, cells were washed twice with phosphate buffer solution (PBS) and treated with trypsin for 14 minutes. Then, MDCK cell were resuspended in 10 ml of MEM 10% media and counted. For new flask passages, the cells were diluted 1 in 3 and seeded in 15 ml of media. For inhibition assays, MDCK cells were seed at 2xl0⁴ MDCK cells/well in a 96 well plate. In both cases, cells were incubated at 37°C and 5% CO2. [0424] Note: MDCK cells should be in low passages and test negative for mycoplasma and other pathogens before use. For other respiratory viruses testing cells, time, and virus concentration varies.

[0425] Flu virus stock preparation: 5xl0⁵ MDCK cells were seeded in T75 flask, after 24 hours of incubation at 37°C and 5% CO2, cells were washed twice and inoculated with Flu virus strain A/Puerto Rico/8/1934 (PR8) at 0.01 multiplicity of infection (MOI) for 1 hour at 37°C and 5% CO2. After incubation, 10 ml of MEM 0.35 % of Bovine serum albumin (BSA), 1 ug/ml TPCK-trypsin was added. Supernatant were collected at 24, 48, and 72 hours post infection, aliquoted and kept at -80°C for viral titration.

[0426] Viral titration by plaque forming units: To determine the Plaque formation units (PFU), 10-fold viral dilutions were prepared from the viral stocks. MDCK cells were seeded in 6 well plates. 24 hours later, when the monolayer reached between 80 and 90%, cells were washed twice with PBS and inoculated with viral stock dilutions. Incubated for one hour and cover with semisolid media containing 10 ml ofMEM 0.35% ofBSA, 1 pg/ml TPCK-trypsin, and 0.3% agarose. After 72 hours incubation at 37°C and 5% CO2, all plaques were stained with crystal violet at described below. The PFU were determined by counting plaques in the dilution producing around 50 visible plaques and then applying the following formula: PFU/ml = (N x 10^x)/V where N is the number of plaques, X is the dilution counted, and V is the virus volume used per well.

[0427] Antiviral compounds: Favipiravir, Farudodstat and other DHODH inhibitors were prepared as 10 mM stocks in dimethyl sulfoxide (DMSO) and were soluble when diluted in various reaction mixtures and cell culture media. Favipiravir was tested using concentrations ranging from 200 pM to 1.56 pM, with an estimated IC50 of 25 pM when used alone. Farudodstat tested concentrations were between 200 and 1.56 pM, with an estimated IC50 of 94.7 pM when used alone. Also, combination of Favipiravir with each of the other drugs were tested.

[0428] MDCK viral infection: After 24 hours, those cells in 96 well plates were wash twice with PBS and infected with PR8 Flu virus at 0.01 multiplicity of infection MOI for 1 hour at 37°C and 5% CO2. After incubation, the inoculum was carefully aspirated and replaced with MEM 0.35 % of Bovine serum albumin (BSA), 1 pg/ml TPCK-trypsin, and different concentration of the antiviral drug. [0429] Crystal violet staining: After 48 hours of incubation, the media was aspirated and MDCK cells washed once with PBS. The infectious virus was inactivated by filling each well with 4 % paraformaldehyde and incubating 20 minutes at room temperature (RT). Then, the liquid was aspirated, and the wells were filled with crystal violet. After 10 minutes of incubation at RT, the crystal violet was carefully washed with tap water and the plates were dried overnight. At this point, the EC50 could be visually estimated.

[0430] OD readings: Dried plate was treated with 1% SDS to solubilize the stain. This process took 20 minutes with constant shaking until the color was uniform. Then, the optical densities (OD) of each well were measured at 590 nm.

[0431] ICso calculation: To calculate the IC50 concentrations, the log of the uM drug concentrations was compared with the % of inhibition based on the OD readings using excel software. IC50 was calculated using a four-parameter logistic nonlinear regression model by GraphPad Prism.

[0432] Synergistic interaction analysis: The SynergyFinder2.0 was used to calculate the highest single agent (HSA) synergy score of two-drug combinations from different pairwise combinations. Areas with synergy score less than -10: the interaction between two drugs is likely to be antagonistic; from -10 to 10: the interaction between two drugs is likely to be additive; larger than 10: the interaction between two drugs is likely to be synergistic.

Equivalents

[0433] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

Claims

CLAIMS What is claimed is:

1. A combination product comprising:

(i) Favipiravir and

(ii) DHODH inhibitor for the treatment of infection caused by an RNA virus.

2. The combination product of claim 1, wherein Favipiravir is a nucleoside base (Favipiravir), favipiravir ribonucleotide, or nucleotide triphosphate (Favipiravir-NTP)

3. The combination product of claim 1, wherein the DHODH inhibitor is selected from:

• merimepodib;

• leflunomide;

• brequinavir;

• terifluomide;

• EICAR;

• atovaquone; • farudodstat; or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

4. The combination product of claim 1, wherein the DHODH inhibitor is farudodstat:

5. The combination product comprising:

(i) favipiravir and

(ii) farudodstat.

6. The combination product any one of preceding claims, wherein the combination product is a kit of parts comprising components (i) and (ii), for sequential, separate, or simultaneous use.

7. The combination product according to any one of claims 1-6, wherein the combination product is a pharmaceutical composition comprising components (i) and (ii) and a pharmaceutically acceptable carrier.

8. A pharmaceutical composition comprising (i) favipiravir or pharmaceutically acceptable salt, solvate, or tautomer thereof; (ii) DHODH inhibitor or pharmaceutically acceptable salt, solvate, or tautomer thereof and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition of claim 8 comprising (i) favipiravir or pharmaceutically acceptable salt, solvate, or tautomer thereof; (ii) farudodstat or pharmaceutically acceptable salt, solvate, or tautomer thereof and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition any one of claim 8, 9, further comprising an additional pharmaceutically active agent.

11. A method of inhibiting of RNA replication of virus, comprising of administering to a subject a combination product of any one of claims 1-7 or the pharmaceutical composition of any one of claims 8-10.

12. A method of treating a viral infection caused by an RNA virus, comprising of administering to a subject a combination product of any one of claims 1-7 or a pharmaceutical composition of any one of claims 8-10.

13. A method of treating RNA viral infection of claim 12 wherein virus selected from Measles, Mumps, Respiratory Syncytial Virus, SARS-CoV-2, Metapneumovirus, Poliovirus, Enterovirus, Chikungunya virus, Hepatitis A virus, Hepatitis C virus, Hepatitis E virus, West Nile virus, Zika virus, Dengue virus, Lassa Fever virus, Junin South American hemorrhagic fever virus, Marburg virus, Ebola virus, Norovirus (human caliciviruses) infections, Rift Valley Fever virus, Nipah virus, Hendra virus, HIV-1, HTLV-1, HTLV-2, rotavirus, seasonal and pandemic coronaviruses, Picobirnaviruses, Toroviruses, Astroviruses, and Herpesviruses.

14. The method of claim 12, wherein viral infection is SARS-CoV-2 virus infection.

15. The method of any one of claims 11-14, wherein the subject is a mammal.

16. The method of any one of the claims 11-14, wherein the subject is avian.

17. The method of claim 15, wherein the subject is a human.

18. A kit, comprising:

(i) Favipiravir;

(ii) DHODH inhibitor;

(iii) Instructions for using (i) and (ii) in combination for treating or preventing a viral infection caused by an RNA virus.

19. The kit of claim 18, wherein (i) and (ii) are in separate compositions.

20. The kit of claim 18, wherein (i) and (ii) are in a single composition.