WO2022053993A2 - Treatments for sars-cov-2 infection (covid-19) - Google Patents

Abstract

Active agent combinations are provided for the treatment and/or prevention of COVID-19.

Description

TREATMENTS FOR SARS-COV-2 INFECTION (COVID-19)

FIELD OF THE DISCLOUSRE

The present disclosure relates to treatment methods for SARS-CoV-2 infections and to combination kits and compositions useful for the same.

BACKGROUND OF THE INVENTION

The COVID-19 outbreak apparently began in Wuhan, China, in late 2019, and is caused by a previously unknown coronavirus called SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). COVID-19 is now a global pandemic. Coronaviruses are a large family of viruses which may cause illness in animals or humans. In humans, several coronaviruses are known to cause respiratory infections ranging from the common cold to more severe diseases such as Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS).

Current understanding of COVID-19 indicates that the disease spreads primarily from person to person through small droplets from the nose or mouth, which are expelled when a person with COVID-19 coughs, sneezes, or speaks, and another person breaths in these droplets. Accordingly, the WHO advises that social distancing - staying at least 1 meter away from others - may attenuate disease spread. Secondary routes of infection appear to include touching surfaces that have been contaminated by SARS-CoV-2-containing droplets, then touching of the eyes, nose or mouth. Routine hand washing with soap and water or an alcohol-based hand rub can reduce such transmission. The estimated incubation period is between 2 and 14 days with a median of 5 days.

While many people appear to recover from the disease without needing hospital treatment, about 1 in 5 people become seriously ill and develop difficulty breathing. Older people, and those with underlying medical problems like high blood pressure, heart and lung problems, diabetes, or cancer, are at higher risk of developing serious illness. According to the Centers for Disease Control (Atlanta, Georgia; see www.cdc.gov/coronavirus/2019- ncov/hcp/non-us-settings/overview/index.html), among the 44,672 confirmed COVID-19 cases from China reported from December 31, 2019 through February 11, 2020, the clinical presentation was classified as mild, severe, or critical.

Mild (non-pneumonia and mild pneumonia cases) cases represented 80.9% of confirmed patients, and included a large spectrum of illnesses including but not limited to patients having fever, cough, chest pain, nausea, and body pain. Severe (dyspnea, respiratory frequency > 30/min, blood 02 sat <93%, PaO2/FiO2 ratio <300, lung infiltrates >50% within 24-48 hours) cases represented 13.8% of confirmed patients with COVID-19 in China. Critical (respiratory failure, septic shock, and/or multiple organ dysfunction or failure, death) cases represented 4.7% of confirmed patients with COVID-19 in China. 1,023 (49%) deaths were reported among the 2,087 critically ill patients.

As of August 12, 2020, over 20 million people worldwide have been confirmed to have been infected with over 750,000 deaths. Accordingly, it is imperative to develop methods for treatment and/or prevention of COVID-19.

SUMMARY OF THE DISCLOSURE

In one aspect, methods are provided for treating or preventing COVID-19 comprising administering to a person in need of treatment for COVID-19, a therapeutically effective amount of two or more active agents, wherein a first active agent is an RNA-dependent RNA polymerase modulator; and a second active agent is selected from the group consisting of an anti-inflammatory, a viral entry blocker, a viral replication modulator, famotidine, a zinc agent, and mixtures thereof, wherein the active agents are not remdesivir.

In another aspect, kits are provided comprising a plurality of unit dosages, wherein a first unit dosage comprises an RNA-dependent RNA polymerase modulator; and a second unit dosage comprises an anti-inflammatory, a viral entry blocker, a viral replication modulator, famotidine, a zinc agent, or a mixture thereof, wherein the unit dosages do not comprise remdesivir. In another aspect, kits are provided comprising a plurality of unit dosages, wherein each unit dosage comprises an RNA-dependent RNA polymerase modulator; and a second active agent selected from the group consisting of an anti-inflammatory, a viral entry blocker, a viral replication modulator, famotidine, a zinc agent, and mixtures thereof, wherein the unit dosages do not comprise remdesivir.

In certain embodiments, the combination treatments provided herein provide improved (including synergistic) results in the treatment of COVID-19 as compared to treatment with the individual components of the combination.

DETAILED DESCRIPTION OF THE DISCLOSURE

The combination therapies provided herein provide the opportunity for two or more active agents to work synergistically in the treatment of COVID-19 as compared to treatment of the disease with the individual components of the combination. Combination therapies may comprise the administration of two or more active agents, as described herein, or a pharmaceutically acceptable salt of either or both thereof. The active ingredient(s) and pharmaceutically active agents may be administered simultaneously (i.e., concurrently) in either the same or different pharmaceutical compositions or sequentially in any order. The amounts of the active ingredient(s) and pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.

As used herein, the terms "treatment" and "treating" mean (i) ameliorating the referenced disease state, for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing or improving the pathology and/or symptomatology) such as decreasing the severity of disease; or (ii) eliciting the referenced biological effect (e.g., reduction in viral load or reduction in viral RNA). For the treatment of infections caused by SARS-CoV-2, a wide range of symptoms for COVID-19 have been reported, including, fever or chills, cough, shortness of breath or difficulty breathing, fatigue, headache, nasal congestion or runny nose, muscle or body aches, sore throat, new loss of smell or taste, nausea or vomiting, and/or diarrhea. A "therapeutically effective amount" for treatment of COVID-19 as used herein refers to an amount necessary for the "treatment" as defined above.

As used herein, the terms "prevention" and "preventing" mean prophylactic treatment a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; for example, by administration of a compositions as described herein prior to or in anticipation of potential exposure to SARS-CoV-19 including exposure to persons known or suspected to have been infected by SARS-CoV-19. A "therapeutically effective amount" for prevention of COVID-19 as used herein refers to an amount necessary for the "prevention" as defined above.

"Simultaneously" as used herein for the administration of the combinations means administration of each active agent of the combination within about 12 hours of one another. This may include a succession of consecutive administrations of separate unit dosages, each containing one of the active agents, or of one or more fixed dosage combination forms ("FDC"), each dosage form comprising two or more active agents. In certain embodiments, the combination is administered as a FDC containing the two or more active agents. In certain embodiments, the administration is completed in less than 10 hours, or 8 hours, or 6 hours, or 4 hours, 3 hours, or 2 hours, or 1 hour, or 30 minutes, or 15 minutes. Where the therapeutic combination is to be administered more than one time a day, then each individual administration event is considered individually simultaneous when that event is completed within 12 hours, or 10 hours, or 8 hours, or 6 hours, or 4 hours, or less than 3 hours, or 2 hours, or 1 hour, or 30 minutes, or 15 minutes

A "unit dosage" or "unit dose" as used herein refer to the amount of pharmaceutical administered for each individual dosage event. That is, administration that requires, for example, BID administration, comprises two unit doses, one for each dosage event, which together comprise the total daily dose. Accordingly, a FDC pharmaceutical composition herein includes those compositions containing an entire unit dosage of the two or more active ingredients, or an appropriate fraction ( sub-dosage ) thereof. In the latter case, a plurality of sub-dosage units may be administered together, thereby providing the unit dosage of the fixed-dosage combination pharmaceutical. For example, a single unit dosage of the fixed- dosage combination may be essentially evenly divided among 2, 3, 4, 5, 6, or more sub-dosage units that when administered together, provide the single unit dosage in a manner that could be ingested comfortably.

Active Agents

In the treatment methods herein, two or more active agents are administered, where the two or more active agents are (1) a first agent which is an RNA-dependent RNA Polymerase (RdRP) modulator; (2) a second agent selected from the group consisting of antiinflammatories, such as corticosteroids, inflammasome affecting compounds (NLRP3 or interleukin-10 converting enzyme (ICE, caspase-1)), interleukin-1 receptor ( IL-1 R) inhibitors, or IL-6 modulators; viral entry blockers, such as membrane fusion inhibitors, microtubule polymerization inhibitors, TMPRSS2 inhibitors, ACE2 blockers, or spike protein blockers; viral replication modulators, such as neuraminidase inhibitors, alpha-glucosidase inhibitors, M^pro protease inhibitors, M2 protein inhibitors, or other replication modulators identified in repurposing screens; and other SARS-CoV-2 affecting compounds, such as famotidine, zinc compounds (Zn²⁺ compounds), and vitamins such as vitamin C and/or D3. In the present disclosure, the active agents do not include remdesivir.

Any of the active agents, individually, may be utilized as a free base or as a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts of the active agent include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicyclic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g., magnesium), ammonium, NW^{4 +} (wherein W is C_{i 4} alkyl) and other amine salts. Salts of the compounds of the present invention may be made by methods known to a person skilled in the art. For example, treatment of a compound of the present invention with an appropriate base or acid in an appropriate solvent can yield the corresponding salt.

Viral replication modulators are agents that interfere with replication of SARS-CoV-2 within host cells, for example, by inhibiting RNA-dependent RNA Polymerase (RdRP), neuraminidases, alpha-glucosidase, the M2 protein, or the SARS-CoV-2 main protease (M^pro). As used herein, viral replication modulators exclude both remdesivir and zinc agents, as defined below.

RNA-dependent RNA Polymerase (RdRP) is a key part of the replication machinery of SARS-CoV-2 that makes copies of its RNA genome, modulation of which may affect SARS-CoV- 2 replication. See Gao et al. "Structure of the RNA-dependent RNA polymerase from COVID- 19 virus", Science 2020, 368(6492), 779-82. RdRP modulators include (a) RNA chain terminators which compete with natural RNA Polymerase substrates, and whose incorporation into nascent viral RNA results in chain termination, and (b) agents that inhibit polymerase activity, such as by allosteric mechanisms. Examples of RdRP modulators include, for example, galidesivir (BCX4430), sofosbuvir, cordycepin, acyclovir, valacyclovir, gemcitabine, ganciclovir, atazanavir, 3'-deoxyribouracil (d-U), or (d-UTP), 3'- deoxyribocytosine (d-C) or (d-CTP), 3'-deoxyriboguanine (dG) or (d-GTP), 3'-deoxyriboadenine (dA) or (dATP), emtricitabine, zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, entecavir, tenofovir, tenofovir disoproxil, tenofovir alafenamide, adefovir, apricitabine, telbivudine, 0-D-N-4-hydroxycytidine (NHC; EIDD-1931), 0-D-N-4- hydroxycytidine-5'-isopropyl ester (EIDD-2801), enisamium (4-(benzylcarbamoyl)-l- methylpyridinium) iodide), 4-(benzylcarbamoyl)-3-hydroxy-l-methylpyridinium) (VR17-04), darinaparsin, beclabuvir (BMS-791325), dasabuvir (ABT-333), filibuvir (PF-00868554), radalbuvir (GS-9669), setrobuvir, deleobuvir (BI-207127), uprifosbuvir (MK-3682), tegobuvir (GS-9190), holybuvir (SH-229), balapiravir (Ro 4588161; R1626), adafosbuvir (AL-335), (2E)-3- [4-[[[l-[[[3-cyclopentyl-l-methyl-2-(2-pyridinyl)-lH-indol-6- yl]carbonyl]amino]cyclobutyl]carbonyl]amino]phenyl]-2-propenoic acid (BILB 1941); (7R)-14- cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6H-indolo[l,2- e][l,5]benzoxazocine-ll-carboxylic Acid (MK-3281); (2R,4R,5S)-l-(4-tert-butyl-3- methoxybenzoyl)-4-(methoxymethyl)-2-(pyrazol-l-ylmethyl)-5-(l,3-thiazol-2-yl)pyrrolidine- 2-carboxylic acid (GSK-625433); 6-[N-(7-Chloro-l-hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol- 5-yl)(methylsulfonyl)amino]-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide (GSK-2878175); N-[(S)-hydroxyphenoxyphosphinyl]-L-alanine 1-methylethyl ester 6-ester with 2-C-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-2,5-anhydro-3-C-methyl-D- altrononitrile 4-(2-methylpropanoate) (GS-6620); 2'-C-methylguanosine 5'-[2-[(3-hydroxy- 2,2-dimethyl-l-oxopropyl)thio]ethyl N-(phenylmethyl)phosphoramidate] (IDX-184); 27- cyclohexyl-12,13,16,17-tetrahydro-22-methoxy-ll,17-dimethyl-2,19-methano-3,7:4,l- dimetheno-lH,llH-14,10,2,9,ll,17-benzoxathiatetraazacyclodocosine-8,18(9H,15H)-dione 10,10-dioxide (TMC-647055); VX-135 (CAS No. 1632229-35-6), PPI-383 (CAS No. 1444827-44- 4), ABT-072 (CAS No. 1214735-11-1), AT-527, GSK-2485852, BMS-929075, BMS-986094, BMT- 052, BMS-961955, BI207524, BMS-791325, VX-222, N-4-[6-tert-butyl-5-methoxy-8-(6- methoxy-2-oxo-lH-pyridin-3-yl)-3-quinolyl]phenyl]-methanesulfonamide (RG7109); SCH 900188, daclatasvir (BMS-790052), velpatasvir, elbasvir (MK-8742), ledipasvir (GS-5885), ruzasvir (MK-8408), odalasvir (ACH-3102), ombitasvir (ABT-267), ravidasvir (PPI-668), smatasvir (IDX-719), pibrentasvir (ABT-530), TD-6450 (CAS No. 1987917-45-2), GSK2336805, PPI-461 (CAS No. 1263078-82-5), MB-110, AT-777, favipiravir (T-705), ribavirin, baloxavir marboxil, baloxavir acid; (l-[(llS)-6,ll-dihydrodibenzo[b,e]thiepin-ll-yl]-2,3-dihydro-5- hydroxy-3-[(lR)-2,2,2-trifluoro-l-methylethyl]-lH-pyrido[2,l-f][l,2,4]triazine-4, 6-dione)

(RO-7); AL-794 (JNJ-64155806), ALS-033719, epigallocatechin gallate (EGCG), flutamide; L- 742,001 hydrochloride [(Z)-4-[l-benzyl-4-[(4-chlorophenyl)methyl]piperidin-4-yl]-2-hydroxy- 4-oxobut-2-enoic acid hydrochloride; 4-[4-[(4-chlorophenyl)methyl]-l-(phenylmethyl)-4- piperidinyl]-2-hydroxy-4-oxo-2-butenoic acid hydrochloride]; ANA-0 [(5Z)-2-[2-(2-Oxoindol- 3-yl)hydrazinyl]-5-(2-oxo-lH-indol-3-ylidene)-l,3-thiazol-4-one]; flupyranochromene, pimodivir (VX-787, JNJ-63623872), methyl brevifolincarboxylate, dihydromyricetin.

In certain embodiments, the RdRP modulator is galidesivir, sofosbuvir, daclatasvir, velpatasvir, ledipasvir, favipiravir, ribavirin, baloxavir marboxil, emtricitabine, tenofovir, tenofovir disoproxil fumarate, or tenofovir alafenamide.

Alpha-glucosidase is an enzyme that plays a role in host cell N-glycosylation pathways utilized for virus replication. See Williams et al., "a-glucosidase inhibitors as host-directed antiviral agents with potential for the treatment of COVID-19" Biochem. Soc. Trans. (2020) 48 (3): 1287-1295. Inhibition of a-glucosidase may assist in reducing the ability of SARS-CoV-2 to replicate, thereby potentially reducing viral load. Examples of a-glucosidase inhibitors include miglustat, acarbose, miglitol, celgosivir, castanospermine, voglibose (AO-128), 1- deoxynojirimycin, C-6-O-methyl-l-deoxynojirimycin, baicalein, salacinol, amylostatin XG, cyanidin-3-galactoside, chebulagic acid, carbazomarin, fucoidan, (2R,3R,4R,5S)-2- (Hydroxymethyl)-l-[6-[(4-methylcyclohexyl)oxy]hexyl]-3,4,5-piperidinetriol (CM-9-78), and (2R,3R,4R,5S)-l-(7-Ethyl-7-hydroxynonyl)-2-(hydroxymethyl)-3,4,5-piperidinetriol (CM-10- 18). In certain embodiments, the alpha-glucosidase inhibitor is miglustat, acarbose, miglitol, celgosivir, castanospermine, or voglibose. In other embodiments, the alpha-glucosidase inhibitor is miglustat.

Neuraminidase inhibitors have been used as antiviral drugs because they block the function of viral neuraminidases (e.g. of the influenza virus), by preventing its reproduction by budding from the host cell. Such have been proposed for treatment of COVID-19 despite coronaviruses not utilizing neuraminidase for the budding stage of reproduction. See Wang et al, "The anti-influenza virus drug, arbidol is an efficient inhibitor of SARS-CoV-2 in vitro", Cell Discovery 2020, 6, 28. Examples of neuramindase inhibitors include oseltamivir, zanamivir, laninamivir, and peramivir.

M^pro (also known as 3CL^pro)is a protease that has been validated as an antiviral drug target for the original SARS and MERS, both genetically similar to SARS-CoV-2. M^pro inhibitors may include, for example, boceprevir, GC-376, and calpain inhibitors II and XII, ritonavir, lopinavir, chromocarb, telbivudine, vitamin B12, nicotinamide, aminophylline, triflusal, bemegride, aminosalicylate sodium, pyrazinamide, temozolomide, methazolamide, tioxolone, propylthiouracil, cysteamine, methoxamine hydrochloride, zonisamide, (+,-)- octopamine HCI, amiloride hydrochloride, N-((S)-3-cyclohexyl-l-oxo-l-(((S)-l-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)-lH-indole-2-carboxamide (11a), N-((S)-3- (3-fluorophenyl)-l-oxo-l-(((S)-l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan- 2-yl)-lH-indole-2-carboxamide (lib), benzyl ((S)-4-methyl-l-oxo-l-(((S)-l-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate (GC373), and sodium (2S)-2- ((S)-2-(((benzyloxy)carbonyl)amino)-4-methylpentanamido)-l-hydroxy-3-(2-oxopyrrolidin-3- yl)propane-l-sulfonate (GC376). See Ma et al., "Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease" Cell Research 2020, 30, 678-692; Kandeel et al., "Virtual screening and repurposing of FDA approved drugs against COVID-19 main protease" LifeSci. 2020, 251, 117627; Nutho et al., "Why Are Lopinavir and Ritonavir Effective against the Newly Emerged Coronavirus 2019? Atomistic Insights into the Inhibitory Mechanisms" Biochemistry 2020, 59, 1769-1779; and He et al., "Potential of coronavirus 3C-like protease inhibitors for the development of new anti-SARS-CoV-2 drugs: Insights from structures of protease and inhibitors", Int. J. Antimicrob. Agents 2020, 56(2), 106055; Vuong et al., "Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication", Nature Communications 2020, 11, Article number: 4282; and Dai et al., "Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease", Science 2020, 368(6497), 1331-1335. In certain embodiments, the M^pro inhibitor is cysteamine.

The viral M2 protein, an ion channel specified by virion M2 gene, plays an important role in viral replication. Inhibition of M2 may prevent the uncoating of the virus's protective shells, which are the envelope and capsid, thereby preventing release of genetic material in the host cell. Examples of M2 inhibitors include, for example, rimantadine, amantadine , 5- phenyl-N-tricyclo[3.3.1.1^3,7]dec-l-yl-3-isoxazolemethanamine (M2WJ352), 5-(2-thienyl)-N- tricyclo[3.3.1.1^3,7]dec-l-yl-3-isoxazolemethanamine (M2WJ332), 5-cyclopropyl-N- tricyclo[3.3.1.1³'⁷]dec-l-yl-3-isoxazolemethanamine (M2WJ379), 2-(l-piperidi nyl)-N- tricyclo[3.3.1.1³'⁷]dec-l-yl-5-pyrimidinemethanamine, 4-[(tricyclo[3.3.1.1^3,7]dec-l- ylamino)methyl]-l,3-benzenediol, 5-bromo-N-tricyclo[3.3.1.1^3,7]dec-l-yl-2- thiophenemethanamine (BC035), spiro[cyclohexane-l,2'-tricyclo[3.3.1.1³'⁷]decan]-4-amine, spiro[l,3-dithiane-2,2'-tricyclo[3.3.1.1³'⁷]decan]-5-amine, 3-[[[4-

(trimethylsilyl)phenyl]methyl]amino]tricyclo[3.3.1.1³'⁷]decan-l-ol, 4-tricyclo[3.3.1.1^3,7]dec-l- yl-piperidine, 4-tricyclo[3.3.1.1^3,7]dec-l-yl-l-piperidinecarboximidamide, 3-[[(5-(2- thiomethylphenyl)-3-isoxazolyl)methyl]amino]-tricyclo[3.3.1.1³'⁷]decan-l-ol, N-(l,l- dimethylethyl)-3-isoxazolemethanamine, or 3-[[(5-cyclopropyl-3-isoxazolyl)methyl]amino]- tricyclo[3.3.1.1^3,7]decan-l-ol. See Abreu et al., "Amantadine as a drug to mitigate the effects of COVID-19", Medical Hypotheses 2020, 140, 109755; and Jalily et al., "Put a cork in it: Plugging the M2 viral ion channel to sink influenza", Antiviral Res. 2020, 178, 104780. In certain embodiments, the M2 inhibitor is rimantadine.

Anti-inflammatories are compounds that are known to be useful in the reduction of the inflammatory response, and include corticosteroids, agents that reduce or block action of pro-inflammatory mediators such as interleukin-1 and -6 (IL-1 and IL-6), and agents that act to interfere with inflammasome complexes. As used herein, anti-inflammatories exclude non-steroidal anti-inflammatory agents (NSAIDs), including nonselective cyclooxygenase (COX) inhibitors, such as ibuprofen, aspirin (acetylsalicylate), diclofenac, and naproxen, as well as selective COX2 inhibitors, such as celecoxib, rofecoxib, etoricoxib, lumiracoxib, and valecoxib.

Examples of corticosteroids include alclometasone dipropionate, amcinonide, beclometasone, beclometasone dipropionate, betamethasone, betamethasone valerate, budesonide, ciclesonide, clobetasol propionate, clobetasone butyrate, cortisone acetate, desonide, dexamethasone, fluocinonide, fluocinolone acetonide, fluocortolone, fluprednidene acetate, halcinonide, halometasone, hydrocortisone, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, methylprednisolone, mometasone, mometasone furoate, prednicarbate, prednisolone, prednisone, tixocortol pivalate, and triamcinolone acetonide. In certain embodiments, the corticosteroid is hydrocortisone, hydrocortisone acetate, methylprednisolone, prednisolone, or prednisone.

Inflammasome complexes, found in neutrophils and monocytes, are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory response. The nod-like receptor family pyrin domain containing 3 (NLRP3) is one of the most widely studied inflammasomes and is activated to produce downstream factors, including caspase-1, IL-10, and IL-18, which then promote local inflammatory responses and induce pyroptosis, leading to unfavorable effects. Anti-inflammatories herein include compounds that act at NLRP3 or inhibit interleukin-10 converting enzyme (ICE, caspase-1). Examples of NLRP3 acting agents include N-acetylcysteine (NAC), IFM-2427 (IFM Therapeutics/Novartis), N-[[(l,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino]carbonyl]-4-(l- hydroxy-l-methylethyl)-2-furansulfonamide sodium salt (CP-456, 773/MCC950), inzomelid (Inflazome Ltd.), and dapansutrile [3-(methylsulfonyl)propanenitrile, OLT1177]. Examples of interleukin-10 converting enzyme (ICE, caspase 1) inhibitors include pralnacasan (VX-740), belnacasan (VX-765), VRT-043198 (active metabolite of VX-765), Ac-Tyr-Val-Ala-Asp- Chloromethylketone (Ac-YVAD-cmk), Tyr-Val-Ala-Asp-Chloromethylketone (YVAD-cmk), and Ac-YVAD-CHO (L-709049). Further examples of Anti-inflammatory agents include colchicine. In one embodiment, the anti-inflammatory is colchicine or N-acetylcysteine.

IL-1 is the apical pro-inflammatory mediator, inducing both its own production and the synthesis of several secondary inflammatory mediators, such as IL-6. Endogenous IL-1 has been found to be elevated in patients with COVID-19. Examples of interleukin-1 receptor (IL-1R) inhibitors include colchicine, anakinra, hydrocinnamoyl-L-valyl pyrrolidine, and EBI- 005 (CAS No. 1621109-46-3). In certain embodiments, the interleukin-1 receptor (IL-1R) inhibitor is colchicine or anakinra.

IL-6 is a cytokine that plays an important role in inflammatory reaction and immune response. IL-6 has been proposed as one of the most important cytokines involved in COVID- 19-induced cytokine storms. See Luo et al., "Tocilizumab treatment in COVID-19: A single center experience", J. Med. Virol. 2020, 92, 814-818. IL-6 modulators can act through direct interleukin-1 receptor (IL-6R) inhibition or indirectly to reducing serum IL-6 levels. Examples of interleukin-1 receptor (IL-6R) inhibitors include colchicine, tocilizumab, siltuximab, sarilumab, olokizumab (CDP6038), elsilimomab (BMS-945429, ALD518), sirukumab (CNTO 136), levilimab (BCD-089), vobarilizumab (ALX-0061), clazakizumab, gerilimzumab (ARGX- 109, RYI-008), and FM101. Examples of compounds capable of reducing serum IL-6 levels include fingolimod, thalidomide, nivolumab, pembrolizumab; JAK inhibitors such as tofacitinib, upadacitinib, ruxolitinib, and baracitinib; and anti-GM-CSF antibodies, such as gimsilumab. See, Mehta et al., "JAK inhibitors in COVID-19: need for vigilance regarding increased inherent thrombotic risk", Eur. Resp. J. 2020, 2001919 (DOI:

10.1183/13993003.01919-2020). In certain embodiments, the IL-6 modulator is colchicine, thalidomide, or fingolimod.

Viral entry blockers are agents capable of interfering with viral fusion with and/or entry into host cells, and can include membrane fusion inhibitors, microtubule polymerization inhibitors, TMPRSS2 inhibitors, ACE2 blockers, and spike glycoprotein blockers. Examples of membrane fusion inhibitors include umifenovir, enfuvirtide, (5Z)-5-[(5-Phenyl-2- furanyl)methylene]-3-(2-propen-l-yl)-2-thioxo-4-thiazolidinone(U001), EK1

(SLDQINVTFLDLEYEMKKLEEAIKKLEESYIDLKEL), EK1C4 (see Xia et al., Cell Research 2020, 30(4), 343-355), and IPB02 (ISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELK-Chol; see Zhu et al., J. Virol. 2020, 94(14), e00635-20). In certain embodiments, the membrane fusion inhibitor is umifenovir.

Microtubules are key structural elements of the cell cytoskeleton composed of polymers of tubulin. Microtubules are engaged in cellular processes such as transport, cell shape, migration, and mitosis. Coronaviruses interact with microtubules which promotes their internalization into host cells, a step critical for viral pathogenesis. Microtubule polymerization inhibitors are a class of compounds that inhibit the function of cellular microtubules and lead to depolymerization, potentially affecting the ability of COVID-19 to invade host cells. Examples of microtubule polymerization inhibitors include colchicine, podofilox, vinblastine, demecolcine, nocodazole, vincristine, vindesine, vinorelbine, combretastatin, 2-methoxyestradiol, N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4- methoxybenzenesulfonamide (E7010; ABT-751), and VERU-111 (Veru Inc.). In certain embodiments, the microtubule polymerization inhibitor is colchicine.

Transmembrane protease serine 2 (TMPRSS2) is a transmembrane serine protease that is associated with physiological and pathological processes such as digestion, tissue remodelling, blood coagulation, fertility, inflammatory responses, tumor cell invasion, and apoptosis. SARS-CoV-2 appears to be activated by TMPRSS2 and may be inhibited by TMPRSS2 inhibitors. See Hoffmann et al., "SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor", Cell (March 2020), 181(2), 271-280.e8. doi : 10.1016/j. cell.2020.02.052. Inhibitors of TMPRSS2 include bromhexine, camostat (e.g., camostat mesylate), nafamostat (e.g., nafamostat mesylate), gabexate (e.g., gabexate mesylate), aprotinin, withanone, withaferin A , ambroxol, and 4-(2- aminoethyl)benzenesulfonyl fluoride. In certain embodiments, the TMPRSS2 inhibitor is bromhexine, camostat (e.g., camostat mesylate), nafamostat (e.g., nafamostat mesylate), or ambroxol. In other embodiments, the TMPRSS2 inhibitor is bromhexine. In other embodiments, the TMPRSS2 inhibitor is camostat (e.g., camostat mesylate) or nafamostat (e.g., nafamostat mesylate).

The angiotensin-converting enzyme 2 (ACE2) is a component of the counter- regulatory pathway of the renin-angiotensin-aldosterone system (RAAS), which regulates of blood pressure, inflammation, and fibrosis. ACE2 is widely distributed in the human body, including the heart, kidney, small intestine, and lung. Lung ACE2 expression is concentrated mainly in type II alveolar cells and macrophages and modestly in bronchial and tracheal epithelial cells. ACE2 has been shown to be a functional receptor for SARS-CoV-2, leading to viral fusion to the host cell, and ultimately, viral entry; and anti-human ACE2 antibodies can inhibit SARS-CoV-2-S protein-mediated entry into cultured cells in vitro. See Hoffmann et al., supra. ACE2 blockers may block interaction of SARS-CoV-2 with ACE2 through inhibition, or may alter the phosphorylation or glycosylation profiles of ACE2, thus interfering with hostcell entry and subsequent virus replication. Examples of ACE2 blockers include hydroxychloroquine, chloroquine phosphate, metformin, DX600 (Ac- GDYSHCSPLRYYPWWKCTYPDPEGGG-NH2), MLN-4760 ((S,S)-2-(l-Carboxy-2-(3-(3,5- dichlorobenzyl)-3H-imidazol-4-yl)-ethylamino)-4-methylpentanoic acid), N-(2-aminoethyl)-l aziridine-ethanamine, TAPI-2 (N-[2-[2-(hydroxyamino)-2-oxoethyl]-4-methyl-l-oxopentyl]-3- methyl-L-valyl-N-(2-aminoethyl)-L-alaninamide, nicotianamine, and N-[[4-(4-methyl- piperazin-l-yl)phenyl]methyl]-l,2-oxazole-5-carboxamide (SSA09E2). See e.g., Liu et al., "Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS- CoV-2 infection in vitro", Cell Discov. 2020, 6, 16; and Sharma et al., "Metformin in COVID-19: A possible role beyond diabetes", Diabetes Res Clin Pract. 2020, 164, 108183. It has been suggested that certain ACE-1 inhibitors (ACEI) may be useful to block ACE2 interactions with the S-protein binding domain of SARS-CoV-2 as ACE is a homolog of ACE2 with 42% sequence identity and 61% sequence similarity in the catalytic domain. See Sharifkashani et al., "Angiotensin-converting enzyme 2 (ACE2) receptor and SARS-CoV-2: Potential therapeutic targeting", Eur. J. of Pharmacology, 2020, 884, 173455. Accordingly, ACE2 blockers include novel ACE I inhibitors such as captopril, perindopril, ramipril, lisinopril, benazepril, and moexipril. In certain embodiments, the ACE2 blocker is hydroxychloroquine, chloroquine phosphate, metformin, or ramipril.

Spike glycoprotein blockers are agents that are capable of blocking the trimerization of SARS-CoV-2 spike glycoprotein which is key to cell adherence and entry. See Vankadari, "Arbidol: A potential antiviral drug for the treatment of SARS-CoV-2 by blocking trimerization of the spike glycoprotein", Int. J. Antimicrob. Agents 2020, 56(2), 105998. Examples of spike glycoprotein blockers include arbidol, ergoloid, darifenacin, 5-methyltetrahydrofolic acid, buclizine, saquinavir, solifenacin, sorafenib, tetrahydrofolic acid. See, e.g., Bongini et al., "A possible strategy to fight COVID-19: Interfering with spike glycoprotein trimerization" Biochemical and Biophysical Research Communications 2020, 528(1), 35-38. In certain embodiments, the spike glycoprotein blockers is arbidol.

Viral replication modulators also include those agents identified to inhibit viral replication via suitable screening methods. Examples include, for example, astemizole, clofazimine, hanfangchin A (tetrandrine), acitretin, tretinoin, tamibarotene, apilimod, nitazoxanide, sirolimus, MDL-28170, Z LVG CHN2, VBY-825, ONO 5334, AMG-2674, YH-1238, MLN3897, and SDZ-62-434. See, for example, Riva et al., "A Large-scale Drug Repositioning Survey for SARS-CoV-2 Antivirals" bioRxiv 2020.04.16.044016; doi.org/10.1101/2020.04.16.044016; and Zhou et al. "Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2", Cell Discov. 2020, 6, 14 (doi.org/10.1038/s41421- 020-0153-3). In certain embodiments, the viral replication modulator is astemizole, clofazimine, apilimod, nitazoxanide, or sirolimus.

Other active agents may be used in the combinations herein, including, for example, (a) famotidine, which has been shown to have an effect on the progress of COVID-19, but the mechanism is yet to be elucidated (see Loffredo et al., "The Effect of Famotidine on SARS- CoV-2 Proteases and Virus Replication", bioRxiv 2020.07.15.203059 (doi.org/10.1101/2020.07.15.203059); zinc (Zn²⁺) sources, such as zinc picolinate, zine glycinate, zinc gluconate, zinc citrate, zinc acetate, zinc monomethionine, zinc sulfate, or zinc aspartate; and vitamins and antioxidanes, such as vitamin C and/or D3 and glutathione.

In certain embodiments, the second active agent has several of the preceding activities, such as colchicine. Colchicine possesses several apparent mechanisms of action that may be relevant to the treatment of COVID-19, including, inhibiting microtubule polymerization and interfering with the inflammasome complexes.

Combinations of the preceding active agents include, for example, the following combinations (a) - (uuuu):

In general, each of the above-mentioned active agents can be administered in the range of 0.01 to 250 mg per kilogram body weight of the recipient (e.g. a human having been diagnosed with or suspected of having COVID-19) per day, in the range of 0.1 to 100 mg per kilogram body weight per day; in the range 1 to 30 mg per kilogram body weight per day; in the range 0.5 to 20 mg per kilogram body weight per day. Unless otherwise indicated, all weights of active ingredients are calculated as the parent compound (free base) of the active agent. For salts thereof, the weights would be increased proportionally. The desired daily dose may be presented as one, two, three, four, five, six or more unit doses administered at appropriate intervals throughout the day. In some cases the desired dose may be given on alternative days. These unit dosage forms may contain, for example, 1 to 2000 mg; 5 to 500 mg; 10 to 400 mg, 20 to 300 mg of each active ingredient per unit dosage. The combinations may be administered to achieve peak plasma concentrations of each active ingredient. The preceding may be divided among unit dosages as discussed above. Dosages of certain active agents herein may be selected from the following:

In one example, for the treatment combination of favipiravir and bromhexine, a 14 day treatment regimen may include a loading dose of favipiravir of 1600 BID on day 1, followed by 800 mg BID for the remainder of the dosing period; and 16 mg bromhexine TID for each day of the 14 day period. Favipiravir and Bromhexine Hydrochloride Tablets

Brief Manufacturing Process: Sift Favipiravir, Colloidal silicon dioxide (Part-1), Hydroxypropylcellulose (Part-1) and Low Substituted Hydroxy propyl cellulose (LH-21- Part-1 and Part-2) through Mechanical sifter/ Quadro Co-mill fitted with appropriate sieve/ screen. Add and dissolve Hydroxypropyl Cellulose (Part-ll) in purified water under stirring to form clear solution free from lumps. Add and disperse Bromhexine Hydrochloride it into step no. 2 solution under stirring to form uniform dispersion. Add and disperse Colloidal silicon dioxide Part-2 in purified water under stirring to form uniform dispersion free from lumps. Load the material of step no. 1 in suitable Rapid Mixer Granulator and mix it for suitable period of time. Granulate the material of step no. 5 using drug binder dispersion of step no. 3, followed by colloidal silicon dioxide dispersion of step no. 4. Dry the granules of step no. 6 in suitable Fluid Bed Granulator till the desired loss on drying is achieved (IR moisture balance, at 105 C). Mill the dried granules of step no. 7 through a Quadro Co-mill fitted with suitable sieve/screen and pass through Mechanical sifter fitted with appropriate sieve/screen. Mill the oversize granules of Step no. 8 through Quadro Co-mill fitted with appropriate screen/sieve. Sift Sodium Starch Glycollate through Mechanical sifter/ Quadro Co-mill fitted with appropriate sieve/ screen. Load, step no. 8 undersize granules, step no. 9 milled granules and step no. 10 material in suitable blender and blend it for suitable period of time. Sift Sodium Stearyl Fumarate through Mechanical sifter fitted with appropriate screen or sieve. Add material of step no. 12 in to the blend of step no. 11 and blend it for suitable period of time. Compression

14. Compress the lubricated blend of step no. 13 with appropriate tooling using suitable Compression Machine.

Film Coating

15. Disperse Instacoat Universal Yellow A05D04866 in purified water under continuous stirring to form uniform dispersion.

16. Spray the dispersion of step no. 15 onto the core tablets of step no. 14 till a desirable weight gain is achieved.

In yet another example pharmaceutical composition is provided as a kit comprising daclatasvir/Sofosbuvir and Nitazoxanide Tablets (two tablet product is co-packed in blister)

Unit Composition of Daclatasvir/Sofosbuvir

Brief Manufacturing Process:

1. Sift together Daclatasvir Dihydrochloride, Microcrystalline Cellulose (Avicel PH 112) (Part 1), Croscarmellose Sodium (Ac-Di-Sol SD 711) (Part-1) and Colloidal Silicon Dioxide (Aerosil 200 Pharma) (Part 1) through mechanical sifter fitted with suitable sieve / Quadro Co-mill fitted with appropriate screen.

2. Sift together Sofosbuvir, Anhydrous Lactose (Supetab 21 AN) Part-1, Anhydrous Lactose (Supetab 21 AN) Part-2 and sifted material of step 1 through mechanical sifter fitted with suitable sieve / Quadro Co-mill fitted with appropriate screen.

3. Sift Magnesium Stearate (Magnesium Stearate Hyqual VG) (Part-1) through mechanical sifter fitted with suitable sieve / Quadro Co-mill fitted with appropriate screen.

4. Load the material of step 2 in to blender and blend for suitable time.

5. Add the material of step 3 onto step 4 blend in to blender and blend for suitable time.

6. Compact the material of step 5 using Roll Compactor. Sift the compact through appropriate sieve and recompacts the fines.

7. Mill the material of step 6 using Quadro Comil fitted with appropriate screen.

8. Sift the material of step 7 through mechanical sifter fitted appropriate sieve. Collect the oversize and undersize material.

9. Mill the oversize granules of step 8 using Quadro Comil fitted appropriate screen and add the milled granules to undersize material of step 8.

10. Sift the granules step 9 through mechanical sifter fitted with ASTM # 60 Sieve. The oversize granules on ASTM # 60 Sieve should not be less than 70% of premix (not less than 770.28 mg/tablet) Repeat the step No. 6 (for undersize granules from ASTM # 60 Sieve of step 10), 7, 8 & 9 till the oversize granules on ASTM # 60 Sieve is not less than 70%. Record the quantity of oversize granules on ASTM # 60 Sieve and undersize granules from ASTM # 60 Sieve. Mix the material of step 11 (Undersize and oversize granules of ASTM # 60 Sieve) in blender for suitable time. Sift together Microcrystalline Cellulose (Avicel PH 112) (part 2), Croscarmellose Sodium (Ac-Di-Sol SD 711) (Part-2) and Colloidal Silicon Dioxide NF (Aerosil 200 Pharma) (Part-2) through mechanical sifter fitted with suitable sieve / Quadro Co-mill fitted with appropriate screen. Sift Magnesium Stearate (Magnesium Stearate Hyqual VG) (Part-2) through mechanical sifter fitted with suitable sieve / Quadro Co-mill fitted with appropriate screen. Load the material of step 13 in blender with step 12 and blend for suitable time. Add material of step 14 into blender and blend for suitable time. Compression: Compress the tablet with appropriate tooling using Rotary Compression Machine. Coating: Disperse Opadry® II Orange 85F530025 in Purified Water with constant stirring to get a homogenous coating dispersion. Coat the core tablets of step 17 with coating dispersion of step 18 in suitable coating machine to get a desired weight build up.

Nitazoxanide Tablet composition

Brief Manufacturing Process:

1. Co-sift Nitazoxanide, pregelatinized starch, silicified microcrystalline cellulose NF (Part I), Sodium Starch Glycollate (Part I) and Hypromellose through mechanical sifter/Quadro comill fitted with appropriate sieve/screen 2. Sift magnesium stearate (Part I) through mechanical sifter/Quadro comill fitted with appropriate sieve/screen.

3. Load the material of step 1 into blender and blend for suitable time.

4. Add the material of step 2 to step 3 and blend for suitable time.

5. Compact material of step no 4 using roller compactor with suitable compaction parameters.

6. Mill the compacts of step 5 using Quadro comill fitted with appropriate sieve/screen.

7. Sift the material of step 6 through mechanical sifter fitted with #60 ASTM sieve. The oversize granules on #60 ASTM sieve should not be less than 50% w/w of premix blend.

8. If required repeat the step nos 5,6 and 7 for undersize granules from #60 ASTM sieve.

9. Load the #60 ASTM sieve oversize granules and undersize granules into a blender and blend for suitable period. 10. Co-sift Silicified microcrystalline cellulose NF (Part II) and Sodium Starch Glycollate (Part II) through mechanical sifter/Quadro comill fitted with appropriate sieve/screen.

11. Sift Talc and magnesium stearate (Part II) through mechanical sifter/Quadro comill fitted with appropriate sieve/screen.

12. Load the material of step 9 and step 10 into blender and mix for suitable time.

13. Lubricate the blend of step 12 using material of step 11 in blender for suitable time.

14. Compress the lubricated blend of step 13 with suitable tooling using rotatory compression machine. 15. Disperse the Insta Moist Shield Aqua II in Purified water under continuous stirring get homogeneous coating dispersion.

16. Coat the core tablet of step 14 with aqueous coating dispersion of step 15 using suitable tablet coating machine.

Further, the product comprising daclatasvir/Sofosbuvir and Nitazoxanide Tablets as described above is co-packed in blister.

The combination treatments provided herein provide improved results in the treatment of

COVID-19 as compared to treatment with the individual components of the combination.

Pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and intravitreal) administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods may include the step of bringing into association the active ingredients with the carrier, which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product. Each carrier must be acceptable in the sense of being compatible with the other ingredients of the composition and not injurious to the patient.

Compositions suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain the active compound 1) in an optionally buffered, aqueous solution or 2) dissolved and/or dispersed in an adhesive or 3) dispersed in a polymer. A suitable concentration of the active compound is about 1% to 25%, preferably about 3% to 15%. As one particular possibility, the active compound may be delivered from the patch by electrotransport or iontophoresis as generally described in Pharmaceutical Research 3(6), 318 (1986).

Pharmaceutical compositions suitable for oral administration may be presented as discrete units such as capsules, caplets, cachets or tablets each containing a predetermined amount of the active ingredients; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent. Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredients therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.

Pharmaceutical compositions suitable for topical administration in the mouth include lozenges comprising the active ingredients in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Pharmaceutical compositions suitable for topical administration to a dermal surface may be presented as creams, gels, pastes, foams, or sprays. Pharmaceutical compositions may contain in addition to the active ingredient such carriers as are known in the art to be appropriate.

Pharmaceutical compositions for rectal administration may be presented as a suppository with a suitable carrier comprising, for example, cocoa butter or a salicylate or other materials commonly used in the art. The suppositories may be conveniently formed by admixture of the active combination with the softened or melted carrier(s) followed by chilling and shaping in molds.

Pharmaceutical compositions suitable for parenteral administration include aqueous and nonaqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the pharmaceutical composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents; and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. The pharmaceutical compositions may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

In addition to the ingredients particularly mentioned above, the pharmaceutical compositions herein may include other agents conventional in the art having regard to the type of pharmaceutical composition in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavoring agents.

The present disclosure further relates to pharmaceutical kits. The kits can comprise a plurality of unit dosages, each optionally in the form of a plurality of sub-dosages, suitable for the treatment or prevention regimen. The kit can further comprise instructions for administering the contents and packaging. For example, in one embodiment, the kit can comprise a number of unit dosages for administering the therapeutic combination over a 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 day period. The kit can comprise packaged unit dosages of the fixed-dosage combination pharmaceutical composition and the placebo. Non-limiting examples of packages include blister packs, bottles, tubes, bags, containers, and any packaging material suitable for the selected formulation and intended mode of administration. For example, the kit can comprise packaged tablets or capsules of daily dosage units of the fixed-dosage combination pharmaceutical composition and the placebo (e.g. tablets contained in a blister pack or a bottle). The kit can also comprise multiple packages that are each independently associated with unit dosages of individual active agents. For instance, the kit can comprise two or more packages in which each package independently comprises unit dosages for each individual active agent.

Biological Activity The combinations herein may be assayed in a variety of manners to illustrate their efficacy against the SARS-CoV-2 virus, and thereby, COVID-19. The SARS-CoV-2 virus main protease (M^Pro), discussed above, has been sequenced and crystalized . See Zhang et al., "Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved a- ketoamide inhibitors" Science 2020, 368(6489), 409-412. This knowledge has enabled the modeling of the protease with various prospective inhibitors docked therewith. See Sharma et al., "Computational Search for Potential COVID-19 Drugs from FDA-Approved Drugs and Small Molecules of Natural Origin Identifies Several Anti-Virals and Plant Products", ChemRxiv. Preprint, available April 9, 2020 (doi.org/10.26434/chemrxiv.12091356.vl); and Shah et al, "In silico studies on therapeutic agents for COVID-19: Drug repurposing" Life Sci. 2020, 252, 117652.

The effect of the combinations herein on viral load may be assessed, for example, as described in Pujadas et al., "SARS-CoV-2 viral load predicts COVID-19 mortality", Lancet Resp. Med. , Published: August 6, 2020 (doi.org/10.1016/S2213-2600(20)30354-4). Therein nasopharyngeal swab samples were evaluated or SARS-CoV-2 by real-time RT-PCR (Roche cobas 6800; Roche, Basel, Switzerland). Positive samples were assessed by a laboratory- developed quantitative RT-PCR test approved for clinical use and viral loads were calculated with standard curves. A comparison of viral load in samples taken at initiation and during treatment with the combinations herein may be used to illustrate the effect on improving viral load in a patient. See also, Pujadas et al., "Comparison of SARS-CoV-2 detection from nasopharyngeal swab samples by the Roche cobas 6800 SARS-CoV-2 test and a laboratory- developed real-time RT-PCR test", J Med Virol. 2020 (published online May 8, 2020; doi.org/10.1002/jmv.25988); and Pan et al." Viral load of SARS-CoV-2 in clinical samples" Lancet Infect Dis. 2020; 20, 411-412.

Alternatively, reverse transcription loop-mediated isothermal amplification (RT- LAMP) assays may be used to detect genomic RNA of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of COVID-19. RT-LAMP assays can detect as low as 100 copies of SARS-CoV-2 RNA. See, Park et al., "Development of Reverse Transcription Loop-Mediated Isothermal Amplification Assays Targeting Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) , J Mol Diagn. 2020, 22(6), 729-735. A comparison of genomic RNA load in samples taken at initiation and during treatment with the combinations herein may be used to illustrate the effect on improving COVID-19 in a patient

The direct effect of the combinations herein against SARS-CoV-2 infection on in vitro lung tissues may be evaluated using the MucilAir model (3D human airway epithelia) of the human airway, available from Epithelix (www.epithelix.com, Saint-Julien-en-Genevois, France) or MatTek Life Science's 3D tissue models (e.g., EpiAirway; www.mattek.com; Ashland, Mass.).

Additional antiviral assays include, for example, coronavirus antiviral replication assays described in Examples 24, 31, and 32 of US Pub. 2019/0389816; or a cell-based ELISA Screen as described in US Pat. 10,434,116. And, SARSCoV-2 infection of BALB/c mice may be used as an in vivo model for the effectiveness of the combinations herein. See Hassan et al., “A SARS-CoV-2 Infection Model in Mice Demonstrates Protection by Neutralizing Antibodies", Cell 2020, 182(3), 744-753. E4 (doi.org/10.1016/j.cell.2020.06.011).

Each of the citations in this "Biological Activity" section are hereby incorporated by reference in their entireties.

Exemplary Embodiments

[Embodiment 1] A method for treating COVID-19 comprising administering to a person in need of treatment for COVID-19, a therapeutically effective amount of two or more active agents, wherein a first active agent is an RNA-dependent RNA polymerase modulator; and a second active agent is selected from the group consisting of an anti-inflammatory, a viral entry blocker, a viral replication modulator, famotidine, a zinc agent, and mixtures thereof, wherein the active agents are not remdesivir.

[Embodiment 2] The method of [Embodiment 1], comprising administering a first unit dosage comprising the first active agent and a second unit dosage comprising the second active agent.

[Embodiment 3] The method of [Embodiment 1,] comprising administering a single unit dosage comprising the first active agent and the second active agent. [Embodiment 4] The method of any one of [Embodiments 1-3], wherein the second active agent is an anti-inflammatory.

[Embodiment 5] The method of [Embodiment 4], wherein the anti-inflammatory is corticosteroid.

[Embodiment 6] The method of [Embodiment 4], wherein the anti-inflammatory is an IL-1R inhibitor.

[Embodiment 7] The method of [Embodiment 4], wherein the anti-inflammatory is an IL-6 modulator.

[Embodiment 8] The method of [Embodiment 4], wherein the anti-inflammatory is an NLRP3 acting agent.

[Embodiment 9] The method of [Embodiment 4], wherein the anti-inflammatory is a caspase- 1 inhibitor.

[Embodiment 10] The method of any one of [Embodiments 1-3], wherein the second active agent is a viral entry blocker.

[Embodiment 11] The method of [Embodiment 10], wherein the viral entry blocker is a membrane fusion inhibitor.

[Embodiment 12] The method of [Embodiment 10], wherein the viral entry blocker is a microtubule polymerization inhibitor.

[Embodiment 13] The method of [Embodiment 10], wherein the viral entry blocker is a

TMPRSS2 inhibitor.

[Embodiment 14] The method of [Embodiment 10], wherein the viral entry blocker is an ACE2 blocker.

[Embodiment 15] The method of [Embodiment 10], wherein the viral entry blocker is a spike protein blocker.

[Embodiment 16] The method of any one of [Embodiments 1-3], wherein the second active agent is a viral replication modulator.

[Embodiment 17] The method of [Embodiment 16], wherein the viral replication modulator is an alpha-glucosidase inhibitor. [Embodiment 18] The method of [Embodiment 16], wherein the viral replication modulator is an RNA-dependent RNA Polymerase (RdRP) modulator.

[Embodiment 19] The method of [Embodiment 16], wherein the viral replication modulator is a M^pro protease inhibitor.

[Embodiment 20] The method of [Embodiment 16], wherein the viral replication modulator is a M2 protein inhibitor.

[Embodiment 21] The method of [Embodiment 16], wherein the viral replication modulator is a neuraminidase inhibitor.

[Embodiment 22] The method of any one of [Embodiments 1-3], wherein the second active agent is famotidine.

[Embodiment 23] The method of any one of [Embodiments 1-3], wherein the second active agent is a Zn agent.

[Embodiment 24] The method of any one of [Embodiments 1-23], wherein the first active agent is baloxavir.

[Embodiment 25] The method of any one of [Embodiments 1-23], wherein the first active agent is favipiravir.

[Embodiment 26] The method of any one of [Embodiments 1-23], wherein the first active agent is sofosbuvir.

[Embodiment 27] The method of any one of [Embodiments 1-23], wherein the first active agent is emtricitabine.

[Embodiment 28] The method of any one of [Embodiments 1-23], wherein the first active agent is galidesivir.

[Embodiment 29] The method of [Embodiment 1], wherein the first and second active agents are one of the following combinations (a) - (q),

[Embodiment 30] The method of [Embodiment 1], wherein the first and second active agents are baloxavir and clofazimine.

[Embodiment 31] T he method of [Embodiment 1], wherein the first and second active agents are sofosbuvir and clofazimine.

[Embodiment 32] The method of [Embodiment 1], wherein the first and second active agents are galidesivir and baloxavir.

[Embodiment 33] The method of [Embodiment 1], wherein the first and second active agents are sofosbuvir, daclatasvir, and colchicine. [Embodiment 34] The method of [Embodiment 1], wherein the first and second active agents are sofosbuvir and velpatasvir.

[Embodiment 35] The method of [Embodiment 1], wherein the first and second active agents are emtricitabine and miglustat. [Embodiment 36] The method of [Embodiment 1], wherein the first and second active agents are favipiravir and bromhexine.

[Embodiment 37] The method of [Embodiment 1], wherein the first and second active agents are favipiravir and colchicine.

[Embodiment 38] The method of [Embodiment 1], wherein the first and second active agents are sofosbuvir and daclatasvir.

[Embodiment 39] A kit comprising a plurality of unit dosages, wherein a first unit dosage comprises an RNA-dependent RNA polymerase modulator; and a second unit dosage comprises an anti-inflammatory, a viral entry blocker, a viral replication modulator, famotidine, a zinc agent, or a mixture thereof, wherein the unit dosages do not comprise remdesivir.

[Embodiment 40] A kit comprising a plurality of unit dosages, wherein each unit dosage comprises an RNA-dependent RNA polymerase modulator; and a second active agent selected from the group consisting of an anti-inflammatory, a viral entry blocker, a viral replication modulator, famotidine, a zinc agent, n mixtures thereof, wherein the unit dosages do not comprise remdesivir.

* * *

It is to be understood that the description of the present disclosure has been simplified to illustrate elements that are relevant for a clear understanding of the invention, while eliminating, for purposes of clarity, other elements that may be well known. In view of the above description, accompanying drawing figures, and the examples, one of ordinary skill in the art will be able to practice the instant description without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules and compositions described herein. All references made to the examples should not be considered exhaustive, nor limiting, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.

Claims

Claims:

1. A method for treating COVID-19 comprising administering to a person in need of treatment for COVID-19, a therapeutically effective amount of two or more active agents, wherein a first active agent is an RNA-dependent RNA polymerase modulator; and a second active agent is selected from the group consisting of an antiinflammatory, a viral entry blocker, a viral replication modulator, famotidine, a zinc agent, and mixtures thereof, wherein the active agents are not remdesivir.

2. The method of claim 1, comprising administering a first unit dosage comprising the first active agent and a second unit dosage comprising the second active agent.

3. The method of claim 1, comprising administering a single unit dosage comprising the first active agent and the second active agent.

4. The method of any one of claims 1-3, wherein the second active agent is an antiinflammatory.

5. The method of claim 4, wherein the anti-inflammatory is corticosteroid.

6. The method of claim 4, wherein the anti-inflammatory is an IL-1R inhibitor.

7. The method of claim 4, wherein the anti-inflammatory is an IL-6 modulator.

8. The method of claim 4, wherein the anti-inflammatory is an NLRP3 acting agent.

9. The method of claim 4, wherein the anti-inflammatory is a caspase-1 inhibitor.

36 The method of any one of claims 1-3, wherein the second active agent is a viral entry blocker. The method of claim 10, wherein the viral entry blocker is a membrane fusion inhibitor. The method of claim 10, wherein the viral entry blocker is a microtubule polymerization inhibitor. The method of claim 10, wherein the viral entry blocker is a TMPRSS2 inhibitor. The method of claim 10, wherein the viral entry blocker is an ACE2 blocker. The method of claim 10, wherein the viral entry blocker is a spike protein blocker. The method of any one of claims 1-3, wherein the second active agent is a viral replication modulator. The method of claim 16, wherein the viral replication modulator is an alphaglucosidase inhibitor. The method of claim 16, wherein the viral replication modulator is an RNA- dependent RNA Polymerase (RdRP) modulator. The method of claim 16, wherein the viral replication modulator is a M^pro protease inhibitor. The method of claim 16, wherein the viral replication modulator is a M2 protein inhibitor. The method of claim 16, wherein the viral replication modulator is a neuraminidase inhibitor. The method of any one of claims 1-3, wherein the second active agent is famotidine.

37 The method of any one of claims 1-3, wherein the second active agent is a Zn agent. The method of any one of claims 1-23, wherein the first active agent is baloxavir. The method of any one of claims 1-23, wherein the first active agent is favipiravir. The method of any one of claims 1-23, wherein the first active agent is sofosbuvir. The method of any one of claims 1-23, wherein the first active agent is emtricitabine. The method of any one of claims 1-23, wherein the first active agent is galidesivir. The method of claim 1, wherein the first and second active agents are one of the following combinations (a) - (q),

The method of claim 1, wherein the first and second active agents are baloxavir and clofazimine. The method of claim 1, wherein the first and second active agents are sofosbuvir and clofazimine. The method of claim 1, wherein the first and second active agents are galidesivir and baloxavir. The method of claim 1, wherein the first and second active agents are sofosbuvir, daclatasvir, and colchicine. The method of claim 1, wherein the first and second active agents are sofosbuvir and velpatasvir. The method of claim 1, wherein the first and second active agents are emtricitabine and miglustat. The method of claim 1, wherein the first and second active agents are favipiravir and bromhexine. The method of claim 1, wherein the first and second active agents are favipiravir and colchicine. The method of claim 1, wherein the first and second active agents are sofosbuvir and daclatasvir. A kit comprising a plurality of unit dosages, wherein a first unit dosage comprises an RNA-dependent RNA polymerase modulator; and a second unit dosage comprises an anti-inflammatory, a viral entry blocker, a viral replication modulator, famotidine, a zinc agent, or a mixture thereof, wherein the unit dosages do not comprise remdesivir. A kit comprising a plurality of unit dosages, wherein each unit dosage comprises an RNA-dependent RNA polymerase modulator; and a second active agent selected from the group consisting of an anti-inflammatory, a viral entry blocker, a viral replication modulator, famotidine, a zinc agent, and mixtures thereof, wherein the unit dosages do not comprise remdesivir.