WO2021195521A1

WO2021195521A1 - Methods of treating coronavirus infections

Info

Publication number: WO2021195521A1
Application number: PCT/US2021/024399
Authority: WO
Inventors: Christopher Schelling; Juan Jose Marugan; Noel T. Southall; Mark J. Henderson; Marc Ferrer
Original assignee: Acer Therapeutics Inc.; The United States Of America, As Represented By The Secretary, Department Of Health And Human Services
Priority date: 2020-03-26
Filing date: 2021-03-26
Publication date: 2021-09-30

Abstract

Provided herein are methods for treating a viral infection caused by a coronavirus (such as SARS-CoV-2) and coronavirus diseases, such as COVID-19.

Description

METHODS OF TREATING CORONA VIRUS INFECTIONS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. §119(e) of United States Provisional Application No. 63/000,425, filed March 26, 2020, and United States Provisional Application No. 63/023,133, filed May 11, 2020, each of which is hereby incorporated by reference in its entirety.

NAMES OF PARTIES TO A JOINT RESEARCH AGREEMENT

[0002] The subject matter disclosed was developed and the claimed invention was made by, or on behalf of, one or more parties to a joint research agreement that was in effect on or before the effective filing date of the claimed invention; (2) the claimed invention was made as a result of activities undertaken within the scope of the joint research agreement; and (3) the names of the parties to the joint research agreement are: The United States of America, as represented by the Secretary, Department of Health and Human Services and Acer Therapeutics Inc.

FIELD

[0003] Provided herein are methods for treating a viral infection caused by SARS-CoV-2 and coronavirus diseases, particularly COVID-19.

BACKGROUND

[0004] Coronaviruses (CoV) act as cross-species viruses with the potential to rapidly spread into new host species and cause epidemic diseases, as demonstrated by the Middle East respiratory syndrome CoV (MERS-CoV), severe acute respiratory syndrome CoV (SARS-CoV), and the cause of the COVID-19 pandemic, SARS-CoV-2. CoVs represent a group of enveloped, positive-sense, single-stranded viruses with large genomes (27 to 33 kb) and are capable of causing respiratory, enteric, hepatic, and neurological diseases of differing severities.

[0005] CoV infections are difficult to prevent and cure. Although CoV replication machinery exhibits substantial proofreading activity, estimates of the nucleotide mutation rate in CoVs are moderate to high relative to that of other single-stranded RNA viruses. Additionally, the large RNA genome in CoVs allows for extra plasticity in genome modification by recombination. Several drugs, such as ribavirin, lopinavir-ritonavir, interferon, and corticosteroids have been used to treat patients infected with SARS-CoV or MERS-CoV. However, contradictory findings on their efficacy and concerns over tolerability and clinical benefit have limited the use of antiviral therapeutics for CoVs.

[0006] A need exists for therapeutic agents for treating diseases causes by coronaviruses, particularly SARS-CoV-2.

SUMMARY

[0007] Provided herein are methods of treating a viral infection in a subject in need thereof, comprising administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, wherein the viral infection is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

[0008] Provided herein are methods of treating a viral infection in a subject in need thereof, comprising administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, wherein the viral infection is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and wherein the subject does not require hospitalization.

[0009] Also provided herein are methods of treating COVID-19 in a subject in need thereof, comprising administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof.

[0010] Also provided herein are methods of treating COVID-19 in a subject in need thereof, comprising administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, and wherein the subject does not require hospitalization.

[0011] Also provided herein are methods of treating a viral infection in a subject in need thereof, comprising administering a composition comprising a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the viral infection is caused by severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2).

[0012] Also provided herein are methods of treating a viral infection in a subject in need thereof, comprising administering a composition comprising a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the viral infection is caused by severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2), and wherein the subject does not require hospitalization.

[0013] Also provided herein are methods of treating COVID-19 in a subject in need thereof, comprising administering a composition comprising a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0014] Also provided herein are methods of treating COVID-19 in a subject in need thereof, comprising administering a composition comprising a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and wherein the subject does not require hospitalization.

[0015] Provided herein are methods of treating a viral infection in a subject in need thereof, comprising administering a therapeutically effective amount of cephaeline, or a pharmaceutically acceptable salt thereof, wherein the viral infection is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

[0016] Also provided herein are methods of treating COVID-19 in a subject in need thereof, comprising administering a therapeutically effective amount of cephaeline, or a pharmaceutically acceptable salt thereof.

[0017] Also provided herein are methods of treating a viral infection in a subject in need thereof, comprising administering a composition comprising a therapeutically effective amount of cephaeline, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the viral infection is caused by severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2).

[0018] Also provided herein are methods of treating COVID-19 in a subject in need thereof, comprising administering a composition comprising a therapeutically effective amount of cephaeline, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0019] Provided herein are methods of treating a viral infection in a subject in need thereof, comprising administering a therapeutically effective amount of dehydroemetine, or a pharmaceutically acceptable salt thereof, wherein the viral infection is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). [0020] Also provided herein are methods of treating COVID-19 in a subject in need thereof, comprising administering a therapeutically effective amount of dehydroemetine, or a pharmaceutically acceptable salt thereof.

[0021] Also provided herein are methods of treating a viral infection in a subject in need thereof, comprising administering a composition comprising a therapeutically effective amount of dehydroemetine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the viral infection is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

[0022] Also provided herein are methods of treating COVID-19 in a subject in need thereof, comprising administering a composition comprising a therapeutically effective amount of dehydroemetine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION

Definitions

[0023] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. As used herein, the below terms have the following meanings unless specified otherwise. Any methods, devices and materials similar or equivalent to those described herein can be used in the practice of the compositions and methods described herein. The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure. All references referred to herein are incorporated by reference in their entirety.

[0024] It is noted here that as used in this specification and the appended claims, the singular forms “a” “an” and “the” and the like include plural referents unless the context clearly dictates otherwise.

[0025] The term “about” or “approximately” means within ± 30%, 20%, 15%, 10%, 9%, 8%,

7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range. In some embodiments,

“about” means ± 5% of a given value or range. In some embodiments, “about” means ± 4% of a given value or range. In some embodiments, “about” means ± 3% of a given value or range. In some embodiments, “about” means ± 2% of a given value or range. In some embodiments, “about” means ± 1% of a given value or range. In another embodiment, about means ± 0.5% of a given value or range. In some embodiments, “about” means ± 0.05% of a given value or range.

[0026] “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for human or veterinary pharmaceutical use.

[0027] The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene- sulfonic acid, salicylic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2- dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0028] As used herein, the term “administration” refers to introducing an agent into a patient.

For example, a therapeutic amount can be administered to the patient, which can be determined by the treating physician, medical professional, or the like. In some embodiments, an oral route of administration is preferred. The related terms and phrases “administering” and “administration of,” when used in connection with a compound or tablet (and grammatical equivalents) refer both to direct administration, which may be administration to a patient by a medical professional or by self administration by the patient, and/or to indirect administration, which may be the act of prescribing a drug. Administration entails delivery to the patient of the drug.

[0029] The term “dose” or “dosage” refers to the total amount of an active agent (e.g., emetine or a pharmaceutically acceptable salt thereof) administered to a patient in a single day (24-hour period). The desired dose can be administered once daily. In some embodiments, the desired dose may be administered in one, two, three, four or more sub-doses at appropriate intervals throughout the day, where the cumulative amount of the sub-doses equals the amount of the desired dose administered in a single day. The terms “dose” and “dosage” are used interchangeably herein.

[0030] As used herein, “therapeutically effective amount” or “therapeutic amount” refers to an amount of a drug or an agent (e.g., emetine or a pharmaceutically acceptable salt thereof) that when administered to a patient suffering from a condition, will have the intended therapeutic effect, e.g., alleviation, amelioration, palliation or elimination of one or more manifestations of the condition in the patient. The full therapeutic effect does not necessarily occur by administration of one dose, and can occur only after administration of a series of doses and can be administered in one dose form or multiples thereof. For example, 500 mg of the drug can be administered in a single 500 mg strength tablet or two 250 mg strength tablets. Thus, a therapeutically effective amount may be administered in one or more administrations.

[0031] As used herein, the term “patient” refers to a mammal, such as a human, bovine, rat, mouse, dog, monkey, ape, goat, sheep, cow, or deer. A patient as described herein can be a human.

[0032] As used herein, “treatment,” “treating,” and “treat” are defined as acting upon a disease, disorder, or condition with an agent to reduce or ameliorate the harmful or any other undesired effects of the disease, disorder, or condition and/or its symptoms. Treatment, as used herein, covers the treatment of a human patient, and includes: (a) reducing the risk of occurrence of the condition in a patient determined to be predisposed to the disease but not yet diagnosed as having the condition, (b) impeding the development of the condition, and/or (c) relieving the condition, i.e., causing regression of the condition and/or relieving one or more symptoms of the condition. [0033] “COVID-19” refers to the coronavirus disease caused by the virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 was also previously known as the 2019 novel coronavirus.

Emetine, Cephaeline, Dehydroemetine, and Compositions Thereof

[0034] Emetine is used mainly as an antiprotozoal and an emetic. The chemical name of emetine is (2S,3R,l lbS)-2-(((R)-6,7-dimethoxy-l,2,3,4-tetrahydroisoquinolin-l-yl)methyl)-3-ethyl- 9,10-dimethoxy-l,3,4,6,7,l lb-hexahydro-2H-pyrido[2,l-a]isoquinoline, and the compound has the following structure:

[0035] The synthesis of emetine is known in the art. Emetine, or pharmaceutically acceptable salts thereof (such as emetine dihydrochloride hydrate), also are commercially available.

[0036] In some embodiments provided herein, emetine is administered as a hydrochloride salt thereof.

[0037] Cephaeline, also known as (lf?)-l-[[(2ri',3f?,l lbri)-3-ethyl-9,10-dimethoxy-2,3,4,6,7,l lb- hexahydro- l//-pyrido[2, 1 -c/]isoquinolin-2-yl]methyl]-7-methoxy- l ,2,3,4-tetrahydroisoquinolin-6-ol, has the following chemical structure:

[0038] Cephaeline is commercially available.

[0039] Dehydroemetine is also an antiprotozoal agent. The chemical name of this compound is (llbri)-2-[[(lf?)-6,7-Dimethoxy-l,2,3,4-tetrahydroisoquinolin-l-yl]methyl]-3-ethyl-9,10- dimethoxy-4,6,7, 1 1 b-tetrahydro- 1 //-pyrido[2, 1 -ajisoqui noline, and compound has the following structure:

[0040] The synthesis of dehydroemetine may be accomplished via methods known in the art.

[0041] Also provided herein, in some embodiments, are pharmaceutical compositions that comprise compounds as described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients.

[0042] Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g ., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modem Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.). [0043] The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal, and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0044] One mode for administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0045] Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound described herein, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0046] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.

[0047] The compositions that include at least one compound described herein can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer- coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods disclosed herein employ transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g ., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0048] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein. When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0049] The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0050] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

Methods of Treatment

[0051] Provided herein are methods of preventing a viral infection caused by SARS-CoV-2 in a subject in need thereof, comprising administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt of each thereof.

[0052] Provided herein are methods of preventing COVID-19 in a subject in need thereof, comprising administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof.

[0053] Provided herein are methods of preventing a viral infection caused by SARS-CoV-2 in a subject in need thereof, comprising administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt of each thereof, and wherein the subject is a high-risk, symptomatic adult patient with confirmed COVID-19 infection not requiring hospitalization.

[0054] Provided herein are methods of preventing COVID-19 in a subject in need thereof, comprising administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, and wherein the subject is a high-risk, symptomatic adult patient with confirmed COVID-19 infection not requiring hospitalization.

[0055] Provided herein are methods of preventing a viral infection caused by SARS-CoV-2 in a subject in need thereof, comprising administering a therapeutically effective amount of cephaeline, or a pharmaceutically acceptable salt of each thereof.

[0056] Provided herein are methods of preventing COVID-19 in a subject in need thereof, comprising administering a therapeutically effective amount of cephaeline, or a pharmaceutically acceptable salt thereof.

[0057] Provided herein are methods of preventing a viral infection caused by SARS-CoV-2 in a subject in need thereof, comprising administering a therapeutically effective amount of dehydroemetine, or a pharmaceutically acceptable salt of each thereof. [0058] Provided herein are methods of preventing COVID-19 in a subject in need thereof, comprising administering a therapeutically effective amount of dehydroemetine, or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, administration occurs prior to viral infection of the subject.

[0060] In some embodiments, methods of preventing a viral infection caused by SARS-CoV-2 or preventing COVID-19 comprise administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, or cephaeline, or a pharmaceutically acceptable salt thereof, or dehydroemetine, or a pharmaceutically acceptable salt thereof, as a single dose.

[0061] In some embodiments, methods of preventing a viral infection caused by SARS-CoV-2 or preventing COVID-19 comprise administering a booster of a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, or cephaeline, or a pharmaceutically acceptable salt thereof, or dehydroemetine, or a pharmaceutically acceptable salt thereof. The booster may be administered concurrently or separately and may or may not be equivalent in amount to the first dose.

[0062] Provided herein are methods of treating a viral infection in a subject in need thereof, comprising administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, wherein the viral infection is caused by a coronavirus.

[0063] Provided herein are methods of treating a viral infection in a subject in need thereof, comprising administering a therapeutically effective amount of cephaeline, or a pharmaceutically acceptable salt thereof, wherein the viral infection is caused by a coronavirus.

[0064] Provided herein are methods of treating a viral infection in a subject in need thereof, comprising administering a therapeutically effective amount of dehydroemetine, or a pharmaceutically acceptable salt thereof, wherein the viral infection is caused by a coronavirus.

[0065] In some embodiments, the viral infection is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

[0066] Provided herein are methods of treating COVID-19 in a subject in need thereof, comprising administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof. [0067] Provided herein are methods of treating a viral infection in a subject in need thereof, comprising administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, wherein: the viral infection is caused by severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2); the subject does not require hospitalization; and the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 3 mg to about 65 mg per day.

[0068] Also provided herein are methods of treating COVID-19 in a subject in need thereof, comprising administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, wherein: the subject does not require hospitalization; and the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 3 mg to about 65 mg per day.

[0069] Also provided herein are methods of treating a viral infection in a subject in need thereof, comprising administering a composition comprising a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein: the viral infection is caused by severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2); the subject does not require hospitalization; and the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 3 mg to about 65 mg per day.

[0070] Also provided herein are methods of treating COVID-19 in a subject in need thereof, comprising administering a composition comprising a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein: the subject does not require hospitalization; and the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 3 mg to about 65 mg per day.

[0071] In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 1 mg/kg of the subject’s body weight to about 1000 mg/kg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 1 mg/kg of the subject’s body weight to about 500 mg/kg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 1 mg/kg of the subject’s body weight to about 250 mg/kg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 1 mg/kg of the subject’s body weight to about 100 mg/kg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 1 mg/kg of the subject’s body weight to about 50 mg/kg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 1 mg/kg of the subject’s body weight to about 10 mg/kg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 0.1 mg/kg of the subject’s body weight to about 1 mg/kg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 1 mg/kg of the subject’s body weight to about 10 mg/kg per day and administered for 10 days. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 1 mg/kg of the subject’s body weight per day and administered for 10 days.

[0072] In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 0.1 mg/kg of the subject’s body weight per day and administered for more than 1 day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 0.1 mg/kg of the subject’s body weight per day and is administered after the subject is administered an initial dose of more than 0.1 mg/kg of the subject’s body weight. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 0.01 mg/kg of the subject’s body weight to about 0.1 mg/kg of the subject’s body weight per day. [0073] Provided herein are methods of treating COVID-19 in a subject in need thereof, comprising administering a therapeutically effective amount of cephaeline, or a pharmaceutically acceptable salt thereof. day.

[0074] In some embodiments, emetine, or a pharmaceutically acceptable salt thereof, is administered by a subcutaneous injection. In some embodiments, emetine, or a pharmaceutically acceptable salt thereof, is administered as a sterile subcutaneous injection. In some embodiments, emetine, or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments, emetine, or a pharmaceutically acceptable salt thereof, is administered by or intramuscular injection.

[0075] In some embodiments, emetine is administered as ipecac syrup.

[0076] In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 1 mg to about 1000 mg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is 1 mg to about 500 mg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is 1 mg to about 50 mg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is 120 mg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is 100 mg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is 50 mg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is 30 mg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is 1 mg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 1 mg to about 70 mg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 3 mg to about 65 mg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 5 mg to about 15 mg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 5 mg to about 10 mg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about

0.01 mg to about 10 mg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 0.01 mg to about 5 mg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 0.05 mg to about 10 mg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 0.05 mg to about 5 mg per day.

[0077] In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 5 mg to about 7 mg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 6 mg per day.

[0078] In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 10 mg. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 50 mg. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 100 mg. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 150 mg. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 10 mg to about 175 mg.

[0079] In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 65 mg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 60 mg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is 60 mg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 30 mg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 10 mg per day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 5 mg per day.

[0080] In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 10 mg per day for 5 days, 6 days, 7 days, 8 days, 9 days, or 10 days.

[0081] In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 0.01 mg to about 5 mg per day in 3, 4, 5, 6, or 7 doses. In some embodiments, the doses may be given on every other day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 0.5 mg to about 5 mg per day in 3, 4, 5, 6, or 7 doses. In some embodiments, the doses may be given on every other day. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 1 mg to about 5 mg per day in 3, 4, 5, 6, or 7 doses. In some embodiments, the doses may be given on every other day.

[0082] In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 120 mg per day and is administered in one or two doses. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 120 mg per day and is administered subcutaneously in one or two doses.

[0083] In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 60 mg per day and is administered to the subject in need thereof for at least 1 day and up to 10 days. In some embodiments, about 60 mg per day of emetine, or a pharmaceutically acceptable salt thereof, is administered to the subject in need thereof for less than 7 days, less than 6 days, or less than 5 days.

[0084] In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 0.5 mg per day and is administered to the subject in need thereof for at least 1 day and up to 10 days. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 1 mg per day and is administered to the subject in need thereof for at least 1 day and up to 10 days. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 5 mg per day and is administered to the subject in need thereof for at least 1 day and up to 10 days. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 10 mg per day and is administered to the subject in need thereof for at least 1 day and up to 10 days. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 20 mg per day and is administered to the subject in need thereof for at least 1 day and up to 10 days. In some embodiments, the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 30 mg per day and is administered to the subject in need thereof for at least 1 day and up to 10 days. [0085] In some embodiments, about 0.5 mg per day of emetine, or a pharmaceutically acceptable salt thereof, is administered to the subject in need thereof for less than 7 days, less than 6 days, or less than 5 days. In some embodiments, 1 mg per day of emetine, or a pharmaceutically acceptable salt thereof, is administered to the subject in need thereof for less than 7 days, less than 6 days, or less than 5 days. In some embodiments, about 5 mg per day of emetine, or a pharmaceutically acceptable salt thereof, is administered to the subject in need thereof for less than 7 days, less than 6 days, or less than 5 days. In some embodiments, about 10 mg per day of emetine, or a pharmaceutically acceptable salt thereof, is administered to the subject in need thereof for less than 7 days, less than 6 days, or less than 5 days. In some embodiments, about 20 mg per day of emetine, or a pharmaceutically acceptable salt thereof, is administered to the subject in need thereof for less than 7 days, less than 6 days, or less than 5 days. In some embodiments, about 30 mg per day of emetine, or a pharmaceutically acceptable salt thereof, is administered to the subject in need thereof for less than 7 days, less than 6 days, or less than 5 days.

[0086] In some embodiments, about 0.5 mg per day of emetine, or a pharmaceutically acceptable salt thereof, is administered subcutaneously to the subject in need thereof for less than 7 days, less than 6 days, or less than 5 days. In some embodiments, about 1 mg per day of emetine, or a pharmaceutically acceptable salt thereof, is administered subcutaneously to the subject in need thereof for less than 7 days, less than 6 days, or less than 5 days. In some embodiments, about 5 mg per day of emetine, or a pharmaceutically acceptable salt thereof, is administered subcutaneously to the subject in need thereof for less than 7 days, less than 6 days, or less than 5 days. In some embodiments, about 10 mg per day of emetine, or a pharmaceutically acceptable salt thereof, is administered subcutaneously to the subject in need thereof for less than 7 days, less than 6 days, or less than 5 days. In some embodiments, about 20 mg per day of emetine, or a pharmaceutically acceptable salt thereof, is administered subcutaneously to the subject in need thereof for less than 7 days, less than 6 days, or less than 5 days. In some embodiments, about 30 mg per day of emetine, or a pharmaceutically acceptable salt thereof, is administered subcutaneously to the subject in need thereof for less than 7 days, less than 6 days, or less than 5 days.

[0087] In some embodiments, about 10 mg per day of emetine, or a pharmaceutically acceptable salt thereof, is administered to the subject in need thereof for 1 day, followed by about 5 mg per day of emetine, or a pharmaceutically acceptable salt thereof, for up to 13 days, up to 10 days, up to 9 days, or up to 8 days. [0088] Provided herein are methods of treating COVID-19 in a subject in need thereof, comprising administering a therapeutically effective amount of cephaeline, or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, the therapeutically effective amount of cephaeline, or a pharmaceutically acceptable salt thereof, is about 1 mg to about 1000 mg per day. In some embodiments, the therapeutically effective amount of cephaeline, or a pharmaceutically acceptable salt thereof, is 1 mg to about 500 mg per day. In some embodiments, the therapeutically effective amount of cephaeline, or a pharmaceutically acceptable salt thereof, is 1 mg to about 50 mg per day. In some embodiments, the therapeutically effective amount of cephaeline, or a pharmaceutically acceptable salt thereof, is 100 mg per day. In some embodiments, the therapeutically effective amount of cephaeline, or a pharmaceutically acceptable salt thereof, is 50 mg per day. In some embodiments, the therapeutically effective amount of cephaeline, or a pharmaceutically acceptable salt thereof, is 1 mg per day.

[0090] Provided herein are methods of treating COVID-19 in a subject in need thereof, comprising administering a therapeutically effective amount of dehydroemetine, or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, the therapeutically effective amount of dehydroemetine, or a pharmaceutically acceptable salt thereof, is about 1 mg to about 1000 mg per day. In some embodiments, the therapeutically effective amount of dehydroemetine, or a pharmaceutically acceptable salt thereof, is 1 mg to about 500 mg per day. In some embodiments, the therapeutically effective amount of dehydroemetine, or a pharmaceutically acceptable salt thereof, is 1 mg to about 50 mg per day. In some embodiments, the therapeutically effective amount of dehydroemetine, or a pharmaceutically acceptable salt thereof, is 100 mg per day. In some embodiments, the therapeutically effective amount of dehydroemetine, or a pharmaceutically acceptable salt thereof, is 50 mg per day. In some embodiments, the therapeutically effective amount of dehydroemetine, or a pharmaceutically acceptable salt thereof, is 1 mg per day.

[0092] In some embodiments, the subject is a human. In some embodiments, the subject is a human of at least 18 years of age. In some embodiments, the subject is a human less than 18 years of age. [0093] In some embodiments, the subject does not require hospitalization. In some embodiments, the subject does not require admission to a hospital. In some embodiments, the subject has a length of stay in a hospital of less than 1 day. In some embodiments, the subject does not require intensive care unit (ICU) admission. In some embodiments, the subject does not require mechanical ventilation. In some embodiments, the subject does not require supplemental oxygen. In some embodiments, the subject exhibits an oxygen saturation level of between about 90% to about 100%. In some embodiments, the subject exhibits oxygen saturation levels of between about 95% to about 100%. In some embodiments, the subject exhibits oxygen saturation levels below about 95% but does not exhibit difficulty breathing. In some embodiments, the subject exhibits mild to moderate symptoms. Such symptoms include but are not limited to fever, cough, shortness of breath or difficulty breathing, tiredness, aches, runny nose, sore throat, and/or loss of smell or taste. In some embodiments, the subject is a high-risk, symptomatic adult patient with confirmed COVID-19 infection not requiring hospitalization. In some embodiments, a high-risk patient is over 60 years old and/or has hypertension, has diabetes, has a pulmonary dysfunction, has an immune system disorder, or a combination thereof.

[0094] It has been suggested that SARS-CoV-2 enters cells through angiotensin-converting enzyme 2 (ACE2). Lung tissue consequently has become the main invasion target of the SARS- CoV-2 virus as the lung expresses high levels of ACE2. After the virus enters the lungs, tissue- associated macrophages initially respond to the virus via a class of receptors known as pattern- recognition receptors. Once macrophages are activated, a variety of cytokines are released, resulting in the infiltration and activation of multiple other immune cells. These immune cells attack the lung tissue indiscriminately, leading to respiratory distress.

[0095] Cytokine release syndrome (CRS) is a form of systemic inflammatory response syndrome that occurs when large numbers of white blood cells are activated and release inflammatory cytokines, which in turn activate even more white blood cells. Severe cases have been called cytokine storms. CRS occurs when large numbers of white blood cells, including B cells, T cells, natural killer cells, macrophages, dendritic cells, and monocytes are activated and release inflammatory cytokines, which in turn activate yet more white blood cells. This can occur when the immune system is fighting pathogens, as cytokines signal immune cells such as T-cells and macrophages to travel to the site of infection. In addition, cytokines activate those cells, stimulating them to produce more cytokines. Symptoms of CRS include fever, fatigue, loss of appetite, muscle and joint pain, nausea, vomiting, diarrhea, rashes, fast breathing, rapid heartbeat, low blood pressure, seizures, headache, confusion, delirium, hallucinations, tremor, and loss of coordination. Cytokine storm may be the probable reason for many deaths during the 2019-2020 COVID-19 pandemic.

[0096] Thus, in some embodiments, the subject has been exposed to SARS-CoV-2 but does not exhibit symptoms of CRS. In some embodiments, the subject is infected with SARS-CoV-2 but does not exhibit symptoms of CRS. In some embodiments, the subject does not exhibit severe symptoms of CRS (cytokine storm).

[0097] In some embodiments, the subject requires hospitalization. In some embodiments, the subject requires admission to a hospital. In some embodiments, the subject has a length of stay in a hospital of greater than 1 day. In some embodiments, the subject requires intensive care unit (ICU) admission. In some embodiments, the subject requires mechanical ventilation. In some embodiments, the subject requires supplemental oxygen. In some embodiments, the subject exhibits an oxygen saturation level of less than about 90%. In some embodiments, the subject exhibits an oxygen saturation level of between about 50% to about 95%. In some embodiments, the subject exhibits severe symptoms. Such symptoms include but are not limited to trouble breathing, chest pain or pressure, confusion or inability to arouse, and/or blue lips or face. In some embodiments, the subject exhibits severe symptoms of CRS (cytokine storm).

[0098] In some embodiments, methods provided herein further comprise administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent is administered simultaneously, prior, or after administration of emetine, cephaeline, dehydroemetine, or a pharmaceutically acceptable salt of each thereof.

[0099] In some embodiments, the additional therapeutic agent is an antiparasitic agent.

[0100] In some embodiments, the antiparasitic agent is chloroquine, hydroxycloroquine sulfate, mefloquine, or amodiaquine. In some embodiments, the antiparasitic agent is chloroquine or hydroxychloroquine. In some embodiments, the antiparasitic agent is chloroquine. In some embodiments, the antiparasitic agent is hydroxychloroquine. [0101] In some embodiments, the additional therapeutic agent is an antibiotic. Non-limiting examples of an antibiotic include monesin sodium, oligomycin, and dihydrocelastryl diacetate. In some embodiments, the antibiotic is azithromycin.

[0102] In some embodiments, the additional therapeutic agent is a corticosteroid. Non-limiting examples of corticosteroids include prednisone, bethamethasone, hydrocortisone, dexamethasone, fludrocortisone, and the like. In some embodiments, the additional therapeutic agent is dexamethasone.

[0103] In some embodiments, the additional therapeutic agent is a niclosamide, an emricasan compound, a cyclin-dependent kinase (CDK) inhibitor (including but not limited to palbociclib, ribociclib, and abemaciclib), or a proteasome inhibitor (including but not limited to bortzomib, carfilzomib, and ixazomib).

[0104] In some embodiments, the additional therapeutic agent is teriflunomide, hydroxocobalamin, ensulizole, tenonitrozole, isoliquiritigenin, nitazoxanide, febuxostat, leflunomide, vidofludimus, SB-366791, emodin, diphenyl isophthalate, benzoylpas, fenobam, indobufen, 2-(2H-Benzotriazol-2-yl)-4-methylphenol, tiaprofenic acid, flufenamic acid, vitamin B12, cinanserin, 5-Nitro-2-(3-phenylpropylamino)benzoic acid, veliflapon, thiabendazole, SIB 1893, anethole trithione, naringenin, phenazopyridine, fanetizole, terazosin, diacerein, CAY10505, hesperetin, suprofen, ketorolac tromethamine, piperine, pirarubicin, piraxostat, albendazole oxide, tyrphostin AG 494, genistin, fenbufen, apatinib, RITA, BF-170 hydrochloride, OSI-930, tribromsalan, pifexole, formononetin, ebselen, tranilast, benzylparaben, 2-ethoxylethyl-p- methoxycinnamate, baicalein, nemorubicin, rutaecarpine, 2-,ethyl-6-(phenylethynyl)pyridine (MPEP), 5,7-dihydroxyflavone, vitamin B12, pipofezine, flurbiprofen axetil, 2-amino-6- nitrobenzothiazole, malachite green oxalate, enfenamic acid, fenaminosulf, AS-252424, phenserine, epalrestat, alizarin, dalcetrapib, SN-38, echinomycin, (S)-(+)-camptothecin, BI-2536, 10- hydroxycamptothecin, topotecan, delanzomib, volasertib, ispinesib, paclitaxel, FK-506, AVN-944, digoxin, vincristine, idarubicin, thapsigargin, lexibulin, ixazomib, cephalomannine, mitoxantrone, MLN-2238, demecolcine, vinorelbine, bardoxolone methyl, cycloheximide, actinomycin D, AZD- 7762, PF-184, CHIR-124, cyanein, triptolide, KX-01, PF-477736, epirubicin, mycophenolate (mycophenolic acid), daunorubicin, PIK-75, vindesine, torin-2, floxuridine, Go-6976, or OSU- 03012. [0105] In some embodiments, the additional therapeutic agent is an antiviral agent.

[0106] In some embodiments, the antiviral agent is amantadine, ampligen, umifenovir, baloxavir marboxil, ganciclovir, letermovir, moroxydine, nitazoxanide, oseltamavir, peramivir, pleconaril, rimantadine, or zanamivir.

[0107] In some embodiments, the antiviral agent is interferon, ribavirin, adefovir, tenofovir, acyclovir, brivudin, cidofovir, fomivirsen, foscamet, ganciclovir, penciclovir, amantadine, rimantadine, lopinavir, ritonavir, zanamivir, or a combination thereof.

[0108] In some embodiments, the antiviral agent is remdesivir or a pharmaceutically acceptable salt thereof. In some embodiments, the antiviral agent is remdesivir. In some embodiments, the antiviral agent is favipiravir or a pharmaceutically acceptable salt thereof. In some embodiments, the antiviral agent is favipiravir.

[0109] In some embodiments, the antiviral agent is a broad-spectrum inhibitor of a coronavirus. Non-limiting examples of a broad-spectrum inhibitor of a coronavirus are lycorine, mycophenolate mofetil, phenazopyridine, mycophenolic acid, pyrvinium pamoate, monensin sodium, cycloheximide, cetylpyridinium chloride, oligomycin, promazine, diperodon, dihydrocelastryl diacetate, tetrandrine, pristimerin, and chloroquine.

[0110] In some embodiments, the additional therapeutic agent is an agent that can inhibit an inflammatory response. In some embodiments, such an agent may be useful for controlling a cytokine storm. Non-limiting examples of such agents include sphingosine 1 -phosphate receptor 1 modulators (i.e. ozanimod, fmgolimod, etc.), COX inhibitors (i.e., mesalamine, celecoxib, etc.), CCR2 inhibitor (PF-041789-3), anti-TNF agents, statins (i.e. simvastatin), OX40-Ig fusion proteins, and PPARa./PPARy agonists i.e. gemfibrozil, pioglitazone, rosiglitazone, 15d-PGJ2, ciglitazone, troglitazone, etc.). In some embodiments, the agent useful for controlling a cytokine storm is ozanimod or fmgolimod.

[0111] In some emboidments, the additional therapeutic agent is an anti-IL-6 therapeutic agent. Non-limiting examples of an anti-IL-6 therapeutic agent include tocilizumab, sarilumab, siltuximab, and other agents that target the IL-6 receptor. [0112] In some embodiments, the additional therapeutic agent is bamlanivimab (LY-CoV555). In some embodiments, the additional therpeutic agent is baricitinib or a combination of baricitinib and remdesivir.

[0113] In some embodiments, the additional therapeutic agent is bamlanivimab and etesevimab. In some embodiments, the additional therapeutic agent is etesevimab (LY-C0VOI6, JS016).

[0114] In some embodiments, the additional therapeutic agent is regdanvimab.

[0115] In some embodiments, the additional therapeutic agent is casirivimab, imdevimab, or a combination thereof (formerly REGN-COV2).

[0116] In some embodiments, the additional therapeutic agent is MP0420 (ensovibep), CPI-006, artesunate/pyronaridine (pyramax), Mitigare/Colcrys (Colchicine), GSK4182136/GSK4182137 (VIR-7831/VIR-7832), carrageenan nasal spray (carragelose), regdanvimab/CT-P59 (Regkirona), CD24Fc/SACCOVID (MK-7110), niclosamide(Niclocide), UNI91103, camostat mesilate (Foipan/Foistar), SNG001, aviptadil/RLF-100 (Zyesami), APN01, PMX-30063 (Brilacidin), STI- 2020 (COVI-AMG/COVI-DROPS), abivertinib (STI-5656), or lanadelumab (Takhzyro).

[0117] In some embodiments, the additional therapeutic agent is casirivimab, imdevimab, a combination of casirivimab and imdevimab, baricitinib, remdesivir, PTC299, PRO 140 (leronlimab), LY-CoV555 (bamlanivimab), lenzilumab, ivermectin, aviptadil (RLF-100), metformin, AT-527, tocilizumab, niclosamide, famotidine, lopinavir-ritonavir (kaletra), infliximab, AZD7442, abivertinib CT-P59, heparin, GSK4182136, JS016, sarilumab, CD24Fc, adalimumab, STI-1499, dexamethasone, PB1046, galidesivir, bucillamine, PF-07304814 (PF-00835321), apixaban, ianadelumab, hydrocortisone, canakinumab, colichicine, BLD-2660, favilavir-avifavir (avigan), gelsolin, MK-4482, TXA127, apilimod dimesylate, SAR443122, INOpulse, ABX464, AdMSCs, losmapimod, mavrilimumab, acalabrutinib, gimsilumab, otilimab, dapagliflozin, ravulizumab, or a combination thereof.

[0118] In some embodiments, methods provided herein further comprise administering to the subject convalescent plasma.

[0119] In some embodiments, the additional therapeutic agent is an anticoagulation drug. In some embodiments, the anti coagulation drug is enoxaparin. [0120] Provided herein are methods of treating a viral infection in a subject in need thereof, comprising administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of remdesivir, or a pharmaceutically acceptable salt thereof, wherein the viral infection is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

[0121] Also provided herein are compositions comprising a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of remdesivir, or a pharmaceutically acceptable salt thereof.

[0122] Also provided herein are methods of treating COVID-19 in a subject in need thereof, comprising administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of remdesivir, or a pharmaceutically acceptable salt thereof.

[0123] Also provided herein are methods of treating COVID-19 in a subject in need thereof, comprising administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of remdesivir, or a pharmaceutically acceptable salt thereof, wherein the subject does not require hospitalization.

[0124] Also provided herein are methods of treating COVID-19 in a subject in need thereof, comprising administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of remdesivir, or a pharmaceutically acceptable salt thereof, wherein the subject is a high-risk, symptomatic adult patient with confirmed COVID-19 infection not requiring hospitalization.

[0125] Provided herein are methods of treating a viral infection in a subject in need thereof, comprising administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an agent useful for controlling a cytokine storm, or a pharmaceutically acceptable salt thereof, wherein the viral infection is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

[0126] Also provided herein are compositions comprising a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an agent useful for controlling a cytokine storm, or a pharmaceutically acceptable salt thereof. [0127] Also provided herein are methods of treating COVID-19 in a subject in need thereof, comprising administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an agent for controlling a cytokine storm, or a pharmaceutically acceptable salt thereof.

[0128] Also provided herein are methods of treating COVID-19 in a subject in need thereof, comprising administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an agent for controlling a cytokine storm, or a pharmaceutically acceptable salt thereof, wherein the subject does not require hospitalization.

[0129] Also provided herein are methods of treating COVID-19 in a subject in need thereof, comprising administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an agent for controlling a cytokine storm, or a pharmaceutically acceptable salt thereof, wherein the subject is a high-risk, symptomatic adult patient with confirmed COVID-19 infection not requiring hospitalization.

[0130] Provided herein are methods of preventing a viral infection caused by SARS-CoV-2 in a subject in need thereof, comprising administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of remdesivir, or a pharmaceutically acceptable salt thereof.

[0131] Provided herein are methods of preventing COVID-19 in a subject in need thereof, comprising administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of remdesivir, or a pharmaceutically acceptable salt thereof.

[0132] Provided herein are methods of preventing a viral infection caused by SARS-CoV-2 in a subject in need thereof, comprising administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of remdesivir, or a pharmaceutically acceptable salt thereof, wherein the subject is a high-risk, symptomatic adult patient with confirmed COVID-19 infection not requiring hospitalization.

[0133] Provided herein are methods of preventing COVID-19 in a subject in need thereof, comprising administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of remdesivir, or a pharmaceutically acceptable salt thereof, wherein the subject is a high-risk, symptomatic adult patient with confirmed COVID-19 infection not requiring hospitalization.

[0134] It is understood that modifications which do not substantially affect the activity of the various embodiments of this disclosure are also included within the definition of the disclosure provided herein. Accordingly, the following examples are intended to illustrate but not limit the present disclosure.

EXAMPLES

Example 1:

[0135] Patients, at least 18 years of age and with confirmed COVID-19, are administered 1 mg per day of emetine (or a pharmaceutically acceptable salt thereof), via subcutaneous injection, for 10 days. Primary Endpoints are as follows: virological clearance at day 6 post-inclusion or time to clinical improvement (defined as the time from randomization to an improvement of two points (from status at randomization) on a seven-category ordinal scale or live discharge from the hospital, whichever comes first).

Example 2:

[0136] This is multicenter, Phase 2/3, randomized open-label, placebo-controlled trial of the safety and efficacy of emetine combined with standard of care versus standard of care alone for the treatment of high risk adults with confirmed SARS-CoV-2 infection not requiring hospitalization. This is a two part study with a dose finding (Phase 2) portion in Part A and an efficacy portion (Phase 3) in Part B. Eligible subjects will be randomized to the designated treatment groups for Part A (dose finding) and Part B (efficacy). There will be no stratification. Subjects in both Part A and Part B of the study will be evaluated for up to 28 days after the last dose of study treatment.

[0137] This Phase 2/3 trial will implement an adaptive study design since there is no single universally accepted endpoint or regulatory guidance for subjects with SARS-CoV-2 infection who do not require hospitalization. At the end of Part A, viral, clinical, and safety endpoints will be analyzed. In addition, the endpoint proposed for Part B with the highest conditional power will be selected as the primary endpoint for the final analysis and others will be used as key secondary endpoints. [0138] Patient inclusion criteria is as follows:

• Provide written, informed consent to participate in the study and follow the study procedures

• Male or non-pregnant females who meet the following criteria prior to randomization: o Not hospitalized o SARS-CoV-2 infection confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) or other validated test <4 days prior to randomization o Age >60

OR o Age >18 with at least one of the following risk factors for severe SARS CoV-2 infection: Presence of pulmonary disease, specifically moderate or severe persistent asthma, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, emphysema Diabetes mellitus (type 1 or type 2), requiring oral medication or insulin for treatment Hypertension, requiring at least 1 oral medication for treatment History of organ or stem cell transplant Human immunodeficiency virus (HIV) infection with undetectable HIV RNA level

• Women of childbearing potential must agree to either abstinence or use at least one primary form of contraception not including hormonal contraception from the time of screening through 60 days after the last dose. Males must use a condom and spermicide from screening through 60 days after the last dose of study drug if the female partner(s) is of childbearing potential and must not donate sperm from screening through 60 days after the last dose of study drug. This criterion also applies to males who are surgically sterile.

[0139] In Part A of the study, treatment groups are summarized in Table 1. Table 1

SC = subcutaneous; SQ = subcutaneous

[0140] In Part B of the study, treatment groups are summarized in Table 2.

Table 2

SC = subcutaneous; SQ = subcutaneous

[0141] Study objectives and endpoints for Part A and potential objectives and endpoints for Part B (which will be determined after completion of Part A) are summarized in Table 3.

Table 3

Example 3:

[0142] This is a multicenter, Phase 2/3, randomized, double-blind, placebo-controlled trial of the safety and efficacy of emetine combined with standard of care versus standard of care alone for the treatment of mildly symptomatic, high-risk adults with confirmed SARS-CoV-2 infection not requiring hospitalization. This is a 3-part study with a PK/safety portion (Part A), a dose finding portion (Phase 2) in Part B, and an efficacy portion (Phase 3) in Part C. Eligible subjects will be randomized to the designated treatment groups for Part A, Part B, and Part C. There will be no stratification.

[0143] This Phase 2/3 trial will implement an adaptive study design since there is no single universally accepted endpoint or regulatory guidance for subjects with SARS-CoV-2 infection who do not require hospitalization. The safety and PK data collected in Part A will be used to determine the dose, endpoints, and safety monitoring required in subsequent parts of the study. The primary and secondary endpoints as well as the dose and schedule chosen for the efficacy portion of the study (Part C) will be determined based on the outcomes from Part A and Part B.

[0144] Since most mildly ill patients with SARS-CoV-2 can be managed in an ambulatory setting or at home through telemedicine and/or remote visits, study participants may participate in this study by visits to the study site or by home visits conducted by a home health agency. If study participants are treated at home, the investigator will provide supervision through telemedicine, where necessary.

[0145] An independent, external, and multidisciplinary data monitoring committee (DMC) will convene after the completion of Part A for a safety review and will convene after Part B to determine the dose and primary efficacy analysis for Part C.

[0146] Participants are eligible to be included in the study only if all of the following criteria apply.

[0147] Inclusion/exclusion criteria may be modified after Part A is completed and the PK and safety data are evaluated, based on recommendations from the DMC.

[0148] Age: Participant must be >18 years of age inclusive, at the time of signing the informed consent form (ICF). [0149] Type of Participant and Disease Characteristics: Participants who are:

• Not hospitalized

• SARS-CoV-2 infection confirmed by reverse transcription polymerase chain reaction (RT- PCR) or other validated test <4 days prior to randomization

• Participants with mildly symptomatic disease for SARS-CoV-2, defined as: Presence of fever (>100.4°F/38°C, taken orally), cough, sore throat, malaise, headache, muscle pain, or new loss of taste or smell Without shortness of breath or dyspnea (respiratory rate [RR] < 20, SpCk > 93% on room air) or abnormal chest imaging

• Age >60 or Age >18 with at least one of the following risk factors for severe SARS-CoV-2 infection: Presence of pulmonary disease, specifically moderate or severe persistent asthma, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, emphysema Diabetes mellitus (type 1 or type 2), requiring oral medication or insulin for treatment Hypertension, requiring at least 1 oral medication for treatment History of organ or stem cell transplant Human immunodeficiency virus (HIV) infection with undetectable HIV RNA level Obesity (BMI > 30)

[0150] Sex: Male and/or non-pregnant female:

• Male participants: Males must use a condom and spermicide from screening through 60 days after the last dose of study drug if the female partner(s) is of childbearing potential and must not donate sperm from screening through 60 days after the last dose of study drug. This criterion also applies to males who surgically sterile. • Female participants: Women of childbearing potential must agree to either abstinence or use at least one primary form of contraception not including hormonal contraception from the time of screening through 60 days after the last dose.

Screening Period:

[0151] The Screening Period will occur from Day -4 to Day 0 after the subject has been documented as SARS-CoV-2 positive using a qualitative RT-PCR or other validated test. During this time, screening tests will be performed and the onset of and a list of specific symptoms related to SARS-CoV-2 will be documented.

Treatment Period:

Part A: PK and Safety:

[0152] In Part A of the study, approximately 45 subjects will be randomized in to 1 of 4 treatment arms (2 active and 2 placebo) as described in Table 4.

Table 4: Treatment Arms- Part A

SQ = subcutaneous ^a standard of care as defined in the NIH guidelines excluding other antiviral agents Source: https://www.covidl9treatmentguidelines.nih.gov/ [0153] A blinded interim analysis will be performed after the completion of Part A. The DMC will evaluate the safety, PK, and preliminary viral and clinical endpoints data from Part A and determine if the trial should begin enrollment in Part B using the existing doses or if any modifications should be made to the dose and/or regimen based on PK or safety.

Part B: Phase 3 (Dose Finding):

[0154] In Part B of the study, 105 subjects will be randomized to 1 of 4 treatment arms (2 active and 2 placebo), as described in Table 5. Efficacy results including viral load and clinical endpoints from Part B will be combined with data from Part A to determine the emetine dose and schedule to be used in Part C (Efficacy).

Table 5: Treatment Arms- Part B

SQ = subcutaneous ^a Dosage and schedule may change based on findings in Part A ^b standard of care as defined in the NIH guidelines excluding other antiviral agents Source: https://www.covidl9treatmentguidelines.nih.gov/

Part C: Phase 3 (Efficacy):

[0155] In Part C of the study, 300 subjects will be randomized in a 2: 1 ratio to one of 2 treatment arms (active: placebo), as described in Table 6. Table 6: Treatment Arms- Part C

N/A = not applicable; SQ = subcutaneous ^a Dosage and schedule may change based on findings in Parts A and B ^b standard of care as defined in the NIH guidelines excluding other antiviral agents Source: https://www.covidl9treatmentguidelines.nih.gov/

Follow-up Period:

[0156] Subjects in Parts A, B, and C of the study will be evaluated for 56 days. Treatment Duration:

[0157] Part A: 1 day in Treatment Arms 1 and 2; 4 days in Treatment Arms 3 and 4

[0158] Part B: 1 day in Treatment Arms 1 and 2; 4 days in Treatment Arms 3 and 4

[0159] Part C: 1 day in Treatment Arms 1 and 2 OR 4 days in Treatment Arms 1 and 2

[0160] The study objectives and endpoints are presented in Table 7 for Part A

(pharmacokinetics [PK] and Safety) and in Table 8 for Part B and Part C (Dose finding and Efficacy). Table 7. Objectives and Endpoints (Part A- PK and Safety)

AE = adverse event; AUC = area under the concentration-time curve; Cmax = maximum plasma concentration; Cmin = minimum plasma concentration; Ct = cycle threshold; ECG = electrocardiogram, ICU = intensive care unit; IgG = immunoglobulin G; IgM = immunoglobulin M; IFNy = interferon gamma; IL-6 = interleukin 6; LDH = lactate dehydrogenase; NEWS-2= National Early Warning Score 2; PK = pharmacokinetics; RT-PCR = reverse transcription polymerase chain reaction; SAE = serious adverse events; SARS-CoV-2 = severe acute respiratory syndrome coronavirus-2; SOC = standard of care; SpCk = oxygen saturation by pulse oximetry; SQ = subcutaneous; Tmax = time to maximum plasma concentration; TNFa = tumor necrosis factor, alpha.

Table 8. Objectives and Endpoints (Part B and Part C)

[0161] Although the invention has been described with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the specific examples and studies detailed above are only illustrative of the invention. It should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method of treating a viral infection in a subject in need thereof, comprising administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, wherein the viral infection is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and wherein the subject does not require hospitalization.

2. A method of treating COVID-19 in a subject in need thereof, comprising administering a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, and wherein the subject does not require hospitalization.

3. A method of treating a viral infection in a subject in need thereof, comprising administering a composition comprising a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the viral infection is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and wherein the subject does not require hospitalization.

4. A method of treating COVID-19 in a subject in need thereof, comprising administering a composition comprising a therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and wherein the subject does not require hospitalization.

5. The method of any one of claims 1-4, wherein the subject does not exhibit severe symptoms of Cytokine Release Syndrome (cytokine storm).

6. The method of any one of claims 1-5, wherein the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is 1 mg per day.

7. The method of any one of claims 1-5, wherein the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is about 5 mg to about 15 mg per day.

8. The method of any one of claims 1-5, wherein the therapeutically effective amount of emetine, or a pharmaceutically acceptable salt thereof, is 60 mg per day.

9. The method of any one of claims 5-8, wherein emetine, or a pharmaceutically acceptable salt thereof, is administered by a subcutaneous injection.

10. The method of claim 9, emetine is administered as a hydrochloride salt thereof.

11. The method of any one of the preceding claims, further comprising administering one or more of an additional therapeutic agent.

12. The method of claim 11, wherein the additional therapeutic agent is an antiparasitic agent.

13. The method of claim 12, wherein the antiparasitic agent is chloroquine or hydroxychloroquine.

14. The method of claim 11, wherein the additional therapeutic agent is an antibiotic.

15. The method of claim 14, wherein the antibiotic is azithromycin.

16. The method of claim 11, wherein the additional therapeutic agent is an antiviral agent.

17. The method of claim 16, wherein the antiviral agent is interferon, ribavirin, adefovir, tenofovir, acyclovir, brivudin, cidofovir, fomivirsen, foscarnet, ganciclovir, penciclovir, amantadine, rimantadine, lopinavir, ritonavir, zanamivir, or a combination thereof.

18. The method of claim 16, wherein the antiviral agent is remdesivir.

19. The method of claim 11, wherein the additional therapeutic agent is an agent useful for controlling a cytokine storm.

20. The method of claim 19, wherein the agent useful for controlling a cytokine storm is ozanimod or fmgolimod.