Nedulcitinib for delivery by nebulized oral inhalation

Abstract

Provided herein is a method for treating a subject with respiratory disorder when the subject is receiving high-flow oxygen through a nasal cannula, comprising administering to the subject a pharmaceutical composition comprising a therapeutic agent (such as nedulcitinib) or its pharmaceutical acceptable salt by oral aerosol inhalation.Administering high-flow supplemental oxygen to a subject suffering from respiratory disorder may create positive pressure in the subject's respiratory system, preventing effective delivery of the inhaled pharmaceutical composition to the subject's airways and lungs.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 63 / 338,621, filed May 5, 2022, which is incorporated herein by reference in its entirety.

[0002] Field Provided herein is a method of treating a subject with respiratory disorders when the subject is receiving high-flow oxygen through a nasal cannula at a rate of about 30 L / min or more, comprising administering to the subject a pharmaceutical composition comprising a therapeutic agent (such as a JAK inhibitor) or a pharma- ceutical acceptable salt thereof by oral nebulization.Also provided herein is a method of treating a subject with respiratory disorders when the subject is receiving high-flow oxygen through a nasal cannula at a rate of about 30 L / min or more, comprising administering to the subject a pharmaceutical composition comprising nezulcitinib or a pharma- ceutical acceptable salt thereof by oral nebulization. [Background technology]

[0003] Latest Technology For subjects suffering from respiratory disorders, ambient atmospheric oxygen concentrations may not be sufficient to prevent hypoxemia. By providing supplemental oxygen, the subject receives a faster or more concentrated supply of oxygen than is present in the atmosphere, normalizing the subject's blood oxygen saturation. The delivery method for supplemental oxygen depends on the subject's needs, with low-flow oxygen delivering a low dose via a nasal cannula or simple face mask, typically at a rate of about 4-8 L / min, and high-flow oxygen delivering a more concentrated dose via non-invasive ventilation or high-flow nasal cannula, typically at a rate of about 30-60 L / min.

[0004] However, subjects suffering from a variety of respiratory disorders, including, but not limited to, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), pneumonitis, interstitial lung disease (including idiopathic pulmonary fibrosis), acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, sarcoidosis, bronchiolitis obliterans with organizing pneumonia (also known as COS), primary graft dysfunction (PGD), acute rejection (AR), lymphocytic bronchiolitis (LB), chronic transplant pulmonary dysfunction (CLAD), graft-versus-host disease (GVHD), and coronavirus infections, may also benefit from administration of an inhaled pharmaceutical composition, such as one comprising a JAK inhibitor.

[0005] Administration of an inhaled pharmaceutical composition simultaneously with administration of high-flow supplemental oxygen via a nasal cannula can pose challenges in adequately delivering the pharmaceutical composition to the subject's respiratory system while maintaining an increased flow of oxygen to the subject's lungs (hence, has not been used in human subjects previously). Various references utilizing various models suggest that this challenge can be addressed by reducing the flow of oxygen during administration of the pharmaceutical composition or by administering the pharmaceutical composition in-line with the flow of oxygen such that the pharmaceutical composition is delivered to the subject through a nasal cannula. See, e.g., Reminiac et al. J. Aerosol Med. Pulm. Drug Deliv. 2016, 29(2):134-141; Alconforado et al., Pharmaceutics, 2019, 11, 320; Li et al, Pharmaceutics, 2019, 11, 225; and Ari et al, Can. J. Respir. Ther., 2021, 57:22-25. Subjects suffering from respiratory disorders would benefit from both therapeutic intervention and supplemental oxygen. Thus, there remains a need for methods for treating subjects with respiratory disorders with therapeutic agents, such as JAK inhibitors, where the subjects are also receiving high-flow supplemental oxygen via nasal cannula. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Reminiac et al.J.Aerosol Med.Pulm.Drug Deliv.2016,29(2):134-141 [Non-Patent Document 2] Alconforado et al.,Pharmaceutics,2019,11,320 [Non-Patent Document 3] Li et al,Pharmaceutics,2019,11,225 [Non-Patent Document 4] Ari et al,Can.J.Respir.Ther.,2021,57:22-25 Summary of the Invention

[0007] When high-flow supplemental oxygen is administered to a subject suffering from respiratory disorders, it creates positive pressure in the subject's respiratory system, which may prevent effective delivery of the inhaled pharmaceutical composition to the subject's airways and lungs. Current recommendations for optimal administration of inhaled aerosolized pharmaceutical compositions to a subject who is also receiving nasal high-flow supplemental oxygen specify either (a) reducing the flow rate of supplemental oxygen during administration to improve inhaled drug delivery, and then returning to high flow rate when administration is completed, and / or (b) administering the pharmaceutical composition in-line through a nasal cannula high-flow supplemental oxygen system. However, it has now been discovered that pharmaceutical compositions of JAK inhibitors (such as nezulinib) can be optimally administered to a subject in need thereof via nebulized oral inhalation, while the subject also receives nasal high-flow supplemental oxygen at an uninterrupted rate of about 30 L / min or more through a high-flow nasal cannula throughout the administration of the pharmaceutical composition.

[0008] Provided herein is a method for treating a respiratory disorder in a subject in need thereof, comprising administering a pharmaceutical composition to the subject by oral nebulization while the subject is receiving high-flow oxygen through a nasal cannula at a rate of about 30 L / min or more. In some embodiments, the pharmaceutical composition comprises a JAK inhibitor (such as nezulinib), or a pharmaceutical acceptable salt thereof.

[0009] Also provided herein is a method for treating a SARS-CoV-2 pulmonary infection in a subject in need thereof, comprising administering a pharmaceutical composition to the subject by oral nebulization while the subject is receiving high-flow oxygen through a nasal cannula at a rate of about 30 L / min or greater. In some embodiments, the pharmaceutical composition comprises a JAK inhibitor, such as nezulinib, or a pharma- ceutical acceptable salt thereof. [Brief description of the drawings]

[0010] [Figure 1] 1 shows subject plasma concentrations of nezulcitinib as a function of time when subjects received a 3 mg dose via nebulized oral inhalation while also receiving low-flow oxygen via nasal cannula at a rate of 6 L / min. [Diagram 2] Target plasma concentrations of nezulcitinib as a function of time are shown comparing therapeutic administration route and supplemental oxygen delivery rate: a 3 mg dose administered via nebulized oral inhalation while also receiving nasal low-flow oxygen at a rate of 6 L / min versus a 3 mg dose administered nasally while also receiving high-flow oxygen via a nasal cannula circuit at a rate of 30 L / min. [Diagram 3]Further comparison of therapeutic administration routes and supplemental oxygen delivery rates is shown, specifically target plasma concentrations of nezulcitinib as a function of time when subjects received a 3 mg dose via nebulized oral inhalation while also receiving low-flow nasal oxygen at a rate of 6 L / min, a 3 mg dose via nasal inhalation while receiving high-flow oxygen via a nasal cannula circuit at a rate of 30 L / min, or 3 mg via nebulized oral inhalation while receiving high-flow oxygen via a nasal cannula at a rate of 30 L / min. [Figure 4] 1 shows the plasma concentration of nezulcitinib as a function of time in subjects receiving a 3 mg dose via nebulized oral inhalation while also receiving low-flow nasal oxygen at a rate of 6 L / min or high-flow oxygen via a high-flow nasal cannula at a rate of 30 L / min. [Diagram 5] FIG. 1 shows the plasma concentration of nezulcitinib as a function of time in subjects receiving a 3 mg dose via nebulized oral inhalation while receiving either low-flow nasal oxygen at a rate of 6 L / min, high-flow oxygen via high-flow nasal cannula at a rate of 30 L / min, or high-flow oxygen via high-flow nasal cannula at a rate of 50 L / min. [Figure 6] 4 shows the plasma concentration of nezulcitinib as a function of time in subjects receiving a 3 mg dose via nebulized oral inhalation while also receiving either low-flow nasal oxygen at 6 L / min, high-flow oxygen via a high-flow nasal cannula at a rate of 30 L / min, or high-flow oxygen via a high-flow nasal cannula at a rate of 50 L / min, compared to subjects receiving a 9 mg dose of nezulcitinib via nebulized oral inhalation while also receiving high-flow oxygen via a high-flow nasal cannula at a rate of 50 L / min. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The following description sets forth exemplary embodiments of the present technology, however, it should be recognized that such description is not intended to limit the scope of the present disclosure, but is instead provided as a description of exemplary embodiments.

[0012] definition When describing this disclosure including its various aspects and embodiments, the following terms have the following meanings unless otherwise stated.

[0013] The term "about" means plus or minus 5 percent of the specified value.

[0014] "AUC 0~24 " refers to the area under the plasma concentration versus time curve from 0 to 24 hours after administration.

[0015] "AUC 0~∞ " refers to the area under the plasma concentration-time curve extrapolated from time 0 to infinity.

[0016] "C max " means maximum observed plasma concentration.

[0017] The term "PK" means pharmacokinetics.

[0018] "T max " refers to the time to maximum plasma concentration.

[0019] "t 1 / 2 " refers to terminal elimination half-life.

[0020] The term "therapeutically effective amount" means an amount sufficient to effect treatment when administered to a subject in need of treatment.

[0021] The term "treating" or "treatment" means improving or inhibiting the medical condition, disease or disorder being treated in a subject (especially a human), or alleviating the symptoms of the medical condition, disease or disorder.

[0022] "Subject" or "patient" refers to an animal, such as a mammal, who has been or will be the object of treatment, observation, or experiment. The methods described herein can be useful in both human therapy and veterinary applications. In some embodiments, the subject or patient is a mammal. In some embodiments, the subject or patient is a human.

[0023] The term "pharmaceutically acceptable salt" refers to a salt that is acceptable for administration to a subject or mammal, such as a human (a salt that has acceptable mammalian safety for a given dosing regimen). Representative pharmaceutically acceptable salts include salts of acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, edisylic acid, fumaric acid, gentisic acid, gluconic acid, glucuronic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalenesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6-disulfonic acid, nicotinic acid, nitric acid, orotic acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and xinafoic acid, and the like.

[0024] The term "salt thereof" refers to a compound in which a hydrogen of an acid is replaced by a cation, such as a metal cation or an organic cation. For example, the cation can be a protonated form of a compound of formula 1, i.e., one or more amino groups are protonated by an acid. Typically, the salt is a pharma- ceutically acceptable salt, although this is not necessary for salts of intermediate compounds that are not intended for administration to a patient.

[0025] Provided herein is a method for treating a pulmonary disease, disorder, or condition in a subject in need thereof while the subject is receiving high flow oxygen through a nasal cannula, the method comprising administering to the subject by oral nebulization a pharmaceutical composition comprising a therapeutic agent, or a pharma- ceutically acceptable salt thereof, while the subject is receiving high flow oxygen through a nasal cannula at a rate of about 30 L / min or greater.

[0026] It is contemplated that administering a pharmaceutical composition comprising a therapeutic agent as described herein to a subject by oral nebulization while the subject is receiving high-flow oxygen through a nasal cannula at a rate of about 30 L / min or greater is unexpectedly superior to administration through an in-line high-flow circuit, contrary to current recommendations in the art.Furthermore, it is contemplated that administration by oral nebulization to subjects receiving high-flow and low-flow oxygen results in surprisingly similar exposures.

[0027] In some embodiments, the pulmonary disease, disorder, or condition is an inflammatory or fibrotic disease of the airways. In some embodiments, the pulmonary disease, disorder, or condition is a respiratory disorder. In some embodiments, the pulmonary disease, disorder, or condition is lung transplant rejection. In some embodiments, the pulmonary disease, disorder, or condition is asthma.

[0028] In some embodiments, the respiratory disorder is a viral infection, lung transplant rejection, asthma, chronic obstructive pulmonary disease, cystic fibrosis, pneumonia, idiopathic pulmonary fibrosis, acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans, sarcoidosis, eosinophilic disease, helminth infection, pulmonary arterial hypertension, lymphangioleiomyomatosis, bronchiectasis, infiltrative lung disease, drug-induced pneumonia, fungal pneumonia, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, eosinophilic granulomatosis with polyangiitis, idiopathic acute eosinophilic pneumonia, idiopathic chronic eosinophilic pneumonia, hypereosinophilic syndrome, Löffler's syndrome, bronchiolitis obliterans with organizing pneumonia, pulmonary graft versus host disease, and immune checkpoint inhibitor-induced pneumonia.

[0029] In some embodiments, the viral infection is influenza, hi some embodiments, the viral infection is a coronavirus infection.

[0030] In some embodiments, the therapeutic agent is any therapeutic agent described herein, for example, an additional therapeutic agent described herein. In some embodiments, the therapeutic agent is a JAK inhibitor. In some embodiments, the therapeutic agent is an inhaled JAK inhibitor. Non-limiting examples of inhaled JAK inhibitors include GDC-0214 / RG6151, GDC-4379 / RG6244, TD-8236, AZD0449, AZD4604, and KN-002. In some embodiments, the JAK inhibitor is suitable for local administration to the lungs (i.e., a "lung-selective JAK inhibitor"), such as for treating respiratory diseases. Such compounds are known in the art, and include, for example, TD-8236 (disclosed in U.S. Pat. No. 10,100,049). In some embodiments, the JAK inhibitor is compound 1.

[0031] Provided herein is a method for treating a respiratory disorder in a subject in need thereof when the subject is receiving high-flow oxygen through a nasal cannula, comprising administering to the subject a pharmaceutical composition comprising a JAK inhibitor, or a pharma- ceutically acceptable salt thereof, by oral nebulization while the subject is receiving high-flow oxygen through a nasal cannula at a rate of about 30 L / min or more. In some embodiments, the JAK inhibitor is a lung-selective JAK inhibitor. In some embodiments, the JAK inhibitor is compound 1. Compound 1 (also known as the compound of formula 1, nezulcitinib, i.e., ((S)-(3-(dimethylamino)azetidin-1-yl)(2-(6-(2-ethyl-4-hydroxyphenyl-1H-indazol-3-yl)-5-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-6-yl)methanone) having the following structure: [ka] is a pan-JAK inhibitor suitable for direct administration to the lung and is disclosed in U.S. Patent No. 10,947,229. Nedulcitinib can be prepared, for example, as described in U.S. Patent No. 10,947,229 and U.S. Patent No. 10,844,057.

[0032] Provided herein is a method for treating a respiratory disorder in a subject in need thereof when the subject is receiving high flow oxygen through a nasal cannula, comprising administering to the subject by oral nebulization a pharmaceutical composition comprising nezulcitinib, or a pharma- ceutically acceptable salt thereof, while the subject is receiving high flow oxygen through a nasal cannula at a rate of about 30 L / min or greater.

[0033] In some embodiments, the respiratory disorder is selected from the group consisting of coronavirus infection, lung transplant rejection, asthma, chronic obstructive pulmonary disease, cystic fibrosis, pneumonia, idiopathic pulmonary fibrosis, acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans, sarcoidosis, eosinophilic disease, helminth infection, pulmonary arterial hypertension, lymphangioleiomyomatosis, bronchiectasis, infiltrative lung disease, drug-induced pneumonia, fungal pneumonia, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, eosinophilic granulomatosis with polyangiitis, idiopathic acute eosinophilic pneumonia, idiopathic chronic eosinophilic pneumonia, hypereosinophilic syndrome, Löffler's syndrome, bronchiolitis obliterans with organizing pneumonia, pulmonary graft-versus-host disease, and immune checkpoint inhibitor-induced pneumonia. In some embodiments, the respiratory disorder is asthma or chronic obstructive pulmonary disease. In some embodiments, the respiratory disorder is asthma. In some embodiments, the respiratory disorder is chronic obstructive pulmonary disease. In some embodiments, the respiratory disorder is lung transplant rejection. In some embodiments, the respiratory disorder is a coronavirus infection.

[0034] Also provided herein is a method for treating a SARS-CoV-2 pulmonary infection in a subject in need thereof while the subject is receiving high-flow oxygen through a nasal cannula, comprising administering to the subject a pharmaceutical composition comprising nezulcitinib, or a pharma- ceutically acceptable salt thereof, by oral nebulization while the subject is receiving high-flow oxygen through a nasal cannula at a rate of about 30 L / min or greater.

[0035] In some embodiments, the coronavirus infection is caused by SARS-CoV-1, SARS-CoV-2, or MERS-CoV. In some embodiments, the coronavirus infection is caused by SARS-CoV-1. In some embodiments, the coronavirus infection is caused by SARS-CoV-2. In some embodiments, the coronavirus infection is caused by MERS-CoV.

[0036] In some embodiments, the subject has acute lung injury associated with COVID-19. In some embodiments, the subject does not have acute lung injury associated with COVID-19.

[0037] In some embodiments, the subject has a baseline level of C-reactive protein of about 150 mg / L or less.

[0038] In some embodiments, the method reduces the viral load of the coronavirus in the respiratory system of the subject. In some embodiments, the method reduces the viral load in the lungs of the subject. In some embodiments, the reduction in the viral load of the coronavirus is measured by taking and analyzing a nasal swab from the subject. In some embodiments, the method reduces the viral load of SARS-CoV-2 in the respiratory system of the subject. In some embodiments, the method reduces the viral load of SARS-CoV-2 in the lungs of the subject. In some embodiments, the reduction in the viral load of SARS-CoV-2 is measured by taking and analyzing a nasal swab from the subject.

[0039] In some embodiments, the subject is suffering from one or more of hypoxia, hypoxemia, dyspnea, shortness of breath, and low oxygen levels.

[0040] In some embodiments, the pharmaceutical composition is administered to the subject in an outpatient setting. In some embodiments, the pharmaceutical composition is administered to the subject, where the subject is not hospitalized. In some embodiments, the pharmaceutical composition is administered to the subject prior to hospitalization. In some embodiments, the pharmaceutical composition is administered to the subject during hospitalization.

[0041] In some embodiments, the method reduces time to recovery and / or time to discharge from a hospital or medical facility, hi some embodiments, the method results in reduced hospital stay, reduced time in ICU, and / or reduced time to discharge.

[0042] In some embodiments, the subject is receiving high flow oxygen through a nasal cannula at a rate of about 30 L / min to about 50 mL / min. In some embodiments, the subject is receiving high flow oxygen through a nasal cannula at a rate of about 30 L / min. In some embodiments, the subject is receiving high flow oxygen through a nasal cannula at a rate of about 50 mL / min.

[0043] In some embodiments, the pharmaceutical composition comprises about 1 mg to about 10 mg of nezulcitinib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 3 mg to about 9 mg of nezulcitinib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 3 mg of nezulcitinib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 9 mg of nezulcitinib, or a pharma- ceutically acceptable salt thereof.

[0044] In some embodiments, the pharmaceutical composition comprises about 1 mg / 1 mL to about 10 mg / 1 mL (free base equivalent) of nezulcitinib. In some embodiments, the pharmaceutical composition comprises about 3 mg / 1 mL to about 9 mg / 1 mL (free base equivalent) of nezulcitinib. In some embodiments, the pharmaceutical composition comprises about 3 mg / 1 mL (free base equivalent) of nezulcitinib. In some embodiments, the pharmaceutical composition comprises about 3 mg / 1 mL (free base equivalent) of nezulcitinib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 9 mg / 1 mL (free base equivalent) of nezulcitinib.

[0045] In some embodiments, the pharmaceutical composition has a pH in the range of about 3.5 to about 4.5, hi some embodiments, the pharmaceutical composition has a pH of about 4.0.

[0046] In some embodiments, the pharmaceutical composition further comprises a buffering agent, hi some embodiments, the buffering agent is citric acid.

[0047] In some embodiments, the pharmaceutical composition further comprises a tonicity agent, hi some embodiments, the tonicity agent is sodium chloride.

[0048] In some embodiments, the pharmaceutical composition is administered by inhalation. In some embodiments, the pharmaceutical composition is administered by nebulization inhalation. In some embodiments, the pharmaceutical composition is administered by oral nebulization inhalation.

[0049] In some embodiments, the pharmaceutical composition is administered once daily. In some embodiments, the pharmaceutical composition is administered twice daily.

[0050] In some embodiments, the pharmaceutical composition is administered for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 28 days, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 2 months, or 3 months. In some embodiments, the pharmaceutical composition is administered until the subject is discharged from the hospital. In some embodiments, the pharmaceutical composition is administered to the subject for up to 7 days, or up to 10 days, or up to 14 days, or up to 21 days, or up to 28 days, or until discharged from the hospital. In some embodiments, the pharmaceutical composition is administered to the subject for up to 7 days, or until discharged from the hospital. In some embodiments, the pharmaceutical composition is administered to the subject for up to 14 days, or until discharged from the hospital. In some embodiments, the pharmaceutical composition is administered to the subject for up to 21 days, or until discharged from the hospital. In some embodiments, the pharmaceutical composition is administered to the subject for up to 28 days, or until discharge from the hospital.

[0051] In some embodiments, the pharmaceutical composition is administered at a higher loading dose on the first day of administration, followed by lower doses on the following days.

[0052] In some embodiments, the method includes administering one or more additional therapeutic agents or treatments to the subject. In some embodiments, the additional therapeutic agent is an antiviral agent, an anti-inflammatory agent, or an antibody. In some embodiments, the additional therapeutic agent is an antiviral agent. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent. In some embodiments, the additional therapeutic agent is an antibody.

[0053] In some embodiments, the method results in an increase in oxygen levels in the subject's blood. In some embodiments, the method results in an improvement or elimination of fever in the subject. In some embodiments, the method prevents the need for the subject to be weaned off supplemental oxygen or placed on a ventilator. In some embodiments, the method increases the number of ventilator-free days (VFD) in the subject. In some embodiments, the method increases the number of ICU (intensive care unit) bed days in the subject. In some embodiments, the method results in an improvement or elimination of shortness of breath. In some embodiments, the method reduces the risk of death in the subject.

[0054] In some embodiments, the method reduces lung inflammation caused by respiratory distress. In some embodiments, the method prevents, reduces, or eliminates acute lung injury and / or acute respiratory distress syndrome caused by respiratory distress.

[0055] In some embodiments, the method reduces lung inflammation caused by coronavirus infection. In some embodiments, the method prevents, reduces, or resolves acute lung injury and / or acute respiratory distress syndrome caused by coronavirus infection. In some embodiments, the method prevents, reduces, or stops cytokine storm caused by coronavirus infection. In some embodiments, the method results in an increase in oxygen levels in the subject's blood. In some embodiments, the method results in improvement or resolution of fever in the subject.

[0056] In some embodiments, the method reduces inflammation in the lungs caused by COVID-19. In some embodiments, the method prevents, reduces, or resolves acute lung injury and / or acute respiratory distress syndrome caused by COVID-19. In some embodiments, the method prevents, reduces, or stops cytokine storm caused by COVID-19. In some embodiments, the method results in an increase in oxygen levels in the blood of the subject. In some embodiments, the method results in an improvement or resolution of fever in the subject. In some embodiments, the method prevents the need for the subject to be weaned off supplemental oxygen or to be placed on a ventilator. In some embodiments, the method increases the number of ventilator-free days in the subject. In some embodiments, the method increases the number of ICU (intensive care unit) bed days in the subject. In some embodiments, the method results in an improvement or resolution of shortness of breath. In some embodiments, the method reduces the risk of death in the subject.

[0057] In some embodiments, the method prevents the subject from being hospitalized.In some embodiments, the method prevents serious complications in the subject.In some embodiments, serious complications include, for example, lung injury, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), organ failure, pneumonia, acute liver injury, blood clots, respiratory failure, need for additional oxygen supplementation, non-invasive ventilation, mechanical ventilation, acute cardiac injury, secondary infection, acute kidney injury, septic shock, disseminated intravascular coagulation, multisystem inflammatory syndrome (MIS-C), rhabdomyolysis, arrhythmia, cytokine storm and cardiovascular shock.

[0058] In some embodiments, the subject is at high risk for developing severe complications from coronavirus. In some embodiments, the subject has been identified as at high risk for developing severe complications from coronavirus by biomarker testing. In some embodiments, the subject has been identified as at high risk for developing severe complications from coronavirus based on LDH (lactate dehydrogenase) levels. In some embodiments, the subject has been identified as at high risk for developing severe complications from coronavirus based on LDH-isoform 3 levels. In some embodiments, the subject has been identified as at high risk for developing severe complications from coronavirus based on levels of surfactant protein-D (SPD), receptor for advanced glycation end products (RAGE), one or more cytokines, C-reactive protein (CRP), D-dimer, fibrinogen, and / or ferritin. In some embodiments, the cytokine is IL-6. In some embodiments, the subject has diabetes, obesity, cardiovascular disease (such as coronary artery disease, myocardial infarction, history of cerebrovascular disease, or peripheral artery disease), hypertension, or pulmonary disease. In some embodiments, the subject has coronary artery disease, myocardial infarction, a history of cerebrovascular disease, peripheral arterial disease, pulmonary disease (such as asthma, COPD, or idiopathic pulmonary fibrosis (IPF)). In some embodiments, the subject has been identified as being at high risk for developing severe complications from coronavirus based on a chest x-ray. In some embodiments, the subject has CXR abnormalities consistent with viral pneumonia.

[0059] In some embodiments, the method reduces the rate of medical interventions associated with coronavirus infection, as measured by the number of emergency department visits, hospitalizations, physician visits, and emergency care visits associated with coronavirus infection.

[0060] In some embodiments, the pharmaceutical composition inhibits viral entry or fusion of coronavirus virions with endosomal membranes in cells of a subject. In some embodiments, the pharmaceutical composition inhibits Abelson kinase in a subject. In some embodiments, the pharmaceutical composition inhibits Abelson kinase in a subject. In some embodiments, the Abelson kinase is Abl1 and Abl2. In some embodiments, the Abelson kinase is Abl1. In some embodiments, the Abelson kinase is Abl2. In some embodiments, the pharmaceutical composition inhibits coronavirus replication in a subject.

[0061] In some embodiments, the subject has a COVID-19 associated inflammatory syndrome (i.e., multisystem inflammatory syndrome, MIS-C). In some embodiments, the subject is a pediatric subject.

[0062] In some embodiments, the methods prevent long term pulmonary dysfunction or "long COVID" in a subject.

[0063] In some embodiments, the method results in an increase in RFD (respiratory failure free days) in a coronavirus-infected subject. In some embodiments, the method results in an increase in ventilator-free days (VFD) in a coronavirus-infected subject.

[0064] In some embodiments, the methods increase the ratio of arterial oxygen pressure to fractional inspired oxygen (PaO2 / FiO2) in a subject.

[0065] In some embodiments, the method reduces mortality in a subject population.

[0066] In some embodiments, the method reduces thrombus formation in a subject.

[0067] In some embodiments, the methods result in a reduced need for supplemental oxygen, non-invasive ventilation, or mechanical ventilation in a subject.

[0068] In some embodiments, the subject is classified as moderate, severe, or critical. In some embodiments, the subject is 60 years of age or younger. In some embodiments, the subject is over 60 years of age. In some embodiments, the subject is suffering from pneumonia when the pharmaceutical composition is administered. In some embodiments, the subject is suffering from bilateral pneumonia when the pharmaceutical composition is administered. In some embodiments, administration of the pharmaceutical composition results in prevention or attenuation of formation of lung lesions / lung lesion opacities / lung damage, improvement of the subject as monitored by chest imaging, CT scan, or chest x-ray, increase in ventilator-free days (VFD), increase in ICU-free days, increase in PaO2 / FiO2 ratio, or increase in SaO2 / FiO2 ratio. In some embodiments, administration of the pharmaceutical composition to a subject infected with coronavirus occurs when the subject is in respiratory failure but before mechanical ventilation is required.

[0069] In some embodiments, the methods result in an increase in the number of days without supplemental oxygen for the subject.

[0070] In some embodiments, the pharmaceutical composition is administered to the subject at a critical inflection point of the disease before ALI develops, preventing progression to ALI. In some embodiments, the pharmaceutical composition is administered to the subject during an early stage of coronavirus infection, before ALI develops, preventing progression to ALI. In some embodiments, the pharmaceutical composition is administered over a short period of time. In some embodiments, the pharmaceutical composition is administered to the subject before ARDS develops, preventing progression to ARDS. In some embodiments, administration of the pharmaceutical composition to a coronavirus-infected subject occurs before the subject has ALI and / or ARDS to prevent ALI and / or ARDS in the subject.

[0071] In some embodiments, the subject has one or more underlying conditions, such as asthma, COPD, cardiovascular disease, diabetes, chronic lung disease, a cardiac condition, cancer, bone marrow or organ transplant, immune deficiency, HIV, taking immune-compromising medications, obesity, chronic kidney disease, a neurodevelopmental condition, hypertension, or liver disease.

[0072] In some embodiments, the subject is 80 years or older, 70 years or older, 65 years or older, 60 years or older, 50 years or older, 40 years or older, 10 years or younger, 10-20 years, 20-30 years, 30-40 years, 40-50 years, 50-60 years, 20-40 years, 40-60 years, 60-80 years, 60 years or younger, or over 60 years old. In some embodiments, the subject is 16 years or older. In some embodiments, the subject is 18 years or older. In some embodiments, the subject is 12 years or older.

[0073] In some embodiments, the method blocks or inhibits neutrophilia and / or formation of neutrophil extracellular traps (NETs) in a subject.

[0074] In some embodiments, the methods reduce the risk of thrombosis or thromboembolism in a subject.

[0075] In some embodiments, the methods reduce the incidence of thrombosis or thromboembolism in a subject population.

[0076] In some embodiments, the maximum plasma concentration (Cmax) of the compound of formula 1 in a subject is less than 350 ng / mL. In some embodiments, the maximum plasma concentration of the compound of formula 1 in a subject is less than 300 ng / mL. In some embodiments, the maximum plasma concentration of the compound of formula 1 in a subject is less than 250 ng / mL. In some embodiments, the maximum plasma concentration of the compound of formula 1 in a subject is less than 200 ng / mL. In some embodiments, the maximum plasma concentration of the compound of formula 1 in a subject is less than 150 ng / mL. In some embodiments, the maximum plasma concentration of the compound of formula 1 in a subject is less than 100 ng / mL. In some embodiments, the maximum plasma concentration of the compound of formula 1 in a subject is less than 50 ng / mL. In some embodiments, the maximum plasma concentration of the compound of formula 1 in a subject is less than 40, 30, 25, 20, 15, or 10 ng / mL. In some embodiments, the maximum plasma concentration of the compound of formula 1 in a subject is less than JAK IC 50 In some embodiments, the plasma concentration of JAK IC 50 IC of IL-13-induced STAT6 phosphorylation in the human bronchial epithelial cell line BEAS-2B 50In some embodiments, the maximum plasma concentration in the subject of the compound of formula 1 is less than the plasma concentration required to inhibit Janus kinase by 50%. In some embodiments, the compound of formula 1, or a pharma- ceutically acceptable salt thereof, is administered to the subject at a dose of about 1 mg to about 10 mg. In some embodiments, the compound of formula 1, or a pharma- ceutically acceptable salt thereof, is administered to the subject at a dose of about 1 mg. In some embodiments, the compound of formula 1, or a pharma- ceutically acceptable salt thereof, is administered to the subject at a dose of about 3 mg. In some embodiments, the compound of formula 1, or a pharma- ceutically acceptable salt thereof, is administered to the subject at a dose of about 9 mg. In some embodiments, the compound of formula 1, or a pharma- ceutically acceptable salt thereof, is administered to the subject at a dose of about 10 mg. In some embodiments, the compound of formula 1, or a pharma- ceutically acceptable salt thereof, is administered to the subject at a dose of about 1 mg to about 3 mg. In some embodiments, the compound of formula 1, or a pharma- ceutically acceptable salt thereof, is administered to the subject at a dose of about 3 mg to about 10 mg. In some embodiments, the compound of formula 1, or a pharma- ceutically acceptable salt thereof, is administered to the subject at a dose of about 2 mg, or about 4 mg, or about 5 mg, or about 6 mg, or about 7 mg, or about 8 mg, or about 9 mg. In some embodiments, the compound of formula 1, or a pharma- ceutically acceptable salt thereof, is administered once a day. In some embodiments, the compound of formula 1, or a pharma- ceutically acceptable salt thereof, is administered twice a day. In some embodiments, the compound of formula 1, or a pharma- ceutically acceptable salt thereof, is administered at a double dose on day 1.

[0077] In some embodiments, administration of a compound of formula 1, or a pharma- ceutical acceptable salt thereof, results in a plasma AUC of less than 500 ng*hr / mL, or less than 250 ng*hr / mL, or less than 100 ng*hr / mL, or less than 50 ng*hr / mL. 0~24 results.

[0078] In some embodiments, administration of the compound of Formula 1, or a pharma- ceutically acceptable salt thereof, is with a T max, or T of about 1 hour max results.

[0079] In some embodiments, the subject is symptomatic. In some embodiments, the subject is hospitalized. In some embodiments, the subject requires supplemental oxygen. In some embodiments, the subject has acute lung injury associated with COVID-19.

[0080] In some embodiments, the subject is 12 years of age or older. In some embodiments, the subject is under 12 years of age. In some embodiments, the subject is a pediatric subject 2 years of age or older.

[0081] In some embodiments, the subject has mild to moderate COVID-19. In some embodiments, the subject has severe COVID-19. In some embodiments, the subject is at high risk of progressing to severe COVID-19 and / or hospitalization.

[0082] In some embodiments, the method results in an improvement in the subject's Patient Global Assessment of Symptoms. In some embodiments, the method results in an improvement in the subject's Patient Global Rating of Change. In some embodiments, the method results in an improvement in the levels of LDH (lactate dehydrogenase), surfactant protein-D (SPD), receptor for advanced glycation end products (RAGE), one or more cytokines, C-reactive protein (CRP), D-dimer, fibrinogen, and / or ferritin in the subject. In some embodiments, the method improves the Borg Dyspnea Score in the subject. In some embodiments, the method reduces the C-reactive protein level (CRP) in the subject. In some embodiments, the method reduces the D-dimer value in the subject. In some embodiments, the method reduces the cytokine level in the subject. In some embodiments, the cytokine is IL-6.

[0083] In some embodiments, the method results in an improvement in the level of receptor for advanced glycation end products (RAGE) in the subject. In some embodiments, the method results in a decrease in the level of receptor for advanced glycation end products (RAGE) in the subject. In some embodiments, the method results in a decrease in lung injury to the subject.

[0084] In some embodiments, the method results in an improvement in the level of C-reactive protein (CRP) in the subject. In some embodiments, the method results in a decrease in the level of C-reactive protein (CRP) in the subject. In some embodiments, the method results in an improvement in the level of IL-6 in the subject. In some embodiments, the method results in a decrease in the level of IL-6 in the subject. In some embodiments, the method results in an improvement in the level of IFNγ in the subject. In some embodiments, the method results in a decrease in the level of IFNγ in the subject. In some embodiments, the method results in an improvement in the level of IP-10 in the subject. In some embodiments, the method results in a decrease in the level of IP-10 in the subject. In some embodiments, the method results in a decrease in the level of IL-10 in the subject. In some embodiments, the method results in a decrease in the level of MCP-1 in the subject. In some embodiments, the method results in an improvement in the modified Borg dyspnea score in the subject.

[0085] In some embodiments, the method results in a reduced risk of mortality in the subject.

[0086] In some embodiments, the method includes administering to the subject one or more additional therapeutic agents or treatments. In some embodiments, the subject receives standard of care co-treatment. In some embodiments, the subject is also treated with a corticosteroid. In some embodiments, the subject is also treated with dexamethasone. In some embodiments, the subject is also treated with an antiviral agent. In some embodiments, the subject is also treated with multiple antiviral agents. In some embodiments, the subject is also treated with remdesivir.

[0087] In some embodiments, the subject suffers from hypertension and / or diabetes.

[0088] In some embodiments, the subject is suffering from moderate COVID-19 when treatment with Compound 1, or a pharma- ceutically acceptable salt thereof, is initiated. In some embodiments, the subject is suffering from severe COVID-19 when treatment with Compound 1, or a pharma- ceutically acceptable salt thereof, is initiated.

[0089] In some embodiments, the subject has acute lung injury associated with COVID-19. In some embodiments, the subject requires supplemental oxygen upon admission. In some embodiments, the subject requires supplemental oxygen but is not on ventilation or high-flow oxygen upon admission. In some embodiments, the subject requires invasive mechanical ventilation or extracorporeal membrane oxygenation upon admission. In some embodiments, the subject is on non-invasive ventilation or high-flow oxygen equipment upon admission.

[0090] In some embodiments, the method prevents, reduces, or resolves acute lung injury and / or acute respiratory distress syndrome caused by COVID-19. In some embodiments, the method prevents, reduces, or stops cytokine storm caused by COVID-19. In some embodiments, the method allows the subject to be relieved from ventilation or supplemental oxygen. Nedulcitinib

[0091] Chemical structures are named herein according to the IUPAC rules as implemented in ChemDraw software (PerkinElmer, Inc., Cambridge, Mass.). Compound 1, nezulcitinib, is designated as (S)-(3-(dimethylamino)azetidin-1-yl)(2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)-5-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-6-yl)methanone. Additionally, the imidazo moiety of the tetrahydroimidazopyridine substructure exists in tautomeric forms, as exemplified below for fragments of compound 1. [ka]

[0092] According to IUPAC convention, these representations number the atoms of the imidazole moiety differently: (1H-indazol-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine (structure A) versus (1H-indazol-3-yl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine (structure B). Although structures are shown or named in a particular form, it will be understood that the disclosed compounds also include their tautomers.

[0093] Compound 1 can exist as a pure enantiomer or as an enriched mixture. The depiction or naming of a particular stereoisomer means that the depicted stereocenter has the designated stereochemistry, and unless otherwise indicated, it is understood that minor amounts of other stereoisomers may also be present, provided that the utility of the depicted or named compound is not precluded by the presence of another stereoisomer.

[0094] Compound 1 also contains several basic groups (e.g., amino groups), and therefore such compounds can exist as the free base or in various salt forms, such as mono-protonated, di-protonated, tri-protonated salt forms, or mixtures thereof, all of which are included within the scope of this disclosure, unless otherwise indicated.

[0095] The present disclosure also includes isotopically labeled compounds of formula 1, i.e., compounds of formula 1 in which one or more atoms have been replaced or enriched with an atom having the same atomic number but an atomic mass different from the atomic mass predominant in nature. Examples of isotopes that can be incorporated into compounds of formula 1 include: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O, and 18 Examples include, but are not limited to, O. Pharmaceutical Compositions

[0096] Compound 1 and its pharmaceutically acceptable salts are typically used in the form of pharmaceutical compositions or preparations.Such pharmaceutical compositions can be advantageously administered to subjects by inhalation.Furthermore, pharmaceutical compositions can be administered by any acceptable administration route, including but not limited to oral, rectal, nasal, topical (including transdermal) and parenteral administration modes.

[0097] Provided herein is a pharmaceutical composition comprising a pharma- ceutically acceptable carrier or excipient and Compound 1, where "Compound 1" means Compound 1, or a pharma- ceutically acceptable salt thereof, as defined above. Optionally, such pharmaceutical compositions may contain other therapeutic and / or formulating agents as desired. When discussing the composition and its uses, Compound 1 may also be referred to herein as the "active agent."

[0098] The pharmaceutical compositions of the present disclosure typically contain a therapeutically effective amount of Compound 1. However, those skilled in the art will recognize that the pharmaceutical compositions may contain amounts greater than the therapeutically effective amount, i.e., bulk compositions, or amounts less than the therapeutically effective amount, i.e., individual unit doses designed to be administered multiple times to achieve a therapeutically effective amount or an amount sufficient to produce a desired biological effect, such as reducing the viral load of coronavirus.

[0099] Typically, such pharmaceutical compositions contain from about 0.01 to about 95% by weight of the active agent, for example, from about 0.05 to about 30% by weight, and from about 0.1% to about 10% by weight of the active agent.

[0100] Any conventional carrier or excipient can be used in the pharmaceutical composition comprising Compound 1. The selection of a particular carrier or excipient, or combination of carriers or excipients, depends on the mode of administration used to treat a particular subject or type of medical condition or disease state. In this respect, the preparation of a pharmaceutical composition suitable for a particular mode of administration is well within the scope of a person skilled in the pharmaceutical arts. Moreover, the carrier or excipient used in the pharmaceutical composition of the present disclosure is commercially available. By way of further illustration, conventional formulation techniques are described in Remington: The Science and Practice of Pharmacy, 20th Edition, Lippincott Williams&White, Baltimore, Maryland (2000), and HC Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition, Lippincott Williams&White, Baltimore, Maryland (1999).

[0101] Representative examples of materials which may act as pharma- ceutically acceptable carriers include, but are not limited to, the following: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; celluloses, such as microcrystalline cellulose, and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic compatible substances used in pharmaceutical compositions.

[0102] Pharmaceutical compositions are typically prepared by thoroughly and intimately mixing or blending the active agent with a pharma- ceutically acceptable carrier and one or more optional ingredients.

[0103] In one embodiment, the pharmaceutical composition is suitable for inhalation administration.The pharmaceutical composition for inhalation administration is typically in the form of aerosol or powder.This composition is generally administered using an inhalation delivery device, such as dry powder inhaler (DPI), metered dose inhaler (MDI), nebulizer inhaler or similar delivery device.

[0104] In some embodiments, the pharmaceutical composition is administered by inhalation using a nebulizer inhaler.This type of nebulizer device typically produces a high-velocity air flow, which causes the pharmaceutical composition to atomize as mist and is carried to the subject's airway.Therefore, when formulated for use in a nebulizer inhaler, the therapeutic agent can be dissolved in a suitable carrier to form a solution.Alternatively, the therapeutic agent can be micronized or nano-pulverized and combined with a suitable carrier to form a suspension.

[0105] Representative pharmaceutical compositions for use in nebulizer inhalers include a solution or suspension containing about 0.05 μg / 1 mL to about 20 mg / 1 mL of compound 1 and an excipient compatible with nebulizer formulations. In some embodiments, pharmaceutical compositions for use in nebulizer inhalers include a solution or suspension containing about 1 mg / 1 mL to about 10 mg / 1 mL (free base equivalent) of compound 1 and an excipient compatible with nebulizer formulations. In some embodiments, pharmaceutical compositions for use in nebulizer inhalers include a solution or suspension containing about 3 mg / 1 mL to about 9 mg / 1 mL (free base equivalent) of compound 1 and an excipient compatible with nebulizer formulations. In some embodiments, pharmaceutical compositions for use in nebulizer inhalers include a solution or suspension containing about 3 mg / 1 mL (free base equivalent) of compound 1 and an excipient compatible with nebulizer formulations. In some embodiments, pharmaceutical compositions for use in nebulizer inhalers include a solution or suspension containing about 9 mg / 1 mL (free base equivalent) of compound 1 and an excipient compatible with nebulizer formulations.

[0106] Nebulizer devices suitable for administering therapeutic agents by inhalation have been described in the art, and examples of such devices are commercially available. For example, representative nebulizer devices or products include the Respimat Softmist inhaler (Boehringer Ingelheim), the AERx Pulmonary Delivery System (Aradigm Corp.), the PARI LC Plus Examples include Reusable Nebulizer (Pari GmbH).

[0107] In some embodiments, the nebulizer is a jet nebulizer, an ultrasonic nebulizer, or a mesh nebulizer. In some embodiments, the nebulizer is a jet nebulizer. In some embodiments, the nebulizer is an ultrasonic nebulizer. In some embodiments, the nebulizer is a mesh nebulizer. In some embodiments, the nebulizer is an active mesh nebulizer. Non-limiting examples of active mesh nebulizers include Aeroneb (Aerogen) and eFlow (PARI). In some embodiments, the nebulizer is a passive mesh nebulizer. A non-limiting example of a passive mesh nebulizer is Microair NE-US22 (Omron).

[0108] Nebulizer droplet size distribution is a parameter that can affect the in vivo deposition of a therapeutic agent in the lungs. Droplet size can be influenced by the formulation, the nebulizer device, or both. In some embodiments, the atomized particles delivered (i.e., particles of therapeutic agent delivered via a nebulizer) are comprised of particles having a substantially average diameter of, for example, about 1 μm to about 30 μm, about 5 μm to about 30 μm, about 10 μm to about 30 μm, about 15 μm to about 30 μm, about 10 μm to about 20 μm, about 10 μm to about 15 μm, about 1 μm to about 20 μm, about 1 μm to about 10 μm, about 1 μm to about 5 μm, less than about 30 μm, less than about 25 μm, less than about 20 μm, less than about 15 μm, less than about 10 μm, less than about 9 μm, less than about 8 μm, less than about 7 μm, less than about 6 μm, less than about 5 μm, less than about 4 μm, less than about 3 μm, less than about 2, or less than about 1 μm.

[0109] In some embodiments, the delivered atomized particles are comprised of particles having a substantially average diameter of about 1 μm to about 10 μm. In some embodiments, the delivered atomized particles are comprised of particles having a substantially average diameter of about 1 μm to about 10 μm. In some embodiments, the delivered atomized particles are comprised of particles having a substantially average diameter of less than about 10 μm. In some embodiments, the delivered atomized particles are comprised of particles having a substantially average diameter of less than about 5 μm.

[0110] In some embodiments, about 60% to about 95% of the delivered atomized particles are composed of particles having an average diameter of, for example, about 1 μm to about 5 μm, about 1 μm to about 10 μm, less than about 15 μm, less than about 10 μm, less than about 9 μm, less than about 8 μm, less than about 7 μm, less than about 6 μm, less than about 5 μm, less than about 4 μm, less than about 3 μm, less than about 2 μm, or less than about 1 μm. In some embodiments, about 65% to about 95% of the delivered atomized particles are composed of particles having an average diameter of, for example, about 1 μm to about 10 μm, less than about 15 μm, less than about 10 μm, less than about 9 μm, less than about 8 μm, less than about 7 μm, less than about 6 μm, less than about 5 μm, less than about 4 μm, less than about 3 μm, less than about 2 μm, or less than about 1 μm. In some embodiments, about 70% to about 90% of the delivered atomized particles are composed of particles having an average diameter of, for example, about 1 μm to about 10 μm, less than about 15 μm, less than about 10 μm, less than about 9 μm, less than about 8 μm, less than about 7 μm, less than about 6 μm, less than about 5 μm, less than about 4 μm, less than about 3 μm, less than about 2 μm, or less than about 1 μm. In some embodiments, about 70% to about 85% of the delivered atomized particles are composed of particles having an average diameter of, for example, about 1 μm to about 10 μm, less than about 15 μm, less than about 10 μm, less than about 9 μm, less than about 8 μm, less than about 7 μm, less than about 6 μm, less than about 5 μm, less than about 4 μm, less than about 3 μm, less than about 2 μm, or less than about 1 μm. In some embodiments, about 70% to about 80% of the delivered atomized particles are composed of particles having an average diameter of, for example, about 1 μm to about 10 μm, less than about 15 μm, less than about 10 μm, less than about 9 μm, less than about 8 μm, less than about 7 μm, less than about 6 μm, less than about 5 μm, less than about 4 μm, less than about 3 μm, less than about 2 μm, or less than about 1 μm.

[0111] In some embodiments, administration via a nebulizer is driven by an oxygen flow rate of, for example, about 10 L / min to about 1 L / min, about 10 L / min to about 2 L / min, about 8 L / min to about 3 L / min, about 8, less than about 4 L / min, about 8 L / min to about 5 L / min, about 8 L / min to about 6 L / min, less than about 9 L / min, less than about 8 L / min, less than about 7 L / min, less than about 6 L / min, less than about 5 L / min. In some embodiments, the nebulizer is driven by an oxygen flow rate of about 8 L / min to about 6 L / min. In some embodiments, the pharmaceutical composition for use in a nebulizer inhaler has a pH in the range of about 3 to about 8. In some embodiments, the pharmaceutical composition for use in a nebulizer inhaler has a pH in the range of about 3.5 to about 4.5. In some embodiments, the pharmaceutical composition for use in a nebulizer inhaler has a pH of about 4.0.

[0112] In some embodiments, the pharmaceutical composition for use in a nebulizer inhaler further comprises a buffering agent, hi some embodiments, the buffering agent is citric acid.

[0113] In some embodiments, the pharmaceutical composition for use in a nebulizer inhaler further comprises a tonicity agent, hi some embodiments, the tonicity agent is sodium chloride.

[0114] Provided herein is a method for treating a respiratory disorder in a subject in need thereof who is receiving high-flow supplemental oxygen via nasal cannula, comprising administering to the subject a pharmaceutical composition comprising nezulcitinib, or a pharma- ceutically acceptable salt thereof, by oral nebulization, wherein the flow of supplemental oxygen to the subject is not reduced or interrupted throughout the administration of the pharmaceutical composition.

[0115] The following non-limiting examples illustrate representative pharmaceutical compositions of the present disclosure.

[0116] Nebulizer Composition Compound 1 (25 mg) is dissolved in a solution containing 1.5 to 2.5 equivalents of hydrochloric acid, followed by the addition of sodium hydroxide to adjust the pH to 3.5 to 5.5, and the addition of 3 wt% glycerol. The solution is stirred well until all components are dissolved. This solution is administered using a nebulizer device that provides about 0.1 mg to about 4 mg of Compound 1 per dose.

[0117] Compound 1, or its pharma- ceutically acceptable salt, is typically administered once a day or multiple times a day, although other dosage forms may be used.The amount of active agent administered per dose or the total amount administered per day is typically determined by a physician in light of the relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound administered and its relative activity, the age, weight and response of the individual subject, the severity of the subject's symptoms, etc.

[0118] Utilities In some embodiments of the method provided herein, the therapeutic agent is a JAK inhibitor.In some embodiments, the JAK inhibitor is designed for treating inflammatory and fibrotic diseases of the airway.In some embodiments, the compound is designed to deliver a potent anti-cytokine agent directly to the site of action of respiratory disease in the lung, while limiting exposure to the whole body.Such lung-selective JAK inhibitors are known in the art, and include, for example, TD-8236 (disclosed in US Patent 10,100,049).

[0119] Compound 1 is designed for the treatment of inflammatory and fibrotic diseases of the airways. In particular, the compound is designed to deliver a potent anti-cytokine agent directly to the site of respiratory disease action in the lungs while limiting systemic exposure.

[0120] Compound 1 is a potent inhibitor of the JAK family of enzymes: JAK1, JAK2, JAK3, and TYK2, as well as a potent inhibitor of proinflammatory and profibrotic cytokines. It is recognized that the broad anti-inflammatory effects of systemically available JAK inhibitors may suppress normal immune cell function and increase the risk of infection. In contrast, Compound 1 allows for the direct delivery of potent anti-cytokine agents to the site of action of respiratory disorders in the lungs, while limiting systemic exposure.

[0121] Compound 1 has been evaluated in Phase 1 clinical trials in humans administered 1 mg, 3 mg, and 10 mg by nebulized inhalation for up to 7 days. max (Maximum plasma concentration) values ​​are fully corrected for JAK IC 50 , i.e., less than the plasma concentration required to inhibit Janus kinase by 50%. The pharmacokinetics of inhaled Compound 1 are consistent with low plasma exposure following inhalation administration. Maximum plasma exposure of Compound 1 was 1.1 mg / mL at the dose levels of 3 and 10 mg, respectively, and was 1.1 mg / mL at the plasma levels of 1.1 mg / mL, i.e., less than the plasma concentration required to inhibit Janus kinase by 50%. 50The absolute NK cell counts were approximately 20-fold and 7-fold lower than those observed with compound 1. Additionally, to evaluate the potential for systemic pharmacological effects associated with JAK inhibition with compound 1, absolute NK cell counts were evaluated after multiple doses. No reduction in NK cells was observed relative to baseline in participants receiving placebo or compound 1 at any of the dose levels (1, 3, or 10 mg) investigated in this study. The lack of reduction in NK cell counts is also consistent with the lack of systemic JAK inhibition. In contrast, a significant reduction in NK cell counts has been observed with systemic JAK inhibitors such as tofacitinib (Weinhold, KJ, et al., Reversibility of peripheral blood leukocyte phenotypic and functional changes after exposure to and withdrawal from tofacitinib, a Janus kinase inhibitor, in healthy volunteers. Clin Immunol. 191, 10-20, 2018). Other systemically mediated hematological changes associated with JAK inhibition, including reductions in neutrophils and hemoglobin, as well as lipid changes, were not observed with inhaled administration of compound 1. These results support a favorable safety and tolerability profile and PK below levels expected to exert systemic effects.

[0122] The anti-inflammatory activity of JAK inhibitors has been firmly demonstrated in preclinical models of asthma (Malaviya et al., Int.Immunopharmacol., 2010,10,829-836; Matsunaga et al., Biochem.and Biophys.Res.Commun., 2011,404,261-267; Kudlacz et al., Eur.J.Pharmacol, 2008,582,154-161).Therefore, JAK inhibitors, such as the lung-selective JAK inhibitors described herein, are expected to be useful in treating inflammatory respiratory disorders such as asthma.

[0123] Cytokines involved in asthmatic inflammation that signal through the JAK-STAT pathway include IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-11, IL-13, IL-23, IL-31, IL-27, thymic stromal lymphopoietin (TSLP), interferon-γ (IFNγ) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Compound 1 is therefore expected to be useful in treating inflammatory respiratory disorders, particularly asthma. Asthma has been classified into Th2-low and Th2-high subtypes (Simpson et al, Respirology, 2006, 11, 54-61). IL-4, IL-13, IL-5, and TSLP are involved in Th2-high asthma, while IL-23 / IL-12, IL-6, IL-27, and IFNγ are involved in Th2-low asthma. Based on its pan-JAK inhibitory profile, compound 1 potently inhibits mediators of both Th2-high and Th2-low asthma, and is therefore expected to be useful in treating both Th2-high and Th2-low asthma.

[0124] In addition to asthma, pulmonary inflammation and fibrosis are also characteristics of other respiratory diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), pneumonia, interstitial lung disease (including idiopathic pulmonary fibrosis), acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans, and sarcoidosis. Thus, JAK inhibitors, such as the lung-selective JAK inhibitors described herein as well as compound 1, are also expected to be useful in treating chronic obstructive pulmonary disease, cystic fibrosis, pneumonia, interstitial lung disease (including idiopathic pulmonary fibrosis), acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans, and sarcoidosis.

[0125] In comparison to the corresponding fluorinated analogues, compound 1 has been shown to have similar JAK activity, but as shown in the assay section, has the advantage of being significantly less susceptible to sulfation metabolism, which is important since sulfation metabolism occurs in the lungs and can result in a rapid decrease in exposure of the active parent compound.

[0126] Compound 1 has demonstrated inhibition of inflammation-related cytokines and is therefore believed to be useful in the treatment of certain respiratory diseases and disorders, as described in more detail below.

[0127] Eosinophilic airway inflammation is a hallmark of diseases collectively referred to as eosinophilic lung diseases (Cottin et al., Clin. Chest. Med., 2016, 37(3), 535-56). Eosinophilic diseases are associated with IL-4, IL-13, and IL-5 signaling. Eosinophilic lung diseases include infections (especially helminth infections), drug-induced pneumonias (e.g. induced by therapeutic agents such as antibiotics, phenytoin, and l-tryptophan), fungal pneumonias (e.g. allergic bronchopulmonary aspergillosis), hypersensitivity pneumonitis, and eosinophilic granulomatosis with polyangiitis (previously known as Churg-Strauss syndrome). Eosinophilic lung diseases of unknown etiology include idiopathic acute eosinophilic pneumonia, idiopathic chronic eosinophilic pneumonia, hypereosinophilic syndrome, and Löffler syndrome.

[0128] Polymorphisms in the IL-6 gene have been associated with elevated IL-6 levels and increased risk of developing pulmonary arterial hypertension (PAH) (Fang et al., J. Am. Soc. Hypertens., 2017, 11(3), 171-177). Supporting a role for IL-6 in PAH, inhibition of the IL-6 receptor chain gp130 ameliorated disease in a rat model of PAH (Huang et al., Can. J. Cardiol., 2016, 32(11), 1356.e1-1356.e10).

[0129] Cytokines such as IFNγ, IL-12 and IL-6 are involved in various non-allergic lung diseases such as sarcoidosis and lymphangioleiomyomatosis (El-Hashemite et al., Am. J. Respir. Cell. Mol. Biol., 2005, 33, 227-230, and El-Hashemite et al., Cancer Res., 2004, 64, 3436-3443). Compounds of the present disclosure have also been shown to inhibit IL-6 and IFNγ signaling.

[0130] Bronchiectasis and infiltrative lung diseases are diseases associated with chronic neutrophilic inflammation.

[0131] Pathological T cell activation is important in the pathogenesis of multiple respiratory diseases. Autoreactive T cells play a role in bronchiolitis obliterans with organizing pneumonia (also called COS). Similar to COS, the pathogenesis of lung transplant rejection is associated with aberrant T cell activation of recipient T cells by the transplanted donor lung. Lung transplant rejection can occur early as primary graft dysfunction (PGD), organizing pneumonia (OP), acute rejection (AR) or lymphocytic bronchiolitis (LB), or many years after lung transplantation as chronic pulmonary allograft dysfunction (CLAD). CLAD was previously known as bronchiolitis obliterans (BO) but is now considered a syndrome that may have different pathological manifestations including BO, restrictive CLAD (rCLAD or RAS) and neutrophilic allograft dysfunction. Chronic pulmonary graft dysfunction (CLAD) is a major challenge in the long-term management of lung transplant recipients, as the transplanted lung gradually loses function (Gauthier et al., Curr Transplant Rep., 2016, 3(3), 185-191). As CLAD is poorly responsive to treatment, there is still a need for effective compounds that can prevent or treat this condition. Several JAK-dependent cytokines, such as IFNγ and IL-5, are upregulated in CLAD and lung transplant rejection (Berastegui et al, 1733189417441_0 2017,31,e12898). Furthermore, high pulmonary concentrations of CXCR3 chemokines such as CXCL9 and CXCL10, downstream of JAK-dependent IFN signaling, are associated with worse prognosis in lung transplant patients (Shino et al,PLOS One,2017,12(7),e0180281). Systemic JAK inhibition has been shown to be effective in kidney transplant rejection (Vicenti et al.,American Journal of Transplantation,2012,12,2446-56). Thus, JAK inhibitors may be effective in preventing or delaying lung transplant rejection and CLAD. Similar T cell activation events described as the basis of lung transplant rejection are also thought to be the main drivers of pulmonary graft-versus-host disease (GVHD), which can occur after hematopoietic stem cell transplantation. Similar to CLAD, pulmonary GVHD is a chronic progressive condition with extremely poor outcomes and no currently approved treatments. A retrospective multicenter surveillance study of 95 patients with steroid-refractory acute or chronic GVHD who received the systemic JAK inhibitor ruxolitinib as salvage therapy demonstrated complete or partial responses to ruxolitinib in the majority of patients, including those with pulmonary GVHD (Zeiser et al, Leukemia, 2015, 29, 10, 2062-68). Because systemic JAK inhibition is associated with severe adverse events and a small therapeutic index, there remains a need for inhaled lung-directed nonsystemic JAK inhibitors to prevent or delay lung transplant rejection or pulmonary GVHD. Compound 1 possesses the characteristics required to meet this need. More recently, with the increased use of immune checkpoint inhibitors, another T cell-mediated lung disease, immune checkpoint inhibitor-induced pneumonia, has emerged. Cancer patients treated with these T cell stimulants can develop fatal pneumonia.

[0132] The mixed lymphocyte reaction assay is an in-vitro assay that mimics transplant rejection. Compound 1 was shown to effectively inhibit IFNγ secretion.

[0133] Thus, in some embodiments, the present disclosure provides a method for treating a respiratory disorder in a subject in need thereof when the subject is receiving high flow oxygen through a nasal cannula, the method comprising administering to the subject a pharmaceutical composition comprising Compound 1, or a pharma- ceutically acceptable salt thereof, by oral aerosol inhalation while the subject is receiving high flow oxygen through a nasal cannula at a rate of about 30 L / min or greater.

[0134] In some embodiments, the respiratory disorder is selected from the group consisting of coronavirus infection, lung transplant rejection, asthma, chronic obstructive pulmonary disease, cystic fibrosis, pneumonia, idiopathic pulmonary fibrosis, acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans, sarcoidosis, eosinophilic disease, helminth infection, pulmonary arterial hypertension, lymphangioleiomyomatosis, bronchiectasis, infiltrative lung disease, drug-induced pneumonia, fungal pneumonia, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, eosinophilic granulomatosis with polyangiitis, idiopathic acute eosinophilic pneumonia, idiopathic chronic eosinophilic pneumonia, hypereosinophilic syndrome, Löffler's syndrome, bronchiolitis obliterans with organizing pneumonia, pulmonary graft-versus-host disease, and immune checkpoint inhibitor-induced pneumonia. In some embodiments, the respiratory disorder is asthma or chronic obstructive pulmonary disease. In some embodiments, the respiratory disorder is asthma. In some embodiments, the asthma is moderate to severe asthma. In some embodiments, the asthma is mild to moderate asthma. In some embodiments, the asthma is Th2 high asthma. In some embodiments, the asthma is Th2 low asthma. In some embodiments, the respiratory disorder is chronic obstructive pulmonary disease. In some embodiments, the respiratory disorder is lung transplant rejection. In some embodiments, the respiratory disorder is coronavirus infection.

[0135] In some embodiments, the disclosure provides a method of preventing or delaying lung transplant rejection in a subject in need thereof when the subject is receiving high flow oxygen through a nasal cannula, the method comprising administering to the subject a pharmaceutical composition comprising Compound 1, or a pharma- ceutically acceptable salt thereof, by oral nebulization inhalation while the subject is receiving high flow oxygen through a nasal cannula at a rate of about 30 L / min or greater. In some embodiments, the lung transplant rejection is selected from the group consisting of primary graft dysfunction, organizing pneumonia, acute rejection, lymphocytic bronchiolitis, and chronic lung transplant dysfunction. In some embodiments, the lung transplant rejection is acute lung transplant rejection. In some embodiments, the lung transplant rejection is chronic lung transplant dysfunction. In some embodiments, the lung transplant rejection is selected from the group consisting of bronchiolitis obliterans, restrictive chronic lung transplant dysfunction, and neutrophilic graft dysfunction. In some embodiments, the pharmaceutical composition is administered by inhalation.

[0136] The present disclosure further provides a method of treating asthma in a subject in need thereof when the subject is receiving high flow oxygen through a nasal cannula, the method comprising administering to the subject a pharmaceutical composition comprising Compound 1, or a pharma- ceutically acceptable salt thereof, by oral aerosol inhalation while the subject is receiving high flow oxygen through a nasal cannula at a rate of about 30 L / min or greater.

[0137] When used to treat asthma, compound 1 is typically administered in a single dose or multiple doses per day, although other dosage forms may also be used. The amount of active agent administered per dose or the total amount administered per day is typically determined by a physician in light of the relevant circumstances, including the condition being treated, the selected administration route, the age, weight and response of the individual subject, the severity of the subject's symptoms, etc.

[0138] The present disclosure further provides a method of treating a respiratory disorder (including but not limited to those described herein) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising Compound 1, or a pharma- ceutically acceptable salt thereof, by oral aerosol inhalation while the subject is receiving high-flow oxygen through a nasal cannula at a rate of about 30 L / min or greater.

[0139] When used to treat respiratory disorders (including but not limited to those described herein), Compound 1 is typically administered in a single dose or multiple doses per day, although other dosage forms may be used. The amount of active agent administered per dose or the total amount administered per day is typically determined by a physician in light of the relevant circumstances, including the condition being treated, the selected route of administration, the age, weight and response of the individual subject, the severity of the subject's symptoms, etc.

[0140] Human coronaviruses are common respiratory pathogens that typically induce mild upper respiratory tract disease. Two highly pathogenic viruses, severe acute respiratory syndrome-related coronavirus (SARS-CoV-1) and Middle East respiratory syndrome-related coronavirus (MERS-CoV), have caused severe respiratory syndromes with mortality rates exceeding 10% and 35%, respectively (Assiri et al., N Engl J Med., 2013, 369, 407-1). The recent emergence of coronavirus disease 2019 (COVID-19) and the resulting pandemic have created a global medical emergency. Similar to SARS-CoV-1 and MERS-CoV, a subset of patients (~16%) may develop severe respiratory disease manifested by acute lung injury (ALI) (~5%) leading to ICU admission, respiratory failure (~6.1%) and death (Wang et al., JAMA, 2020, 323, 11, 1061-1069; Guan et al., N Engl J Med., 2020, 382, ​​1708-1720; Huang et al., The Lancet, 2020.395(10223), 497-506; Chen et al., The Lancet, 2020, 395(10223), 507-13). A subgroup of COVID-19 patients appears to have a hyperinflammatory “cytokine storm” leading to acute lung injury and acute respiratory distress syndrome (ARDS). This cytokine storm can also spread to the systemic circulation, leading to sepsis and ultimately multiple organ dysfunction syndrome. The abnormal cytokine signaling seen in COVID-19 is characterized by increased expression of interferons (IFNs), interleukins (ILs), and chemokines, leading to ALI and associated mortality.

[0141] Infection with mouse-adapted strains of 2003 SARS-CoV-1 and 2012 MERS-CoV, as well as transgenic mice expressing the human SARS-CoV-1 receptor hACE2 infected with human SARS-CoV-1, show elevated JAK-dependent cytokines such as IFNγ, IL-6, and IL-12, and downstream chemokines such as chemokine (CC motif) ligand 10 (CCL10), CCL2, and CCL7 (McCray et al., J Virol., 2007, 81(2), 813-21; Gretebeck et al., Curr Opin Virol. 2015, 13, 123-9.; Day et al., J Virol., 2013, 117-12; al.,Virology.2009,395(2),210-22. Recently, it has been shown that, similar to SARS-CoV-1 and MERS-CoV, patients with severe COVID-19 have elevated Th17, which can be driven by IL-6 and IL-23 via signal transducer and activator of transcription 3, STAT3 (Huang et al.,Lancet 2020,395,497-506). Mouse Th17 cells produce large amounts of IL-17 in response to IL-23, which can be blocked with JAK inhibitors (Wu et al.,J Microbiol Immunol Infect.,2020,S1684118220300657). Although IFN responses can be protective in viral infections, there is evidence that a delayed response in humans contributes to virus-induced acute respiratory distress syndrome (Chen et al.,Annu Rev Immunol.,2007,25(1),443-72). Similarly, mice lacking the IFNα / β receptor IFNR1 are protected from lethal SARS-CoV-1 infection (Channappanavar R, Fehr AR, Vijay R, Mack M, Zhao J, Meyerholz DK,et al.Dysregulated Type I Interferon).

[0142] Concerns have also been raised about a possible increased risk of thromboembolism with systemic JAK inhibitors, which is of particular concern given the observation of severe hypercoagulability in patients with COVID-19.

[0143] Compound 1 is a lung-selective, inhaled pan-JAK inhibitor that addresses the shortcomings of oral JAK inhibitors by avoiding systemic immunosuppression, thromboembolism, and further infections that lead to worsening mortality.

[0144] Additionally, compound 1 has been used and can be used alone or in combination with standard treatments including remdesivir and corticosteroids such as dexamethasone.

[0145] Compound 1 acts via a mechanism of action that may attenuate the cytokine storm associated with coronavirus infection.

[0146] Compound 1 is being tested in a Phase 2 clinical trial in subjects infected with COVID. There was no statistically significant difference between Compound 1 and placebo in RFD from randomization to day 28 in the ITT (median: 21 vs. 21 days, p=0.61), no difference in the change from baseline at day 7 in the SaO2 / FiO2 ratio, the proportion of subjects in each category of the 8-point clinical status scale, and the proportion of subjects alive and free of respiratory failure at day 28, but Compound 1 showed a favorable trend for improvement when compared to placebo in 28-day all-cause mortality (total deaths: 6 vs. 13, HR: 0.42, p=0.08) and time to recovery (median: 10 vs. 11 days, HR: 1.27, p=0.12).

[0147] Importantly, in a post-hoc analysis of subjects with baseline CRP (n=201), in subjects with CRP<150 mg / L (n=171), there were the following improvements in subjects treated with Compound 1 when compared to placebo: -28-day all-cause mortality (total mortality: 1 vs. 9, HR: 0.097, p=0.009) - Time to recovery (median: 10 vs. 11 days, HR: 1.48, p=0.02)

[0148] In subjects with CRP>150 mg / L (n=30), there was no difference in time to recovery or 28-day all-cause mortality between subjects treated with Compound 1 or placebo.

[0149] Thus, Compound 1 is particularly suited for treating the subpopulation of subjects with baseline CRP (C-reactive protein) levels of less than 150 mg / L. In some embodiments, the subject has a baseline C-reactive protein level of about 150 mg / L or less.

[0150] C-reactive protein (CRP) is a protein found in plasma whose circulating concentrations are elevated in response to inflammation. It is an acute-phase protein of hepatic origin that is increased following secretion of interleukin-6 by macrophages and T cells. In healthy adults, normal concentrations of CRP vary between 0.8 mg / L and 3.0 mg / L. However, some healthy adults have shown CRP elevations of 10 mg / L.

[0151] Compound 1 was well tolerated. Adverse events and serious adverse events occurred in 34.0% and 9.7% of subjects treated with Compound 1, and 41.2% and 15.7% of subjects treated with placebo, respectively. Adverse events of liver abnormalities or disease occurred in 9.7% and 7.8% of subjects treated with Compound 1 and placebo, respectively. Serious infections and venous thromboembolism occurred in 1.0% and 0% of subjects treated with Compound 1, and 2.0% and 4.9% of subjects treated with placebo, respectively.

[0152] Plasma exposure of compound 1 was low, consistent with what would be expected for a lung-selective drug.

[0153] Furthermore, coronaviruses enter host cells by fusing with the cell membrane, a necessary step for viral replication. Abelson kinase inhibitors have been reported to be potent inhibitors of SARS-CoV-1 and MERS-CoV fusion (Coleman et al., Journal of Virology, 2016, 90, 19, 8924-8933; Sisk et al., Journal of General Virology, 2018, 99, 619-630), supporting that Abelson kinase inhibitors may be useful in treating coronavirus-infected patients by reducing their viral load. Compound 1 has been shown to potently inhibit Abl2.

[0154] Thus, without being limited to this theory, Compound 1 may be uniquely suited for the treatment of coronavirus as a compound that can be selectively delivered to the lungs, has pan-JAK inhibitory activity that can attenuate the cytokine storm associated with COVID-19, and has Abelson kinase inhibitory activity that can reduce coronavirus viral load in a subject.

[0155] In some embodiments, the disclosure provides a method for treating a SARS-CoV-2 pulmonary infection in a subject in need thereof, the method comprising administering to the subject by oral nebulization inhalation a pharmaceutical composition comprising nezulcitinib, or a pharma- ceutically acceptable salt thereof, while the subject is receiving high-flow oxygen through a nasal cannula at a rate of about 30 L / min or greater.

[0156] Abl kinase has also been reported to play a positive role in regulating endothelial barrier function and vascular leakage during acute lung injury. Therefore, compound 1, or its pharma- ceutical acceptable salts, may also act by enhancing endothelial cell-cell contacts and promoting adhesion of endothelial cells to the extracellular matrix.

[0157] Another hypothesis is that compound 1 may have a direct effect on coronaviruses, counteracting or mitigating the increased localized viral replication that may be caused by the use of compounds that cause immune suppression.

[0158] It has also been reported that the ability of neutrophils to form neutrophil extracellular traps (NETs) may contribute to organ damage and mortality in COVID-19 patients (Barnes et al., J. Exp. Med., 2020, 217, 6, e20200652, 1-7). Aberrant NET formation is associated with lung disease, thrombosis, airway mucus secretion, and cytokine production. Thus, compound 1, or a pharma- ceutically acceptable salt thereof, may be useful for (a) blocking or inhibiting neutrophilia and / or neutrophil extracellular trap (NET) formation in coronavirus-infected subjects, (b) reducing the risk of thrombosis in coronavirus-infected subjects, and / or (c) reducing the incidence of thrombosis in a coronavirus-infected subject population.

[0159] Multisystem inflammatory syndrome in children (MIS-C) is a condition in which various parts of the body become inflamed, including the heart, lungs, kidneys, brain, skin, eyes, or digestive tract. MIS-C has been linked to exposure to COVID-19 and appears to be a rare but serious complication associated with COVID-19. MIS-C involves inflammation of the lungs. Compound 1 is therefore expected to be useful in preventing or treating MIS-C.

[0160] Furthermore, respiratory epithelial cell death due to influenza virus infection is responsible for the induction of inflammatory responses. It has been shown that influenza A virus infection induces pyroptosis and apoptosis of respiratory epithelial cells via the type I interferon signaling pathway (Lee et al., Journal of Virology, 2018, 92, 14, e00396-18). The type I interferon (IFN)-mediated JAK-STAT signaling pathway promotes the switch from apoptosis to pyroptosis, possibly by inhibiting apoptosis via induction of the expression of the Bcl-xL anti-apoptotic gene. Furthermore, inhibition of JAK-STAT signaling suppressed pyroptosis but enhanced apoptosis in infected PL16T cells. This suggests that the type I IFN signaling pathway plays an important role in inducing pyroptosis but suppressing apoptosis in respiratory epithelial cells to initiate a pro-inflammatory response to influenza virus infection. Thus, the compound of formula 1, or a pharma- ceutical acceptable salt thereof, is expected to be useful for treating subjects infected with influenza. Based on its mechanism of action, the compound of formula 1, or a pharma- ceutically acceptable salt thereof, is expected to prevent or treat pulmonary inflammation and / or ALI and / or ARDS in subjects infected with influenza.

[0161] Also provided herein is the use of Compound 1 in medical therapies and the manufacture of formulations or medicaments for treating, preventing, delaying, or ameliorating diseases and disorders suitable for treatment with a JAK inhibitor, particularly respiratory disorders, lung transplant rejection, and coronavirus infections.

[0162] Combination therapy In some embodiments, the methods described herein include administering one or more additional therapeutic agents or treatments to the subject.Compound 1, or its pharmaceutically acceptable salt, can be used in combination with one or more additional therapeutic agents or treatments that act by the same or different mechanisms to treat disease.Different therapeutic agents or treatments can be administered sequentially or simultaneously, in separate compositions or in the same composition. Classes of therapeutic agents useful in combination therapy include IL-6 inhibitors, IL-6 receptor antagonists, IL-6 receptor agonists, IL-2 inhibitors, antivirals, anti-inflammatory agents, sodium-glucose cotransporter 2 inhibitors, vaccines, ACE2 inhibitors, antibiotics, antiparasitics, sphingosine 1-phosphate receptor modulators, TMPRSS2 inhibitors, TNF alpha inhibitors, anti-TNF, membrane hemagglutinin fusion inhibitors, inhibitors of terminal glycosylation of ACE2, CCR5 inhibitors, stem cells, allogeneic mesenchymal stem cells, CRISPR therapy, CAR-T therapy, TCR-T therapy, virus-neutralizing monoclonal antibodies, protease inhibitors, SARS-CoV-2 antibodies, siRNA, plasma-derived immunoglobulin therapy, S protein modulators, PLX stem cell therapy, chimeric humanized viral inhibitors, multipotent adult progenitor cell therapy, anti-viroporins, umbilical cord-derived mesenchymal stem cells, polymerase inhibitors, autologous adipose-derived mesenchymal stem cells, angiotensin-converting Enzyme 2 inhibitors, immunoglobulin agonists, nucleoside reverse transcriptase inhibitors, cytotoxic T lymphocyte protein-4 inhibitors, pulmonary surfactant associated protein D modulators, protease inhibitors, nuclear factor kappa B inhibitors, xanthine oxidase inhibitors, endoplasmin modulators, CCL26 gene inhibitors, TLR modulators, TLR agonists, TLR-2 agonists, TLR-6 agonists, TLR-9 agonists, TLR-4 agonists, TLR-7 agonists, TLR-3 agonists, opioid receptor antagonists, moesin inhibitors, angiotensin-converting enzyme 2 modulators, MEK protein kinase inhibitors, CD40 ligand receptor agonists, CD70 antigen modulators, amyloid protein deposition inhibitors, apolipoprotein gene stimulators, bromodomain-containing protein 2 inhibitors, bromodomain-containing protein 4 inhibitors, IL-15 receptor agonists,Immunoglobulin gamma Fc receptor III agonists, MEK-1 protein kinase inhibitors, Ras gene inhibitors, interferon beta ligands, galectin-3 inhibitors, heat shock protein inhibitors, elongation factor 1 alpha 2 modulators, VEGF-1 receptor modulators, angiotensin II AT-2 receptor agonists, Basigin inhibitors, viral envelope glycoprotein inhibitors, gelsolin stimulating factor, trypsin inhibitors, GM-CSF ligand inhibitors, urokinase plasminogen activator inhibitors, serine protease inhibitors, PDE3 inhibitors, PDE4 inhibitors, C-reactive protein inhibitors, chemokine CC22 ligand inhibitors, GM-CSF receptor antagonists, hemoglobin capture receptor antagonists, metalloprotease 1 inhibitors, metalloprotease 3 inhibitors, metalloprotease inhibitors, small molecule inducible cytokine A17 ligand inhibitors, VEGF gene inhibitors, coronavirus spike glycoprotein inhibitors, nuclear protein inhibitors, ATP-binding cassette transporter B5 modulators, vimentin modulators, stem cell antigen 1 inhibitors, casein kinase II inhibitors, complement C5a factor inhibitors, aldose reductase inhibitors, calpain-I inhibitors, calpain-II inhibitors, calpain-IX inhibitors, proto-oncogene Mas agonists, non-nucleoside reverse transcriptase inhibitors, interferon gamma ligand inhibitors, CD4 modulators, TGFB2 gene inhibitors, interleukin-1 beta ligand inhibitors, inosine monophosphate dehydrogenase inhibitors, angiotensin-converting enzyme 2 stimulators, adenosine A3 receptor agonists, palmitoyl protein thioesterase 1 inhibitors, Btk tyrosine kinase inhibitors, NK1 receptor antagonists, acetaldehyde dehydrogenase inhibitors, CGRP receptor antagonists, prostaglandin E synthase-1 inhibitors, VIP receptor agonists, nuclear factor kappa B gene modulators, Grp78 calcium-binding protein inhibitors, Jun N-terminal kinase inhibitors, transferrin modulators, p38 MAP kinase modulators, CCR5 chemokine antagonists, APOA1 gene stimulators, bromodomain-containing protein 2 inhibitors, bromodomain-containing protein 4 inhibitors, BMP10 gene inhibitors,BMP15 gene inhibitors, adrenergic receptor antagonists, human papillomavirus E6 protein modulators, human papillomavirus E7 protein modulators, Ca2+ release-activated Ca2+ channel 1 inhibitors, amyloid protein deposition inhibitors, gamma-secretase inhibitors, 2,5-oligoadenylate synthetase stimulators, interferon type I receptor agonists, ribonuclease stimulators, S-phase kinase-associated protein 2 inhibitors, dehydropeptidase-1 modulators, calcium channel modulators, signal transduction inhibitors, CD24 modulators, cyclin E inhibitors, cyclin-dependent kinase-2 inhibitors, cyclin-dependent kinase-5 inhibitors, cyclin-dependent kinase-9 inhibitors, GM-CSF ligand inhibitors, interferon receptor modulators, interleukin-29 ligands, cyclin-dependent kinase-7 inhibitors, MCL1 gene inhibitors, complement factor C5 inhibitors, heparin agonists, exo-alpha-sialidase modulators, muscarinic receptor antagonists, IL-8 receptor antagonists, vitamin D3 receptor agonists, high mobility group Protein B1 inhibitors, CASP8-FADD-like regulator inhibitors, ecto-NOX disulfide thiol exchanger 2 inhibitors, sphingosine kinase inhibitors, sphingosine-1-phosphate receptor-1 antagonists, stimulator of interferon genes protein, topoisomerase inhibitors, X-linked inhibitor of apoptosis protein inhibitor, angiopoietin-2 inhibitors, neuropilin 2 inhibitors, listeriolysin stimulator of interferon gamma receptor agonists, MAPK gene modulators, GM-CSF ligand inhibitors, immunoglobulin G receptor inhibitors, Immunoglobulin G1 modulators, immunoglobulin kappa modulators, kallikrein modulators, mannan-binding lectin serine protease inhibitors, ubiquitin modulators, IL12 gene stimulators, xanthine oxidase inhibitors, dihydroorotate dehydrogenase inhibitors, IL-17 antagonists, MAP kinase inhibitors, PARP inhibitors, poly ADP-ribose polymerase 1 inhibitors, poly ADP-ribose polymerase 2 inhibitors, dipeptidyl peptidase I inhibitors, Btk tyrosine kinase inhibitors, type I IL-1 receptor antagonists,Exportin 1 inhibitors, Hyaluronidase inhibitors, Sodium glucose transporter-2 inhibitors, Dihydroceramide delta 4 desaturase inhibitors, Sphingosine kinase 2 inhibitors, Interferon beta ligands, ICAM-1 stimulators, TNF antagonists, Vascular cell adhesion protein 1 agonists, COVID-19 spike glycoprotein modulators, Complement C1s subcomponent inhibitors, NMDA receptor epsilon 2 subunit inhibitors, Tankyrase-1 inhibitors, Protein translation initiation inhibitors, Sigma receptor modulators, Sigma R1 receptor modulators, Sigma R2 receptor modulators, Antihistamines, Anti-C5aR, RNAi. Corticosteroids, BCR-ABL, Tyrosine kinase inhibitors, Colony stimulating factors, Inhibitors of tissue factor (TF), Recombinant granulocyte-macrophage colony stimulating factor (GM-CSF), Gardos channel blockers, Heat shock protein 90 (Hsp90) inhibitors, Alpha blockers, Cap-binding complex modulators modulators, LSD1 inhibitors, CRAC channel inhibitors, RNA polymerase inhibitors, CCR2 antagonists, DHODH inhibitors, blood thinners, anticoagulants, factor Xa inhibitors, SSRIs, SNRIs, sigma-1 receptor activators, beta blockers, caspase inhibitors, serine protease inhibitors, IL-23A modulators, NLRP3 inhibitors, angiopoietin-Tie2 signaling pathway modulators, mannan-binding lectin-associated serine protease-2 modulators, PDE These include, but are not limited to, PD-1 / PD-L1 checkpoint inhibitors, vasoactive intestinal polypeptide, microtubule depolymerizing agents, (PD)-1 checkpoint inhibitors, Axl kinase inhibitors, (PD)-1 / PD-L1 checkpoint inhibitors, PD-L1 checkpoint inhibitors, T cell CD6I receptor modulators, factor XIIa antagonists, oral spleen tyrosine kinase (SYK) inhibitors, CK2 inhibitors, NMDA receptor antagonists, SK2 inhibitors, antiandrogens, and tankyrase-2 inhibitors.

[0163] Specific therapeutic agents that may be used in combination with Compound 1 include cidofovir triphosphate, cidofovir, abacavir, ganciclovir, stavudine triphosphate, 2'-O-methylated UTP, desidustat, amphotericin, sodium trans crocetinate, CT-P59, Ab8, heparin, apixaban, GC373, GC376, oleandrin, GS-441524, sertraline, lanadelumab, zircoplan, abatacept, CLBS119, ranitidine, risankizumab, AR-711, AR-701, MP0423, and bempegaldesleukin. , Melatonin, Carvedilol, Mercaptopurine, Paroxetine, Casirivimab, Imdevimab, ADG20, Emricasan, Dapanstril, Cenicriviroquinfliximab, DWRX2003, AZD7442, MAN-19, LAU-7b, Niclosamide, ANA001, Fluvoxamine, Narsoplimab, Sarconeos, GIGA-2050, VERU-111, REGN-COV2, Icatibant, Cenicriviroc, NTR-441, LAM-002A, Oseltamivir, VHH72-Fc, MK-4482, EB05, OB-00 2, CM-4620-IE, IMU-838, SNG001, NT-17, BOLD-100, WP1122, itolizumab, PB1046, fostamatinib, colchicine, M5049, EDP1815, ABX464, CPI-006, azelastine, galadacimab, silmitasertib, lopinavir, ritonavir, remdesivir, chloroquine, hydrochloroquine, convalescent plasma transfusion, azithromycin, tocilizumab, famotidine, sarilumab, interferon beta, interferon beta-1a, interferon beta-1b, peginterferon Feron lambda-1a, Favipiravir, ASDC-09, Dapagliflozin, CD24Fc, Ribavirin, Umifenovir, Nitric oxide, APN01, Teicoplanin, Oritavancin, Dalbavancin, Monensin, Ivermectin, Darunavir, Cobicistat, Fingolimod, Camostat, Galidecil, Thalomid, Leronlimab, Remestemcel-L, Canakinumab, TAK-888, Azuvudine, BPI-002, AT-100, T-89, Neumifil, GreMERSfi, Liposomal curcumin, OYA-1, Oxypurinol,Mosedipimod, PUL-042, naltrexone, metenkephalin, COVID-EIG, TNX-1800, ATR-002, 177Lu-EC-amifostine, 99mTc-EC-amifostine, apabetalone, STI-6991, STI-4398, antroquinonol, ZIP-1642, DPX-COVID-19, belapectin, GX-19, AdCOVID, siltuximab, IBIO-200, plitidepsin, C-21, meplasmab, pathogen-specific aAPC, LV-SMENP-DC, ARMS-I, rhu-pGSN, PRTX-007, CK-0802, namilumab, upamostat, NI-007, COVID-HIG, CYNK-001, nafamo Stat, Brilacidin, Mavrilimumab, IPT-001, PittCoVacc, Allo-APZ2-Covid19, ENU-200, VIR-7832, VIR-7831, Pritumumab, Ampion, TZLS-501, Sodium Pyruvate, Silmitasertib, CoroFlu, BDB-1, AT-001, BLD-2660, 20-Hydroxyecdysone, IFX-1, Elsulfavirine, Emapalumab, CEL-1000, Travedersen, VBI-2901, ASC-09, TJM-2, RPH-104, Tranexamic Acid, WP-1122, Olokizumab, APN-01, Danoprevir, Piclidenoson, FW-1022, CORAVAX, Lamellasome COVID-19, COVID-19 XWG-03, EIDD-2801, AVM-0703, DC-661, acalabrutinib, bitespiramicin, Allocetra, tradipitant, bacTRL-Tri, Ad5-nCoV, EPV-CoV19, ADX-629, zavegepant, mercaptamine, sonlichromanol, aviptadil, fenretinide, IT-139, nitazoxanide, apabetalone, lucinactant, bacTRL-Spike, SAB-185, NVX-CoV2373, CM-4620, INO-4800, eicosapentaenoic acid, itanapracedide, lintatolimod, XAV-19, niclosamide, ciclesonide, DAS181, ORBCEL-C, Metablok, dantrolene, CD24-IgFc, fadracilib, gimsilumab, celiclib, Cyto-MSC, ST-266,MRx-0004, ravulizumab, tafoxiparin, DAS-181, BMS-986253, cholecalciferol, nafamostat, ChAdOx1 nCoV-19, idronoxyl, LY-3127804, ATYR-1923, VPM-1002, Mycobacterium w, lenzilumab, Polyoxidonium, conestat alpha, ubiquitin proteasome modulator, COVID-19 virus main protease Mpro inhibitor, mRNA-1273, clevudine, bucillamine, sodium metaarsenite, bidofludimus, DARPin, COV-ENT-1, KTH-222, mefparib, brensocative, zanubrutinib, anakinra, serinexol, sarilumab, a Stridrimer, dapagliflozin propanediol, opaganib, BNT-162c2, BNT-162b2, BNT-162b1, BNT-162a1, ifenprodil, PIC1-01, 2X-121, zotatifin, aplidine, cloperastine, clemastine, dosiparstat, abdoralimab, VIR-2703, ALN-COV, intravenous immunoglobulin (IVIg), apremilast, biclomac, baloxavir Marboxil, emtricitabine, tenofovir, novaferon, secukinumab, valsartan, imatinib, omalizumab, leucine, sovosbuvir, alovudine, zidovudine, R-107, AB-201, sargramostim, LYT-100, senicapoc, fluvoxamine, aspirin, losartan, ADX-1612, ADX-629, cilikumab, otilimab, STI-1499, TR-C19, ABX-464, interferon alfa 2b, arbidol, S309, bufidemstat, AT-5 27, ibudilast, Orsola, bemcentinib, eculizumab, JS016, FSD-201, LY-CoV555, avifavir, OP-101, RLF-100, DMX-200, 47D11, Remsima, TYR1923, dexamethasone, EDP-1815, PTC29, ravexim, foralumab, budesonide, molnupiravir, ensovibep, dalcetrapib, FSD201, pralatrexate, proxalutamide, clofazimine, and merimepodib.

[0164] In some embodiments, the JAK inhibitor, or a pharmaceutically acceptable salt thereof, is used in combination with an antiviral agent and / or a corticosteroid. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used in combination with an antiviral agent. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used in combination with a corticosteroid. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used in combination with an antiviral agent and a corticosteroid. In some embodiments, the antiviral agent is remdesivir. In some embodiments, the antiviral agent is favipiravir. In some embodiments, the antiviral agent is molnupiravir. In some embodiments, the antiviral agent is ritonavir boosted nilumatruvir. In some embodiments, the corticosteroid is dexamethasone.

[0165] Also provided herein is a pharmaceutical composition comprising a JAK inhibitor, or a pharma- ceutically acceptable salt thereof, and one or more other therapeutic agents. Also provided herein is a pharmaceutical composition comprising Compound 1, or a pharma- ceutically acceptable salt thereof, and one or more other therapeutic agents. The therapeutic agent may be selected from the above-identified classes of drugs and the above-specified drug list. In some embodiments, the pharmaceutical composition is suitable for pulmonary delivery. In some embodiments, the pharmaceutical composition is suitable for inhalation or nebulization administration. In some embodiments, the pharmaceutical composition is a dry powder or liquid composition.

[0166] For all of the methods described herein, the method includes administering to a subject a JAK inhibitor, or a pharma- ceutically acceptable salt thereof, and one or more other therapeutic agents.Furthermore, for all of the methods described herein, the method includes administering to a subject Compound 1, or a pharma- ceutically acceptable salt thereof, and one or more other therapeutic agents.

[0167] When used in combination therapy, the agents may be formulated in a single pharmaceutical composition, or the agents may be provided in separate compositions that are administered at the same time or at different times, by the same or different routes of administration.Such compositions may be packaged separately, or may be packaged together as a kit.Two or more therapeutic agents in the kit may be administered by the same or different routes of administration. EXAMPLES

[0168] Example 1 - Clinical Trial: A Phase 1, Open-Label Study Evaluating the Pharmacokinetics and Safety of Inhaled Nedulcitinib Administered in the Setting of a Supplemental Oxygen Scenario in Healthy Participants Test Purpose Part A: Evaluated nezulcitinib plasma PK following a single inhaled dose administered in the setting of various supplemental oxygen scenarios in healthy participants. Part B: The safety and tolerability of nezulcitinib after a single inhaled dose administered in the setting of various supplemental oxygen scenarios in healthy participants was evaluated.

[0169] This was a phase 1, open-label, fixed-sequence, 4-period study to evaluate the PK and safety of a single inhaled dose of nezulcitinib administered under different supplemental oxygen scenarios.

[0170] In subjects hospitalized with ALI due to COVID-19, supplemental oxygen is commonly used and may be coadministered with nezulcitinib in clinical settings. High-flow supplemental oxygen is known to reduce the delivered dose of inhaled medications. Therefore, evaluating the safety and PK of inhaled nezulcitinib administered in the setting of various supplemental oxygen scenarios in healthy participants was important to guide possible dose adjustments and dosing instructions in future studies.

[0171] Study participants Fourteen healthy adult male and female participants were enrolled. Participants met all of the following inclusion criteria: Healthy adult men and women, aged 18 to 65 years at the time of the screening visit. Pregnancy Concerns: o Female subjects must not be of childbearing potential, or if of childbearing potential, not be pregnant or nursing, and agree to use highly effective contraception throughout the study and until 30 days after the final dose of nezulcitinib. o Male subjects must agree to use condoms to prevent potential exposure to a fetus or partner via semen, and must also agree to use highly effective pregnancy prevention measures with female partners of reproductive potential throughout the study and until 30 days after the final dose of nezulcitinib. Body mass index (BMI) of 18.0 kg / m at the screening visit 2 More than 35.0kg / m 2 or less and weigh at least 50 kg at the time of the screening visit. Be medically healthy, free of clinically significant medical history, physical exam, spirometry, laboratory profile, vital signs, or ECG at screening and prior to Phase 1 dosing, as deemed by the investigator or designee, including: o Liver function tests (i.e., alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], gamma-glutamyltransferase [GGT], and bilirubin) must be normal or below the upper limits deemed medically acceptable as determined by the investigator and sponsor's medical monitor. Absolute lymphocyte counts within normal range or as deemed medically acceptable by the investigator and Sponsor's medical monitor. Participants must have a negative QuantiFeron® Test result at screening. Forced expiratory volume in 1 second (FEV1) ≥ 80% predicted at screening. ·Able to understand and tolerate the use of a nebulizer device and breathing through the procedures required for supplemental oxygen at the Screening Visit and on Day -1 of Period 1. ·Understand the study procedures in the Informed Consent Form (ICF) and be willing and able to comply with the protocol.

[0172] Participants were free to withdraw from the study at any time for any reason and could be withdrawn from the study by the investigator following an adverse event or non-compliance with study criteria (e.g. pregnancy, drug or alcohol use).

[0173] Participant's participation period The length of study participation for each participant was approximately 50 days, consisting of a screening period up to 28 days prior to the first dose, followed by up to four treatment periods consisting of a single dose on Day 1 of each period, with a washout period of at least 5 days between each nezulcitinib dose, and a follow-up period of 7 days (± 2 days) after the last nezulcitinib dose.

[0174] The washout period was based on the PK of nezulcitinib, not on supplemental oxygen, because in healthy participants, the effects of supplemental oxygen (i.e., changes in pulse oximetry, respiratory rate, and blood pH) were expected to normalize within minutes after cessation of supplemental oxygen. The washout between doses was considered sufficient to prevent carryover effects of the preceding nezulcitinib dose.

[0175] Test Product The formulation, nezulcitinib inhalation solution, consisted of 3 mg of nezulcitinib in a sterile aqueous solution containing 10 mM citrate buffer with 150 mM sodium chloride at pH 4.0. It was a clear, colorless to yellow solution. The formulation was manufactured in a strength of 3 mg / mL (as free base equivalent). It was supplied in unit-dose low-density polyethylene (LDPE) vials manufactured by Blow-Fill-Seal (BFS) technology and individually packaged in sealed foil-laminated pouches. The formulation was administered using the Aerogen Solo nebulizer system (manufactured by Aerogen Limited, Ireland). The unit dose composition of the formulation (3 mg / 1 mL) is shown in Table 1. [Table 1]

[0176] Dosage, Formulation, Route, and Administration Regimen Participants received a single inhaled dose of nezulcitinib using a nebulizer device under different supplemental oxygen and fasting conditions on day 1 of each dosing period. The dosing was as follows: Administration A (study): Nezulinib 3 mg was delivered via nasal inhalation while supplemental oxygen was delivered at a flow rate of 30 L / min using an Aerogen Solo integrated into a high-flow nasal cannula circuit. Administration B (reference): Nedulcitinib 3 mg was delivered by oral inhalation via an Aerogen Solo interfaced with an Aerogen Ultra handheld device in the presence of supplemental oxygen delivery via a low-flow nasal cannula at 6 L / min. · Administration C (Study): Nedulcitinib 3 mg was delivered by oral inhalation via an Aerogen Solo interfaced with an Aerogen Ultra handheld device in the presence of supplemental oxygen delivery via a high-flow nasal cannula at 30 L / min. Dose D1 (study): 3 mg of nezulcitinib was delivered by oral inhalation via an Aerogen Solo connected to an Aerogen Ultra handheld device in the presence of supplemental oxygen delivery via a high-flow nasal cannula at 50 L / min. Dose D2 (study): Nezucitinib 9 mg was delivered by oral inhalation via an Aerogen Solo connected to an Aerogen Ultra handheld device in the presence of supplemental oxygen delivery via a high-flow nasal cannula at 50 L / min.

[0177] Time 0 was defined as the start of the nezulcitinib inhalation session for each dose administration.

[0178] Supplemental oxygen was administered approximately 5 minutes prior to the dose to allow participants to acclimate to the oxygen regimen corresponding to the duration of the dose they were about to receive.

[0179] The CRU pharmacy provided each dose in an individual unit-dose container for each participant and study period.

[0180] Single and multiple doses of nezulcitinib 1, 3, and 10 mg were found to be safe and well tolerated in healthy adult participants. Systemic exposure (AUC0–24) and Cmax increased dose-proportionally after single and multiple doses of nezulcitinib in the range of 1–10 mg. The 3 mg dose selected in this study was consistent with that of a recently completed Phase 2 study. Furthermore, the 3 mg dose ensured adequate characterization of the PK profile of nezulcitinib. Dose levels of nezulcitinib up to 9 mg were also evaluated (dose D2). This dose level was within the range of doses previously tested in healthy participants and participants with COVID-19 in previous clinical trials (up to 10 mg nezulcitinib).

[0181] Several factors are known to affect the delivery of inhaled medications administered in the presence of high-flow oxygen therapy, including the gas flow rate and the location of the nebulizer device within the high-flow circuit. Previous in vitro studies have shown that to maximize the amount of medication delivered during high-flow oxygen therapy, the gas flow rate should be low and the nebulizer should be placed just before or just after the humidification chamber. This scenario was evaluated in Administration A.

[0182] A flow rate of 30 L / min for doses A and C was chosen as being at the lower end of the clinically relevant range with the goal of maximizing drug delivery. Although oral inhalation in the presence of high-flow nasal oxygen therapy (administration C) has been shown to be suboptimal, this condition may be the most generalizable as it can be performed without the limitations of incorporating nebulizer devices into the various high-flow systems available and used in clinical settings worldwide.

[0183] Based on previous experience in Phase 2 trials of COVID-19, the reference condition of oral inhalation in the presence of low-flow nasal oxygen therapy (treatment B) was selected. The majority of subjects in this study received nezulcitinib in this setting. Furthermore, the plasma concentrations of nezulcitinib in this setting were found to be similar to those in healthy subjects when nezulcitinib was administered by oral inhalation in the absence of supplemental oxygen therapy.

[0184] Pharmacokinetic Sampling To determine plasma nezulcitinib concentrations, blood samples were collected pre-dose and serially up to 48 hours post-dose on Day 1 of each period.

[0185] Pharmacokinetic parameters and analysis The following non-compartmental PK parameters were calculated for nezulcitinib, as appropriate: plasma: AUC0~t: area under the concentration-time curve from time 0 to the last observed nonzero concentration, calculated by the linear trapezoidal method. AUC0~24: Area under the concentration-time curve from 0 to 24 hours, calculated by the linear trapezoidal method. AUC0~inf: area under the concentration-time curve extrapolated from time 0 to infinity. AUC0~inf was calculated as the sum of AUC0~t and the ratio of the last measurable plasma concentration to the elimination rate constant. · AUC%extrap: Percentage of AUC0~inf extrapolated, expressed as (1-AUC0~t / AUC0~inf)*100. · CL / F: Apparent total clearance after oral (extravascular) administration calculated as Dose / AUC0~inf. · Cmax: maximum observed concentration. · Tmax: time to reach Cmax. If the maximum occurs at more than one time point, Tmax is defined as the first time point having this value. Kel: Apparent first-order terminal elimination rate constant calculated from a semi-logarithmic plot of the plasma concentration versus time curve. The parameter was calculated by linear least-squares regression analysis using the maximum number of points in the terminal log-linear phase (e.g., 3 or more nonzero plasma concentrations). t 1 / 2 The apparent first-order terminal elimination half-life was calculated to be 0.693 / Kel. Vz / F: Apparent volume of distribution during terminal elimination after oral (extravascular) administration, calculated as Dose / (AUC0~inf*Kel).

[0186] The calculations of non-compartmental PK parameters for various nezulcitinib doses are shown in Table 2. [Table 2]

[0187] Kel, AUC0~inf, AUC%extrap, CL / F, Vz / F, or t 1 / 2 Values ​​were not reported for cases that did not show a terminal log-linear phase in the concentration-time profile.

[0188] PK parameters were not calculated for participants with fewer than three consecutive time points with detectable concentrations.

[0189] PK parameters were summarized by dose using descriptive statistics.

[0190] Analysis of variance (ANOVA) was performed on natural logarithm (ln) transformed AUC0~t, AUC0~24, AUC0~inf, and Cmax using appropriate statistical procedures.

[0191] Twelve participants were estimated to provide 90% power to detect a two-fold difference between the geometric mean values ​​of the PK parameters AUC0~inf of the study (A, C, or D) and the reference dose (B). Thus, similarity was concluded if the 90% confidence intervals (CIs) of the ratios of the geometric least squares means (LSMs) of AUC0~t, AUC0~inf, and Cmax of nezulcitinib fell between 0.50 and 2.00.

[0192] Safety assessment Safety was monitored by reported symptoms / AEs, vital signs, 12-lead safety ECG, spirometry, weight monitoring, pulse oximetry, clinical laboratory tests (including but not limited to hematology, clinical chemistry profile, coagulation and urinalysis), and a physical examination including at least examination of the respiratory, cardiovascular, and gastrointestinal systems, with the option for further focused testing of additional systems as needed based on AEs.

[0193] Safety analysis We performed the following analyses but did not perform formal inferential statistics on safety assessments.

[0194] Descriptive statistics were calculated for quantitative safety data, and frequency counts were compiled for qualitative safety data categories.

[0195] Adverse events AEs were coded using the most recent version of the Medical Dictionary for Regulatory Activities (MedDRA®).

[0196] A list of AE data for each participant was provided, including verbatim term, preferred term, system organ class (SOC), administration, severity, and relationship to drug.

[0197] Treatment-emergent adverse events (AEAEs) were summarized by SOC, preferred term, and frequency and percentage of participants reporting each observed event. The frequency of participants experiencing AEAEs was summarized overall, by study part, and by administration. AEs were also summarized by relationship to administration (study drug) and severity.

[0198] Medical History and Physical Examination Medical history was enumerated for each participant.

[0199] Clinically significant changes in physical examination were captured as AEs.

[0200] Laboratory test results, electrocardiogram, spirometry, pulse oximetry, and vital sign measurements All clinical laboratory results, 12-lead safety ECGs, spirometry measurements, pulse oximetry, vital sign measurements, and their changes from baseline were summarized by study portion, dose, and collection time point.

[0201] Concomitant medications Concomitant medications were coded using the most recent World Health Organization (WHO) drug dictionary and listed for each participant.

[0202] Test Design This was a phase 1, open-label, fixed-sequence, 4-period study to evaluate the PK and safety of a single inhaled dose of nezulcitinib administered under different supplemental oxygen scenarios.

[0203] Fourteen healthy adult male and female participants were enrolled. Participants were screened within 28 days prior to their first dose.

[0204] On day 1 of each period, participants received a single inhaled dose of nezulcitinib under one of the supplemental oxygen scenarios. Blood samples for assessment of plasma nezulcitinib concentrations were collected before and up to 48 hours after each nezulcitinib dose. There was a washout period of at least 5 days between each nezulcitinib dose.

[0205] Safety (i.e., physical examination, vital signs, 12-lead safety ECG, spirometry, clinical laboratory tests, and AEs) was assessed throughout the study, and blood, urine, and exhaled breath samples were collected for safety assessments. Blood oxygen levels were monitored by pulse oximetry before and during administration of supplemental oxygen. Participants were not substituted.

[0206] Remaining and Observation Participants were admitted to the Clinical Research Unit (CRU) on day -1 of each study period and remained until 48 hours on day 3 of each study period after completion of study assessments. Participants were admitted earlier than day -1 for COVID-19 testing not related to the study protocol, as required by the CRU. Participants may have been asked to remain in the CRU longer at the discretion of the investigator or designee. At site preference, participants were confined for the duration of the study (i.e., during the washout period).

[0207] All participants who received at least one dose of nezulcitinib (including those who terminated the study early) returned to the CRU 7 days (± 2) after their last dose of nezulcitinib for follow-up procedures to determine the presence or absence of AEs that occurred after the date of their last visit.

[0208] Study completion was defined as the date of the last scheduled study procedure.

[0209] Study Endpoints The study endpoints in Part A were AUC0~t, AUC0~24, AUC0~inf, AUC%extrap, Cmax, Tmax, CL / F, Vz / F, Kel, and t 1 / 2 Similarity was determined when the 90% confidence intervals of the geometric least squares mean ratios of AUC0~t, AUC0~inf, and Cmax of nezulcitinib were within 0.50 and 2.00.

[0210] Part B study endpoints were treatment-emergent adverse events, physical examination, vital signs, 12-lead safety ECG, spirometry, pulse oximetry, and clinical laboratory tests.

[0211] result All 14 subjects completed all 3 periods (treatment), and 13 subjects completed all 4 periods (1 subject withdrew consent after the end of period 3 due to personal schedule conflicts).

[0212] Seven subjects completed treatment D1 (3 mg dose of nezulcitinib via nebulized oral inhalation using a high-flow nasal cannula at a rate of 50 L / min) and six subjects completed treatment D2 (9 mg dose of nezulcitinib via nebulized oral inhalation using a high-flow nasal cannula at a rate of 50 L / min).

[0213] Adverse events occurred in two subjects (14.3%): two episodes of nasal congestion in one subject, and one episode of nosebleed in another. All adverse events were mild in severity and considered unrelated to the study drug. Furthermore, all adverse events resolved during the course of the study, and no adverse events led to discontinuation or withdrawal from the study.

[0214] Other Subject Safety Assessments: There were no clinically relevant changes seen in safety laboratory measurements (clinical chemistry and hematology parameters), safety electrocardiograms, vital sign assessments, pulse oximetry, or spirometry.

[0215] The plasma concentrations of nezulcitinib in subjects as a function of time are shown in Figures 1-6. Surprisingly, administration of 3 mg of nezulcitinib via nebulized oral inhalation in the presence of nasal high-flow oxygen at a flow rate of 30 L / min (administration C, test) resulted in a sustained increase in plasma concentrations when compared to nasal administration of 3 mg of nezulcitinib via a high-flow circuit at a flow rate of 30 L / min (administration A, test), and resulted in similar plasma concentrations when compared to nebulized oral inhalation of 3 mg of nezulcitinib in the presence of nasal low-flow oxygen at a flow rate of 6 L / min (administration B, reference), as can be seen in Figure 3.

[0216] Increasing the nasal high-flow oxygen cannula flow rate from 30 L / min (Dose C, Study) to 50 L / min (Dose D1, Study) did not affect plasma concentrations associated with administration of 3 mg nezulcitinib by nebulized oral inhalation. Furthermore, increasing the nebulized oral inhalation dose from 3 mg nezulcitinib (Dose D1, Study) to 9 mg nezulcitinib (Dose D2, Study) at a nasal high-flow oxygen cannula flow rate of 50 L / min resulted in an approximately dose-proportional increase in plasma concentrations, as can be seen in Figure 6.

[0217] As can be seen in Figure 4, subjects receiving a 3 mg dose of nezulcitinib by oral nebulization while receiving high-flow supplemental oxygen at a rate of 30 L / min via a high-flow nasal cannula (administration C, test) showed comparable plasma concentrations of active agent when compared to subjects receiving a similar 3 mg dose of nezulcitinib by oral nebulization while only receiving low-flow supplemental oxygen at a rate of 6 L / min (administration B, reference), indicating that administration of nezulcitinib by oral nebulization can provide adequate active agent to the subject's respiratory system regardless of the rate at which supplemental nasal oxygen is being administered in parallel. This result is further supported in Figure 5, where subjects receiving a 3 mg dose of nezulcitinib by oral nebulization while also receiving high-flow supplemental oxygen at a rate of 50 L / min via a high-flow nasal cannula (administration D1, test) showed similar plasma concentrations of nezulcitinib as subjects receiving administrations B or C.

[0218] In summary, administering a pharmaceutical composition comprising nezulcitinib, or a pharma- ceutically acceptable salt thereof, to a subject by oral nebulization while the subject is receiving high-flow oxygen through a nasal cannula at a rate of about 30 L / min or more has been found to be unexpectedly superior to administering through an in-line high-flow circuit, contrary to current recommendations in the art.Furthermore, administration by oral nebulization to subjects receiving high-flow and low-flow oxygen surprisingly results in similar exposure.Thus, it has now been found that administering a pharmaceutical composition comprising nezulcitinib, or a pharma-ceutically acceptable salt thereof, to a subject in need thereof via a high-flow nasal circuit is unnecessary and inferior to oral nebulization, and there is no need to reduce the flow of oxygen when the pharmaceutical composition is being administered to the subject.

[0219] Example 2 - Administration of Nezulcitinib Inhalation Solution to Subjects Receiving Oxygen via High Flow Nasal Cannula (HFNC) The nezulcitinib solution for inhalation used in this example is a clear, colorless to yellow solution, consisting of 3 mg of nezulcitinib in a sterile aqueous solution containing 10 mM citrate buffer with 150 mM sodium chloride at pH 4.0. The nezulcitinib inhalation solution is provided in unit-dose, low-density polyethylene (LDPE) vials manufactured by Blow-Fill-Seal (BFS) technology and individually packaged in sealed foil-laminated pouches. Each pouch contains one unit vial containing 1 mL of nezulcitinib inhalation solution at a concentration of 3 mg / mL. Pouches of nezulcitinib inhalation solution should be stored at 2°C to 8°C.

[0220] Nezulcitinib inhalation solution can be administered by oral inhalation using the Aerogen Solo+Ultra nebulizer system to subjects receiving supplemental oxygen via HFNC. Administration of nezulcitinib inhalation solution can follow the following representative procedure.

[0221] 1. If oxygen flow is greater than 50 L / min, reduce flow to 50 L / min, adjust FiO2 if necessary, and allow subject to acclimate to adjustments while preparing the equipment.

[0222] 2. Make sure you have all the supplies you need: (i) Aerogen Controller (can be used for multiple subjects) (ii) Aerogen Solo nebulizer (used for up to 1 week for each subject). (iii) A new Aerogen Ultra handset and filters (single use, daily discarded) (iv) 3 vials of nezulcitinib inhalation solution (3 mg of nezulcitinib per vial for a total dose of 9 mg)

[0223] 3. Verify that the subject ID number on the pouch label matches the subject ID of the subject receiving the dose and record the lot number, dose, and dose volume in the subject's source record.

[0224] 4. Assemble the Aerogen Solo nebulizer system according to the product instructions, leaving the medication reservoir open and connecting it to a clean Aerogen controller.

[0225] 5. Open each pouch of nezulcitinib inhalation solution and remove a vial. Open and remove one vial and squeeze the entire contents into the reservoir cup of the Aerogen Solo, then have the subject nebulize the contents of the vial (for approximately 3 minutes), repeating this 3 times for each of the 3 vials with a 1 minute break between each vial (see step 10 below). IMPORTANT: To avoid irritation from inhaling the aerosol if it is too cold, do not use nezulcitinib inhalation solution directly from the refrigerator. Warm in your hands if necessary.

[0226] 6. Close the nebulizer reservoir.

[0227] 7. After placing nebulizer solution into the reservoir, do not tilt the nebulizer handset more than 45 degrees (up, down, left, right).

[0228] 8. Ensure that all parts of the nebulizer are tightly connected and the reservoir is closed.

[0229] 9. Give the subject the Aerogen Ultra handset and, if possible, ensure that the subject is sitting upright (>45 degrees) with elbows resting on a tray or firm support and holding the device in the proper orientation. If the subject is unable to hold the nebulizer device for administration, staff may assist. Instruct the subject to form a seal around the mouthpiece with their lips and practice breathing in and out normally through the device mouthpiece for a few minutes to become accustomed to oral breathing in the presence of nasal high-flow oxygen. It is important that the subject is able to breathe comfortably through their mouth during the administration procedure.

[0230] 10. Press the off / on button to begin administration of study medication. Instruct the subject to breathe normally through the mouthpiece during administration. The start and end times of inhalation should be recorded in the subject's source notebook. Nebulization time for each 1 mL vial should take approximately 3 minutes. Administration should be completed within approximately 15 minutes after nebulization begins, with a 1-minute pause between vials. If longer interruptions are required for reoxygenation, administration time will increase. Subjects will receive three 1 mL vials of nezulinib inhalation solution for a total of 9 mg. The contents of each vial should be expressed into a nebulizer (Aerogen Solo) and administered as follows: (a) Proceed to spray the complete 1 mL volume for vial #1 (approximately 3 minutes). CAUTION: During administration, bubbles may form in the Aerogen Solo reservoir cup. Medicine will continue to be delivered despite the bubbles. Stop the controller when the nebulizer cup is empty and no mist is visible coming from the nebulizer (approximately 3 minutes after the start of administration of each vial). (b) The nebulizer is turned off, and the subject should then remove the nebulizer mouthpiece from their mouth and pause for approximately one minute or more to rest and reoxygenate, if necessary. During the pause, if saliva accumulation occurs during the oral inhalation procedure, the subject should be instructed to expectorate or swallow, and another 1 mL vial should be added to the nebulizer during the pause. (c) After approximately 1 minute, the subject should replace the nebulizer mouthpiece in their mouth and resume dosing by activating the nebulizer until the entire contents of the vial has been administered (approximately 3 minutes). (d) Once the second vial is completed, steps (b) and (c) are completed again to administer the third vial.

[0231] 11. Once administration of nezulcitinib inhalation solution is complete, remove the Aerogen Solo nebulizer from the Ultra handset and store for up to 7 days for reuse in the same subject. The Ultra handset and filters should be discarded after each use.

[0232] 12. The Aerogen USB Controller may be used for multiple subjects and should be cleaned between each administration by wiping it clean with an alcohol-based disinfectant wipe or a quaternary ammonium compound-based disinfectant wipe. Do not (i) spray liquids directly onto the Aerogen USB Controller, (ii) immerse the Aerogen USB Controller in liquids, or (iii) sterilize (autoclave) the Aerogen USB Controller.

[0233] Although the present disclosure has been described with reference to particular aspects or embodiments thereof, it will be understood by those skilled in the art that various modifications can be made or equivalents can be substituted without departing from the true spirit and scope of the present disclosure.Furthermore, to the extent permitted by applicable patent laws and regulations, all publications, patents, and patent applications cited herein are incorporated by reference in their entirety to the same extent as if each document was individually incorporated by reference herein.

Claims

1. A method for treating a respiratory disorder in a subject in need thereof when the subject is receiving high flow oxygen through a nasal cannula, comprising administering to the subject by oral nebulization a pharmaceutical composition comprising nezulcitinib, or a pharma- ceutically acceptable salt thereof, while the subject is receiving high flow oxygen through a nasal cannula at a rate of about 30 L / min or greater.

2. 10. The method of claim 1, wherein the subject is receiving high flow oxygen through a nasal cannula at a rate of about 30 L / min to about 50 mL / min.

3. The method of claim 1 or 2, wherein the pharmaceutical composition comprises about 1 mg to about 10 mg of nezulcitinib, or a pharma- ceutically acceptable salt thereof.

4. 4. The method of any one of claims 1 to 3, wherein the pharmaceutical composition comprises about 3 mg of nezulcitinib, or a pharma- ceutically acceptable salt thereof.

5. 5. The method of any one of claims 1 to 4, wherein the pharmaceutical composition comprises about 3 mg / 1 mL (free base equivalent) of nezulcitinib, or a pharma- ceutically acceptable salt thereof.

6. The method of any one of claims 1 to 5, wherein the pharmaceutical composition has a pH in the range of about 3.5 to about 4.

5.

7. 7. The method of claim 1, wherein the pharmaceutical composition has a pH of about 4.

0.

8. The method of claim 1 , wherein the pharmaceutical composition further comprises a buffering agent.

9. The method of claim 8 , wherein the buffer is citric acid.

10. The method of claim 1 , wherein the pharmaceutical composition further comprises an isotonicity agent.

11. The method of claim 10, wherein the tonicity agent is sodium chloride.

12. 12. The method of any one of claims 1 to 11, wherein the pharmaceutical composition is administered once daily.

13. 13. The method of any one of claims 1 to 12, wherein the respiratory disorder is selected from the group consisting of viral infection, lung transplant rejection, asthma, chronic obstructive pulmonary disease, cystic fibrosis, pneumonia, idiopathic pulmonary fibrosis, acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans, sarcoidosis, eosinophilic disease, helminth infection, pulmonary arterial hypertension, lymphangioleiomyomatosis, bronchiectasis, infiltrative lung disease, drug-induced pneumonia, fungal pneumonia, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, eosinophilic granulomatosis with polyangiitis, idiopathic acute eosinophilic pneumonia, idiopathic chronic eosinophilic pneumonia, hypereosinophilic syndrome, Löffler's syndrome, bronchiolitis obliterans with organizing pneumonia, pulmonary graft versus host disease, and immune checkpoint inhibitor-induced pneumonia.

14. 14. The method of any one of claims 1 to 13, wherein the respiratory disorder is a coronavirus infection.

15. 15. The method of claim 14, wherein the coronavirus infection is caused by SARS-CoV-1, SARS-CoV-2, or MERS-CoV.

16. 15. The method of claim 14, wherein the coronavirus infection is caused by SARS-CoV-2.

17. 17. The method of any one of claims 1 to 16, wherein the subject has acute lung injury associated with COVID-19.

18. 18. The method of any one of claims 1-17, wherein the subject has a baseline level of C-reactive protein of about 150 mg / L or less.

19. 14. The method of any one of claims 1 to 13, wherein the respiratory disorder is asthma or chronic obstructive pulmonary disease.

20. 14. The method of any one of claims 1 to 13, wherein the respiratory disorder is lung transplant rejection.

21. 1. A method for treating a SARS-CoV-2 pulmonary infection in a subject in need thereof, comprising administering to the subject by oral nebulization a pharmaceutical composition comprising nezulcitinib, or a pharma- ceutically acceptable salt thereof, while the subject is receiving high-flow oxygen through a nasal cannula at a rate of about 30 L / min or greater.

22. 22. The method of claim 21, wherein the subject is receiving high flow oxygen through a nasal cannula at a rate of about 30 L / min to about 50 mL / min.

23. The method of claim 21 or 22, wherein the pharmaceutical composition comprises from about 1 mg to about 10 mg of nezulcitinib, or a pharma- ceutically acceptable salt thereof.

24. 24. The method of any one of claims 21 to 23, wherein the pharmaceutical composition comprises about 3 mg of nezulcitinib, or a pharma- ceutically acceptable salt thereof.

25. 25. The method of any one of claims 21 to 24, wherein the pharmaceutical composition comprises about 3 mg / 1 mL (free base equivalent) of nezulcitinib, or a pharma- ceutically acceptable salt thereof.

26. 26. The method of any one of claims 21 to 25, wherein the pharmaceutical composition has a pH in the range of about 3.5 to about 4.

5.

27. 27. The method of any one of claims 21 to 26, wherein the pharmaceutical composition has a pH of about 4.

0.

28. 28. The method of any one of claims 21 to 27, wherein the pharmaceutical composition further comprises a buffering agent.

29. 29. The method of claim 28, wherein the buffer is citric acid.

30. 30. The method of any one of claims 21 to 29, wherein the pharmaceutical composition further comprises an isotonicity agent.

31. 31. The method of claim 30, wherein the tonicity agent is sodium chloride.

32. 32. The method of any one of claims 21 to 31, wherein the pharmaceutical composition is administered once a day.

33. 33. The method of any one of claims 21 to 32, wherein the subject has acute lung injury associated with COVID-19.

34. 34. The method of any one of claims 21 to 33, wherein the subject has a baseline level of C-reactive protein of about 150 mg / L or less.

35. A method for treating a pulmonary disease, disorder, or condition in a subject in need thereof while the subject is receiving high flow oxygen through a nasal cannula, comprising administering to the subject by oral nebulization a pharmaceutical composition comprising a therapeutic agent, or a pharma- ceutically acceptable salt thereof, while the subject is receiving high flow oxygen through a nasal cannula at a rate of about 30 L / min or more.

36. 36. The method of claim 35, wherein the subject is receiving high flow oxygen through a nasal cannula at a rate of about 30 L / min to about 50 mL / min.

37. 37. The method of claim 35 or 36, wherein the therapeutic agent is a JAK inhibitor.

38. 38. The method of any one of claims 35 to 37, wherein the therapeutic agent is nezulcitinib and the pharmaceutical composition comprises from about 1 mg to about 10 mg of nezulcitinib, or a pharma- ceutically acceptable salt thereof.

39. 39. The method of any one of claims 35 to 38, wherein the pulmonary disease, disorder, or condition is a respiratory disorder.

40. 40. The method of claim 39, wherein the respiratory disorder is a viral infection, lung transplant rejection, asthma, chronic obstructive pulmonary disease, cystic fibrosis, pneumonia, idiopathic pulmonary fibrosis, acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, bronchiolitis obliterans, sarcoidosis, eosinophilic disease, helminth infection, pulmonary arterial hypertension, lymphangioleiomyomatosis, bronchiectasis, infiltrative lung disease, drug-induced pneumonia, fungal pneumonia, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, eosinophilic granulomatosis with polyangiitis, idiopathic acute eosinophilic pneumonia, idiopathic chronic eosinophilic pneumonia, hypereosinophilic syndrome, Löffler's syndrome, bronchiolitis obliterans with organizing pneumonia, pulmonary graft versus host disease, and immune checkpoint inhibitor-induced pneumonia.

41. 2. The method of any one of the preceding claims, wherein the nebulizer is a mesh nebulizer.

42. 13. The method of any one of the preceding claims, wherein the delivered atomized particles consist essentially of particles having an average diameter of less than about 10 μm.

Images