CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority to U.S. Provisional Application No.

63/006,052, filed April 6, 2020 and U.S. Provisional Application No. 63/050,409, filed July 10, 2020, each of which is incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention provides methods of treating, stabilizing or lessening the severity or progression of an acute respiratory disorder.

BACKGROUND OF THE INVENTION

[0003] In December 2019, Wuhan, the capital of Hubei province in China, became the center of an outbreak of pneumonia of unknown cause. By January 2020, scientists had isolated a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; previously known as 2019-nCoV), from these patients with virus-infected pneumonia (Phelan AL, el al ., “The Novel Coronavirus Originating in Wuhan, China: Challenges for Global Health Governance”, JAMA , Jan. 30, 2020; Gorbalenya AE, et al., “Severe acute respiratory syndrome- related coronavirus: The species and its viruses - a statement of the Coronavirus Study Group”, bioRxiv , Forthcoming 2020.), which was later designated coronavirus disease 2019 (COVID-19) in February 2020 by the World Health Organization (WHO). There are presently no effective therapies or vaccines for the treatment of diseases associated with SARS-CoV-2.

SUMMARY OF THE INVENTION

[0004] The present disclosure provides methods of treating, stabilizing or lessening the severity or progression of a disease or disorder associated with a coronavirus. In some embodiments, the present disclosure provides methods of treating, stabilizing or lessening the severity or progression of a disease or disorder associated with SARS-CoV-2. In some embodiments, the present disclosure provides a method of treating a respiratory disease or disorder associated with SARS-CoV-2. In some such embodiments, the disease or disorder associated with SARS-CoV-2 is COVID-19.

[0005] In some aspects, the present disclosure provides methods of treating, stabilizing or lessening the severity or progression of a disease or disorder associated with a coronavirus (e.g., SARS-CoV-2), the method comprising administering to a patient in need thereof an effective amount of a compound of formula I: or a pharmaceutically acceptable salt or hydrate thereof. The compound of formula I is also referred to herein as “Compound I”. In some embodiments, Compound I is in the form of a dihydrochloride salt. Compound I, or a pharmaceutically acceptable salt thereof, may also exist in a hydrate form. In some embodiments, Compound I is in the form of a dihydrochloride monohydrate. Accordingly, in some embodiments, provided methods comprise administering to a patient in need thereof an effective amount of Compound I-a: [0006] In some aspects, the present disclosure provides methods of treating, stabilizing or lessening the severity or progression of a disease or disorder associated with a coronavirus (e.g., SARS-CoV-2), the method comprising administering to a patient in need thereof an effective amount of a compound of formula II: or a pharmaceutically acceptable salt thereof. The compound of formula I is also referred to herein as “Compound II”. In some embodiments, Compound II is in the form of a monohydrochloride salt. Accordingly, in some embodiments, provided methods comprise administering to a patient in need thereof an effective amount of Compound Il-a:

[0007] In some aspects, the present disclosure provides methods of treating, stabilizing or lessening the severity or progression of a disease or disorder associated with a coronavirus (e.g., SARS-CoV-2), the method comprising administering to a patient in need thereof an effective amount of a fusion protein comprising a human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) domain linked to a modified Fc portion of human immunoglobulin G1 (IgGl). In some embodiments, the fusion protein is abatacept.

[0008] In some embodiments, the present disclosure provides a method of treating a disease or disorder associated with a coronavirus (e.g., COVID-19), the method comprising administering to a patient in need thereof about 400 mg of Compound I. In some embodiments, the dose of Compound I is decreased from about 400 mg to about 300 mg. In some embodiments, the dose of Compound I is decreased from about 300 mg to about 200 mg. In some embodiments, Compound I is administered once a day for one or more 28-day cycles. In some embodiments, Compound I is administered once a day for at least six 28-day cycles.

[0009] In some embodiments, the present disclosure provides a method of treating a disease or disorder associated with a coronavirus (e.g., COVID-19), the method comprising administering to a patient in need thereof a dose of about 240 mg to about 520 mg of Compound I. In some embodiments, Compound I is administered in a dose of about 300 mg of Compound

I. In some embodiments, Compound I is administered in a dose of about 360 mg of Compound

I. In some embodiments, Compound I is administered in a dose of about 400 mg of Compound

I. In some embodiments, Compound I is administered in a dose of about 500 mg of Compound

I.

[0010] In some embodiments, a maximum plasma concentration (Cmax) in a patient is about 625 ng/mL about 1 day post administration of Compound I. In some embodiments, a maximum plasma concentration (Cmax) in a patient is about 863 ng/mL about 14 days post administration of Compound I.

[0011] In some embodiments, Compound I is administered once a day for 14 days. In some embodiments Compound I is administered once a day for between 1 and 14 days.

[0012] In some embodiments, the present disclosure provides a method of treating a disease or disorder associated with a coronavirus (e.g., COVID-19), the method comprising administering to a patient in need thereof about 0.92 mg of Compound II. In some embodiments, the dose of Compound II is titrated up to a dose of about 0.92 mg daily. In some embodiments, Compound II is administered at a dose of about 0.23 mg daily on days 1-4. In some embodiments, Compound II is administered at a dose of about 0.46 mg daily on days 5-7. In some embodiments, Compound II is administered at a dose of about 0.92 mg on day 8 and every day thereafter.

[0013] In some embodiments, the present disclosure provides a method of treating a disease or disorder associated with a coronavirus (e.g., COVID-19), the method comprising administering to a patient in need thereof a dose of abatacept according to Table 1.

TABLE 1

[0014] In some embodiments, the present disclosure provides a method of treating a disease or disorder associated with a coronavirus (e.g., COVID-19), the method comprising administering to a patient in need thereof a dose of abatacept in an amount that is about 10 mg/kg per dose. In some embodiments, a dose of abatacept is administered to a patient in need thereof on the first day of treatment. In some embodiments, a second dose of abatacept is administered between 6 and 14 days after an initial dose of abatacept.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 is a schematic depiction of the mechanism of action of fedratinib.

[0016] Figure 2 is a schematic depiction of the mechanism of action of ozanimod.

[0017] Figure 3 is a schematic depiction of the mechanism of action of abatacept.

Definitions

[0018] The term “about” as used herein when referring to a measurable value such as a parameter, an amount, a temporal duration, and the like, is meant to encompass variations of +/- 10% or less, preferably +1-5% or less, more preferably +/-1% or less, and still more preferably +/-0.1% or less of and from the specified value, insofar such variations are appropriate to perform in the disclosed invention. As an example, when the term “about” is used in combination with a certain number of days, it includes said specific number of days plus or minus 1 day, e.g., “about 6 days” includes any number of days between 5 and 7. It is to be understood that the value to which the modifier “about” refers is itself also specifically, and preferably, disclosed.

[0019] Unless specifically indicated otherwise, the word “or” is used in the inclusive sense of “and/or” and not the exclusive sense of “either/or.”

[0020] The terms “treat” or “treating,” as used herein, refers to partially or completely alleviating, inhibiting, delaying onset of, preventing, ameliorating and/or relieving a disorder or condition, or one or more symptoms of the disorder or condition. As used herein, the terms “treatment,” “treat,” and “treating” refer to partially or completely alleviating, inhibiting, delaying onset of, preventing, ameliorating and/or relieving a disorder or condition, or one or more symptoms of the disorder or condition, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In some embodiments, the term “treating” includes preventing or halting the progression of a disease or disorder. In other embodiments, treatment may be administered in the absence of symptoms.

For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence. Thus, in some embodiments, the term “treating” includes preventing relapse or recurrence of a disease or disorder.

[0021] The expression “unit dosage form” as used herein refers to a physically discrete unit of inventive formulation appropriate for the subject to be treated. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of specific active agent employed; specific composition employed; age, body weight, general health, sex and diet of the subject; time of administration, and rate of excretion of the specific active agent employed; duration of the treatment; drugs and/or additional therapies used in combination or coincidental with specific compound(s) employed, and like factors well known in the medical arts. Detailed Description of Certain Embodiments

COVID-19

[0022] COVID-19 is an acute respiratory disease associated with the coronavirus SARS-

CoV-2. A feature of SARS-CoV-2 infection is that while the majority of patients experience relatively mild symptoms, a small proportion will develop a life threatening illness characterized by a myeloid cell driven hyper-inflammatory response leading to life-threatening hypoxia and severe acute respiratory distress syndrome (ARDS) that is the principal cause of mortality (Huang C, etal ., “Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China”, Lancet , 395(10223):497-506, Feb. 15, 2020; Guan WJ, et al., “Clinical Characteristics of Coronavirus Disease 2019 in China”, N. Engl. J Med., Feb. 28, 2020). This occurs 7-10 days after the initial appearance of symptoms, and may present as a benign initial respiratory oxygen dependence that quickly requires substantial ventilatory support (over hours). ARDS is more common in older people, male, with pre-existing co-morbidities, particularly cardiovascular and cerebrovascular disease and diabetes. ARDS syndrome occurs in 3-30% of patients and is severe enough to require ICU admission and ventilatory support in 6-20% of patients. Once a patient requires intubation, mortality rates can be up to 50%. In SARS-CoV-2 disease, the lung pathology has been attributed to a similar myeloid cell inflammatory cell infiltrate. Cellular analysis by single cell RNA-sequencing of bronchoalveolar lavage (BAL), in 6 patients including; 3 with mild disease and 3 with severe disease, showed as marked increase in abnormal monocyte-derived macrophage cell infiltrate (Liao M, etal., “The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing”, medRxiv, Forthcoming 2020.). Analysis of patient plasma in 41 patients shows increased levels of IL-Ib, IL-IRa, IL-7, IL-8, IL-9, IL-10, basic FGF (bFGF), GCSF, GM-CSF, IFNγ , IP10, MCP1, MIP1A, MIP1B, PDGF, TNF-a, and VEGF in SARS-CoV-2 patients as compared to healthy controls. Moreover, SARS-CoV-2 patients admitted to ICU patients showed higher plasma levels of IL-2, IL-7, IL-10, GMCSF, IL-6, IP 10, MCP1, MIP1A, and TNF-a than non-ICU patients (Huang C, etal., “Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China”, Lancet, 395(10223):497-506, Feb. 15, 2020).

[0023] Unfortunately, the pathogenesis of COVID-19 still remains unclear, and there are currently no effective therapies. Therefore, there remains an unmet need for therapies that lessen the severity of symptoms associated with a coronavirus (e.g., SARS-CoV-2), reduce the incidence of infection of a coronavirus (e.g., SARS-CoV-2) in a population, and/or improve overall clinical outcomes in patients susceptible to or infected with a coronavirus (e.g., SARS- CoV-2).

Compound I

[0024] Fedratinib (INREBIC®) is approved for the treatment of adult patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF). Fedratinib 400 mg once daily provides clinically meaningful reductions in spleen volume and symptoms in patients with MF including those previously exposed to ruxolitinib.

[0025] The synthesis of the Compound I is disclosed in Example 90 of U.S. Patent

7,528,143, issued May 5, 2009, which is hereby incorporated by reference in its entirety. Compound I, also known as fedratinib, is a potent and selective inhibitor of JAK2 kinase activity that in cellular assays inhibits JAK2 signaling, cellular proliferation driven by mutant JAK2 or mutant MPL, and induces apoptosis in cells expressing constitutively active JAK2.

[0026] The mechanism of action of fedratinib suggests a role in modulating a maladaptive immune response. Janus kinases (JAKs) play a central role in regulating hematopoiesis and modulating immune cell function. They mediate the signaling of cytokine receptors, including the receptors for thrombopoietin, erythropoietin, interleukins, and interferons. Under normal conditions, JAK2 is activated following ligand binding to receptors. Activated JAK2 induces STAT (signal transducer and activator of transcription) proteins to dimerize and translocate to the nucleus to regulate transcription of target genes (Vainchenker W, et al ., “JAK inhibitors for the treatment of myeloproliferative neoplasms and other disorders”, FlOOORes , 2018;7:82; Kesarwani M, et al ., “Targeting substrate-site in Jak2 kinase prevents emergence of genetic resistance”, Sci Rep.; 5: 14538, Sep. 30, 2015). Fedratinib is an oral, small molecule kinase inhibitor with higher selectivity for JAK2 over other JAK family members, including JAK1, JAK3 and tyrosine kinase 2 (TYK2) (Wemig G, et al., “Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera”, Cancer Cell, 13 (4): 311-20 (Apr. 2008); Zhou T, et al., “Specificity and mechanism-of-action of the JAK2 tyrosine kinase inhibitors ruxolitinib and SAR302503 (TG101348)”, Leukemia , 2014 Feb;28(2):404-7, Feb. 2014 ; INREBIC®. [Prescribing Information], Summit, NJ: Celgene Corporation;2019, available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/21 2327s0001bl.pdf). Fedratinib binds to and prevents the activation of JAK2. As a result, STAT phosphorylation and dimerization is prevented leading to downregulation of inflammatory cytokine signaling through inflammatory cytokine receptors, such as IL-6 receptor (IL6R), TNF family receptors, and IFNy receptor (IFNyR), and reduces cytokine production by myeloid precursors (Vainchenker W, el al ., “JAK inhibitors for the treatment of myeloproliferative neoplasms and other disorders”, FlOOORes , 2018;7:82). Figure 1.

[0027] Fedratinib has been studied extensively in the treatment of patients with myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF). Fedratinib has demonstrated clinical efficacy in a randomized, placebo-controlled, Phase 3 study (JAKARTA [EFC12153]) in patients with intermediate-2 or high-risk MF who were previously untreated and in the singlearm Phase 2 JAKARTA2 study (ARE) 12181) in patients with intermediate- 1 with symptoms, intermediate-2 or high-risk MPN-associated myelofibrosis who have been previously treated with ruxolitinib. (A. Pardanani, etal. , JAMA Oncol , 1(5):643-651 (2015); and C. Harrison, et al. , The Lancet Haematology, 4(7):E317-E324 (July 1, 2017), each of which is incorporated herein by reference in its entirety).

[0028] Both JAKARTA and JAKARTA 2 studies met the primary endpoint of spleen response rate and secondary endpoint of symptom response rate. The most common non- hematologic treatment-emergent adverse events (TEAEs) of all grades reported in the fedratinib 400 mg daily dose group for JAKARTA were diarrhea 66%, nausea 62%, vomiting 39%, and fatigue 19%. The most common hematologic TEAEs of all grades and Grade > 3 events were anemia 74% (> Grade 3, 34%), thrombocytopenia 47% (> Grade 3, 12%) and neutropenia 23%

(> Grade 3, 5%) (Inrebic®, 2019).

[0029] For Cycle 1, the most common TEAEs of all grades and Grade 3 and 4 events reported in the fedratinib 400 mg daily dose group were diarrhea 51.7% (2.5%), nausea 46.8% (< 1%), vomiting 30% (< 1%), elevated creatinine 47.9%, aspartate aminotransferase (AST) 33.3%, alanine aminotransferase (ALT) 28%, lipase 33% (6.4%) and amylase 16.7% (2%). For TEAEs of anemia and thrombocytopenia, no significant difference between fedratinib 400 mg daily dose group and placebo group were noted suggesting the rates of anemia and thrombocytopenia observed in Cycle 1 are related to the underlying disease itself.

[0030] Fedratinib (INREBIC®) was approved by Food and Drug Administration (FDA) on August 16, 2019 for the treatment of adult patients with intermediate-2 or high-risk primary or secondary (postpolycythemia vera or post-essential thrombocythemia) myelofibrosis (MF).

[0031] Consistent with its mechanism of action, fedratinib demonstrates anti- inflammatory properties in the clinic by modulating cytokines associated with active inflammation. Fedratinib inhibits STAT3 phosphorylation in whole blood from MF patients (Pardanani, 2015). A single administration of the recommended fedratinib dose results in maximal inhibition of STAT3 phosphorylation (-50% reduction) within 2 hours of dosing and is maintained with daily administration. Changes in plasma levels of 28 of 97 measured cytokines and circulating proteins were observed over the first 3 cycles of fedratinib treatment in MF patients, indicating early and continued modulation (Pardanani A, et al ., “A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis”, Blood Cancer J. : 5:e335, Aug. 7, 2015). Among them, fedratinib decreases levels of cytokines associated with COVID-19 severity and mortality such as TNFα (1.7-1.9 fold), IP10 (1.4-1.5 fold) and CRP (3.4-5.3 fold), respectively (Pardanani A, etal., “A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis”, Blood Cancer J. 2015 Aug 7;5:e335; Huang C, etal., “Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China”, Lancet, 395(10223):497-506, Feb. 15, 2020; Zhou F, et al., “Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study”, Lancet, 395(10229): 1054-62, Mar. 28, 2020; Ruan Q, et al., “Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China”, Intensive Care Med. Mar. 3, 2020).

[0032] Fedratinib has demonstrated anti-inflammatory properties in the clinic by modulating cytokines that are associated with active inflammation. In MF patient samples, fedratinib has been shown to reduce cytokines that are associated with COVID-19 and severity such as TNFa (1.7-1.9 fold), IP10 (1.4-1.5 fold), IL-18 (1.6 fold), ILIRA (2 fold) and RANTES/CCL5 (2.2-3.5 fold), including those cytokines that are predictive of COVID-19 mortality such as CRP (3.4-5.3 fold). In MF patients’ samples, fedratinib reduces pSTAT3 by -50% at (steady state), thereby it blunts STAT3 and NFKB activation upstream of pro- inflammatory cytokine/chemokine production. There is similarly preclinical evidence supporting an anti-inflammatory role for fedratinib. Fedratinib does not display off-target effects on IL-2 or IL-15-JAK3-STAT5-mediated signaling that sustained other regulatory and effector T cell types, indicating that JAK2 selectivity may be advantageous in a setting where blunting inflammatory responses while sparing other anti-viral immune responses is desirable (Betts BC, et al ., “Janus kinase-2 inhibition induces durable tolerance to alloantigen by human dendritic cell-stimulated T cells yet preserves immunity to recall antigen”, Blood , 118(19):5330-9, Nov. 10, 2011). Fedratinib was similarly found to inhibit IL-17 and IL-22 expression in pro-inflammatory murine Thl7 cells, which have been implicated in COVID-19-associated ARDS (Wu D and Yang XO, “TH17 responses in cytokine storm of COVID-19: An emerging target of JAK2 inhibitor Fedratinib”, J. Microbiol. Immunol. Infect. Mar. 11, 2020). Evidence also suggests that fedratinib decreases Thl7 cell expansion/activation in allogeneic mixed leukocyte reaction (MLR) and murine cell models (Betts BC, et al., “Janus kinase-2 inhibition induces durable tolerance to alloantigen by human dendritic cell-stimulated T cells yet preserves immunity to recall antigen”, Blood , 118(19):5330-9, Nov. 10, 2011). In addition, a recent publication reveals fedratinib restricts pro-inflammatory function of Th17 cells that are increased in COVID-19 associated ARDS. Fedratinib displays activity against AAKl/GAK (IC50: 960/30 nM), proteins involved in clathrin-mediated endocytosis, the inhibition of which has been shown to reduce viral infection in vitro (Stebbing, 2020). Knockdown of JAK2 or pharmacological JAK1/2 inhibition demonstrates synergy with anti-viral therapy in TGEV-infected cells, inhibiting phosphorylation of p65 (NF-KB pathway activation) and reducing viral titers, respectively (Yang CW, et al., “Targeting Coronaviral Replication and Cellular JAK2 Mediated Dominant NF- kappaB Activation for Comprehensive and Ultimate Inhibition of Coronaviral Activity”, Sci Rep. 7(1):4105, Jun. 22, 2017).

[0033] Unlike ruxolitinib, which inhibits JAK 1/2 and thereby a wide range of cytokines and T cells, fedratinib is JAK2 selective inhibits only a narrow range of cytokines. In addition, IL-6 has been shown to play a role in COVID-19 associated cytokine storm and tocilizumab has been effectively shown to improve the clinical outcome. Fedratinib has been shown to reduce IL-6 in supernatants of allogeneic MLRs. Taken together, these data indicate that fedratinib may be effective in the treatment of patients infected with COVID-19 by inhibiting 1) pro- inflammatory cytokine production associated with COVID-19 disease severity and 2) NFKB pathway activation and coronavirus replication.

Compound II

[0034] Compound II, also known as ozanimod (and marketed as ZEPOSIA®) is the S- enantiomer of 5-(3-(l-(2-hydroxyethylamino)-2,3-dihydro-lH-inden-4-yl)-l,2 ,4-oxadiazol-5- yl)-2-isopropoxybenzonitrile, the synthesis of which is reported at columns 217 and 218 of U.S. patent 8,481,573.

[0035] Ozanimod (marketed as Zeposia®) is approved for multiple sclerosis.

Ozanimod is an orally bioavailable small molecule sphingosine 1 -phosphate 1 receptor (S1P1 receptor) modulator that has been recently approved by FDA for the treatment of adult patients with Relapsing Multiple Sclerosis (MS). Ozanimod is additionally being developed for adult patients with moderate to severe inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD).

[0036] Ozanimod is an agonist of the S1P1 and S1P5 receptors. The agonism of SIP directly causes its internalization and degradation through the ubiquitin-proteosome pathway.

The loss of SIP leads to a decrease in the total lymphocyte count in circulation, specifically CD4+ CCR7+ and CD8+ CCR7+ T cells. The decrease is due sequestration of lymphocyte subsets in peripheral lymphoid organs, preventing their trafficking to inflamed tissue sites.

[0037] S1P1 receptor modulators have demonstrated efficacy in animal models of viral infections. In models using the human H1N1 influenza virus, a selective for S1P1 receptor modulator has demonstrated reduction in lung inflammation, cytokine storm and increased survival. This treatment did not affect viral clearance, neutralizing antibodies titers or function of cytotoxic T cells. Based on the S1P1 receptor expression in lung endothelial cells and lymphocytes, the proposed mechanism of action for a S1P1 receptor modulator includes a direct effect on the release of cytokines by lung endothelial cells as well as prevention of innate immune cell infiltration in the lung. [0038] S1P1 receptor modulators such as ozanimod could be beneficial in patients with COVID-19. The clinical experience with ozanimod is currently restricted to its clinical benefits after chronic treatment in MS and IBD. The mechanism of action is not fully elucidated but involves decrease in trafficking of lymphocytes to sites of inflammation. Ozanimod reduces numbers of blood lymphocytes (-25% after 2-3 weeks of treatment and -45% after 8 weeks of treatment). Levels of B cells, CD4+ T cells and less so CD8+ T cells are reduced after ozanimod treatment. NK cells, monocytes and the CD8+ T cell function are not altered. A similar effect has been reported after treatment with fmgolimod (GILENYA®) by reducing cytokine release and antigen presentation lymphocytes (CD 19+ B and CD4+ T cells) but preserving host cell response (CD8+ T, NK, and NKT cells). An open label study is currently enrolling COVID-19 positive patients in China to evaluate the effects of fmgolimod treatment in the severity of COVID-19 pneumonia. Ozanimod treatment could be beneficial in COVID-19 by directly reducing release of pro-inflammatory cytokines as well as preventing infiltration of immune cells into the lung in patients with an aberrant immune response. Figure 2.

Abatacept

[0039] Abatacept is a soluble fusion protein that consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to the modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1 (IgGl).

[0040] Abatacept (marketed as ORENCIA®) is approved for, and tested in, multiple autoimmune diseases. Intravenous (IV) abatacept is approved for adult rheumatoid arthritis (RA) in the United States of America (USA), the European Union (EU), Japan, Latin America, and other countries. IV abatacept is also approved for juvenile idiopathic arthritis (JIA) in the USA, EU, and other countries, and SC abatacept is approved for JIA in the US and EU. A subcutaneous (SC) formulation of abatacept in a prefilled syringe for SC administration for adult RA patients has been approved in the USA, EU, and several other countries, and an autoinjector formulation has been approved in the USA, EU, and a few other countries. Abatacept (IV and SC) is also approved for psoriatic arthritis (PsA) in the US, the EU, and other countries. The IV and SC formulations of abatacept are being studied for the treatment of a number of immune- mediated disorders; results from completed clinical studies in RA, JIA, and PsA are reported. Safety data from studies in psoriasis, multiple sclerosis (MS), Crohn’s disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE), primary Sjogren’s Syndrome (pSS), and lupus nephritis (LN) are also summarized. The studies in MS, CD, UC, SLE, pSS, and LN have been terminated. Current studies evaluating abatacept include an ongoing Phase 3 study in Idiopathic Inflammatory Myositis (SC formulation), a Phase 4 exploratory study in early RA, and a Phase 2 study in Treatment Resistant Nephrotic Syndrome (IV formulation).

[0041] Abatacept prevents the full activation of T-cells (see Figure 3). Abatacept, a selective co-stimulation modulator, is a soluble fusion protein that consists of the extracellular domain of human cytotoxic T lymphocyte (T cell)-associated antigen 4 (CTLA4) linked to the modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1 (IgGl). Abatacept binds to CD80/CD86 receptors on antigen-presenting cells, thereby inhibiting their binding to the costimulatory molecule CD28 on T cells. By inhibiting full T cell activation, abatacept also affects the downstream inflammatory cascade.

[0042] Abatacept has demonstrated the ability to modulate the maladaptive immune response in multiple models of cytokine storm. (1) The most relevant data for the use of ORENCIA® in the setting of COVID-19 comes from a mouse model of flu-induced pneumonia. In this model, treatment with CTLA4-Ig decoupled the protective and immunopathological memory T cell responses following secondary infection without effecting viral clearance. (2) In a large case series of patients undergoing haploidentical HSCT addition of ORENCIA® to a conventional Post-transplant Cyclophosphamide regimen resulted in a dramatic reduction in the incidence of cytokine release syndrome (CRS, 91.8% to 5.8%) and its severity. (3) In a small case series of sJIA patients with macrophage activation syndrome (MAS) addition of ORENCIA® to Anakinra resulted in significant attenuation of symptoms and improvements in inflammatory markers. (4) The use of CTLA4-IG in mouse models of both Toxic Shock and Staph B induced cytokine storm resulted in significant reductions in morbidity (including lung damage and edema) and mortality, and lower levels of both IL-6 and IFN-Υ . (5) Finally, ORENCIA® treatment has recently been shown to be highly effective in hyper-inflammatory states, such as myocarditis, induced by treatment with immune checkpoint inhibitors for malignant disease. [0043] Abatacept has a well-established safety profile based on 15+ years of clinical development and real-world experience. Pooled safety data from the randomized placebo- controlled, double blind studies did not suggest a substantial increased risk for viral infection: reported PTs of infections that could be caused by virus in abatacept group and placebo group were upper respiratory tract infection (11.9% vs 12.1%), nasopharyngitis (11.8% vs 10%), bronchitis (6.5% vs 5.8%), influenza (5.8% vs 5.9%), pharyngitis (3.5% vs 3.3%), rhinitis (2.4% vs 1.3%), conjunctivitis (2.1% vs 1.5%), gastroenteritis (2.0% vs 3.0%), oral herpes (1.8% vs 1.3%), herpes zoster (1.5% vs 1.4%), pneumonia (1.8% vs 1.1%). With regard to serious infections during the double-blind period the rates were low and comparable between abatacept and placebo. In addition, both post-marketing epidemiology programs and review of safety surveillance data did not reveal evidence that suggested a marked increase in the risk of serious viral infection in abatacept recipients compared to RA patients receiving standard of care.

Methods of Treating a Disease or Disorder Associated with SAR-CoV-2

[0044] In some embodiments, the present disclosure methods of treating, stabilizing or lessening the severity or progression of a respiratory disorder. In some embodiments, the present disclosure provides methods of treating, stabilizing or lessening the severity or progression of a disease or disorder associated with a coronavirus. In some embodiments, the present disclosure provides methods of treating, stabilizing or lessening the severity or progression of a disease or disorder associated with SARS-CoV-2. In some embodiments, the present disclosure provides a method of treating a respiratory disease or disorder associated with SARS-CoV-2. In some such embodiments, the disease or disorder associated with SARS-CoV-2 is COVID-19.

[0045] In some embodiments, provided methods of treating or lessening the severity of a respiratory disorder (e.g., a disease or disorder associated with a coronavirus such as SARS- CoV-2) comprise administering to a patient Compound I:

or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, Compound I is in the form of a dihydrochloride salt. Compound I, or a pharmaceutically acceptable salt thereof, may also exist in a hydrate form. In some such embodiments, Compound I is in the form of a dihydrochloride monohydrate. Accordingly, in some embodiments, provided methods comprise administering to a patient in need thereof Compound I-a:

[0046] In some embodiments, provided methods of treating or lessening the severity of a respiratory disorder (e.g., a disease or disorder associated with a coronavirus such as SARS- CoV-2) comprise administering to a patient Compound II: or a pharmaceutically acceptable salt thereof. In some embodiments, Compound II is in the form of a monohydrochloride salt. Accordingly, in some embodiments, provided methods comprise administering to a patient in need thereof Compound Il-a:

[0047] In some embodiments, provided methods of treating or lessening the severity of a respiratory disorder (e.g., a disease or disorder associated with a coronavirus such as SARS- CoV-2) comprise administering to a patient an effective amount of a fusion protein comprising a human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) domain linked to a modified Fc portion of human immunoglobulin G1 (IgGl). In some embodiments, the fusion protein is abatacept.

[0048] In some embodiments, the present disclosure provides a method of reducing the percentage of hospitalized patients requiring critical care and/or mechanical ventilation, as compared to a reference standard, in a patient suffering from or diagnosed with a respiratory disorder (e.g., a disease or disorder associated with a coronavirus such as SARS-CoV-2). In some embodiments, a reference standard is the percentage of hospitalized patients requiring critical care and/or mechanical ventilation who have not been treated with a compound or treatment (e.g., abatacept) disclosed herein. In some embodiments, the present disclosure provides a method of reducing the frequency of respiratory progression characterized by increased oxygen requirement, as compared to a reference standard, in a patient suffering from or diagnosed with a respiratory disorder (e.g., a disease or disorder associated with a coronavirus such as SARS-CoV-2). In some embodiments, a reference standard is respiratory progression characterized by increased oxygen requirement in patients who have not been treated with a compound or treatment (e.g., abatacept) disclosed herein.

[0049] In some embodiments, the present disclosure provides a method of reducing the frequency and duration of SARS-CoV-2 viral shedding in the upper respiratory tract, as compared with a reference standard, in a patient suffering from or diagnosed with a respiratory disorder (e.g., a disease or disorder associated with a coronavirus such as SARS-CoV-2). In some embodiments, a reference standard is the quantity or amount of viral shedding in the upper respiratory tract in patients who have not been treated with a compound disclosed herein.

[0050] In some embodiments, the present disclosure provides a method of improving overall survival in a patient suffering from or diagnosed with a disease or disorder associated with a coronavirus (e.g., COVID-19). In some embodiments, the overall survival is improved relative to a patient that is admitted to an intensive care unit, requires mechanical ventilation, suffers from sepsis or organ failure, develops respiratory failure, or otherwise dies due to the COVID-19 related disease. In some embodiments, overall survival is improved when a patient that is discharged from an intensive care unit 14 days or less post administration of a therapy described herein. In some embodiments, overall survival is improved when a patient does not suffer respiratory failure 14 days or less post administration of a therapy described herein. In some embodiments, overall survival is improved when a patient does not die 14 days or less post administration of a therapy described herein. In some embodiments, overall survival is improved when a patient that is discharged from an intensive care unit 28 days or less post administration of a therapy described herein. In some embodiments, overall survival is improved when a patient does not suffer respiratory failure 28 days or less post administration of a therapy described herein. In some embodiments, overall survival is improved when a patient does not die 28 days or less post administration of a therapy described herein. In some embodiments, overall survival is improved when a patient does not die 60 days or less post administration of a therapy described herein.

[0051] In some embodiments, the present disclosure provides a method of improving a

National Early Warning Score 2 (NEWS 2) in a patient suffering from or diagnosed with a disease or disorder associated with a coronavirus (e.g., COVID-19). In some embodiments, an improvement of NEWS 2 is determined by comparison to a baseline. In some embodiments, an improvement of NEWS 2 is determined by one or more of respiration rate, oxygen saturation, systolic blood pressure, pulse rate, level of consciousness or confusion, temperature.

[0052] In some embodiments, the present disclosure provides a method for decreasing requirement of respiratory progression in a patient suffering from or diagnosed with a disease or disorder associated with a coronavirus (e.g., COVID-19). In some embodiments, the decreased requirement is measured by a reduction in the need additional oxygen requirement or need for advanced ventilator support.

[0053] In some embodiments, the present disclosure provides a method for reducing frequency and duration of SARS-CoV-2 viral shedding in the upper respiratory tract (URT) of a patient suffering from or diagnosed with a disease or disorder associated with a coronavirus (e.g., COVID-19).

[0054] In some embodiments, the present disclosure provides a method for modulating biomarkers associated with COVID-19 disease progression. In some embodiments, the biomarkers are selected from CRP, TNFa, IL-6, ferritin, LDH, and D-dimer. In some embodiments, the biomarkers are IL-6, IL-2, IL-7, GM-CSF, IP-10, MCP-1, MPMα, TNFα, IL- iβ, IL-8, IFN-a, IFN-b and IFN-g.

[0055] In some embodiments, the present disclosure provides a method for treating a patient suffering from or diagnosed with a disease or disorder associated with a coronavirus (e.g., COVID-19), wherein the patient exhibits abnormalities relative to a subject not suffering from or diagnosed with the disease or disorder associated with a coronavirus, wherein the abnormalities are selected from one or more of leukopenia, hyperferritinemia, and elevation of one or more biomarkers selected from CRP, LDH, and IL-6.

[0056] In some embodiments, the present disclosure provides a method of reducing a viral load of SARS-CoV-2 in a patient suffering from or diagnosed with a disease or disorder associated with a coronavirus (e.g., COVID-19). In some embodiments, the method of reducing the viral load is determined by a RT-PCR negative result for the presence of SARS-CoV-2 in the upper respiratory tract (URT), or, as a change from baseline the viral load/titer (quantitatively). [0057] In some embodiments, the present disclosure provides a method of preventing disease progression in a patient suffering from a disease associated with a coronavirus (e.g., COVID-19). In some embodiments, prevention of disease progression is determined relative to development of symptoms (e.g., fever, cough, body aches, loss of taste and/or smell, fatigue, shortness of breath, sore throat, congestion, runny nose, nausea or vomiting, diarrhea, or any combination thereof). In some embodiments, prevention of disease progression is determined by prevention of severe disease, where severe disease is the inability to maintain Sp02 > 93% on room air at sea level. In some embodiments, prevention of disease progression is determined by prevention of critical disease, where critical disease is reliance on oxygen supplementation devices with greater oxygen delivery capacity than low flow nasal cannula.

[0058] In some embodiments, the present disclosure provides a method of improving clinical status in a patient suffering from a disease or disorder associated with a coronavirus (e.g., COVID-19). In some embodiments, improving clinical status of a patient is determined by a change in baseline on an 8-point outcome scale. In some embodiments, a change in baseline on an 8-point outcome scale is measured 28 days after determination of the baseline. In some embodiments, an 8-point outcome scale is an outcome selected from:

1. Death

2. Hospitalized, on invasive mechanical ventilation or ECMO (extra-corporeal membrane oxygenation)

3. Hospitalized, on non-invasive mechanical ventilation or high-flow oxygen devices

4. Hospitalized, requiring supplemental oxygen

5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise)

6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care

7. Not hospitalized, limitation on activities and/or requiring home oxygen

8. Not hospitalized, no limitation on activities [0059] In some embodiments, the present disclosure provides a method of improving mortality rate in a patient suffering from a disease or disorder associated with a coronavirus (e.g., COVID-19), wherein an improvement in mortality rate is determined by survival of a patient 28 days after first administration of a treatment described herein.

[0060] In some embodiments, the present disclosure provides a method of treating a patient suffering from suffering from or diagnosed with a disease or disorder associated with a coronavirus (e.g., COVID-19), wherein a patient exhibits an absence of critical disease, recovery of pulmonary function, shortened hospitalization, improvement in clinical laboratory parameters of inflammation or organ damage, improvement in vital signs, viral clearance, anti-viral response, improvement in oxygenation, changes in serum biomarkers, changes from baseline in gene expression for immune function and cellular pathways, or any combination thereof. In some embodiments, absence of critical disease is determined by a patient being alive and free of respiratory failure 28 days or more after administration of treatments described herein. In some embodiments, recovery of pulmonary function is determined by a patient not requiring supplemental oxygen and/or only relying on room air 28 days or more after administration of treatments described herein. In some embodiments, shortened hospitalization is determined by a patient being alive and discharged from a hospital 28 days or less after administration of treatments described herein. In some embodiments, improvement in vital signs is determined by a return to stable temperature, respiratory rate, heart rate, or blood pressure. In some embodiments, viral clearance is determined by the reduction in amount of viral RNA determined by RT-qPCR. In some embodiments, anti-viral response is determined by the presence of anti viral IgG/IgM titers in serum. In some embodiments, improvement in oxygenation refers to decrease in oxygen supplementation 14 days after administration of treatments described herein. In some embodiments, improvement in clinical laboratory parameters of inflammation or organ damage is determined by reduction in one or more of CRP, ferritin, IL-6, lymphocyte count, cardiac troponin, LDH, D-dimer, pro-calcitonin, C3 and C4. In some embodiments, changes in serum biomarkers are determined by changes from baseline biomarkers of immune function. In some embodiments, changes in whole blood RNA are determined by changes from baseline in gene expression for immune function and cellular pathways.

[0061] In some embodiments, the present disclosure provides a method of treating a patient suffering from suffering from or diagnosed with a disease or disorder associated with a coronavirus (e.g., COVID-19) comprising modulation of JAK-STAT pathway activation and/or changes in immunomodulatory and/or inflammatory cytokines.

[0062] In some embodiments, Compound I, or a pharmaceutically acceptable salt or hydrate thereof, (e.g., Compound I-a), is administered to the patient in a unit dosage form. In some embodiments, the unit dosage form of Compound I or Compound I-a is the molar equivalent of the free base weight of the compound. For example, a 100 mg dose of the free base form of Compound I equates to about 117.30 mg of Compound I in its dihydrochloride monohydrate form (i.e., Compound I-a). In some embodiments, the unit dosage form of Compound I or Compound I-a is about 50 mg, about 100 mg, about 150 mg, or about 200 mg, wherein the amount of Compound I or Compound I-a is the molar equivalent of the free base weight of the compound. In some embodiments, the unit dosage form of Compound I or Compound I-a is 100 mg, wherein the amount of Compound I-a is the molar equivalent of the free base weight of the compound.

[0063] In some embodiments, Compound I, or a pharmaceutically acceptable salt or hydrate thereof, (e.g., Compound I-a), is administered in an oral dosage form. In some such embodiments, the oral dosage form is a capsule. In some embodiments, the oral dosage form is a tablet.

[0064] In some embodiments, Compound I, or a pharmaceutically acceptable salt or hydrate thereof, (e.g., Compound I-a), is administered once daily (QD). In some embodiments, Compound I, or a pharmaceutically acceptable salt or hydrate thereof, (e.g., Compound I-a), is administered at a total daily dose of about 200 mg, about 300 mg or about 400 mg. In some embodiments, Compound I or Compound I-a is administered to the patient at a total daily dose of about 400 mg. In some embodiments, Compound I or Compound I-a is administered to the patient at a total daily dose of about 300 mg. In some embodiments, Compound I or Compound I-a is administered to the patient at a total daily dose of about 200 mg. In some embodiments, the total daily dose of Compound I or Compound I-a is modified due to an adverse event. In some embodiments, the total daily dose of Compound I or Compound I-a is reduced. In some embodiments, the total daily dose of Compound I or Compound I-a is reduced from about 400 mg to about 300 mg. In some embodiments, the total daily dose of Compound I or Compound I- a is reduced to about 200 mg. It will be appreciated that the amount (e.g., total daily dose) of Compound I or Compound I-a is the molar equivalent to, e.g., about 400 mg, about 300 mg or about 200 mg of the free base weight.

[0065] In some embodiments, Compound I, or a pharmaceutically acceptable salt or hydrate thereof, (e.g., Compound I-a), is administered once daily for a 28-day cycle. In some embodiments, Compound I, or a pharmaceutically acceptable salt or hydrate thereof, (e.g., Compound I-a), is administered once daily for two 28-day cycles. In some embodiments, Compound I, or a pharmaceutically acceptable salt or hydrate thereof, (e.g., Compound I-a), is administered once daily for three, four, five, or more 28-day cycles. In some embodiments, Compound I, or a pharmaceutically acceptable salt or hydrate thereof, (e.g., Compound I-a), is administered once daily for six, seven, eight, nine, ten, eleven, twelve or more 28-day cycles. In some embodiments, Compound I, or a pharmaceutically acceptable salt or hydrate thereof, (e.g., Compound I-a), is administered once a day for at least six 28-day cycles. In some embodiments, Compound I, or a pharmaceutically acceptable salt or hydrate thereof, (e.g., Compound I-a), is administered once daily until symptoms of disease are no longer measureable. In some embodiments, Compound I or Compound I-a is administered for the duration of a patient’s life. In some embodiments, Compound I or Compound I-a is administered once daily for one or more 28-day cycles, followed by a dose holiday. A “dose holiday” as used herein refers to a period of time wherein Compound I or Compound I-a is not administered to the patient. In some embodiments, a dose holiday is one day, one week, or one 28-day cycle. In some embodiments, Compound I or Compound I-a is administered once daily for one or more 28-day cycles, followed by a dose holiday, and then resumption of administration of Compound I or Compound I-a once daily at the same dose level prior to the dose holiday. In some embodiments,

Compound I or Compound I-a is administered once daily for one or more 28-day cycles, followed by a dose holiday, and then resumption of administration of Compound I or Compound I-a once daily at a dose level that is 100 mg less than the dose of Compound I or Compound I-a prior to the dose holiday. In some embodiments, the total daily dose of Compound I or Compound I-a is titrated upward by 100 mg following a prior dose reduction. It will be appreciated that the amount (e.g., total daily dose) of Compound I or Compound I-a is the molar equivalent to, e.g., about 400 mg, about 300 mg or about 200 mg of the free base weight.

[0066] In some embodiments, Compound II, or a pharmaceutically acceptable salt thereof, (e.g., Compound Il-a), is administered to the patient in a unit dosage form. In some embodiments, the unit dosage form of Compound II or Compound Il-a is the molar equivalent of the free base weight of the compound. For example, a 1 mg dose of the free base form of Compound II equates to about 1.09 mg of Compound II in its monohydrochloride form (i.e., Compound Il-a). In some embodiments, the unit dosage form of Compound II or Compound Il-a is about 0.23 mg, about 0.46 mg, or about 0.92 mg, wherein the amount of Compound II or Compound Il-a is the molar equivalent of the free base weight of the compound. In some embodiments, the unit dosage form of Compound II or Compound Il-a is 0.92 mg, wherein the amount of Compound Il-a is the molar equivalent of the free base weight of the compound.

[0067] In some embodiments, Compound II, or a pharmaceutically acceptable salt thereof, (e.g., Compound Il-a), is administered in an oral dosage form. In some such embodiments, the oral dosage form is a tablet.

[0068] In some embodiments, abatacept is administered to the patient in a dose selected from Table 1. In some embodiments, abatacept is administered to the patient in a dose that is 10 mg/kg (per kg of patient body weight). In some embodiments, one or more doses of abatacept are administered on the same day. In some embodiments, an additional dose of abatacept is administered to the patient between 6 and 14 days after administration of an initial dose. In some embodiments, the additional dose and the initial dose are the same. In some embodiments, abatacept is administered to the patient on days 1, 15, and 28 of a 28-day cycle.

[0069] In some embodiments, Compound II, or a pharmaceutically acceptable salt thereof, (e.g., Compound Il-a), is administered once daily (QD).

[0070] In some embodiments, the patient has a disease or disorder associated with a coronavirus. In some such embodiments, the coronavirus is SARS-CoV-2. In some embodiments, the disease or disorder associated with SARS-CoV-2 is COVID-19.

[0071] In some embodiments, provided methods comprise administering one or more agents selected from Compound I or a pharmaceutically acceptable salt thereof (e.g., Compound I-a), Compound II or a pharmaceutically acceptable salt thereof (e.g., Compound Il-a), and abatacept. In some embodiments, provided methods comprise administering Compound I or a pharmaceutically acceptable salt thereof (e.g., Compound I-a) and Compound II or a pharmaceutically acceptable salt thereof (e.g., Compound Il-a. In some embodiments, provided methods comprise administering Compound I or a pharmaceutically acceptable salt thereof (e.g., Compound I-a) and abatacept. In some embodiments, provided methods comprise administering Compound II or a pharmaceutically acceptable salt thereof (e.g., Compound Il-a) and abatacept. In some embodiments, provided methods comprise administering Compound I or a pharmaceutically acceptable salt thereof (e.g., Compound I-a) and Compound II or a pharmaceutically acceptable salt thereof (e.g., Compound Il-a).

[0072] Exemplary embodiments.

[0073] Embodiment 1. A method of treating a respiratory disease in a patient, comprising administering to the patient an effective amount of Compound I: or a pharmaceutically acceptable salt or hydrate thereof.

[0074] Embodiment 2. The method of embodiment 1, wherein the respiratory disease is mediated by a coronavirus.

[0075] Embodiment 3. The method of embodiment 1 or 2, wherein the respiratory disease is mediated by SARS-CoV-2.

[0076] Embodiment 4. The method of any one of embodiments 1-3, wherein the respiratory disease is COVID-19.

[0077] Embodiment 5. The method of any one of embodiments 1-4, wherein the patient has previously tested positive for SARS-CoV-2.

[0078] Embodiment 6. The method of any one of embodiments 1-4, wherein the patient has previously been hospitalized due to complications associated with COVID-19. [0079] Embodiment 7. The method of any one of embodiments 1-6, wherein the patient is characterized by having one or more of the following more of the following: Sp02 < 93% on room air, Pa02/Fi02 < 300 mmHg without mechanical ventilation, respiratory rate > 30 per minute, or positive chest CT or X-ray for pneumonia.

[0080] Embodiment 8. The method of any one of embodiments 1-7, wherein the effective amount of Compound I, or a pharmaceutically acceptable salt or hydrate thereof, is from about 300 mg to about 400 mg, based on the free base weight of Compound I.

[0081] Embodiment 8a. The method of any one of embodiments 1-7, wherein the effective amount of Compound I, or a pharmaceutically acceptable salt or hydrate thereof, is from about 240 mg to about 520 mg, based on the free base weight of Compound I.

[0082] Embodiment 8b. The method of any one of embodiments 1-7, wherein the effective amount of Compound I, or a pharmaceutically acceptable salt or hydrate thereof, is about 400 mg, based on the free base weight of Compound I.

[0083] Embodiment 9. The method of any one of embodiments 1-8, wherein Compound

I, or a pharmaceutically acceptable salt or hydrate thereof, is administered once per day.

[0084] Embodiment 10. The method of any one of embodiments 1-9, wherein

Compound I, or a pharmaceutically acceptable salt or hydrate thereof, is administered once per day during a 28-day cycle.

[0085] Embodiment 11. The method of any one of embodiments 1-10 further comprising administering thiamine.

[0086] Embodiment 12. The method of any one of embodiments 1-11, wherein

Compound I is in the form of a dihydrochloride monohydrate.

[0087] Embodiment 13. A method of modulating one or more pro-inflammatory cytokines in a patient suffering from COVID-19, comprising administering to the patient an effective amount of Compound I:

or a pharmaceutically acceptable salt or hydrate thereof.

[0088] Embodiment 14. The method of embodiment 13, wherein the one or more pro- inflammatory cytokines are selected from one or more of TNFα, IP10, IL-6, IL-18, IL-IRA, RANTES/CCL5, and CRP.

[0089] Embodiment 15. A method of reducing coronavirus replication in a patient, comprising administering to the patient an effective amount of Compound I: or a pharmaceutically acceptable salt or hydrate thereof.

[0090] Embodiment 16. A method of inhibiting NFκB pathway activation in a patient suffering from COVID-19, comprising administering to the patient an effective amount of Compound I: or a pharmaceutically acceptable salt or hydrate thereof.

[0091] Embodiment 17. A method of inhibiting AAK1/GAK in a coronavirus, comprising administering an effective amount of Compound I: or a pharmaceutically acceptable salt or hydrate thereof.

[0092] Embodiment 18. The method of embodiment 17, wherein the coronavirus is

SARS-CoV-2.

[0093] Embodiment 19. A method of inhibiting one or more inflammatory cytokines in a patient suffering from COVID-19, comprising administering to the patient an effective amount of a JAK2 inhibitor.

[0094] Embodiment 20. The method of embodiment 19, wherein the JAK2 inhibitor is

Compound I: or a pharmaceutically acceptable salt or hydrate thereof. [0095] Embodiment 21. A method of treating a respiratory disease in a patient, comprising administering to the patient an effective amount of Compound II: or a pharmaceutically acceptable salt thereof.

[0096] Embodiment 22. The method of embodiment 21, wherein the respiratory disease is mediated by a coronavirus.

[0097] Embodiment 23. The method of embodiment 21 or 22, wherein the respiratory disease is mediated by SARS-CoV-2.

[0098] Embodiment 24. The method of any one of embodiments 21-23, wherein the respiratory disease is COVID-19.

[0099] Embodiment 25. The method of any one of embodiments 21-24, wherein the patient has previously tested positive for SARS-CoV-2.

[0100] Embodiment 26. The method of any one of embodiments 21-24, wherein the patient has previously been hospitalized due to complications associated with COVID-19.

[0101] Embodiment 27. The method of any one of embodiments 21-26, wherein the patient is characterized by having one or more of the following more of the following: Sp02 < 93% on room air, Pa02/Fi02 < 300 mmHg without mechanical ventilation, respiratory rate > 30 per minute, or positive chest CT or X-ray for pneumonia. [0102] Embodiment 28. The method of any one of embodiments 21-27, wherein the effective amount of Compound II, or a pharmaceutically acceptable salt thereof, is from about 0.23 to about 0.92 mg, based on the free base weight of the Compound II.

[0103] Embodiment 29. The method of any one of embodiments 21-28, wherein the effective amount of Compound II, or a pharmaceutically acceptable salt thereof, is about 0.92 mg, based on the free base weight of Compound II.

[0104] Embodiment 30. The method of any one of embodiments 21-29, wherein

Compound II, or a pharmaceutically acceptable salt thereof, is administered once per day.

[0105] Embodiment 31. The method of any one of embodiments 21-30, wherein

Compound II, or a pharmaceutically acceptable salt thereof, is administered once per day during a 28-day cycle.

[0106] Embodiment 32. The method of any one of embodiments 21-31, wherein

Compound II is in the form of a monohydrochloride salt.

[0107] Embodiment 33. A method of reducing cytokine activation in a patient suffering from COVID-19, comprising administering an effective amount of Compound II: or a pharmaceutically acceptable salt thereof.

[0108] Embodiment 34. The method of embodiment 33, wherein the cytokine is selected from one or more of IL-6, IL-8, and TNF. [0109] Embodiment 35. A method of reducing a lung inflammation in a patient suffering from COVID-19, comprising administering to the patient an effective amount of Compound II: or a pharmaceutically acceptable salt thereof.

[0110] Embodiment 36. A method of inhibiting inflammatory cytokines in a patient suffering from COVID-19, comprising administering to the patient an effective amount of a S1P1 inhibitor.

[0111] Embodiment 37. The method of embodiment 36, wherein the S1P1 inhibitor is

Compound II: or a pharmaceutically acceptable salt thereof.

[0112] Embodiment 38. A method of treating a respiratory disease in a patient, comprising administering to the patient an effective amount of a fusion protein comprising a human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) domain linked to a modified Fc portion of human immunoglobulin G1 (IgGl).

[0113] Embodiment 39. The method of embodiment 38, wherein the respiratory disease is mediated by a coronavirus.

[0114] Embodiment 40. The method of embodiment 38 or 39, wherein the respiratory disease is mediated by SARS-CoV-2.

[0115] Embodiment 41. The method of any one of embodiments 38-40, wherein the respiratory disease is COVID-19.

[0116] Embodiment 42. The method of any one of embodiments 38-41, wherein the patient has previously tested positive for SARS-CoV-2.

[0117] Embodiment 43. The method of any one of embodiments 38-42, wherein the patient has previously been hospitalized due to complications associated with COVID-19.

[0118] Embodiment 44. The method of any one of embodiments 38-43 wherein the patient is characterized by having one or more of the following more of the following: Sp02 < 93% on room air, Pa02/Fi02 < 300 mmHg without mechanical ventilation, respiratory rate > 30 per minute, or positive chest CT or X-ray for pneumonia.

[0119] Embodiment 45. The method of any one of embodiments 38-44, wherein the effective amount of the fusion protein comprising a human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) domain linked to a modified Fc portion of human immunoglobulin G1 (IgGl) is from about 50 mg to about 125 mg.

[0120] Embodiment 45a. The method of any one of embodiments 38-44, wherein the effective amount of the fusion protein comprising a human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) domain linked to a modified Fc portion of human immunoglobulin G1 (IgGl) is provided in Table 1. [0121] Embodiment 45b. The method of any one of embodiments 38-44, wherein the effective amount of the fusion protein comprising a human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) domain linked to a modified Fc portion of human immunoglobulin G1 (IgGl) is from about 500 mg to about 1000 mg.

[0122] Embodiment 45c. The method of any one of embodiments 38-44, wherein the effective amount of the fusion protein comprising a human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) domain linked to a modified Fc portion of human immunoglobulin G1 (IgGl) is about 10 mg/kg, based on the body weight in kg of the patient.

[0123] Embodiment 46. The method of any one of embodiments 38-45, wherein the effective amount of the fusion protein comprising a human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) domain linked to a modified Fc portion of human immunoglobulin G1 (IgGl) is administered once per week.

[0124] Embodiment 46a. The method of any one of embodiments 38-45, wherein the effective amount of the fusion protein comprising a human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) domain linked to a modified Fc portion of human immunoglobulin G1 (IgGl) is administered on day 1, day 15, and day 28 of a 28-day cycle.

[0125] Embodiment 47. The method of any one of embodiments 38-46, wherein the fusion protein is abatacept.

[0126] Embodiment 48. A method of reducing a cytokine activation in a patient suffering from COVID-19, comprising administering to the patient an effective amount of a fusion protein comprising a human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) domain linked to a modified Fc portion of human immunoglobulin G1 (IgGl).

[0127] Embodiment 49. A method of inhibiting T-cell activation in a patient suffering from COVID-19, comprising administering to the patient an effective amount of a fusion protein comprising a human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) domain linked to a modified Fc portion of human immunoglobulin G1 (IgGl).

[0128] Embodiment 50. A method of treating a respiratory disease in a patient, comprising administering to the patient an effective amount of one or more therapies selected from: a compound of formula I: or a pharmaceutically acceptable salt or hydrate thereof; a compound of formula II: or a pharmaceutically acceptable salt thereof; and/or a fusion protein comprising a human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) domain linked to a modified Fc portion of human immunoglobulin G1 (IgGl).

[0129] Embodiment 50a. A method of treating a respiratory disease in a patient, comprising administering to the patient an effective amount of one or more therapies selected from: a compound of formula I-a:

a compound of formula Il-a: and/or a fusion protein comprising a human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) domain linked to a modified Fc portion of human immunoglobulin G1 (IgGl).

[0130] Embodiment 51. The method of embodiment 50, wherein the respiratory disease is mediated by a coronavirus.

[0131] Embodiment 52. The method of embodiment 50 or 51, wherein the respiratory disease is mediated by SARS-CoV-2.

[0132] Embodiment 53. The method of any one of embodiments 50-52, wherein the respiratory disease is COVID-19.

[0133] Embodiment 54. The method of any one of embodiments 50-53, wherein the patient has previously tested positive for SARS-CoV-2. [0134] Embodiment 55. The method of any one of embodiments 50-54, wherein the patient has previously been hospitalized due to complications associated with COVID-19.

[0135] Embodiment 56. The method of any one of embodiments 50-55, wherein the patient is characterized by having one or more of the following more of the following: Sp02 < 93% on room air, Pa02/Fi02 < 300 mmHg without mechanical ventilation, respiratory rate > 30 per minute, or positive chest CT or X-ray for pneumonia.

[0136] Embodiment 57. The method of any one of embodiments 50-56 wherein one or more therapies is administered once per day.

[0137] Embodiment 58. The method of any one of embodiments 50-56 wherein one or more therapies is administered once per week.

[0138] Embodiment 59. The method of any one of embodiments 50-58, further comprising administering an additional agent selected from chloroquine, hydroxychloroquine, azithromycin, lopinavir, ritonavir, lopinavir, ritonavir, favipiravir, avifavir, interferon-beta, corticosteroids (e.g., dexamethasone, (prednisone, methylprednisolone), NSAIDs (e.g., ibuprofen, aspirin), acetaminophen, vitamin C, vitamin D, baricitinib, convalescent plasma (from patients who have recovered from COVD-19), REGN10933 antibody, REGN10987 antibody, LY-CoV555 antibody, VIR-7831 antibody, VIR-7832 antibody, ABX464, tocilizumab, and combinations thereof.

[0139] Each of the references listed herein is hereby incorporated by reference in its entirety.

EXAMPLES

Example 1.

[0140] Protocol Summary. The study will enroll patients to receive a compound disclosed herein (e.g., fedratinib (Compound I-a), ozanimod (Compound Il-a), or abatacept) in addition to standard of care (SOC). The study population will consist of subject who are 18 years of age or older with laboratory (RT-PCR) confirmed infection with SARS-CoV-2, and who are hospitalized with moderate to severe symptoms including one or more of the following: Sp02 < 93% on room air, Pa02/Fi02 < 300 mmHg but not requiring mechanical ventilation, respiratory rate > 30 per minute, or positive chest CT or X-ray for pneumonia. Safety and preliminary efficacy will be assessed based on subjects enrolled with treatment for 14 days, and 7-day and 28-day follow-up visits. The primary endpoint will be determination of the proportion of subjects admitted to intensive care unit, mechanical ventilation, sepsis, organ failure, or death due to COVID-19 related disease.

[0141] Objectives. The primary objective of the study is to evaluate the efficacy of a study compound (e.g., fedratinib (Compound I-a), ozanimod (Compound Il-a), or abatacept) in reducing the percentage of hospitalized patients requiring critical care and/or mechanical ventilation. The secondary objectives are:

• National Early Warning Score (NEWS) 2

• Frequency of respiratory progression characterized by increased oxygen requirement or more advanced ventilator support.

• Frequency and duration of SARS-CoV-2 viral shedding in upper respiratory tract specimen

• Safety of fedratinib in adult patients with COVID-19 respiratory disease

• Frequency of serious adverse events

• All cause mortality

• Time to discharge

• Modulation of biomarkers associated with COVID-19 disease progression (e.g., Cardiac Troponin, CPK, CRP, Ferritin, LDH, TNFa, IL-6, D-dimer, IL-6, TNFa, IFN-gamma, phospho-STAT3)

[0142] The exploratory objectives are:

• To evaluate the reduction in and/or clearance of SARS-CoV-2

• To evaluate the pharmacodynamics as measured by changes in JAK-STAT pathway phosphorylation and expression of downstream immunomodulatory and/or inflammatory cytokines (for fedratinib (Compound I-a) treated patients)

• To evaluate molecular and cellular biomarkers which may be prognostic and/or predictive of response including but not limited to: - Flow cytometry for immune cell profiling

Genetic sequencing for predisposition variants including clonal hematopoiesis

[0143] Study Endpoints are summarized in Table 2.

TABLE 2 [0144] Study Desisn. This is an open label, multicenter randomized trial to evaluate the efficacy and safety of Fedratinib in moderate to severe symptomatic hospitalized patients with COVID-19 respiratory disease. The study consists of two phases: Part 1 Single Arm phase and Part 2 Randomization phase.

[0145] Part 1: Single Arm Phase. Eligible subjects will be enrolled to receive study drug plus SOC. The safety and preliminary efficacy will be assessed based on subjects enrolled with treatment for 14 days, and 7-day and 28-day follow-up visits. The data collected from this phase will be reviewed for recommendation to move into Part 2.

[0146] Part 2: Randomization Phase. Eligible subjects will be randomized 1:1 to receive study drug plus SOC or SOC. Safety and efficacy will be assessed for 14 days, and 7-day and 28-day follow-up visits.

[0147] Study Population / Estimated No. Patients. Study population consist of subjects 18 years of age or older with laboratory (RT-PCR) confirmed infection with SARS- CoV-2 who are hospitalized with moderate to severe symptoms including one or more of the following: Sp02 < 93% on room air; Pa02/Fi02 < 300 mmHg but not requiring mechanical ventilation; Respiratory Rate > 30 per minute; or Positive Chest CT or X-ray for pneumonia. Approximately 125 subjects will be enrolled: 25 subjects will be enrolled in Part 1 single arm phase and 100 subjects in Part 2 randomization phase.

[0148] Inclusion Criteria. Subjects must satisfy the following criteria to be enrolled in the study:

1. Subject is at least 18 years of age at the time of signing the informed consent form (ICF)

2. Is willing and able to adhere to the study visit schedule and other protocol requirements.

3. Confirmed RT-PCR positive for SARS-CoV-2 within 14 days prior to treatment

4. Hospitalized with one or more of the following: a. P02 < 93% on room air, b. Pa02/Fi02 < 300 mmHg but not requiring mechanical ventilation, c. Respiratory Rate > 30, d. Positive CT or Chest X-ray for pneumonia. 5. Subject must understand and voluntarily sign an ICF prior to any study -related assessments/procedures being conducted.

6. Subject is willing and able to adhere to the study visit schedule and other protocol requirements

7. A female of childbearing potential (FCBP) must: a. Have a negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the subject practices true abstinence* from heterosexual contact. b. Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with highly effective contraception** without interruption, prior to starting investigational product, during the study therapy (including dose interruptions), and for 30 days after discontinuation of study therapy.

Note: A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

8. Male subjects must: a. Practice true abstinence* (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 30 days following investigational product discontinuation, or longer if required for each compound and/or by local regulations, even if he has undergone a successful vasectomy.

* True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post ovulation methods) and withdrawal are not acceptable methods of contraception]

** Agreement to use highly effective methods of contraception that alone or in combination result in a failure rate of a Pearl index of less than 1% per year when used consistently and correctly throughout the course of the study. Such methods include: Combined (estrogen and progestogen containing) hormonal contraception: Oral; Intravaginal; Transdermal; Progestogen-only hormonal contraception associated with inhibition of ovulation: Oral; Injectable hormonal contraception; Implantable hormonal contraception; Placement of an intrauterine device; Placement of an intrauterine hormone-releasing system; Bilateral tubal occlusion; Vasectomized partner.

[0149] Exclusion Criteria. The presence of any of the following will exclude a subject from enrollment: 1. Any of the following laboratory abnormalities: a. Platelets < 50,000/μL b. Absolute neutrophil count (ANC) < 1.0 x 10 ⁹ /L c. Estimated glomerular filtration rate < 30 mL/min/1.73 m ² (as per the Modification of Diet in Renal Disease [MDRD] formula) d. Serum amylase or lipase > 1.5 x ULN (upper limit of normal)

2. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x ULN

3. Subject with previous exposure to Janus kinase (JAK) inhibitor(s) within 30 days prior to study treatment (for patients receiving fedratinib (Compound I-a))

4. Subject is pregnant or lactating female

5. Subject with prior history of encephalopathy, including Wernicke’s (for patients receiving fedratinib (Compound I-a))

6. Subject with signs or symptoms of encephalopathy including Wernicke’s (e.g., severe ataxia, ocular paralysis or cerebellar signs) (for patients receiving fedratinib (Compound I-a))

7. Subject with concomitant treatment with or use of pharmaceutical, herbal agents or food known to be strong or moderate inducers of Cytochrome P450 3 A4 (CYP3 A4), or dual CYP2C19 and CYP3A4 inhibitors (for patients receiving fedratinib (Compound I-a))

8. Subject with uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4)

9. Subject with presence of any significant gastric or other disorder that would inhibit absorption of oral medication

10. Subject is unable to swallow capsule

11. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.

12. Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.

13. Subject has any condition that confounds the ability to interpret data from the study.

[0150] For subjects assigned to fedratinib (Compound I-a):

[0151] Subjects will receive oral thiamine supplementation 100 mg daily and continue throughout the study period. Subjects will receive daily prophylaxis for nausea and vomiting.

[0152] The fedratinib (Compound I-a) dose in this study is 400 mg/day. If a subject experience a Grade 3 drug related toxicity (except Grade > 3 AST, ALT, total bilirubin, or renal insufficiency; Grade > 2 peripheral neuropathies), then fedratinib dose may be reduced to 300 mg at the discretion of the treating physician.

[0153] The following are specific examples of fedratinib (Compound I-a) stopping criteria:

1. Subject is no longer able to take medication by mouth

2. Hematological a. Grade 4 or Grade 3 thrombocytopenia with major bleeding b. Grade 4 neutropenia

3. Non-hematological a. Drug-related nonhematological Grade 4 or unmanageable Grade 3 toxicity b. Grade > 3 AST, ALT, or total bilirubin c. Grade > 3 renal insufficiency d. Grade > 2 peripheral neuropathy e. Grade > 2 nausea, vomiting, diarrhea, or constipation that does not respond to adequate therapeutic or supportive measures within 48 hours

[0154] All subjects will be monitored for adverse events during the study. All subjects discontinued from protocol-prescribed therapy for any reason will be followed for a period of 30 days following the last dose of study drug to collect safety data.

[0155] Overview of Efficacy Assessments:

• Vital Signs including pulse oximetry

• NEWS 2 Scoring System

• Biomarkers (Cardiac Troponin, CPK, CRP, D-dimer, Ferritin, IL-6, LDH)

• Viral load,

• CXR and/or CT Chest

[0156] Overview of Safety Assessments:

• Vitals

• TEAE and SAE

Safety Labs (Chemistry, Hematology, etc.) Example 2.

[0157] Protocol Summary. The study will enroll patients to receive a fedratinib in addition to standard of care (SOC). The study population will consist of subject who are 18 years of age or older with laboratory (RT-PCR) confirmed infection with SARS-CoV-2, and who are hospitalized with moderate to severe symptoms including one or more of the following:

Sp02 < 93% on room air, Pa02/Fi02 < 300 mmHg but not requiring mechanical ventilation, respiratory rate > 30 per minute, or positive chest CT or X-ray for pneumonia. Safety and preliminary efficacy will be assessed based on subjects enrolled with treatment for 14 days, and 7-day and 28-day follow-up visits. The primary endpoint will be determination of the proportion of subjects admitted to intensive care unit, mechanical ventilation, sepsis, organ failure, suffer respiratory failure, or death due to COVID-19 related disease.

[0158] Objectives. The primary objective of the study is to evaluate the efficacy of fedratinib and standard of care (SOC) in reducing the percentage of hospitalized patients requiring critical care and/or mechanical ventilation. The secondary objectives are to evaluate:

• Clinical status assessment using the 8-point ordinal scale

• National Early Warning Score (NEWS) 2

• Frequency of respiratory progression characterized by increased oxygen requirement or more advanced ventilator support.

• Frequency and duration of SARS-CoV-2 viral shedding in upper respiratory tract specimen

• Safety of fedratinib in adult patients with COVID-19 respiratory disease

• Frequency of serious adverse events

• All-cause mortality

• Modulation of biomarkers associated with COVID-19 disease progression (e.g., Cardiac Troponin, CPK, CRP, Ferritin, TNFa, IL-6, LDH, and D-dimer)

[0159] The exploratory objectives are:

• To evaluate the reduction in and/or clearance of SARS-CoV-2 viral titers and production of anti-SARS-CoV-2 antibodies • To evaluate the pharmacodynamics as measured by changes in JAK-STAT pathway phosphorylation and expression of downstream immunomodulatory and/or inflammatory cytokines (for fedratinib (Compound I-a) treated patients)

• To evaluate molecular and cellular biomarkers which may be prognostic and/or predictive of response including but not limited to:

- Flow cytometry for immune cell profiling

- Genetic sequencing for predisposition variants including clonal hematopoiesis

- Expression and activation of cellular proteins involved in viral entry and replication

[0160] Study Endpoints are summarized in Table 3.

TABLE 3

[0161] Study Desisn. This is an open-label, multicenter trial to evaluate the efficacy and safety of fedratinib in symptomatic hospitalized patients with COVID-19 respiratory disease.

The study consists of two phases: Part 1 Single Arm Phase and Part 2 Randomized Phase. Eligible subjects are hospitalized with a documented positive SARS-CoV-2 infection but not requiring invasive mechanical ventilation as well as one or more of the following respiratory parameters: peripheral oxygen saturation (Sp02) < 93% on room air; partial pressure of oxygen / fraction of inspired oxygen (Pa02/Fi02) < 300 mmHg based on available arterial blood gas (ABG) analysis; respiratory rate > 24 breaths per minute; or positive chest x-ray or computed tomography (CT) for pneumonia.

[0162] Part 1: Single Arm Phase. Eligible subjects (N = approximately 30) will be enrolled to receive study drug plus SOC. The safety and preliminary efficacy will be assessed based on subjects enrolled with treatment for 14 days with treatment follow-up (Day 21, about 7 days post-last does of treatment) and safety follow up (Day 44, about 30 days post-last dose of treatment) visits. The data collected from this phase will be reviewed for recommendation to move into Part 2.

[0163] Part 2: Randomization Phase. Eligible subjects (N= 100, 50 in each arm) will be randomized 1 : 1 to receive study drug plus SOC or SOC alone. Subjects will be stratified by age (< 60 versus > 60 years of age) and NEWS2 score (< 5 versus > 5). Safety and efficacy will be assessed for 14 days with treatment follow-up (Day 21, ~7 days post-treatment) and safety follow-up (Day 44, ~30 days post-treatment) visits.

[0164] Study Treatments. Fedratinib will be administered as 400 mg/day orally (4 x

100 mg capsules) for up to 14 days during the inpatient stay given at the same time each day, preferably in the evening with a meal. However, fedratinib may be taken with or without regard to food. A flexible dose modification regimen may be employed to minimize drug toxicity for individual subjects, with possible daily doses of 200 mg, 300 mg, or 400 mg. Treatment with fedratinib should be discontinued for Common Terminology Criteria for Adverse Events (CTCAE) Grade 4 or Grade 3 adverse events.

[0165] Study Population. Study population consist of subjects 18 years of age or older with laboratory (RT-PCR) confirmed infection with SARS-CoV-2 who are hospitalized with moderate to severe symptoms including one or more of the following: Sp02 < 93% on room air; Pa02/Fi02 < 300 mmHg but not requiring mechanical ventilation; Respiratory Rate > 30 per minute; or Positive Chest CT or X-ray for pneumonia. Approximately 125 subjects will be enrolled: 25 subjects will be enrolled in Part 1 single arm phase and 100 subjects in Part 2 randomization phase.

[0166] Inclusion Criteria. Subjects must satisfy the following criteria to be enrolled in the study:

1. Subject is at least 18 years of age at the time of signing the informed consent form (ICF)

2. Subject is confirmed positive for SARS-CoV-2 for not more than 14 days prior to enrollment

3. Subject is hospitalized, but not requiring invasive mechanical ventilation, with one or more of the following: a. Sp02 < 93% on room air, b. Pa02/Fi02 < 300 mmHg based on available ABG analysis, c. Respiratory Rate > 24 breaths per minute, d. Positive chest X-ray or CT for pneumonia within 3 days prior to enrollment (Part 1) or randomization (Part 2).

4. Subject must understand and voluntarily sign an ICF prior to any study -related assessments/procedures being conducted.

5. Subject is willing and able to adhere to the study visit schedule and other protocol requirements

6. A female of childbearing potential (FCBP) must: a. Have a negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the subject practices true abstinence* from heterosexual contact. b. Either commit to true abstinence* from heterosexual contact (source documented) or agree to use, and be able to comply with highly effective contraception** without interruption, prior to starting investigational product, during the study therapy (including dose interruptions), and for 30 days after discontinuation of study therapy.

Note: A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

7. Male subjects must: a. Practice true abstinence* or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 30 days following investigational product discontinuation, or longer if required for each compound and/or by local regulations, even if he has undergone a successful vasectomy.

* True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception],

** Agreement to use highly effective methods of contraception that alone or in combination result in a failure rate of a Pearl index of less than 1% per year when used consistently and correctly throughout the course of the study. Such methods include: Combined (estrogen and progestogen containing) hormonal contraception: Oral; Intravaginal; Transdermal; Progestogen-only hormonal contraception associated with inhibition of ovulation: Oral; Injectable hormonal contraception; Implantable hormonal contraception; Placement of an intrauterine device; Placement of an intrauterine hormone-releasing system; Bilateral tubal occlusion; Vasectomized partner.

[0167] Exclusion Criteria. The presence of any of the following will exclude a subject from enrollment:

1. Any of the following laboratory abnormalities: a. Platelet count < 50,000/μL b. Absolute neutrophil count (ANC) < 1.0 x 10 ⁹ /μL c. Creatine clearance < 30 mL/min per Cockcroft-Gault formula) d. Serum amylase or lipase > 1.5 x upper limit of normal (ULN) e. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x ULN

2. Subject has been hospitalized due to COVID-19 for more than 5 days.

3. Subject with previous exposure to Janus kinase (JAK) inhibitor(s) within 30 days prior to study treatment

4. Subject is receiving an anti-IL-6 treatment

5. Subject is currently participating in another clinical study or was previously participating in a clinical study within the last 30 days (or 5 half-lives) using an investigational agent or experimental therapeutic devices.

6. Subject is pregnant or lactating female

7. Subject with prior history of encephalopathy, including Wernicke’s

8. Subject with signs or symptoms of encephalopathy including Wernicke’s (e.g., severe ataxia, ocular paralysis or cerebellar signs)

9. Subject with concomitant treatment with or use of pharmaceutical, herbal agents or food known to be strong or moderate inducers of Cytochrome P450 3 A4 (CYP3 A4), or dual CYP2C19 and CYP3A4 inhibitors 10. Subject with uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4)

11. Subject with presence of any significant gastric or other disorder that would inhibit absorption of oral medication

12. Subject is unable to swallow capsule

13. Subject with a history of hypersensitivity to fedratinib or its excipients.

14. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.

15. Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.

16. Subject has any condition that confounds the ability to interpret data from the study.

[0168] Subjects will receive oral thiamine supplementation 100 mg daily and continue throughout the study period. Subjects will receive daily prophylaxis for nausea and vomiting.

[0169] The fedratinib dose in this study is 400 mg/day. If a subject experiences a Grade 3 drug related toxicity (except Grade > 3 AST, ALT, total bilirubin, or renal insufficiency; Grade > 2 peripheral neuropathies), then fedratinib dose may be reduced to 300 mg at the discretion of the treating physician.

[0170] The following are specific examples of stopping criteria:

1. Subject is no longer able to take medication by mouth

2. Hematological c. Grade 4 or Grade 3 thrombocytopenia with major bleeding d. Grade 4 neutropenia

3. Non-hematological f. Drug-related nonhematological Grade 4 or unmanageable Grade 3 toxicity g. Grade > 3 AST, ALT, or total bilirubin h. Grade > 3 renal insufficiency i. Grade > 2 peripheral neuropathy j. Grade > 2 nausea, vomiting, diarrhea, or constipation that does not respond to adequate therapeutic or supportive measures within 48 hours [0171] The most common adverse events associated with fedratinib are hematological and gastrointestinal events. Hematological adverse events associated with JAK2 inhibitors are dose dependent and mechanism-based.

[0172] For Grade 2 nausea, vomiting, or diarrhea, hold fedratinib up to 2 days and restart when the event resolves to < Grade 1.

[0173] For Grade 3 and 4 nausea, vomiting, or diarrhea, hold fedratinib up to 2 days and restart when the event resolves to < Grade 1 at one dose level decrement (100 mg daily decrease).

[0174] Treatment with fedratinib should be discontinued for Common Terminology

Criteria for Adverse Events (CTCAE) Grade 3 or Grade 4 adverse events that are attributed to fedratinib or cannot be attributed by the Investigator to an identifiable cause such as underlying illness or disease progression, other concurrent illness, or concomitant medication such as:

• Grade 3 thrombocytopenia with major bleeding or Grade 4 thrombocytopenia

• Grade 4 neutropenia

• Grade 3 or 4 AST, ALT, or total bilirubin increases

• Other Grade 3 and 4 non-hematologic toxicities

[0175] Overview on Management of Gastrointestinal Adverse Events (Fedratinib).

Gastrointestinal adverse events, specifically nausea, vomiting and diarrhea, are commonly associated with fedratinib treatment and require multifaceted management using dose adjustment, active treatment or prophylaxis with anti-emetics, and monitoring.

[0176] Management of Nausea and Vomiting. Subject management of nausea and vomiting during treatment with fedratinib will be done according to the following steps:

• In order to mitigate for nausea and vomiting events, it is recommended to take fedratinib with food during an evening meal.

• Anti-nausea/vomiting treatment given prophylactically according to local practice (e.g., ondansetron or other 5-HT3 antagonists) is to be administered for all subjects assigned to fedratinib and must be administered before the first fedratinib dose. • Hold/reduce the dose of fedratinib according to guidance above for Grades 2, 3, and 4 events of nausea, vomiting, or diarrhea.

• In case the subject is discharged from the hospital during fedratinib treatment, the subject will be instructed to contact the study site in case nausea/vomiting occurs and provisions will be made so that the subject can continue anti-nausea/vomiting prophylaxis in an outpatient setting.

[0177] Management of Diarrhea. Management of diarrhea during treatment with fedratinib will be done according to the following steps:

• Loperamide should be administered as soon as the subject experiences any grade diarrhea.

• Loperamide should not be administered prophylactically as fedratinib is also associated with constipation.

• Treat with loperamide as per local practice at the onset of diarrhea. Consider starting loperamide at a 4 mg loading dose and then 2 mg after each diarrheal bowel movement without exceeding 16 mg/24 hours.

• Dietary modifications including adequate hydration, avoidance of lactose containing foods and alcohol, small meals with rice, bananas, bread, etc.

• Hold/reduce the dose of fedratinib according to guidance above for severe events of diarrhea.

• In case the subject is discharged from the hospital during fedratinib treatment, the subject will be instructed on the management of diarrhea and to contact the study site in case diarrhea occurs and provisions will be made that the subject has loperamide available as an outpatient.

[0178] Management of Encephalopathy, Including Wernicke’s (Fedratinib). A potential case of encephalopathy, including Wernicke’s, is a medical emergency. Management of potential cases during treatment with fedratinib will be done according to the following steps. In case of signs or symptoms that may indicate encephalopathy including Wernicke’s:

• Discontinue fedratinib, • Obtain sample for thiamine level assessment,

• Empirically start intravenous (IV) thiamine, see Section [0179] below for details,

• Report the event as an AESI to the Sponsor,

• Obtain a neurological consult,

• Perform a brain magnetic resonance imaging (MRI),

• If WE is ruled out, assess for other causes of encephalopathy and treat accordingly.

[0179] Thiamine Monitoring and Correction. All subjects will receive thiamine supplementation of at least 100 mg/daily orally over the course of the study to be started before the first dose of fedratinib and ongoing while on study.

• Thiamine levels are assessed at screening, Day 1 and Day 21.

• In case the subject is discharged from the hospital during fedratinib treatment, they will continue thiamine supplementation for the duration of the study in an outpatient setting.

• For thiamine levels < 30 nM/L with or without signs or symptoms of WE:

• Immediate treatment with thiamine (preferably IV) at therapeutic dosages (e.g., 500 mg infused over 30 minutes 3 times daily for 2 to 3 days or alternatively intramuscular (IM) in equivalent doses accordingly to local standard of care);

• Report the event as an AESI to the Sponsor;

• This will be followed by 250 mg to 500 mg IV thiamine infused once a day for 3 to 5 days or alternatively IM in equivalent doses accordingly to local standard of care;

• And then continue at an oral minimum daily dose of 100 mg thiamine for at least until Day 44 even after the subject has discontinued from the study;

• Fedratinib will be discontinued.

• Thiamine supplementation should be administered as a thiamine only formulation.

• If thiamine levels are low, ensure that magnesium levels are normal or corrected if low. • Continue supplementation until thiamine levels are restored to the normal range and the subject has adequate oral intake to support dietary needs.

[0180] All subjects will be monitored for adverse events during the study. All subjects discontinued from protocol-prescribed therapy for any reason will be followed for a period of 30 days following the last dose of study drug to collect safety data.

[0181] Pre-dose samples of peripheral blood, serum, buccal swabs, and nasopharyngeal swabs for pharmacodynamic assessments and exploratory analyses, as described in Section 6.1, will be collected in subjects of all study phases and treatment arms who consent to their collection. Peripheral blood and serum will be collected at screening and/or Day 1 of study treatment, whenever blood samples are collected for assessing disease status throughout treatment, at the end of treatment, and at follow-up as applicable (Table 3). Nasopharyngeal and buccal swabs will only be collected at screening and/or Day 1 of treatment, Day 5, Day 15, and Day 21.

[0182] Samples may be collected and processed as multiple samples to allow for the described and future retrospective analyses. One PK blood sample will be collected in subjects assigned to fedratinib treatment at each of the visits on Days 3, 5, 8, 12, and 15; independent from fedratinib dosing.

[0183] The date/time when subjects took their previous dose of fedratinib, date/time of fedratinib dosing on the day of clinical visit, and the date/time that blood is collected must be recorded in the eCRF. Explanation should be provided in the source documents and eCRF for any missed or mishandled samples.

[0184] Approximately 3 mL of whole blood will be drawn through an indwelling venous cannula or by venipuncture. Detailed instructions for sample collection, processing, storage, shipping and handling will be contained in a separate laboratory manual provided to the sites.

[0185] Overview of Efficacy Assessments: Safety of fedratinib is evaluated based on the incidence of treatment-emergent adverse events (TEAEs) and changes in clinical laboratory parameters and vital signs. Safety assessments will be comprised of:

• Record of adverse events (AEs) and serious adverse events (SAEs) at each study visit

• Physical examination • Vital signs

• Oxygen supplementation

• Chest x-ray or CT

• Laboratory assessments: hematology, serum chemistry, thiamine level, coagulation, urinalysis, serum/urine pregnancy tests

• Electrocardiogram (ECG)

[0186] NEWS2 Scoring System. The NEWS2 is an aggregate scoring system in which a score is allocated to physiological measurements already recorded in routine practice when patients present to or are being monitored in hospital. Six simple physiological parameters form the basis of the scoring system:

1. respiration rate,

2. oxygen saturation,

3. systolic blood pressure,

4. pulse rate,

5. level of consciousness or new confusion,

6. temperature.

[0187] The NEWS2 will be assessed along with the daily assessments at approximately the same time each day, with each parameter being scored and the cumulative result indicating the clinical risk and urgency of response required, which will be entered into the appropriate eCRF.

[0188] Standard of care therapy for COVID-19 is currently evolving and will follow emerging guidance documents (e.g., the “Clinical management of severe acute respiratory infection (SARI) when COVID-19 is suspected” interim guidance from the WHO [13 March 2020] and local institutional guidelines) (World Health Organization, 2020). Drug therapy of respiratory compromised patients may include, but is not limited to, antivirals, hydroxychloroquine, antibiotics, or supporting agents. Example 3.

[0189] Background. Abatacept is a recombinant fusion protein (MW 92 kDa) consisting of the extracellular domain of human CTLA4 and a fragment (hinge - CH2 - CH3 domains) of the Fc domain of human immunoglobulin (Ig) GI that has been modified to prevent complement fixation and antibody-dependent cellular cytotoxicity. Abatacept is a selective costimulation modulator that inhibits T-cell activation by binding to CD80 and CD86 on antigen presenting cells, thereby blocking the interaction with CD28 on T-cells that provides a costimulatory signal necessary for full activation of T-cells. By inhibiting CD28 mediated T-cell activation upstream of inflammatory cytokines, such as TNF, abatacept utilizes a unique mechanism of action that offers significant therapeutic benefit to patients with a variety autoimmune-mediated diseases. Abatacept, 250 mg for intravenous (IV) infusion, is indicated to treat subjects with rheumatoid arthritis (RA) age 18 and older and subjects with polyarticular juvenile idiopathic arthritis (pJIA) age 6 to 17.

[0190] Abatacept was studied in the setting of a pathological response to a viral infection in a murine model of influenza. This study examines whether abatacept will prevent development of severe lung injury while not inhibiting an effective memory antiviral response in the setting of secondary infection. CTLA-4 is central to the regulation of T cell activation, CTLA-4Ig clearly has effect on other cell types. Since CTLA-4 regulates interactions with T cells and professional antigen presenting cells (APC), it is not surprising that effects on APC populations (i.e. dendritic cells, macrophages, B cells) can also be seen, in vitro and clinically. Indeed, in vitro work has demonstrated reverse signaling via CD80 or CD86 in APCs although the full impact of this may not be fully understood.

[0191] Treatment with abatacept has also been shown to have broad effects on cytokines in rheumatoid arthritis (RA) patients. Abatacept shows an impact within 24 hours in human in vitro mixed-lymphocyte reactions (MLR) on IL-2, TNF-a, and IFN-g. In vivo, abatacept reduces the levels of multiple cytokines in RA patients including TNF-a, sIL-2R and IL-6. In addition, abatacept suppresses multiple biomarkers (cytokines and chemokines) in the synovium from RA patients.

[0192] The best evidence for abatacept’ s direct effects on APCs comes from reports on both in vitro and in vivo effects on macrophages and B cells. Abatacept inhibits pro- inflammatory cytokine (TNFa, IL-12, INF-g) secretion by in vitro activated human macrophages. Abatacept can also downregulate production of IL-6, TNFa, ILl-b and TGFp from activated synovial macrophages from RA patients. B cell populations are notably decreased in RA synovium of abatacept-treated patients.

[0193] The FDA has recently proposed an example for scheme for classifying the severity of COVID-19 disease. This classification is based on positive RT-PCR, symptoms, vital signs and respiratory or other organ compromise and ranges from infection with no symptoms to critical disease. In this example, severe disease is primarily defined by the inability to maintain an Sp02 > 93% on room air at sea level and critical disease by reliance on oxygen supplementation devices with greater oxygen delivery capacity than low flow nasal cannula.

[0194] Protocol Summary. The present example provides a randomized, double-blind placebo controlled study of intravenous (IV) abatacept for the purpose of efficacy and safety signal detection. Participants (> 18 years of age) will be those with confirmed COVID-19 disease who are hospitalized (or in the Emergency Department awaiting hospitalization) with respiratory compromise requiring supplemental oxygen but not requiring ventilatory support. Participants will be assessed for clinical responses to abatacept for 28 days and monitored for safety and some efficacy outcomes for a total of 60 days.

[0195] Objectives. The primary, secondary, and exploratory objectives and endpoints are provided in the following table:

Abbreviations: CRP = C-Reactive Protein; HR = heart rate; IgG = immunoglobulin G; IgM = immunoglobulin M; IL-6 = interleukin-6; LDH = lactate dehydrogenase; : RT-qPCR = Reverse- transcription quantitative polymerase chain reaction; SAE = serious adverse event; BP = blood pressure.

[0196] The study will include 129 randomized subjects in a 2:1 ratio, abatacept: placebo, both on standard of care. There will be 2 treatment arms, abatacept plus standard of care versus placebo plus standard of care. Both arms will last for 60 days with a primary endpoint at Day 28. The study treatment comprises Abatacept 10 mg/kg IV, reconstitutes in 100 mL of an appropriate diluent and administered over 30 minutes. The minimum total dose will be 500 mg and the maximum total dose will be 30 minutes. The minimum total dose will be 500 mg and the maximum total dose will be 1000 mg.

[0197] Screening Period. Eligibility will be based on specified inclusion and exclusion criteria, medical history, disease activity, and safety assessments. Screening and randomization must be completed within 48 hours of signing the informed consent form. Screening will include testing for viral hepatitis but the decision to randomize will not be based on review of these screening labs. Participants that are randomized to abatacept and experience a secondary infection, serious medical complication or require mechanical ventilation prior to study drug infusion should not receive any study drug infusion but remain in the trial and complete all other study procedures.

[0198] Double-blind Treatment Period, Days 1-28. On Day 1, eligible participants will be randomized to receive an intravenous (IV) infusion of abatacept or placebo. Randomization will be on a 2: 1 ratio, abatacept vs placebo, both with standard of care. In some embodiments, a dose of abatacept is administered to a patient in need thereof in an amount of about 10 mg/kg. In some embodiments, on Day 1, a second dose is administered to the patient in need thereof in an amount of about 10 mg/kg.

[0199] Participants will receive medical care following local standards. Daily progress will be recorded in the study record as required. Participants who, in the opinion of the treating physician, require immunotherapy rescue (e.g., tocilizumab) should continue to complete treatment period and post-treatment follow-up observation.

[0200] Post-Treatment Follow-up Period, Days 29-60. Participants who complete the

28 day double-blind treatment period will be monitored for study endpoints and will have follow-up information captured on Days 35, 42, 49 and 60, to perform safety and clinical status assessments. If routine safety labs are performed in this period, they should also be captured in the study record. Medical care in this period will also follow local standards and there will be no restrictions on treatment choices.

[0201] Post hospitalization. Participants who are discharged from hospital care at any point before the end of this 60-day period will have remote follow-up visits. Post-hospital care is not considered part of this trial but outcomes up to 60 days are of interest. Participants who are discharged, whether home or to any form of assisted care facility, will be contacted remotely by the study team (e.g. phone, e-mail) to ascertain clinical status, weekly until Day 60. As a rule, remote contact should be performed approximately every 7 days. If the participants is discharged prior to Day 28, one of the remote contacts should be on Day 28 (± 2 days) to coincide with the study primary endpoint. If discharge occurs after Day 28, remote contacts should occur as close as possible to study Days 35, 42, 49, and 60, at approximately 7 day intervals. Level of activity (i.e. ambulatory status), oxygen requirement (e.g., home oxygen therapy), current location (e.g. home) and any intercurrent adverse event (e.g., infection) will be assessed and added to the study record.

[0202] Study Population (Inclusion Criteria). For entry into the study, the following criteria must be met:

[0203] 1) Signed Written Informed Consent a. Participant is willing to participate in the study and has signed the ICF. [0204] 2) Type of Participant and Target Disease Characteristics a. Adults with a confirmed virological diagnosis of SARS-CoV-2 infection (by RT-PCR). Any positive test, at either the time of or prior to hospitalization, is suitable. Results must be documented. b. Hospitalized (or in the Emergency Department (“ED”) awaiting a bed after hospitalization) c. Respiratory compromise as defined by requirement of oxygen supplementation to maintain oxygen saturation > 93% but not requiring mechanical ventilation. d. Abnormal chest X-ray consistent with COVID-19 and not indicated in other serious medical conditions that would serve as an exclusionary criteria.

[0205] 3) Age and Reproductive Status. Investigators shall counsel women of childbearing potential (WOCBP) participants, and male participants who are sexually active with WOCBP, on the importance of pregnancy prevention and the implications of an unexpected pregnancy. • The investigator shall evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.

• Local laws and regulations may require the use of alternative and/or additional contraception methods. a. Female Participants i. Females, ages > 18 years or local age of majority. ii. Women who are not of childbearing potential are exempt from contraceptive requirements iii. Women participants must have documented proof that they are not of childbearing potential. iv. WOCBP must have a negative highly sensitive urine/serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) performed during screening prior to the start of study treatment.

1. If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive v. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy vi. WOCBP must agree to follow instructions for method(s) of contraception as described below and included in the ICF. vii. WOCBP are permitted to use hormonal contraception methods viii. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:

1. Is not a WOCBP

OR 2. Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency during the intervention period and for at least 70 days and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction for the same time period b. Male Participants ix. Males, ages > 18 years or local age of majority. x. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception as described below. xi. Azoospermic males are exempt from contraceptive requirements. xii. No additional contraceptive measures are required to be used

[0206] Study Population (Exclusion Criteria).

[0207] 1) Medical Conditions c. Women who are breastfeeding d. Participants with recent acute infection defined as: xiii. Any acute infection within 60 days prior to randomization that required hospitalization or treatment with parenteral antibiotics (not COVID-19 related). xiv. Any acute infection within 30 days prior to randomization that required oral antimicrobial or antiviral therapy. e. Participants with history of chronic or recurrent bacterial infection (e.g., chronic pyelonephritis, osteomyelitis, bronchiectasis). f. Medical history of known or suspected active or latent tuberculosis (TB), active hepatitis B, hepatitis C or HIV infection. g. Tuberculosis (“TB”) risk will be further ascertained by review of history and most recent chest X-ray. h. Hepatitis B vims (HBV) testing will be ordered (surface antigen and core antibody). If either is positive, reflex testing for HBV DNA by PCR will be obtained. i. Hepatitis C vims (HCV) testing will be ordered (HCV antibody). If positive, reflex testing for HCV RNA by PCR will be obtained. a. Current clinical findings of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, pulmonary, psychiatric, cardiac, endocrine, neurological, or cerebral disease, including severe and uncontrolled infections, such as sepsis and opportunistic infections (except COVID-19). Caution should be used when randomizing participants with severe COPD or frequent COPD exacerbations. Concomitant medical conditions that, in the opinion of the Investigator, might place the participant at unacceptable risk for participation in this study. b. Participants who have received any live vaccines within 3 months of the study dmg administration or are scheduled to receive live vaccines during the study. Study participants should not be administered a live vims vaccine for a minimum of 3 months following the last dose of study medication. Participants who are in close contact with others who have received a live vaccine may be enrolled at the

Investigator's discretion. c. Participants with a history of (within 12 months of signing the ICF), or known current problems with dmg or alcohol abuse history or known cirrhosis, including alcoholic cirrhosis. d. Participants who are impaired, incapacitated, or incapable of completing study related assessments.

[0208] 2) Prior/Concomitant Therapy j. Participants who have been exposed within 1 month or five half-lives, whichever is longer, to any treatment with an approved or investigational targeted immunotherapy including, but not limited to, infliximab, etanercept, anakinra, rituximab, tocilizumab, golimumab, certolizumab, sirolumab, tofacitinib, baricitinib, upadacitinib, or filgotinib. k. Systemic corticosteroid within 2 weeks of randomization at doses above prednisone 10 mg, or other equivalent. l. Prior exposure to abatacept.

[0209] 3) Physical and Laboratory Test Findings m. Hemoglobin (Hgb) < 8.5 g/dL. n. White Blood Count (WBC) < 3,000/mm3 (3 x 109/L). o. Platelets < 75, 000/mm3 (100x 109/L). p. Serum creatinine > 2x ULN. q. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 x ULN. r. Any test results that, in the opinion of the Investigator, might place the participants at unacceptable risk for participation in this study.

[0210] 4) Allergies and Adverse Drug Reaction s. Hypersensitivity to the IP and/or its excipients

[0211] 5) Other Exclusion Criteria t. Prisoners or participants who are involuntarily incarcerated. u. Participants who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.

[0212] Treatment

[0213] The selection and timing of dose for each participant is as follows: Abbreviation: IV = intravenous: kg = Kilogram; mg = miligram;

[0214] The dose of abatacept will be 10 mg/kg with a maximum dose of 1000 mg. Study medication will be administered in a fixed volume of 100 mL at a constant infusion rate over approximately 30 minutes. The IV line must be flushed with 25 mL of D5W or NS solution at the end of the infusion. The administration window will be within 24 hours of randomization.

[0215] Concomitant Therapy

[0216] Standard of Care. The management of COVID-19 is ever evolving. Beyond routine management and supportive care for hospitalized patients, specific COVID-19 therapies are not defined but new relevant insight have emerged. Current specific therapeutics fall into 3 categories, antiviral, immune-based and, most recently, antithrombotic therapies. The following outlines current guidelines to help inform care for participants enrolled in the study.

[0217] Antiviral Agents. Early repurposing of available antiviral agents was utilized based on empirical or in vitro evidence. All were initially developed as therapies for other viral infection like HIV (e.g., lopinavir-ritonavir) and Ebola (remdesivir). The results for many of these initial efforts have been reported. Currently, only limited use of remdesivir is supported by available clinical data. Other compounds (e.g., lopinavir-ritonavir, chloroquine or hydroxychloroquine) are not recommended outside of the context of a clinical trial. Use of remdesivir is not required but is encouraged as part of standard of care in this study. Because abatacept is a large protein, drug-drug interactions are not anticipated. Infusion of abatacept and remdesivir should not be given concurrently in order not to confound attribution of possible infusion reactions or hypersensitivity events. Data from ACTT1 suggest clinically meaningful improvements associated with use in severe to critical patients. Some but not all subject enrolled in this study may be treated with remdesivir. In order to control for the impact of remdesivir use, subject will be stratified at randomization by remdesivir use. Remdesivir use will be defined as yes if the participant has already been dosed or the decision to dose has been made because remdesivir is available.

[0218] Immune-based Therapies. Multiple therapies with immunomodulatory properties have been proposed for management of COVID-19 and have been used off label. The most common are anti-malarial agents (i.e., chloroquine & hydroxychloroquine, with or without + Azithromycin) and corticosteroids. Other immunotherapies have been propose and many are currently being studied. Use of these targeted therapies are restricted. The following are guidance for other immune-based therapies.

[0219] In some embodiments, use of anti-malarial therapies is not recommended.

Available data does not suggest robust efficacy but suggests possible toxicities. A recent report suggests use of hydroxychloroquine in COVID-19 patients may lead to corrected QT interval prolongation. If hydroxychloroquine is used in study participants, the clinical team may strongly consider ECG monitoring.

[0220] In some embodiments, routine use of systemic corticosteroids (CS) is not recommended unless indicated for other reasons (e.g., hypersensitivity reaction). Use of CS will be allowed but may be minimized as much as possible. Prior use of CS at doses above prednisone 10 mg per day, or equivalent, in the 2 weeks prior to randomization is an exclusion criteria. Use of topical or inhaled CS is not restricted.

[0221] Antithrombotic Therapies. COVID-19 has been recognized as being associated with higher risk of thrombotic events above the rate observed in hospitalized, ill patients. The optimal assessment, screening, prophylaxis and treatment of these is unknown. Our study will access changes in D-dimers as an exploratory marker and not as a guide to clinical decisions.

Any prophylaxis, anticoagulant or antiplatelet, for venous or arterial thrombosis may follow standard of care for other hospitalized adults. If during the course of this study, evidence emerges to support COVID- 19-specific prophylaxis as reflected in guidelines (e.g., NIH COVID-19 Treatment Guidelines), consideration should be given to follow these.

[0222] Oxygen Supplementation. Oxygen supplementation is an element of standard of care for the management of COVID-19. The protocol does not mandate nor advice use of any specific device and amount of oxygen. All decision on oxygen supplementation will follow local practice and will be captured in the study record. [0223] Rescue Therapy. This protocol does not define nor require rescue therapy but it recognizes that off-label use of targeted immunotherapies (e.g., tocilizumab) for some participants has been defined by institutional treatment protocol or used on an ad hoc basis.

These agents may be used at the discretion of the clinical team. Participants who are treated with one of these agents after randomization may remain in the study and followed for outcome assessment.

[0224] Other Therapies. Use of Angiotensin-Converting Enzyme (ACE) Inhibitors,

Angiotensin Receptor Blockers (ARBs) or HMG-CoA Reductase Inhibitors (Statins) previously prescribed for cardiovascular disease (or other indications) may be continued when feasible.

[0225] Efficacy Assessments.

[0226] Primary and Secondary Objectives

[0227] Prevention of Disease Progression. The primary objective will be to determine the impact of therapy on prevention of disease progression as defined using a composite endpoint. This endpoint will be reached if the participant ever requires use of invasive mechanical ventilation or death. Invasive mechanical ventilation is defined as the delivery of positive pressure to the lungs via an endotracheal tube (or tracheostomy).

[0228] Improvement in clinical status. The following 8-point scale will be used in this study:

1. Death

2. Hospitalized, on invasive mechanical ventilation or ECMO (extra-corporeal membrane oxygenation)

3. Hospitalized, on non-invasive mechanical ventilation or high-flow oxygen devices

4. Hospitalized, requiring supplemental oxygen

5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise) 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care

7. Not hospitalized, limitation on activities and/or requiring home oxygen

8. Not hospitalized, no limitation on activities

[0229] Patients may change between states in this scale multiple times during any 24- hour period. The study team will record in the study record only the worst (i.e., lowest) state for each day (midnight to midnight). The determination of the worst state to be recorded may be made as soon as possible after the completion of the day to be assessed.

[0230] ICU admission is defined as transfer of care within the hospital to a specialized medical care unit distinct from routine or intermediate (i.e., stepdown) care. Given the increased demand for ICU beds as a consequence of the COVID-19 pandemic, all forms of ICUs (e.g., surgical) and non-ICU beds have been converted into ICU care beds. Progression into any of these may be considered to meet these criteria.

[0231] Other elements of each point have been defined with the exception of ECMO

(extra-corporeal membrane oxygenation). This scale captures similar information to the primary endpoint but has the advantage of capturing improvement. The “limitations of activities” includes need for home oxygen therapy. Based on inclusion criteria, all study subjects will be in category 3 or 4, and may be extracted from the clinical record.

[0232] Improvement in Mortality. Mortality for this endpoint may be based on all-cause mortality at Day 28 which represent participants who are in state 1 of the Ordinal 8-point Outcome Scale.

[0233] For participants deaths, data will be collected on whether the death occurred after withdrawal of care and, if so, the reason for withdrawal of care will be recorded (e.g., brain death, patient/family request, resource constraint).

[0234] Absence of Critical Disease. This endpoint is related to the primary endpoint. It is defined as the proportion of participants alive and free of respiratory failure on Day 28. Respiratory failure is defined by the type of resources required as defined by the use of any of these: mechanical ventilation, ECMO or oxygen delivery by noninvasive positive pressure or high-flow nasal cannula. Participants in state 4-8 of the Ordinal 8-point Outcome Scale meet this definition.

[0235] Recovery of Pulmonary Function. All participants randomized will be oxygen dependent and dependence on oxygen has been noted to be prolonged even after hospital discharge. We will assess recovery of pulmonary function by determining the proportion of patients returning to room air by Day 28. Participants in state 5, 6 and 8 of the Ordinal 8-point Outcome Scale meet this definition. Some participants in state 7 will also meet this definition.

[0236] Shortened hospitalization. This endpoint will be defined as the proportion of participants alive and discharged home by Day 28. Home as a location will include any new facility that provides ongoing support short of full medical care such as a rehabilitation facility or assisted living facility. Participants in state 7-8 of the Ordinal 8-point Outcome Scale meet this definition.

[0237] Length of hospitalization will be defined as the number of days from the day of randomization to the date of discharge or Day 28, whichever is sooner, measured in days.

[0238] Exploratory Objectives

[0239] Clinical Laboratory Parameters of Inflammation or Organ Damage. Multiple clinical laboratory abnormalities have been reported as suggestive of progression to worse COVID-19 disease and may serve as markers of general and specific organ injury. These will be referred to as clinical laboratory parameters of inflammation or organ damage. They will include: C-reactive protein, lymphocyte count, interluekin-6 (IL-6), D-dimer, ferritin, lactate dehydrogenase (LDH), complement component 3 (C3), complement component 4 (C4), procalcitonin and cardiac troponin I. These clinical labs will be captured and reported starting on Day 1 and weekly afterwards up to Day 28.

[0240] Disease Signs. COVID-19 presents like most viral pneumonias with a constellation of clinical signs and symptoms. Among the signs are fever, cough, dyspnea and fatigue. Monitoring of these in a study such as this is challenging due to the difficulties in utilizing outcome instruments not routinely used in clinical practice. Fever and dyspnea assessment are part of routine care in the form of vital signs. We will use vital signs (body temperature, blood pressure (BP), respiratory rate (RR), and heart rate (HR)) as surrogates. Since vital signs are captured on multiple occasions in hospitalized participants, only selected values that reflect the range of vital signs for every study day will be entered into the study record based on the following guidance. Fever will be captured using daily temperature assessments. Only the highest and lowest daily recorded temperature will be entered into the study record. Temperature will be summarized as number of days from Day 1 to Day 28 with a temperature above 38.0°C and the highest recorded daily temperature. Dyspnea will be captured using the RR. Only the highest and lowest daily recorded RR will be entered into the study record. Similarly, only the highest and lowest daily recorded HR and will be entered into the study record. The highest and lowest daily recorded BP (based on systolic value) will be entered into the study record.

[0241] Viral Clearance and Anti-viral Response. Assessment of the host viral response and the clearance of SARS-CoV-2 may be used to understand the natural history of COVID-19. Developing any novel therapy that may impact viral clearance, whether with anti-viral therapies which should enhance clearance or immunomodulatory therapy which may impair viral clearance, warrants monitoring. Serial testing of SARS-CoV-2 infected patients using reverse transcriptase quantitative PCR (RT-qPCR) has identified the temporal change in viral load. Most patients infected with SARS-CoV-2 appear to show the highest titers at onset and clear the virus within 7 days but others, especially those that develop more severe forms of COVID-19, may take up to 3 weeks. Methods for assessing humoral host responses to components of SARS- CoV-2 as well as viable virus via plaque assays have also been developed.

[0242] These methodologies were developed for research purposes and are only now being developed for wider clinical use. In this study, serial testing of participants may be performed to monitor the impact of study drug on viral clearance. Viral load determination via RT-qPCR and IgM and IgG anti -viral humoral responses may be performed.

[0243] Improvement in Oxygenation: Pulse Oximetry and Arterial Blood Gas. The clinical pneumonitis seen in symptomatic patients with COVID-19 may require continuous oxygen supplementation. Continuous oxygen delivery systems increase the fraction of inspired oxygen (Fi02 or concentration) delivered to patients. Initial, non-ventilatory, support includes delivery via low or high flow nasal cannula or nonrebreather mask for spontaneously breathing patients. More significant respiratory compromise may require ventilatory support, which is divided into noninvasive and invasive ventilation. Noninvasive ventilation (NIV) avoids the use of an endotracheal tube and is delivered through an alternative interface (e.g., full face mask, oronasal mask).

[0244] Oxygen supplementation may require ongoing assessment of efficiency of oxygenation. Pulse oximetry measures peripheral arterial oxygen saturation (Sp02) and has become the standard for continuous, noninvasive assessment of oxygenation. Since pulse oximetry cannot measure arterial oxygen tension (Pa02) and other critical parameters needed for optimal management of mechanical ventilation, analysis of arterial blood using arterial blood gas (ABG) testing may be required. Sites are expected to provide standard supportive management for respiratory disease and complications. Decisions on management of oxygen supplementation and monitoring will follow local practices and standards and will not be guided by this protocol. Therefore, this study may not require ABG testing.

[0245] Since assessing oxygenation status is impacted primarily by Fi02, improvement in oxygenation will be defined as the minimum change from baseline oxygen requirement, as defined by the difference between the Fi02 at the time of randomization on Day 1 and the lowest value on the day of assessment. The values used to estimate Fi02 will be provided in the statistical analysis plan for non-ventilatory and noninvasive ventilation method and oxygen setting used. The lowest daily Sp02, as captured by pulse oximetry and recorded in the hospital record, will also be reported.

[0246] Disease symptoms. Vital signs (body temperature, blood pressure (BP), respiratory rate (RR), and heart rate (HR)) will be measured as surrogates for measuring fever and dyspnea.

[0247] Clinical biomarker profiling. Multiple clinical laboratory abnormalities have been reported as suggestive of progression to worse COVID-19. Among them are C-reactive protein, lymphocyte count, interluekin-6 (IL-6), D-dimer, ferritin and lactate dehydrogenase (LDH),

Other have been reported less commonly but are considered relevant to monitoring patients at risk for severe disease, including procalcitonin and cardiac troponin. These clinical labs will be captured and reported.