METHOD OF TREATING PATIENTS INFECTED WITH A VIRAL INFECTION WITH AN INHIBITOR OF SMALL UBIQUITIN LIKE MODIFIER

ACTIVATING ENZYME

FIELD

[0001] The present disclosure relates to methods of therapeutically or prophylactically treating a subject with a viral infection such as coronavirus disease (COVID). In particular, the present disclosure provides methods for therapeutically or prophylactically treating a viral infection by administering a small ubiquitin-like modifier (SUMO) activating enzyme (SAE) inhibitor, such as Compound 1-263 a.

BACKGROUND

[0002] Coronaviruses are common, diverse viruses that infect many mammalian and avian species. Coronaviruses infections can result in respiratory, gastrointestinal, and central nervous system diseases. Coronavirus virions comprise an envelope, a helical capsid, and a single-stranded and positive-sense RNA genome. The coronavirus genome is the largest among all RNA viruses and typically ranges between 27 and 32 kb. (Lig, F., J. Vir. 89(4):1954-64 (2015)).

[0003] Coronaviruses belong to the Coronaviridae family in the order of Nidovirales and can be classified into at least three major genera: alpha, beta, and gamma (formerly group

I, 2, and 3 respectively). Alphacoronaviruses include human coronavirus NL63 (HCoV- NL63), porcine transmissible gastroenteritis coronavirus (TGEV), PEDV, and porcine respiratory coronavirus. Betacoronaviruses include SARS-CoV, MERS-CoV, bat coronavirus HKU4, mouse hepatitis coronavirus (MHV), bovine coronavirus (BCoV), human coronavirus OC43, and SARS-CoV-2. (Lig, F., J. Vir. 89(4): 1954-64 (2015)).

[0004] Coroanviruses pose health threats to humans and animals. The alphacoronavirus

HCoV-NL63 is a prevalent human respiratory pathogen that is often associated with common colds in healthy adults and acute respiratory diseases in young children. (Lig, F.,

J. Vir. 89(4):1954-64 (2015)).

[0005] Coronaviruses can also result in more severe health problems. Two betacoronavirues, SARS-CoV and MERS-CoV, are highly pathogenic human pathogens. SARS-CoV caused the SARS epidemic in 2002 to 2003, which resulted in over 8,000 infections and a fatality rate of approximately 10%. (Lig, F., ./. Vir. 89(4): 1954-64 (2015)). MERS-CoV emerged in 2012 and at the end of November 2019, 2,494 laboratory-confirmed cases of MERS had been confirmed by the World Health Organization (WHO), including 858 associated deaths — a fatality rate of 34.4%. (World Health Organization, MERS Situation Update, (Nov. 2019), available at http://applicatiots.emxO.who.int/docs/BMRPUB-CSR-241-2019- EN .pdf 1 ).

[0006] In December 2019, an unprecedented outbreak of pneumonia of unknown aetiology emerged in Wuhan City, Hubei province in China. The causative agent was subsequently determined to be a novel coronavirus named SARS-CoV2. SARS-CoV2 is a betacoronavirus and related to SARS-CoV and MERS-CoV. SARS-CoV2 infection results in COVID-19, which affects the lower respiratory tract and manifests as pneumonia. (Sohrabi, C., et ah, Int. ./. Surgery , 76, 71-76 (2020)).

[0007] Most SARS-CoV2 infected patients develop mild symptoms such as dry cough, sore throat, and fever. The majority of symptoms have spontaneously resolve. However, some infected patients have developed various fatal complications including organ failure, septic shock, pulmonary oedema, severe pneumonia, and Acute Respiratory Distress Syndrome (ARDS). (Sohrabi, C., et ah, Int. J. Surgery , 76, 71-76 (2020)).

[0008] A case study of COVID-19 in mainland China found an overall case-fatality rate

(CFR) of 2.3%. Cases in those aged 70 to 79 years had an 8% CFR and cases in those aged 80 years and older had a 14.8% CFR. The CFR was elevated among patients with preexisting comorbid conditions — 10.5% for cardiovascular disease, 7.3% for diabetes, 6.3% for chronic respiratory disease, 6.0% for hypertension, and 5.6% for cancer. (Wu,

Z., et ak, JAMA , Published online February 24, 2020, available at https://jamanetwork.eom/j ournal s/i ama/fuHartide/2762130).

[0009] Despite rigorous global containment and quarantine efforts, the incidence of

COVID-19 continues to rise. COVID-19 was declared a pandemic by the WHO in 2020. There are currently no effective treatments or vaccines available for COVID-19. (Sohrabi, C., et ak, Int. J. Surgery , 76, 71-76 (2020)).

[0010] Small ubiquitin-like modifier (SUMO) activating enzyme (SAE) inhibitors are an example of small molecules that may be used for targeted therapies. SUMO is a member of the ubiquitin-like protein (Ubl) family that covalently conjugate to cellular proteins in a manner similar to ubiquitin (Ub)-conjugation (Kerscher, O. et al, Annu Rev Cell Dev Biol. 22:159-80 (2006)). Mammalian cells express three major SUMO isoforms: SUMOl, SUM02, and SUM03. SUM02 and SUM03 share approximately 95% amino acid sequence homology but have approximately 45% sequence homology with SUMOl (Kamitani, T., et al., J Biol Chem. 273(18): 11349-53 (1998)). SUMO proteins can conjugate to a single lysine residue of a protein (monosumoylation) or to a second SUMO protein that is already conjugated to a protein forming a SUMO chain (polysumoylation ). Only SUM02/3 can form such chains because they possess internal consensus SUMO modification sites (Tatham, M. H., et al., J Biol Chem. 276(38):35368-74 (2001)). An additional isoform, SUM04, is found in kidney, lymph node and spleen cells, but it is not known whether SUM04 can conjugate to cellular proteins.

[0011] SUMOl, SUM02 and SUM03 are activated in an ATP-dependent manner by SAE (see, for example, U.S. Patent Application Publication No. 2010/0160177 Al (FIG. IB), U.S. Patent 9,434,765 B2 (FIG. 2), and Gareau, J.R., et al, Nat Rev Mol Cell Biol. 11:861-871 (2010) (Figure 1)). SAE is a heterodimer that consists of SAE1 (SUMO- activating enzyme subunit 1) and SAE2 (UBA2). SAE, like other El activating enzymes, uses ATP to adenylate the C-terminal glycine residue of SUMO. In a second step, a thioester intermediate is then formed between the C-terminal glycine of SUMO and a cysteine residue in SAE2. Next, SUMO is transferred from the El to the cysteine residue of the SUMO conjugating enzyme (E2), UBC9. Unlike the Ub pathway that contains many E2 enzymes, Ubc9 is currently the only known conjugating enzyme for SUMO and functions with SUMOl, SUM02, and SUM03 proteins. SUMO proteins then conjugate to the target protein, either directly or in conjunction with an E3 ligase, through isopeptide bond formation with the epsilon amino group of a lysine side chain on a target protein. Several SUMO E3 ligases, including PIAS (protein inhibitor of activated signal transducer and activator of transcription protein) proteins and Ran-binding protein 2 (RanBP2), and polycomb 2 (Pc2), have been identified (Johnson, E. S., and Gupta, A. A, Cell. 106(6):735-44 (2001); Pichler, A., etal, Cell. 108(1): 109-20 (2002); Kagey, M. H., et al, Cell. 113(1): 127-37 (2003)). Once attached to cellular targets, SUMO modulates the function, subcellular localization, complex formation and/or stability of substrate proteins (Miiller, S., et al, Nat Rev Mol Cell Biol. 2(3):202-10 (2001)). SUMO- conjugation is reversible through the action of de-sumoylating enzymes called SENPs (Hay, R. T., Trends Cell Biol. 17(8): 370-6 (2007)) and the SUMO proteins can then participate in additional conjugation cycles.

[0012] SAE-initiated SUMO-conjugation plays a major role in regulating diverse cellular processes, including cell cycle regulation, transcriptional regulation, cellular protein targeting, maintenance of genome integrity, chromosome segregation, and protein stability (Hay, R. T Mol Cell. 18(1):1-12 (2005); Gill, G, Genes Dev. 18(17):2046-59 (2004)). For example, SUMO-conjugation causes changes in the subcellular localization of RanGAPl by targeting it to the nuclear pore complex (Mahajan, R., el al ., Cell. 88(1):97-1070 (1997)). Sumoylation counteracts ubiquitination and subsequently blocks the degradation of IKB, thereby negatively regulating NF-kB activation (Desterro, J. M., et al., Mol Cell. 2(2):233-9 (1998)). Sumoylation has been reported to play an important role in transcription exhibiting both repressive and stimulatory effects. Many of the transcriptional nodes that are modulated play important roles in cancer. For example, sumoylation stimulates the transcriptional activities of transcription factors such as p53 and HSF2 (Rodriguez, M. S., et al., EMBO J. 18(22):6455-61 (1999); Goodson, M. L., et al., J Biol Chem. 276(21): 18513-8 (2001)). In contrast, SUMO-conjugation represses the transcriptional activities of transcription factors such as LEF (Sachdev, S., et al., Genes Dev. 15(23):3088-103 (2001)) and c-Myb (Bies, J., et al., J Biol Chem. 277(11):8999- 9009 (2002)). Thus, SUMO-conjugation controls gene expression and growth control pathways that are important for cancer cell survival.

[0013] Altered expression of SAE pathway components have been noted in a variety of cancer types: (Moschos, S. J., et al., Hum Pathol. 41(9): 1286-980 (2010)); including multiple myeloma (Driscoll, J. J., et al., Blood. 115(14):2827-34 (2010)); and breast cancer (Chen, S. F., et al., Chin J Cancer. 30(9):638-44 (2011)). In addition, preclinical studies indicate that Myc-driven cancers may be especially sensitive to SAE inhibition (Kessler, J. D., et al., Science. 335(6066):348-53 (2012); Hoellein, A., et al., Blood. 124(13):2081-90 (2014)). Since SUMO-conjugation regulates essential cellular functions that contribute to the growth and survival of tumor cells, targeting SAE could represent an approach to treat proliferative disorders such as cancer. (He, X., et al, Nature Chemical Biology . 13: 1164-1171 (2017)). Thus, some cancers may be SAE-mediated disorders. [0014] Compound 1-263, described herein, is presently formulated as an intravenous (IV) injectable solution, and is a first in class small molecule inhibitor of SUMOylation. As described above, SUMOylation is a post-translational modification that attaches a SUMO protein to protein substrates, regulating their activity, subcellular localization and stability. Compound I-263a inhibits SUMOylation by forming an irreversible adduct with SUMO when SUMO is bound to Sumo Activating Enzyme (SAE), preventing its ligation to substrate proteins. There is developing evidence that SUMOylation also plays a key role in regulating innate immune responses.

[0015] Compound I-263a is currently being evaluated in an ongoing first-in-human phase

1 study in patients with advanced or refractory solid tumors or lymphomas, and an ongoing phase 1/2 study of the combination with rituximab in patients with relapsed/refractory indolent or aggressive CD20+ non-Hodgkin’s Lymphoma (NHL).

SUMMARY

[0016] In one aspect, the present disclosure relates to methods of therapeutically or prophylactically treating a subject suffering from a viral infection, comprising administering to the subject a therapeutically effective amount of an active agent, wherein the active agent is I-263a or a pharmaceutically acceptable salt thereof. In some embodiments, the active agent is I-263a.

[0017] In some embodiments, the viral infection is caused by a virus selected from the group consisting of at least one alphacoronavirus, at least one betacoronavirus, and at least one deltacoronavirus.

[0018] In some embodiments, the at least one alphacoronavirus is selected from the group consisting of human coronavirus NL63 (HCoV-NL63), porcine transmissible gastroenteritis coronavirus (TGEV), PEDV, and porcine respiratory coronavirus.

[0019] In some embodiments, the at least one betacoronavirus is selected from the group consisting of SARS-CoV, MERS-CoV, bat coronavirus HKU4, mouse hepatitis coronavirus (MHV), bovine coronavirus (BCoV), human coronavirus OC43, and SARS- CoV-2.

[0020] In some embodiments, the betacoronavirus is SARS-CoV2. In some embodiments, the viral infection is COVID-19. [0021] In some embodiments, the subject is greater than 55 years old. In some embodiments, the subject further has cardiovascular disease, diabetes, chronic respiratory disease, hypertension, cancer, or combinations thereof.

[0022] In some embodiments, the therapeutically effective amount is between about 3 mg and about 90 mg. Additional suitable doses are provided below. Suitable doses include 3, 5, 10, 15, 20, 25, 40, 60, 75 or 90 mg. In some embodiments, the therapeutically effective amount is 40 mg. In some embodiments, the therapeutically effective amount is 60 mg.

[0023] In some embodiments, the 1-263 a or the pharmaceutically acceptable salt thereof is administered as a single dose. In some embodiments, the I-263a or the pharmaceutically acceptable salt thereof is administered once in a seven-day treatment cycle. In some embodiments, the I-263a or the pharmaceutically acceptable salt thereof is administered twice in a seven-day treatment cycle. In some embodiments, the I-263a or the pharmaceutically acceptable salt thereof is administered on day 1 and day 4 of the seven-day treatment cycle. In some embodiments, the seven-day treatment cycle is repeated at least once. In some embodiments, the treatment cycle is followed by one- week rest. In some embodiments, the treatment cycle is followed by two-week rest. In some embodiments, the 1-263 a or the pharmaceutically acceptable salt thereof is administered on Days 1, 4, 8, and 11 of a 3-week cycle. In some embodiments, the I- 263a or the pharmaceutically acceptable salt thereof is administered on Days 1, and 4 of a 3-week cycle. In some embodiments, the I-263a or the pharmaceutically acceptable salt thereof is administered on Days 1, and 8 of a 3-week cycle.

[0024] In some embodiments, the I-263a or the pharmaceutically acceptable salt is administered orally, systemically, parenterally, topically, mucosally, intramuscularly, intravenously, intraperitoneally, intradermally, subcutaneously, intranasally, intravaginally, intrarectally, transdermally, sublingually, via an aerosol route, or via inhalation.

[0025] In some embodiments, the 1-263 a or the pharmaceutically acceptable salt thereof is administered intravenously. In some embodiments, the I-263a or the pharmaceutically acceptable salt thereof is formulated as a 10 mg/ml solution.

[0026] In some embodiments, the 1-263 a or the pharmaceutically acceptable salt thereof is administered over a time period of up to 4 hours. In some embodiments, the I-263a or the pharmaceutically acceptable salt thereof is administered over a time period of 60 + 10 minutes.

[0027] In some embodiments, the method further comprises determining presence of the virus in a nasopharyngeal or blood sample from the subject before or after administering the 1-263 a or the pharmaceutically acceptable salt thereof. In some embodiments, the presence of the virus is determined by PCR.

[0028] In some embodiments, the method further comprises determining National Early

Warning Score (NEWS) of the subject before or after administering the I-263a or the pharmaceutically acceptable salt thereof.

[0029] In some embodiments, administering the I-263a or the pharmaceutically acceptable salt thereof induces Type-I IFN gene expression. In some embodiments, administering the I-263a or the pharmaceutically acceptable salt thereof induces immune cell activation. In some embodiments, administering the I-263a or the pharmaceutically acceptable salt thereof induces cytokine or chemokine production.

[0030] In one aspect, the present disclosure relates to methods of therapeutically or prophylactically treating a subject suffering from a viral infection, comprising administering to the subject a therapeutically effective amount of an active agent, wherein the active agent is I-263a or a pharmaceutically acceptable salt thereof and at least one additional active agent. In some embodiments, the active agent is I-263a.

[0031] In some embodiments, the at least one additional active agent is an antiviral agent, an antibiotic, a corticosteroid, interferon beta Bl, tocilizumab or a combination thereof.

[0032] In some embodiments, the antibiotic is azithromycin.

[0033] In some embodiments, the antiviral agent is selected from the group consisting of chloroquine, hydroxychloroquine, remdesivir, bortezomib, ixazomib, ponatinib, lopinavir/ritonavir, darunavir/cobicistat antiviral IgG, antiviral IgM, anti-IL-6 agents, azidothymidine (AZT), or pharmaceutically acceptable salts thereof, and combinations thereof.

[0034] In some embodiments, the viral infection is caused by a virus selected from the group consisting of at least one alphacoronavirus, at least one betacoronavirus, and at least one deltacoronavirus. [0035] In some embodiments, the at least one alphacoronavirus is selected from the group consisting of human coronavirus NL63 (HCoV-NL63), porcine transmissible gastroenteritis coronavirus (TGEV), PEDV, and porcine respiratory coronavirus.

[0036] In some embodiments, the at least one betacoronavirus is selected from the group consisting of SARS-CoV, MERS-CoV, bat coronavirus HKU4, mouse hepatitis coronavirus (MHV), bovine coronavirus (BCoV), human coronavirus OC43, and SARS- CoV-2.

[0037] In some embodiments, the betacoronavirus is SARS-CoV2. In some embodiments, the viral infection is COVID-19.

[0038] In some embodiments, the therapeutically effective amount of I-263a is between about 3 mg and about 90 mg. In some embodiments, the therapeutically effective amount of I-263a is 40 mg. In some embodiments, the therapeutically effective amount of I-263a is 60 mg.

[0039] In some embodiments, the 1-263 a or the pharmaceutically acceptable salt thereof is administered as a single dose. In some embodiments, the I-263a or the pharmaceutically acceptable salt thereof is administered once in a seven-day treatment cycle. In some embodiments, the I-263a or the pharmaceutically acceptable salt thereof is administered twice in a seven-day treatment cycle. In some embodiments, the I-263a or the pharmaceutically acceptable salt thereof is administered on day 1 and day 4 of the seven-day treatment cycle. In some embodiments, the seven-day treatment cycle is repeated at least once. In some embodiments, the treatment cycle is followed by one- week rest. In some embodiments, the treatment cycle is followed by two-week rest. In some embodiments, the 1-263 a or the pharmaceutically acceptable salt thereof is administered on Days 1, 4, 8, and 11 of a 3-week cycle. In some embodiments, the I- 263a or the pharmaceutically acceptable salt thereof is administered on Days 1, and 4 of a 3-week cycle. In some embodiments, the I-263a or the pharmaceutically acceptable salt thereof is administered on Days 1, and 8 of a 3-week cycle.

[0040] In some embodiments, the I-263a or the pharmaceutically acceptable salt is administered orally, systemically, parenterally, topically, mucosally, intramuscularly, intravenously, intraperitoneally, intradermally, subcutaneously, intranasally, intravaginally, intrarectally, transdermally, sublingually, via an aerosol route, or via inhalation. [0041] In some embodiments, the pharmaceutically acceptable salt thereof is administered intravenously. In some embodiments, the pharmaceutically acceptable salt thereof is formulated as a 10 mg/ml solution.

[0042] In some embodiments, the 1-263 a or the pharmaceutically acceptable salt thereof is administered over a time period of up to 4 hours. In some embodiments, the I-263a or the pharmaceutically acceptable salt thereof is administered over a time period of 60 + 10 minutes.

[0043] In some embodiments, the method further comprises determining presence of the virus in a nasopharyngeal or blood sample from the subject before or after administering the 1-263 a or the pharmaceutically acceptable salt thereof. In some embodiments, the presence of the virus is determined by PCR.

[0044] In some embodiments, the method further comprises determining National Early

Warning Score (NEWS) of the subject before or after administering the I-263a or the pharmaceutically acceptable salt thereof.

[0045] In some embodiments, administering the I-263a or the pharmaceutically acceptable salt thereof induces Type-I IFN gene expression. In some embodiments, administering the I-263a or the pharmaceutically acceptable salt thereof induces immune cell activation. In some embodiments, administering the I-263a or the pharmaceutically acceptable salt thereof induces cytokine or chemokine production.

[0046] In some embodiments, the at least one additional active agent is administered orally, systemically, parenterally, topically, mucosally, intramuscularly, intravenously, intraperitoneally, intradermally, subcutaneously, intranasally, intravaginally, intrarectally, transdermally, sublingually, via an aerosol route, or via inhalation.

[0047] In some embodiments, the chloroquine, hydroxychloroquine, or the pharmaceutically acceptable salt thereof is administered in an amount between 300 mg and 500 mg. In some embodiments, the chloroquine, hydroxychloroquine, or the pharmaceutically acceptable salt thereof is administered once or twice daily for up to 5 days.

[0048] In some embodiments, the at least one additional active agent is administered simultaneously with the 1-263 a or the pharmaceutically acceptable salt thereof. In some embodiments, the at least one additional active agent is administered prior to administering the I-263a or the pharmaceutically acceptable salt thereof. In some embodiments, the at least one additional active agent is administered after administering the 1-263 a or the pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE FIGURES

[0049] FIG. 1 is a drawing showing the mechanism of I-263a inhibition of the

SUMOylation enzymatic cascade.

DETAILED DESCRIPTION

Definitions and Abbreviations

[0050] To facilitate an understanding of the present disclosure, a number of abbreviations, terms, and phrases are defined below.

[0051] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

[0052] As used herein, the term "COVID-19” refers to a disease caused by SARS-CoV2 characterized by dry cough, sore throat, and fever. And in serious cases, organ failure, septic shock, pulmonary oedema, severe pneumonia, and Acute Respiratory Distress Syndrome (ARDS).

[0053] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound, or combination of one or more compounds that, when administered (either sequentially or simultaneously) elicits the desired biological or medicinal response, e.g., either destroys the target cancer cells or slows or arrests the progression of the cancer in a patient. The therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the patient and disease condition being treated, e.g., the weight and age of the patient, the severity of the disease condition, the manner of administration and the like, which may readily be determined by one skilled in the art. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of platelet adhesion and/or cell migration.

[0054] As used herein, the term “prophylactically treating” refers to administering to a subject exposed to, or potentially exposed to a virus, such as SARS-CoV2, an amount of an active agent, such as Compound 1-263 a, capable of preventively mitigating a subject’s viral load or preventively mitigating or substantially reducing symptoms associated with an illness or disease caused by a viral infection.

[0055] As used herein, the term “therapeutically treating” refers to administering to a subject with a viral infection an amount of an active agent, such as Compound 1-263 a, capable of providing a therapeutic benefit such as amelioration of symptoms, prevention of an increased viral load, or a decrease in viral load. Viral load may be detected by methods well-known in the art, such as determining viral RNA levels in a nasopharyngeal or blood sample from the subject.

[0056] The term "about" refers to approximately, in the region of, roughly, or around.

When the term "about" is used in conjunction with a number or a numerical range, it means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary from, for example, between 1% and 15% of the stated number or numerical range. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of ±10%.

[0057] As used herein, "subject" generally means a mammal (e.g., human) who has been diagnosed with, exhibits symptoms of, or is otherwise believed to be afflicted with a disease, disorder, or condition (such as cancer).

[0058] The terms "simultaneous" and "simultaneously" refer to the administration of the

1-263 a or a pharmaceutically acceptable salt thereof, and at least one additional active agent, to a subject at the same time, or at two different time points that are separated by no more than 2 hours. The simultaneous administration of the I-263a or a pharmaceutically acceptable salt thereof, and at least one additional active agent may be in a single dosage form or in separate dosage forms.

[0059] The terms "prior to administration" and "after administration" refer to the administration of the I-263a or a pharmaceutically acceptable salt thereof, and at least one additional active agent as disclosed herein, to a patient at two different time points that are separated by more than 2 hours, e.g., about 3 hours, about 4 hours, about 5 hours, about 8 hours, about 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days or even longer. [0060] The term "intermission" refers to a period that is subsequent to the administration of one or more particular pharmaceutically active ingredients to a patient in an intermittent regimen. Intermission refers to a rest period wherein a particular pharmaceutically active ingredient is not administered for at least one day.

[0061] As used herein, the illustrative terms "include", "such as", "for example" and the like (and variations thereof, e.g ., "includes" and "including", "examples"), unless otherwise specified, are intended to be non-limiting. That is, unless explicitly stated otherwise, such terms are intended to imply "but not limited to", e.g. , "including" means including but not limited to.

[0062] Unless otherwise stated, structures depicted herein are meant to include chemical entities which differ only in the presence of one or more isotopically enriched atoms. For example, chemical entities having the present structure except for the replacement of a hydrogen atom by a deuterium or tritium, or the replacement of a carbon atom by a 1 ³ C- or ¹⁴ C-enriched carbon are within the scope of the invention.

[0063] Unless stereochemical configuration is denoted, structures depicted herein are meant to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Therefore, unless otherwise indicated, single stereochemical isomers as well as enantiomeric, racemic and diastereomeric mixtures of the present chemical entities are within the scope of the invention. When a stereochemical configuration is denoted for a compound, the diastereoisomeric or enantiomeric excess of the compound is at least 99.0%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9%.

I-263a

[0064] [(lR,2S,4R)-4-{[5-({4-[(lR)-7-chloro-l,2,3,4-tetrahydroisoqu inolin-l-yl]-5- methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyc lopentyl]methyl sulfamate, or a pharmaceutically acceptable salt thereof, has the following structure: [(lR,2S,4R)-4-{[5-({4-[(lR)-7-chloro-l,2,3,4-tetrahydroisoqu inolin-l-yl]-5-methyl-2- thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxycyclopentyl] methyl sulfamate is referred to herein as Compound I-263a. I-263a is also known as TAK-981.

[0065] Compounds described herein may be in the form of a pharmaceutically acceptable salt. In some embodiments, such salts are derived from inorganic or organic acids or bases. For reviews of suitable salts, see, e.g., Berge et al., J Pharm. Sci., 1977, 66, 1 19 and Remington: The Science and Practice of Pharmacy, 20th Ed., A. Gennaro (ed.), Lippincott Williams & Wilkins (2000).

[0066] Examples of suitable acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, lucoheptanoate, glycerophosphate, hemi sulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3 -phenyl propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.

[0067] Examples of suitable base addition salts include ammonium salts; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; salts with organic bases, such as dicyclohexylamine salts, N-methyl D- glucamine; and salts with amino acids such as arginine, lysine, and the like.

[0068] For example, Berge lists the following FDA-approved commercially marketed salts: anions acetate, besylate (benzenesulfonate), benzoate, bicarbonate, bitartrate, bromide, calcium edetate (ethylenediaminetetraacetate), camsylate (camphorsulfonate), carbonate, chloride, citrate, dihydrochloride, edetate (ethylenediaminetetraacetate), edisylate (1,2 ethanedi sulfonate), estolate (lauryl sulfate), esylate (ethanesulfonate), fumarate, gluceptate (glucoheptonate), gluconate, glutamate, glycollylarsanilate (glycollamidophenylarsonate), hexylresorcinate, hydrabamine (N,N' di(dehydro ^_, abietyl)- ethylene-'di amine), hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate (2 hydroxyethanesulfonate), lactate, lactobionate, malate, maleate, mandelate, mesylate (methane-'sulfonate), methylbromide, methylnitrate, methyl sulfate, mucate, napsylate (2- naphthalene-'sulfonate), nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate (8-chlorotheophyllinate) and triethiodide; organic cations benzathine (N,N' dibenzylethylenediamine), chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N methylglucamine) and procaine; and metallic cations aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.

[0069] Berge additionally lists the following non-FDA-approved commercially marketed

(outside the United States) salts: anions adipate, alginate, aminosalicylate, anhydromethylenecitrate, arecoline, aspartate, bisulfate, butylbromide, camphorate, digluconate, dihydrobromide, disuccinate, glycerophosphate, hemisulfate, hydrofluoride, hydroiodide, methylenebis(salicylate), napadisylate (1,5 naphthalene^di sulfonate), oxalate, pectinate, persulfate, phenylethylbarbiturate, picrate, propionate, thiocyanate, tosylate and undecanoate; organic cations benethamine (N benzylphenethylamine), clemizole (1 p chloro benzyl-2 pyrrolildine-G ylmethylbenzimidazole), diethylamine, piperazine and tromethamine (tris(hydroxymethyl)aminomethane); and metallic cations barium and bismuth.

[0070] SAE inhibitors, as disclosed herein, are described, for example, in US

2016/0009744 and US 9,695,154. They may be prepared by methods known to one skilled in the art and/or according to the methods described in US 2016/0009744 and US 9,695,154, which is hereby incorporated by reference in its entirety. Central to the mechanism of action of useful SAE inhibitors, such as Compound 1-263 a, in combinations and methods of the present disclosure is production of type 1 IFNs and induction of an innate immune response with activation of both natural killer (NK) cells and macrophages. Biochemical assays have demonstrated that Compound I-263a is a mechanism-based inhibitor of SUMO-activating enzyme that potently inhibits enzyme activity by forming a covalent adduct with SUMO. Strong selectivity for SUMO- activating enzyme was observed over the other closely related ubiquitin-activating enzymes ubiquitin-activating enzyme, Nedd8-activating enzyme, and autophagy related 7 enzyme. Selective and potent inhibition of SUMO-activating enzyme and SUMOylation by Compound 1-263 a has been demonstrated in cultured mouse and human tumor cell lines and the antiproliferative activity of Compound 1-263 a has been determined in a panel of 7 mouse hematologic and solid tumor cell lines.

[0071] The innate immune response, the first line of defense against pathogens, limits viral replication during initial infection especially for respiratory infections and also induces adaptive immune responses responsible for viral clearance and maintenance (memory). Viruses detected by innate immune receptors trigger signaling cascades such as nuclear factor kappa B (NF-KB)-dependent cytokine responses, interferon regulatory factor (IRF)-dependent IFN-a/b responses, and inflammasome/caspase-1 -dependent IL- 1b responses. IFN-a/b are the major cytokines that limit viral replication playing a key immunomodulatory role activating innate immune effector cells as well as dendritic cells, promoting the priming, and sustaining the expansion of, naive T cells. There is evidence that viruses exploit cellular SUMOylation processes and that suppression of SUMOylation results in enhanced anti-viral innate immune responses. There is also recent data indicative of SARS CoV-2 sensitivity to IFN.

[0072] SUMOylation has been shown to play a key role in regulating innate immune responses . (Adorisio, S., et al. Nat. Rev. Mol. Cell. Biol., 11 (12): 861-71 (2010)). A net inhibitory effect of SUMOylation on type 1 interferon (IFN) expression has been demonstrated (Decque, A., et al., Nat. Immunol., 17(2): 140-49 (2016); Crowl, JT, et al., Proc. Natl. Acad. Sci USA, 115(26):6798-6803 (2018)). , such that inhibiting SUMOylation by genetic means resulted in enhanced basal expression levels and sensitization of induction of type 1 IFNs by pathogenic stimuli. Induction of Type I IFN signaling, and stimulation of innate and adaptive immune responses, has been shown to be central to the mechanism of action of TAK-981. Ex vivo analyses have demonstrated Type I IFN-dependent activation of macrophages (upregulation of CD80, CD86 and FcgR’s) and NK cells (upregulation of CD69 and CD107) by TAK-981, resulting in enhanced phagocytic and cytotoxic activity, respectively, against Daudi target cells. TAK-981 also promoted maturation of mouse bone marrow-derived dendritic cells (DCs) and human PBMC-derived DCs, upregulating the T cell co-stimulatory markers CD40, CD80, and CD86 and promoting release of type 1 IFNs and pro-inflammatory chemokines. In vivo, TAK-981 has been shown to enhance antigen cross presentation and T cell priming by DCs, generating T cell dependent anti-tumor immune responses. In addition, TAK-981 has also been shown to directly stimulate T cells ex vivo, upregulating expression of Type I IFNs and in OT-1 T cells enhancing sensitivity and response to antigen. METHODS OF TREATING A VIRAL INFECTION

[0073] I-263a or a pharmaceutically acceptable salt thereof, may be administered alone, or in combination with at least one additional agent. 1-263 a and the at least one additional active agent may be administered in a single dosage form or as separate dosage forms. In some embodiments, when administered as a separate dosage form, the at least one additional active agent antibody may be administered prior to, at the same time as, or following administration of I-263a or a pharmaceutically acceptable salt thereof.

[0074] Administration of an effective amount of Compound I-263a in humans can provide formation of a Compound 1-263 a-SUMO adduct, inhibition of SUMOylation, and may increase in Type I IFN signaling and lymphocyte activation. Without wishing to be bound by theory, the administration of Compound I-263a may induce a Type I IFN response in patients with COVID-19, including cancer patients with COVD-19 and non cancer patients with COVID-19, and this may result in improved SARS-CoV-2 clearance by the immune system.

[0075] In some embodiments, when administered as a separate dosage form, one or more doses of I-263a or a pharmaceutically acceptable salt thereof, may be administered prior to the at least one additional active agent. In some embodiments, the at least one additional active agent is administered prior to the administration of Compound I-263a or a pharmaceutically acceptable salt thereof. As used herein, the administration in "combination" of Compound I-263a or a pharmaceutically acceptable salt thereof and at least one additional active agent refers not only to simultaneous or sequential administration of the agents, but also to the administration of the agents during a single treatment cycle, as understood by one skilled in the art. When Compound 1-263 a or a pharmaceutically acceptable salt thereof is administered in combination with the at least one additional active agent, a therapeutically effective amount of the combination is administered.

[0076] Compound I-263a may be administered by any method known to one skilled in the art. For example, in some embodiments, Compound I-263a may be administered in the form of a pharmaceutical composition of I-263a and a pharmaceutically acceptable carrier, such as those described herein. In some embodiments, the pharmaceutical composition is suitable for oral administration. In some embodiments, the pharmaceutical composition is a tablet or a capsule that is suitable for oral administration. In some other embodiments, the pharmaceutical composition is a liquid dosage form suitable for oral administration. In some embodiments, the pharmaceutical composition is suitable for intravenous administration. In some embodiments, the pharmaceutical composition is suitable for subcutaneous administration. In some embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

[0077] The at least one additional active agent may be administered by any method known to one skilled in the art. In some embodiments, the at least one additional active agent is administered intravenously (IV). In some embodiments, the at least one additional active agent is administered subcutaneously (SC). In some embodiments, the at least one additional active agent is administered orally. For example, the at least one additional active agent may be administered in the form of a second composition, in some embodiments, a pharmaceutical composition of the at least one additional active agent and a pharmaceutically acceptable carrier. In some aspects, the pharmaceutical composition is suitable for oral administration. In some embodiments, the pharmaceutical composition is a tablet or a capsule that is suitable for oral administration. In some other embodiments, the pharmaceutical composition is a liquid dosage form suitable for oral administration. In some embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

[0078] The amounts or suitable doses of the methods of this disclosure depends upon a number of factors, including the nature of the severity of the condition to be treated, the particular inhibitor, the route of administration and the age, weight, general health, and response of the individual patient. In some embodiments, the suitable dose level is one that achieves a therapeutic response as measured by tumor regression, or other standard measures of disease progression, progression free survival or overall survival. In some embodiments, the suitable dose level is one that achieves this therapeutic response and also minimizes any side effects associated with the administration of the therapeutic agent. The suitable dose levels may be ones that prolong the therapeutic response and/or prolong life.

[0079] It will be understood that a suitable dose of Compound I-263a and at least one additional active agent may be taken at any time of the day or night. In some embodiments, a suitable dose of each agent is taken in the morning. In some other embodiments, a suitable dose of each agent is taken in the evening. In some embodiments, a suitable dose of each of the agents is taken both in the morning and the evening. It will be understood that a suitable dose of each agent may be taken with or without food. In some embodiments a suitable dose of an agent is taken with a meal. In some embodiments a suitable dose of an agent is taken while fasting.

[0080] In some embodiments, Compound 1-263 a or a pharmaceutically acceptable salt thereof is administered as a single dose. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered every other day. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered once every three days. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered on a twice-weekly schedule. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered on a three times a week schedule. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered on a weekly schedule. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered on a once every two weeks schedule.

[0081] In some embodiments, Compound 1-263 a or a pharmaceutically acceptable salt thereof is administered at least 3 times on alternate days within a 7-day cycle. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered on day 1 and day 4 of a 7-day cycle. In some embodiments, Compound I- 263a or a pharmaceutically acceptable salt thereof is administered on consecutive days in a 7-day cycle followed by an intermission. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered for 2 consecutive days followed by an intermission of 5 consecutive days for at least one 7-day cycle. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered for 3 consecutive days followed by an intermission of 4 consecutive days for at least one 7-day cycle. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered for 4 consecutive days followed by an intermission of 3 consecutive days for at least one 7-day cycle. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered for 5 consecutive days followed by an intermission of 2 consecutive days for at least one 7-day cycle. In some embodiments, there will be periods of rest between one or more of the 7-day treatment cycles. In some embodiments, there will be a 7-day rest between one or more of the 7-day treatment cycles.

[0082] The present description contemplates administration of the drug for one or more treatment cycles, for example, 1, 2, 3, 4, 5, 6, or more, treatment cycles. In some embodiments, a treatment cycle is about 7 days to about 56 days, or more. In some embodiments, a treatment cycle is 7 days, 14 days, 21 days, 28 days, 35 days, 42 days, 49 days, or 56 days. In some embodiments, a treatment cycle is 14 days, 21 days, 28 days, or 35 days. In some embodiments, there will be periods of rest within or between one or more of the treatment cycles. For example, in some embodiments, there will be a period of rest at the end of the treatment cycle. In some embodiments, there will be a period of rest between the second and third treatment cycle but not the first and second treatment cycle. In another embodiment, there might be a period of rest between the first and second treatment cycle but not the second and third treatment cycle. Dosing schedules include, for example, administering Compound I-263a once during a treatment schedule, e.g., on day 1 of a 21 day cycle, twice during a treatment cycle, e.g., on days 1 and 15 of a 21 day cycle or on days 1 and 15 of a 28 day cycle, three times during a treatment cycle, e.g., on days 1, 8 and 15 of a 21 day cycle or on days 1, 8 and 15 of a 28 day cycle, four times during a treatment cycle, e.g., on days 1, 4, 8, and 11 of a 14 days cycle, days 0, 3,

7, and 10 of a 14 day cycle, on days 1, 4, 8, and 11 of a 21 day cycle, on days 1, 8, 15, and 22 of a 28 day cycle, or on days 1, 4, 8, and 11 of a 28 day cycle, six times during a treatment cycle, e.g., on days 1, 4, 8, 11, 15, and 18 of a 21 day cycle or on days 1, 4, 8, 11, 15, and 18 of a 28 day cycle, eight times during a treatment cycle, e.g. days 1, 4, 8,

11, 15, 18, 22 and 25 of a 28 day cycle or days 1, 4, 8, 11, 15, 18, 22 and 25 of a 28 day, ten times during a 35 day cycle, e.g. days 1, 4, 8, 11, 15, 18, 22, 25, 29 and 33 of a 35 day cycle. Day 0 of a treating cycle is one day immediately before the day that the treatment cycle starts. Other dosage schedules are encompassed by the present invention.

[0083] In some embodiments, Compound 1-263 a or a pharmaceutically acceptable salt thereof is administered within a 14-day cycle. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered twice weekly on days on 0,

3, 7, and 10 of the 14 day cycle. In some embodiments, Compound 1-263 a or a pharmaceutically acceptable salt thereof is administered twice weekly on days on 1, 4, 8, and 11 of the 14 day cycle. [0084] In some embodiments, Compound 1-263 a or a pharmaceutically acceptable salt thereof is administered within a 21 day cycle. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered twice weekly on days on 1,

4, 8, 11, 15, and 18 of the 21 day cycle. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered twice weekly on days on 1, 4, 8, and 11 of the 21 day cycle. In some embodiments, Compound 1-263 a or a pharmaceutically acceptable salt thereof is administered twice weekly on days on 1, and 4 of the 21 day cycle. In some embodiments, Compound 1-263 a or a pharmaceutically acceptable salt thereof is administered twice weekly on days on 1, and 8 of the 21 day cycle.

[0085] In some embodiments, Compound 1-263 a or a pharmaceutically acceptable salt thereof is administered within a 28 day cycle. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered twice weekly on days on 1,

4, 8, 11, 15, and 18 of the 28 day cycle. In some embodiments, Compound I-263a or a pharmaceutically acceptable salt thereof is administered twice weekly on days on 1, 8, 15, and 22 of the 28 day cycle.

[0086] In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg to about 200 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg to about 100 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg to about 50 mg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg to about 10 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg to about 5 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 1 mg to about 3 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 2 mg to about 5 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 5 mg to about 10 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 5 mg to about 15 mg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 10 mg to about 20 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 15 mg to about 25 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 20 mg to about 30 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 25 mg to about 35 mg. In some embodiments, the amount of Compound I- 263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 30 mg to about 40 mg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 35 mg to about 45 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 40 mg to about 50 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 55 mg to about 65 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 50 mg to about 100 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 90 mg to about 150 mg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 140 mg to about 200 mg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 3 mg to about 160 mg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 1 mg. In some embodiments, the amount of Compound I- 263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 2 mg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 3 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 4 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 6 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 8 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 10 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 12 mg. All dosing amounts refer to the amount of Compound I-263a administered, and do not include the weight amount of any pharmaceutically acceptable salt.

[0087] In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 1 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 3 mg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 6 mg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 10 mg. In some embodiments, the amount of Compound I- 263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 15 mg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 25 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 40 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 60 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 90 mg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 120 mg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 160 mg.

[0088] In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg/kg to about 200 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg/kg to about 100 mg/kg. In some embodiments, the amount of Compound I- 263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg/kg to about 50 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg/kg to about 10 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg/kg to about 5 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 1 mg/kg to about 3 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 2 mg/kg to about 5 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 5 mg/kg to about 10 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 5 mg/kg to about 15 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 10 mg/kg to about 20 mg/kg. In some embodiments, the amount of Compound I- 263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 15 mg/kg to about 25 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 20 mg/kg to about 30 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 25 mg/kg to about 35 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 30 mg/kg to about 40 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 35 mg/kg to about 45 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 40 mg/kg to about 50 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 55 mg/kg to about 65 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 50 mg/kg to about 100 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 90 mg/kg to about 150 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is between about 140 mg/kg to about 200 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 0.5 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 1 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 2 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 3 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 2.5 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 4 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 5 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 6 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 7.5 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 8 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 10 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 12 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 12.5 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 15 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 17.5 mg/kg. In some embodiments, the amount of Compound I-263a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 20 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 25 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 30 mg/kg. All dosing amounts refer to the amount of Compound 1-263 a administered, and do not include the weight amount of any pharmaceutically acceptable salt.

[0089] In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 1 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 3 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 6 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 7.5 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 10 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 15 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 25 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 40 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 60 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 90 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 120 mg/kg. In some embodiments, the amount of Compound 1-263 a or a pharmaceutically acceptable salt thereof that is administered on each day of dosing is about 160 mg/kg.

[0090] In some embodiments, the at least one additional active agent is an antiviral agent, an antibiotic, a corticosteroid, interferon beta Bl, or tocilizumab. In some embodiments, the antibiotic is azithromycin. In some embodiments, the antiviral agent is chloroquine, hydroxychloroquine, remdesivir, bortezomib, ixazomib, ponatinib, lopinavir/ritonavir, darunavir/cobicistat antiviral IgG, antiviral IgM, anti-IL-6 agents, or azidothymidine (AZT).

[0091] In some embodiments the at least one additional active agent is chloroquine or hydroxylchloroquine. In some embodiments, between 300 mg and 500 mg of the chloroquine or hydroxychloroquine is administered to the subject one or twice daily for up to 5 days.

[0092] In some embodiments, the at least one additional active agent is administered on a daily schedule. In some embodiments, the at least one additional active agent is administered every other day. In some embodiments, the at least one additional active agent is administered once every three days. In some embodiments, the at least one additional active agent is administered on a twice-weekly schedule. In some embodiments, the at least one additional active agent is administered on a three times a week schedule. In some embodiments, the at least one additional active agent is administered on a weekly schedule. In some embodiments, the at least one additional active agent is administered on a once every two weeks schedule. In some embodiments, the at least one additional active agent is administered on a once every three weeks schedule. In some embodiments, the at least one additional active agent is administered on a once every four weeks schedule.

PHARMACEUTICAL COMPOSITIONS

[0093] Compound 1-263 a and the at least one additional active agent used in the methods and kits described herein can be formulated into pharmaceutical compositions suitable for administration. The pharmaceutical compositions may comprise pharmaceutically acceptable excipients. A pharmaceutically acceptable excipient, as used herein, includes, but are not limited to, any and all solvents, dispersion media, or other liquid vehicles, dispersion or suspension aids, diluents, granulating and/or dispersing agents, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, binders, lubricants or oil, coloring, sweetening or flavoring agents, stabilizers, antioxidants, antimicrobial or antifungal agents, osmolality adjusting agents, pH adjusting agents, buffers, chelants, cyoprotectants, and/or bulking agents, as suited to the particular dosage form desired. Various excipients for formulating pharmaceutical compositions and techniques for preparing the composition are known in the art (see Remington: The Science and Practice of Pharmacy, 21st Ed., A. R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, MD), 2006; incorporated by reference in its entirety)

[0094] Any of the therapeutic agents described herein may be in the form of a pharmaceutically acceptable salt. In some embodiments, such salts are derived from inorganic or organic acids or bases. For reviews of suitable salts, see, e.g., Berge et ah, J. Pharm. Sci., 1977, 66, 1 19 and Remington: The Science and Practice of Pharmacy, 20th Ed., A. Gennaro (ed.), Lippincott Williams & Wilkins (2000).

[0095] Examples of suitable acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, lucoheptanoate, glycerophosphate, hemi sulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2 hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2 naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3 phenyl propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.

[0096] Examples of suitable base addition salts include ammonium salts; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; salts with organic bases, such as dicyclohexylamine salts, N methyl D glucamine; and salts with amino acids such as arginine, lysine, and the like.

[0097] For example, Berge lists the following FDA-approved commercially marketed salts: anions acetate, besylate (benzenesulfonate), benzoate, bicarbonate, bitartrate, bromide, calcium edetate (ethylenediaminetetraacetate), camsylate (camphorsulfonate), carbonate, chloride, citrate, dihydrochloride, edetate (ethylenediaminetetraacetate), edisylate (1,2 ethane-'di sulfonate), estolate (lauryl sulfate), esylate (ethanesulfonate), fumarate, gluceptate (glucoheptonate), gluconate, glutamate, glycollylarsanilate (glycollamidophenylarsonate), hexylresorcinate, hydrabamine (N,N' di(dehydro ^_, abietyl)- ethylene-'di amine), hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate (2 hydroxyethanesulfonate), lactate, lactobionate, malate, maleate, mandelate, mesylate (methane-'sulfonate), methylbromide, methylnitrate, methyl sulfate, mucate, napsylate (2- naphthalene-'sulfonate), nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate (8-chlorotheophyllinate) and triethiodide; organic cations benzathine (N,N' dibenzylethylenediamine), chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N methylglucamine) and procaine; and metallic cations aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.

[0098] Berge additionally lists the following non-FDA-approved commercially marketed

(outside the United States) salts: anions adipate, alginate, aminosalicylate, anhydromethylenecitrate, arecoline, aspartate, bisulfate, butylbromide, camphorate, digluconate, dihydrobromide, disuccinate, glycerophosphate, hemisulfate, hydrofluoride, hydroiodide, methylenebis(salicylate), napadisylate (1,5 naphthalene^di sulfonate), oxalate, pectinate, persulfate, phenylethylbarbiturate, picrate, propionate, thiocyanate, tosylate and undecanoate; organic cations benethamine (N benzylphenethylamine), clemizole (1 p chloro benzyl-2 pyrrolildine-G ylmethylbenzimidazole), diethylamine, piperazine and tromethamine (tris(hydroxymethyl)aminomethane); and metallic cations barium and bismuth. [0099] The pharmaceutical compositions may comprise pharmaceutically acceptable carriers. As used herein, "pharmaceutically acceptable carrier" refers to a material that is compatible with a recipient subject (a human) and is suitable for delivering an active agent to the target site without terminating the activity of the agent. The toxicity or adverse effects, if any, associated with the carrier preferably are commensurate with a reasonable risk/benefit ratio for the intended use of the active agent.

[0100] Pharmaceutically acceptable carriers that may be used in these compositions include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates or carbonates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene polyoxypropylene block polymers, polyethylene glycol and wool fat.

[0101] The pharmaceutical compositions for use in the methods of the present disclosure may be manufactured by methods well known in the art such as conventional granulating, mixing, dissolving, encapsulating, lyophilizing, or emulsifying processes, among others. Compositions may be produced in various forms, including granules, precipitates, or particulates, powders, including freeze dried, rotary dried or spray dried powders, amorphous powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. Formulations may contain stabilizers, pH modifiers, surfactants, solubilizing agents, bioavailability modifiers and combinations of these.

These pharmaceutical compositions are formulated for pharmaceutical administration to a human being. Such compositions may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intraperitoneal, intramuscular, intra articular, intra synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intravenously or subcutaneously. In some embodiments, the compositions are administered orally. In some embodiments, the compositions are administered intravenously. In some embodiments, the intravenous administration can be intravenous infusion or intravenous injection. In some embodiments, the compositions are administered by an intravenous infusion. In some embodiments, the compositions are administered by an intravenous injection. In some embodiments, the compositions are administered by subcutaneous injection. In some embodiments, the compositions are administered by intravenous infusion and then subsequently administered by subcutaneous injection. In another embodiment, the anti- CD38 antibody is coadministered with human hyaluronidase subcutaneously. These formulations may be designed to be short acting, fast releasing, or long acting. Furthermore, the compositions may be administered in a local rather than systemic means, such as administration (e.g., by injection) at a tumor site.

[0102] Pharmaceutical formulations may be prepared as liquid suspensions or solutions using a liquid, such as an oil, water, an alcohol, and combinations of these. Solubilizing agents such as cyclodextrins may be included. Pharmaceutically suitable surfactants, suspending agents, or emulsifying agents, may be added for oral or parenteral administration. Suspensions may include oils, such as peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. Suspension preparations may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may include alcohols, such as ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol; ethers, such as poly(ethyleneglycol); petroleum hydrocarbons such as mineral oil and petrolatum; and water.

[0103] Sterile injectable forms of these pharmaceutical compositions may be aqueous or oleaginous suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono or di glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as sorbitan alkyl esters, such as Tweens or Spans, and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. Compounds may be formulated for parenteral administration by injection such as by bolus injection or continuous infusion. A unit dosage form for injection may be in ampoules or in multi dose containers.

[0104] These pharmaceutical compositions may be orally administered in any orally acceptable dosage form including capsules, tablets, aqueous suspensions or solutions. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. In the case of tablets for oral use, carriers that are commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. Coatings may be used for a variety of purposes, e.g., to mask taste, to affect the site of dissolution or absorption, or to prolong drug action. Coatings may be applied to a tablet or to granulated particles for use in a capsule.

[0105] Alternatively, these pharmaceutical compositions may be administered in the form of suppositories for rectal administration. These may be prepared by mixing the agent with a suitable non irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0106] These pharmaceutical compositions may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0107] Topical application for the lower intestinal tract may be affected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically transdennal patches may also be used. For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present disclosure include mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions may be formulated in a suitable lotion or cream containing the active component(s) suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and water.

[0108] For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzyl alkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.

[0109] The pharmaceutical compositions may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

[0110] In one embodiment, a compound of formula I-263a is formulated as a solution for intravenous infusion. In some embodiments, a compound of formula I-263a is formulated in a solution with a buffering agent or a PH modifying agent, and a cyclodextrin, such as a beta-cyclodextrin. In one embodiment, the solution includes phosphoric acid and Captisol (betadex sulfobutyl ether sodium) in water.

[0111] In some embodiments, a compound of formula I-263a is formulated as a drug product, wherein the drug product contains compound 1-263 a in a solution of phosphoric acid and Captisol (betadex sulfobutyl ether sodium) in water. In some embodiments, the drug product is packaged with a volume of 10 mL of compound I-263a sterile solution. KITS

[0112] In some embodiments, Compound 1-263 a or the at least one additional active agent described herein may be manufactured for inclusion in a kit. A "kit" is any article of manufacture (e.g., a package or container) comprising at least one reagent or chemotherapeutic agent. A kit for use in the methods herein may comprise I-263a or a pharmaceutically acceptable salt thereof. In some embodiments, the kit may further include at least one additional active agent. In some embodiments, the at least one additional active agent in the kit is an antiviral agent, an antibiotic, a corticosteroid, interferon beta Bl, or tocilizumab. In some embodiments, the antibiotic is azithromycin. In some embodiments, the antiviral agent is chloroquine, hydroxychloroquine, remdesivir, bortezomib, ixazomib, ponatinib, lopinavir/ritonavir, darunavir/cobicistat antiviral IgG, antiviral IgM, anti-IL-6 agents, or azidothymidine (AZT).

[0113] In some embodiments, the present disclosure relates to a kit comprising a medicament for use in treating a viral infection in a subject in need of such treatment.

The kit comprises a medicament comprising I-263a, and instructions for administering I- 263a and at least one additional active agent. The kit may contain a medicament comprising 1-263 and at least one additional active agent and instructions for administering 1-263 and at least one additional active agent, wherein the medicament is in single dosage form or in separate dosage forms.

[0114] In some embodiments, a kit comprising 1-263 and at least one additional active agent may further include another component or reagent. In some embodiments, a reagent in the kit may be a diluent for preparing the I-263a for administration. In some embodiments, a reagent in the kit may be a diluent for preparing the at least one additional active agent for administration. In some embodiments, a component in the kit may be a vessel for mixing the combination of the 1-263 and the at least one additional active agent.

[0115] In order that this present disclosure be more fully understood, the following examples are set forth. These examples are illustrative only and are not intended to limit the scope of the present disclosure in any way. EXAMPLES

Example 1

[0116] Subjects suffering from COVID-19 as diagnosed by detection of the virus in nasopharyngeal or blood samples through PCR analysis will receive 40 or 60 mg of I- 263a. I-263a will be administered intravenously as a 10 mg/ml solution. The solution will be administered over a time of 60 + 10 minutes. The administration time may be expanded to up to 4 hours. I-263a will be administered on days 1 and 4 of a 21-day treatment cycle. After the treatment cycle viral load will be detected by PCR analysis of nasopharyngeal or blood samples. If PK, pharmacodynamics, decrease in viral load and safety data are supportive, the schedule can be modified but cannot exceed administration on days 1, 4, 8 and 11. A ramp-up schedule may also be evaluated.

[0117] The subject’s National Early Warning Score (NEWS) score will be evaluated during and after the 21 -day treatment cycle. A NEWS score evaluates a subject’s respiration rate, peripheral blood, supplemental oxygen, temperature, systolic blood pressure, heart rate and level of consciousness. Higher NEWS scores are associated with increased likelihood of death or admission to an intensive care unit.