Naizuxitinib for delivery by aerosolized oral inhalation

Abstract

Provided herein is a method of treating a subject suffering from a respiratory disorder when the subject receives a high flow of oxygen through nasal intubation, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutic agent, such as nerizitinib, or a pharmaceutically acceptable salt thereof, by oral aerosol inhalation.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] 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. Background Art Technical Field

[0003] Provided herein is a method for treating a subject with a respiratory condition when the subject receives high-flow oxygen at a rate greater than or equal to about 30 L / min through a nasal cannula, the method comprising administering a pharmaceutical composition to the subject by oral atomization inhalation, the pharmaceutical composition comprising a therapeutic agent (such as a JAK inhibitor) or a pharmaceutically acceptable salt thereof. Also provided herein is a method for treating a subject with a respiratory condition when the subject receives high-flow oxygen at a rate greater than or equal to about 30 L / min through a nasal cannula, the method comprising administering a pharmaceutical composition to the subject by oral atomization inhalation, the pharmaceutical composition comprising nezulcitinib or a pharmaceutically acceptable salt thereof.

[0004] Current state of the art

[0005] For subjects with respiratory conditions, the oxygen concentration in the surrounding atmosphere may not be sufficient to prevent hypoxemia. Providing supplemental oxygen (where the subject receives an oxygen supply at a higher rate or higher concentration than the oxygen present in the atmosphere) can help normalize the subject's blood oxygen saturation. The method of delivery of supplemental oxygen depends on the subject's needs, with low-flow oxygen typically providing a lower dose at a rate of about 4 L / min to 8 L / min through a nasal cannula or a simple mask, while high-flow oxygen provides a more concentrated dose at a rate of about 30 L / min to 60 L / min through non-invasive ventilation or a high-flow nasal cannula.

[0006] However, subjects with various respiratory conditions, including but not limited to asthma, 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, sarcoidosis, bronchiolitis obliterans organizing pneumonia (also known as COS), primary graft dysfunction (PGD), acute rejection (AR), lymphocytic bronchiolitis (LB), chronic allogeneic lung transplant dysfunction (CLAD), graft-versus-host disease (GVHD), and coronavirus infection, may also benefit from the administration of inhaled pharmaceutical compositions, such as those comprising JAK inhibitors.

[0007] The administration of an inhaled pharmaceutical composition simultaneously with the administration of high-flow supplemental oxygen via a nasal cannula may cause difficulties in adequately delivering the pharmaceutical composition to the subject's respiratory system while maintaining an increased flow of oxygen into the subject's lungs (and therefore, has not been used in human subjects to date). Various references using various models suggest that this difficulty can be addressed by reducing the oxygen flow during the administration of the pharmaceutical composition, or by administering the pharmaceutical composition in-line with the oxygen flow so that the pharmaceutical composition is delivered to the subject via a nasal cannula. See, for example, 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.

[0008] Subjects affected by respiratory disorders would benefit from both therapeutic intervention and supplemental oxygen.Therefore, there remains a need for methods of treating subjects with respiratory disorders with therapeutic agents, such as JAK inhibitors, wherein the subjects also receive high flow supplemental oxygen via nasal cannula. Summary of the Invention

[0009] Administration of high-flow supplemental oxygen to a subject with a respiratory condition may create positive pressure in the subject's respiratory system, hindering effective delivery of the inhaled pharmaceutical composition throughout the subject's airways and lungs. Current recommendations for optimal administration of inhaled aerosolized pharmaceutical compositions to a subject who is also receiving high-flow nasal supplemental oxygen indicate that: (a) the flow rate of the supplemental oxygen should be reduced during administration to improve inhaled drug delivery and then restored to a high flow rate after administration is complete, and / or (b) the pharmaceutical composition should be administered in series via a nasal cannula high-flow supplemental oxygen system. However, it has now been discovered that pharmaceutical compositions of JAK inhibitors (such as nezumibinib) can be optimally administered to a subject in need via nebulized oral inhalation, while the subject also receives high-flow nasal supplemental oxygen at an uninterrupted rate of greater than or equal to about 30 L / min via a high-flow nasal cannula throughout the administration of the pharmaceutical composition.

[0010] Provided herein is a method for treating a respiratory condition in a subject in need thereof while the subject receives high-flow oxygen via a nasal cannula, the method comprising administering a pharmaceutical composition to the subject by oral aerosol inhalation while the subject receives high-flow oxygen via a nasal cannula at a rate of greater than or equal to about 30 L / min. In some embodiments, the pharmaceutical composition comprises a JAK inhibitor (such as nezumibinib) or a pharmaceutically acceptable salt thereof.

[0011] Also provided herein is a method for treating a SARS-CoV-2 lung infection in a subject in need thereof while the subject receives high-flow oxygen via a nasal cannula, the method comprising administering a pharmaceutical composition to the subject by oral aerosol inhalation while the subject receives high-flow oxygen via a nasal cannula at a rate of greater than or equal to about 30 L / min. In some embodiments, the pharmaceutical composition comprises a JAK inhibitor (such as nezumibinib) or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 Shown are plasma concentrations of nezucitinib as a function of time for subjects who received a 3 mg dose via nebulized oral inhalation while also receiving low-flow oxygen at a rate of 6 L / min via nasal cannula.

[0013] Figure 2 Shown are subject plasma concentrations of nezucitinib as a function of time, comparing the route of treatment administration and rate of supplemental oxygen delivery, i.e., receiving a 3 mg dose via nebulized oral inhalation while also receiving low-flow nasal oxygen at a rate of 6 L / min versus receiving a 3 mg dose via nasal inhalation while also receiving high-flow oxygen at a rate of 30 L / min via a nasal cannula circuit.

[0014] Figure 3 Subject plasma concentrations of nezucitinib as a function of time are shown, further comparing the route of treatment administration and the rate of supplemental oxygen delivery, specifically, receiving a 3 mg dose via nebulized oral inhalation while also receiving low-flow nasal oxygen at a rate of 6 L / min, receiving a 3 mg dose via nasal inhalation while also receiving high-flow oxygen at a rate of 30 L / min via a nasal cannula circuit, or receiving a 3 mg dose via nebulized oral inhalation while also receiving high-flow oxygen at a rate of 30 L / min via a nasal cannula circuit.

[0015] Figure 4 Shown are plasma concentrations of nezucitinib over time in subjects who received 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 at a rate of 30 L / min via a high-flow nasal cannula.

[0016] Figure 5Shown are plasma concentrations of nezucitinib as a function of time in subjects who received a 3 mg dose via nebulized oral inhalation while also receiving low-flow nasal oxygen at a rate of 6 L / min, high-flow oxygen at a rate of 30 L / min via a high-flow nasal cannula, or high-flow oxygen at a rate of 50 L / min via a high-flow nasal cannula.

[0017] Figure 6 Shown are plasma concentrations of nezucitinib as a function of time in subjects who received a 3 mg dose via nebulized oral inhalation while also receiving low-flow nasal oxygen at a rate of 6 L / min, high-flow oxygen at a rate of 30 L / min via a high-flow nasal cannula, or high-flow oxygen at a rate of 50 L / min via a high-flow nasal cannula, compared to subjects who received a 9 mg dose of nezucitinib via nebulized oral inhalation while also receiving high-flow oxygen at a rate of 50 L / min via a high-flow nasal cannula. DETAILED DESCRIPTION

[0018] The following description sets forth exemplary embodiments of the present technology. However, it should be appreciated that such description is not intended to limit the scope of the present disclosure, but rather is provided as a description of exemplary embodiments.

[0019] definition

[0020] When describing the present disclosure, including its various aspects and embodiments, the following terms have the following meanings unless otherwise indicated.

[0021] The term "about" refers to ±5% of the specified value.

[0022] The term "AUC 0-24 ” refers to the area under the plasma concentration versus time curve from time zero to 24 hours after administration.

[0023] The term "AUC 0-∞ ” refers to the area under the plasma concentration-time curve extrapolated from time 0 to infinity.

[0024] The term "C 最大 ” refers to the maximum observed plasma concentration.

[0025] The term "PK" refers to pharmacokinetics.

[0026] The term "T 最大 ” refers to the time to reach maximum plasma concentration.

[0027] The term "t 1 / 2 ” refers to the apparent terminal elimination half-life.

[0028] The term "therapeutically effective amount" refers to an amount sufficient to effect treatment when administered to a subject in need of treatment.

[0029] The terms "treating" or "treatment" refer to the improvement or inhibition of the medical condition, disease or disorder being treated; or the alleviation of the symptoms of a medical condition, disease or disorder in a subject, particularly a human.

[0030] "Subject" and "patient" refer to an animal, such as a mammal, that has been or will be the subject of treatment, observation, or experiment. The methods described herein can be used for 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.

[0031] The term "pharmaceutically acceptable salt" means a salt that is acceptable for administration to a subject or mammal, such as a human (e.g., a salt that has acceptable mammalian safety for a given dosage regimen). Representative pharmaceutically acceptable salts include acetate, ascorbate, benzenesulfonate, benzoate, camphorsulfonate, citrate, ethanesulfonate, edisylate, fumarate, gentisate, gluconate, glucuronate, glutamate, hippurate, hydrobromide, hydrochloride, isethionate, lactate, lactobionate, maleate, malate, mandelate, methanesulfonate, mucate, naphthenate, naphthalene-1,5-disulfonate, naphthalene-2,6-disulfonate, nicotinate, nitrate, orotate, pamoate, pantothenate, phosphate, succinate, sulfate, tartrate, p-toluenesulfonate, and 1-hydroxy-2-naphthoate, etc.

[0032] The term "salt thereof" means a compound formed when the 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 the compound of Formula 1, i.e., a form in which one or more amino groups have been protonated by an acid. Typically, the salt is a pharmaceutically acceptable salt, but this is not necessary for salts of intermediate compounds that are not intended for administration to a subject.

[0033] Provided herein is a method of treating a pulmonary disease, disorder, or condition in a subject in need thereof while the subject is receiving high flow oxygen via nasal cannula, the method comprising administering to the subject by oral nebulization inhalation a pharmaceutical composition comprising a therapeutic agent or a pharmaceutically acceptable salt thereof while the subject is receiving high flow oxygen via nasal cannula at a rate of greater than or equal to about 30 L / min.

[0034] It is expected that administering a pharmaceutical composition comprising a therapeutic agent described herein to a subject by oral aerosol inhalation while the subject is receiving high flow oxygen at a rate greater than or equal to about 30 L / min via a nasal cannula is unexpectedly superior to administering via a series high flow circuit, contrary to current recommendations in the art. Furthermore, administration by oral aerosol inhalation to subjects receiving high and low flow oxygen is expected to surprisingly produce similar exposures.

[0035] In some embodiments, the lung disease, disorder, or condition is an inflammatory or fibrotic disease of the respiratory tract. In some embodiments, the lung disease, disorder, or condition is a respiratory disorder. In some embodiments, the lung disease, disorder, or condition is lung transplant rejection. In some embodiments, the lung disease, disorder, or condition is asthma.

[0036] 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, helminthic infection, pulmonary hypertension, lymphangioleiomyomatosis, bronchiectasis, infiltrative lung disease, drug-induced pneumonia, fungal-induced pneumonia, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, eosinophilic granulomatosis with polyangiitis, idiopathic acute eosinophilic pneumonia, idiopathic chronic eosinophilic pneumonia, hypereosinophilic syndrome, Loeffler's syndrome, bronchiolitis obliterans organizing pneumonia, pulmonary graft-versus-host disease, and immune checkpoint inhibitor-induced pneumonia.

[0037] In some embodiments, the viral infection is influenza. In some embodiments, the viral infection is a coronavirus infection.

[0038] In certain embodiments, the therapeutic agent is any therapeutic agent described herein, such as another therapeutic agent described herein. In certain embodiments, the therapeutic agent is a JAK inhibitor. In certain 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 certain embodiments, the JAK inhibitor is suitable for topical administration to the lungs, such as for the treatment of respiratory diseases (i.e., "lung selective JAK inhibitors"). Such compounds are known in the art and include, for example, TD-8236 (which is disclosed in U.S. Patent No. 10,100,049). In certain embodiments, the JAK inhibitor is Compound 1.

[0039] Provided herein is a method for treating a respiratory condition in a subject in need thereof while the subject receives high-flow oxygen via a nasal cannula, the method comprising administering a pharmaceutical composition comprising a JAK inhibitor or a pharmaceutically acceptable salt thereof to the subject by oral aerosol inhalation while the subject receives high-flow oxygen via a nasal cannula at a rate of greater than or equal to about 30 L / min. In some embodiments, the JAK inhibitor is a lung-selective JAK inhibitor. In some embodiments, the JAK inhibitor is Compound 1.

[0040] Compound 1 (also known as the compound of Formula 1 and as nezucitinib, ((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)) has the following structure:

[0041]

[0042] Nezucitinib is a pan-JAK inhibitor suitable for direct delivery to the lungs, which is disclosed in U.S. Patent No. 10,947,229. Nezucitinib can be prepared, for example, as described in U.S. Patent No. 10,947,229 and U.S. Patent No. 10,844,057.

[0043] Provided herein is a method for treating a respiratory condition in a subject in need thereof while the subject is receiving high-flow oxygen through a nasal cannula, the method comprising administering a pharmaceutical composition comprising nezucitinib or a pharmaceutically acceptable salt thereof to the subject by oral aerosol inhalation while the subject is receiving high-flow oxygen through a nasal cannula at a rate of greater than or equal to about 30 L / min.

[0044] In some embodiments, the respiratory disease 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, helminthic infection, pulmonary hypertension, lymphangioleiomyomatosis, bronchiectasis, infiltrative lung disease, drug-induced pneumonia, fungal-induced pneumonia, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, eosinophilic granulomatosis with polyangiitis, idiopathic acute eosinophilic pneumonia, idiopathic chronic eosinophilic pneumonia, hypereosinophilic syndrome, Loeffler syndrome, bronchiolitis obliterans with organizing pneumonia, pulmonary graft-versus-host disease, and pneumonia induced by immune checkpoint inhibitors. In some embodiments, the respiratory disease is asthma or chronic obstructive pulmonary disease. In some embodiments, the respiratory disease is asthma. In some embodiments, the respiratory disease 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.

[0045] Also provided herein is a method for treating SARS-CoV-2 lung infection in a subject in need thereof while the subject is receiving high-flow oxygen through a nasal cannula, the method comprising administering a pharmaceutical composition comprising nezumitinib or a pharmaceutically acceptable salt thereof to the subject by oral aerosol inhalation while the subject is receiving high-flow oxygen through a nasal cannula at a rate of greater than or equal to about 30 L / min.

[0046] 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.

[0047] 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.

[0048] In some embodiments, the subject has a baseline level of C-reactive protein less than or equal to about 150 mg / L.

[0049] In some embodiments, the method reduces the coronavirus viral load in the respiratory system of a subject. In some embodiments, the method reduces the coronavirus viral load in the lungs of a subject. In some embodiments, the reduction in coronavirus viral load is measured by collecting and analyzing a nasal swab from a subject. In some embodiments, the method reduces the viral load of SARS-CoV-2 in the respiratory system of a subject. In some embodiments, the method reduces the viral load of SARS-CoV-2 in the lungs of a subject. In some embodiments, the reduction in SARS-CoV-2 viral load is measured by collecting and analyzing a nasal swab from a subject.

[0050] In some embodiments, the subject suffers from one or more of hypoxia, hypoxemia, dyspnea, tachypnea, and low oxygen levels.

[0051] In some embodiments, the pharmaceutical composition is administered to a subject in an outpatient setting. In some embodiments, the pharmaceutical composition is administered to a subject while the subject is not hospitalized. In some embodiments, the pharmaceutical composition is administered to a subject prior to hospitalization. In some embodiments, the pharmaceutical composition is administered to a subject during hospitalization.

[0052] In some embodiments, the method results in a reduction in recovery time and / or time to discharge from a hospital or medical facility. In some embodiments, the method results in a reduction in hospital stay, a reduction in time in the ICU, and / or a reduction in time to discharge.

[0053] In some embodiments, the subject receives high flow oxygen via nasal cannula at a rate of about 30 L / min to about 50 mL / min. In some embodiments, the subject receives high flow oxygen via nasal cannula at a rate of about 30 L / min. In some embodiments, the subject receives high flow oxygen via nasal cannula at a rate of about 50 mL / min.

[0054] In some embodiments, the pharmaceutical composition comprises about 1 mg to about 10 mg of nezumitinib or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 3 mg to about 9 mg of nezumitinib or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 3 mg of nezumitinib or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 9 mg of nezumitinib or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments, the pharmaceutical composition comprises about 1 mg / 1 mL to about 10 mg / 1 mL (free base equivalent) of nezumizutinib. In some embodiments, the pharmaceutical composition comprises about 3 mg / 1 mL to about 9 mg / 1 mL (free base equivalent) of nezumizutinib. In some embodiments, the pharmaceutical composition comprises about 3 mg / 1 mL (free base equivalent) of nezumizutinib. In some embodiments, the pharmaceutical composition comprises about 3 mg / 1 mL (free base equivalent) of nezumizutinib or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 9 mg / 1 mL (free base equivalent) of nezumizutinib.

[0056] In some embodiments, the pharmaceutical composition has a pH in the range of about 3.5 to about 4.5. In some embodiments, the pharmaceutical composition has a pH of about 4.0.

[0057] In some embodiments, the pharmaceutical composition further comprises a buffer. In some embodiments, the buffer is citric acid.

[0058] In some embodiments, the pharmaceutical composition further comprises a tonicity agent. In some embodiments, the tonicity agent is sodium chloride.

[0059] In some embodiments, the pharmaceutical composition is administered by inhalation. In some embodiments, the pharmaceutical composition is administered by aerosol inhalation. In some embodiments, the pharmaceutical composition is administered by oral aerosol inhalation.

[0060] In some embodiments, the pharmaceutical composition is administered once daily. In some embodiments, the pharmaceutical composition is administered twice daily.

[0061] 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. 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. In some embodiments, the pharmaceutical composition is administered to the subject for up to 7 days, or until discharged. In some embodiments, the pharmaceutical composition is administered to the subject for up to 14 days, or until discharged. In some embodiments, the pharmaceutical composition is administered to the subject for up to 21 days, or until discharged. In some embodiments, the pharmaceutical composition is administered to the subject for up to 28 days, or until discharged.

[0062] 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.

[0063] In some embodiments, the method comprises administering to the subject one or more additional therapeutic agents or treatments. 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.

[0064] In some embodiments, the method causes an increase in the oxygen level in the subject's blood. In some embodiments, the method causes the subject's fever to improve or subside. In some embodiments, the method causes the subject to remove oxygen supplementation, or prevents the subject from needing to be placed on a ventilator. In some embodiments, the method increases the subject's ventilator-free days (VFD). In some embodiments, the method increases the subject's ICU (intensive care unit)-free days. In some embodiments, the method causes improvement or subsidence of shortness of breath. In some embodiments, the method causes a reduction in the risk of death in the subject.

[0065] In some embodiments, the method reduces lung inflammation caused by a respiratory disorder. In some embodiments, the method prevents, reduces, or resolves acute lung injury and / or acute respiratory distress syndrome caused by a respiratory disorder.

[0066] 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 a 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 a fever in the subject.

[0067] In some embodiments, the method reduces lung inflammation 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 the cytokine storm caused by COVID-19. In some embodiments, the method causes an increase in oxygen levels in the subject's blood. In some embodiments, the method causes the subject's fever to improve or subside. In some embodiments, the method causes the subject to remove oxygen supplementation, or prevents the subject from needing to be placed on a ventilator. In some embodiments, the method increases the number of days the subject is not using a ventilator. In some embodiments, the method increases the number of days the subject is not using an ICU (intensive care unit). In some embodiments, the method causes improvement or subsidence of shortness of breath. In some embodiments, the method causes a reduced risk of death in the subject.

[0068] In certain embodiments, the method prevents the subject from being hospitalized. In certain embodiments, the method prevents the serious complications of the subject. In certain embodiments, serious complications include, for example, lung injury, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), organ failure, pneumonia, acute liver injury, thrombosis, respiratory failure, further needs for oxygen supplementation, non-invasive ventilation, mechanical ventilation, acute heart injury, secondary infection, acute kidney injury, septic shock, disseminated intravascular coagulation, multisystem inflammatory syndrome (MIS-C), rhabdomyolysis, arrhythmia, cytokine storm and cardiovascular shock.

[0069] In certain embodiments, the subject is at high risk of developing severe complications due to coronavirus. In certain embodiments, the subject has been identified as being at high risk of developing severe complications due to coronavirus by biomarker testing. In certain embodiments, based on LDH (lactate dehydrogenase) levels, the subject has been identified as being at high risk of developing severe complications due to coronavirus. In certain embodiments, based on LDH-isoenzyme 3 levels, the subject has been identified as being at high risk of developing severe complications due to coronavirus. In certain embodiments, based on surfactant protein-D (SPD), receptor for advanced glycosylation end products (RAGE), one or more cytokines, C-reactive protein (CRP), D-dimer, fibrinogen and / or ferritin levels, the subject has been identified as being at high risk of developing severe complications due to coronavirus. In certain embodiments, the cytokine is IL-6. In certain embodiments, the subject suffers from diabetes, obesity, cardiovascular disease (such as coronary artery disease, myocardial infarction, history of cerebrovascular accident or peripheral arterial disease), hypertension or lung disease. In some embodiments, the subject has coronary artery disease, myocardial infarction, a history of cerebrovascular accident, peripheral arterial disease, a lung disease such as asthma, COPD, or idiopathic pulmonary fibrosis (IPF). In some embodiments, based on a chest X-ray, the subject has been identified as being at high risk for developing severe complications due to coronavirus. In some embodiments, the subject has a CXR abnormality consistent with viral pneumonia.

[0070] In some embodiments, the method reduces the rate of medical interventions associated with coronavirus infection. In some embodiments, the rate of medical interventions associated with coronavirus infection is measured by the number of emergency room visits, hospitalizations, doctor visits, and urgent care visits associated with coronavirus infection.

[0071] In some embodiments, the pharmaceutical composition inhibits viral entry into a subject's cells or inhibits fusion of coronavirus virions with the endosomal membrane of a subject's cells. In some embodiments, the pharmaceutical composition inhibits one Abelson kinase in a subject. In some embodiments, the pharmaceutical composition inhibits multiple Abelson kinases in a subject. In some embodiments, the Abelson kinases are 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.

[0072] In some embodiments, the subject has a COVID-19 related inflammatory syndrome (i.e., multisystem inflammatory syndrome, MIS-C). In some embodiments, the subject is a pediatric subject.

[0073] In some embodiments, the method prevents long-term lung dysfunction or "long COVID" in a subject.

[0074] In some embodiments, the method results in an increase in the number of RFD (respiratory failure-free days) in a subject infected with a coronavirus. In some embodiments, the method results in an increase in the number of ventilator-free days (VFD) in a subject infected with a coronavirus.

[0075] In some embodiments, the method increases the ratio of arterial oxygen partial pressure to inspired oxygen fraction (PaO2 / FiO2) in the subject.

[0076] In some embodiments, the method reduces mortality in a population of subjects.

[0077] In some embodiments, the method reduces blood clot formation in the subject.

[0078] In some embodiments, the method results in a reduction in the subject's need for oxygen supplementation, noninvasive ventilation, or mechanical ventilation.

[0079] 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 older than 60 years of age. In some embodiments, when the pharmaceutical composition is administered, the subject suffers from pneumonia. In some embodiments, when the pharmaceutical composition is administered, the subject suffers from bilateral pneumonia. In some embodiments, the administration of the pharmaceutical composition results in: preventing or reducing the formation of lung lesions / lung lesion opacities / lung damage, improvements in subjects monitored by chest imaging, CT scans or chest X-rays, increases in ventilator-free days (VFD), increases in ICU-free days, increases in PaO2 / FiO2 ratios or increases in SaO2 / FiO2 ratios. In some embodiments, administration of the pharmaceutical composition to a subject infected with coronavirus is completed when the subject is in respiratory failure, but before mechanical ventilation is required.

[0080] In some embodiments, the method results in an increase in the number of days that the subject does not require supplemental oxygen.

[0081] In some embodiments, the pharmaceutical composition is administered to a subject at a critical inflection point of the disease, before the development of ALI, and prevents progression to ALI. In some embodiments, the pharmaceutical composition is administered to a subject in the early stages of coronavirus infection, before the development of ALI, and the administration prevents 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 a subject before the development of ARDS, and prevents progression to ARDS. In some embodiments, administration of the pharmaceutical composition to a subject infected with a coronavirus is completed before the subject suffers from ALI and / or ARDS to prevent ALI and / or ARDS in the subject.

[0082] In some embodiments, the subject has one or more underlying conditions such as asthma, COPD, cardiovascular disease, diabetes, chronic lung disease, heart disease, cancer, bone marrow or organ transplant, immunodeficiency, HIV, taking medications that weaken the immune system, obesity, chronic kidney disease, a neurodevelopmental condition, hypertension, or liver disease.

[0083] In some embodiments, the subject is 80 years of age or older, 70 years of age or older, 65 years of age or older, 60 years of age or older, 50 years of age or older, 40 years of age or older, 10 years of age or younger, between 10 and 20 years of age, between 20 and 30 years of age, between 30 and 40 years of age, between 40 and 50 years of age, between 50 and 60 years of age, between 20 and 40 years of age, between 40 and 60 years of age, between 60 and 80 years of age, 60 years of age or younger, or over 60 years of age. In some embodiments, the subject is 16 years of age or older. In some embodiments, the subject is 18 years of age or older. In some embodiments, the subject is 12 years of age or older.

[0084] In some embodiments, the method blocks or inhibits neutrophilia and / or neutrophil extracellular trap (NET) formation in the subject.

[0085] In some embodiments, the method reduces the risk of thrombosis or thromboembolism in the subject.

[0086] In some embodiments, the method reduces the incidence of thrombosis or thromboembolism in a subject population.

[0087] 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 ng / mL, 30 ng / mL, 25 ng / mL, 20 ng / mL, 15 ng / mL, or 10 ng / mL. In some embodiments, the maximum plasma concentration of the compound of Formula 1 in a subject is less than the concentration required to achieve JAK IC 50 In some embodiments, the desired plasma concentration is determined by determining the IC of IL-13-induced STAT6 phosphorylation in the human bronchial epithelial cell line BEAS-2B. 50 To calculate JAK IC 50 In some embodiments, the maximum plasma concentration of the compound of Formula 1 in the subject is 50% lower than the plasma concentration required to inhibit Janus kinase. In some embodiments, the compound of Formula 1 or a pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, the compound of Formula 1 or a pharmaceutically acceptable salt thereof is administered twice daily. In some embodiments, the compound of Formula 1 or a pharmaceutically acceptable salt thereof is administered at two doses on the first day.

[0088] In some embodiments, administration of a compound of Formula 1 or a pharmaceutically acceptable salt thereof results in a plasma AUC of 0-24 Less than 500ng*hr / mL, or less than 250ng*hr / mL, or less than 100ng*hr / mL, or less than 50ng*hr / mL.

[0089] In some embodiments, administration of a compound of Formula 1 or a pharmaceutically acceptable salt thereof results in a T between 0.5 hr and 4 hr, or between 0.5 hr and 2 hr. 最大 , or about 1 hr T 最大 .

[0090] 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.

[0091] In some embodiments, the subject is 12 years of age or older. In some embodiments, the subject is less than 12 years of age. In some embodiments, the subject is a pediatric subject two years of age or older.

[0092] 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 developing severe COVID-19 and / or being hospitalized.

[0093] In certain embodiments, the method results in an improvement in the overall patient assessment of the subject's symptoms. In certain embodiments, the method results in an improvement in the overall patient change rating of the subject. In certain embodiments, the method results in an improvement in the levels of LDH (lactate dehydrogenase), surfactant protein-D (SPD), receptor for advanced glycosylation end products (RAGE), one or more cytokines, C-reactive protein (CRP), D-dimer, fibrinogen and / or ferritin in the subject. In certain embodiments, the method improves the Borg dyspnea score of the subject. In certain embodiments, the method reduces the C-reactive protein level (CRP) in the subject. In certain embodiments, the method reduces the D-dimer level in the subject. In certain embodiments, the method reduces the cytokine levels in the subject. In certain embodiments, the cytokine is IL-6.

[0094] In some embodiments, the method results in an improvement in the level of the receptor for advanced glycation end products (RAGE) in a subject. In some embodiments, the method results in a decrease in the level of the receptor for advanced glycation end products (RAGE) in a subject. In some embodiments, the method results in a decrease in lung injury in a subject.

[0095] In some embodiments, the method results in an improvement in C-reactive protein (CRP) levels in a subject. In some embodiments, the method results in a reduction in C-reactive protein (CRP) levels in a subject. In some embodiments, the method results in an improvement in IL-6 levels in a subject. In some embodiments, the method results in a reduction in IL-6 levels in a subject. In some embodiments, the method results in an improvement in IFNγ levels in a subject. In some embodiments, the method results in a reduction in IFNγ levels in a subject. In some embodiments, the method results in an improvement in IP-10 levels in a subject. In some embodiments, the method results in a reduction in IP-10 levels in a subject. In some embodiments, the method results in a reduction in IL-10 levels in a subject. In some embodiments, the method results in a reduction in MCP-1 levels in a subject. In some embodiments, the method results in an improvement in the improved Borg dyspnea score of a subject.

[0096] In some embodiments, the method results in a reduced risk of death in the subject.

[0097] In some embodiments, the method comprises administering one or more additional therapeutic agents or treatments to the subject. In some embodiments, the subject is co-treated with standard of care. 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.

[0098] In some embodiments, the subject suffers from hypertension and / or diabetes.

[0099] In some embodiments, the subject has moderate COVID-19 when treatment with Compound 1 or a pharmaceutically acceptable salt thereof is initiated. In some embodiments, the subject has severe COVID-19 when treatment with Compound 1 or a pharmaceutically acceptable salt thereof is initiated.

[0100] 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 upon admission but is not receiving ventilation or high-flow oxygen. In some embodiments, the subject requires invasive mechanical ventilation or extracorporeal membrane oxygenation upon admission. In some embodiments, the subject is receiving non-invasive ventilation or a high-flow oxygen device.

[0101] 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 a cytokine storm caused by COVID-19. In some embodiments, the method results in the removal of ventilation or supplemental oxygen in the subject.

[0102] Nezucitinib

[0103] Chemical structures herein are named according to IUPAC conventions implemented in ChemDraw software (PerkinElmer, Inc., Cambridge, MA). Compound 1, nezucitinib, 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.

[0104] In addition, the imidazole portion of the tetrahydroimidazopyridine moiety exists in tautomeric forms, and the fragment of compound 1 is shown below

[0105]

[0106] According to IUPAC convention, these representations result in different numbering of the atoms of the imidazole portion: (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). It should be understood that although a structure is shown or named in a particular form, the disclosed compounds also include tautomers thereof.

[0107] Compound 1 can exist as a pure enantiomer or as an enriched mixture. The description or naming of a specific stereoisomer refers to the indicated stereochemistry of the indicated stereocenter, but it is understood that minor amounts of other stereoisomers may also be present unless otherwise indicated, provided that the utility of the described or named compound is not abrogated by the presence of another stereoisomer.

[0108] Compound 1 also contains several basic groups (such as amino groups), and thus the compound can exist as a free base or in various salt forms, such as a monoprotonated salt form, a diprotonated salt form, a triprotonated salt form, or a mixture thereof. Unless otherwise indicated, all of these forms are included within the scope of the present disclosure.

[0109] 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 atoms 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, but are not limited to 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O and 18 O.

[0110] Pharmaceutical composition

[0111] Compound 1 and its pharmaceutically acceptable salts are typically used in the form of pharmaceutical compositions or formulations. Such pharmaceutical compositions can advantageously be administered to a subject by inhalation. In addition, the pharmaceutical composition can be administered by any acceptable route of administration, including but not limited to oral, rectal, nasal, topical (including transdermal) and parenteral administration.

[0112] Provided herein are pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and Compound 1, wherein, as defined above, "Compound 1" refers to Compound 1 or a pharmaceutically acceptable salt thereof. Optionally, such pharmaceutical compositions may contain other therapeutic agents and / or formulating agents, if desired. When discussing compositions and uses thereof, Compound 1 may also be referred to herein as the "active agent."

[0113] The pharmaceutical compositions of the present disclosure typically contain a therapeutically effective amount of Compound 1. However, one skilled in the art will recognize that the pharmaceutical composition may contain more than a therapeutically effective amount, i.e., a bulk composition, or less than a therapeutically effective amount, i.e., a single unit dose designed for multiple administration to achieve a therapeutic effect, or an amount sufficient to achieve a desired biological effect (such as reducing the viral load of a coronavirus).

[0114] Typically, such pharmaceutical compositions will contain from about 0.01% to about 95% by weight of the active agent; including, for example, from about 0.05% to about 30%; and from about 0.1% to about 10% by weight of the active agent.

[0115] Any conventional carrier or excipient can be used in a pharmaceutical composition comprising Compound 1. The choice of a particular carrier or excipient, or a combination of carriers or excipients, will depend on the mode of administration used to treat a particular subject or medical condition or type of disease state. In this regard, it is well within the skill of those skilled in the art of pharmaceuticals to prepare a suitable pharmaceutical composition for a particular mode of administration. In addition, the carriers or excipients used in the pharmaceutical compositions of the present disclosure are commercially available. As a 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).

[0116] Representative examples of materials that can be used as pharmaceutically 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; astragalus powder; 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 glycerol, 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; ethanol; phosphate buffered saline; and other nontoxic, compatible substances used in pharmaceutical compositions.

[0117] Pharmaceutical compositions are typically prepared by thoroughly and intimately mixing or blending the active agent with a pharmaceutically acceptable carrier and one or more optional ingredients.

[0118] On the one hand, pharmaceutical composition is suitable for inhalation administration.The pharmaceutical composition for inhalation administration is typically in the form of an aerosol or powder.Such compositions are typically administered using an inhaler delivery device, such as a dry powder inhaler (DPI), a metered dose inhaler (MDI), a nebulizer or similar delivery device.

[0119] In certain embodiments, the pharmaceutical composition is administered by inhaling with a nebulizer. Such a nebulizer device typically produces a high-speed air stream, which causes the pharmaceutical composition to be sprayed in a mist form and is taken into the respiratory tract of the experimenter. Therefore, when formulated for a nebulizer, the therapeutic agent can be dissolved in a suitable carrier to form a solution. Alternatively, the therapeutic agent can be micronized or nano-grinded and combined with a suitable carrier to form a suspensoid.

[0120] Representative pharmaceutical compositions for nebulizers include solutions or suspensions comprising about 0.05 μg / 1mL to about 20 mg / 1mL of compound 1 and excipients compatible with aerosol formulations. In some embodiments, pharmaceutical compositions for nebulizers include solutions or suspensions comprising about 1 mg / 1mL to about 10 mg / 1mL (free base equivalent) of compound 1 and excipients compatible with aerosol formulations. In some embodiments, pharmaceutical compositions for nebulizers include solutions or suspensions comprising about 3 mg / 1mL to about 9 mg / 1mL (free base equivalent) of compound 1 and excipients compatible with aerosol formulations. In some embodiments, pharmaceutical compositions for nebulizers include solutions or suspensions comprising about 3 mg / 1mL (free base equivalent) of compound 1 and excipients compatible with aerosol formulations. In some embodiments, a pharmaceutical composition for use in a nebulizer inhaler comprises a solution or suspension comprising about 9 mg / 1 mL (free base equivalent) of Compound 1 and excipients compatible with nebulized formulations.

[0121] Nebulizer devices suitable for administering therapeutic agents by inhalation are 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 reusable nebulizer (Pari GmbH); and the like.

[0122] 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).

[0123] The droplet size distribution of a nebulizer is a parameter that can affect the in vivo deposition of a therapeutic agent in the lung. Droplet size can be affected by the formulation, the nebulizer device, or both. In some embodiments, the delivered aerosolized particles (i.e., particles of therapeutic agent delivered via a nebulizer) consist essentially of particles having an 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 μm, or less than about 1 μm.

[0124] In some embodiments, the delivered aerosolized particles consist essentially of particles having an average diameter of about 1 μm to about 10 μm. In some embodiments, the delivered aerosolized particles consist essentially of particles having an average diameter of about 1 μm to about 10 μm. In some embodiments, the delivered aerosolized particles consist essentially of particles having an average diameter of less than about 10 μm. In some embodiments, the delivered aerosolized particles consist essentially of particles having an average diameter of less than about 5 μm.

[0125] In some embodiments, about 60% to about 95% of the delivered aerosolized particles consist 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 aerosolized particles consist 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 aerosolized particles consist 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 aerosolized particles consist 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 aerosolized particles consist 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.

[0126] In certain embodiments, use via nebulizer and be provided with power by oxygen flow rate, this flow rate for example about 10L / min to about 1L / min, about 10L / min to about 2L / min, about 8L / min to about 3L / min, about 8L / min is less than about 4L / min, about 8L / min to about 5L / min, about 8L / min to about 6L / min, is less than about 9L / min, is less than about 8L / min, is less than about 7L / min, is less than about 6L / min, is less than about 5L / min.In certain embodiments, nebulizer is provided with power by the oxygen flow rate of about 8L / min to about 6L / min.In certain embodiments, the pharmaceutical composition that is used for the nebulizer has the pH in about 3 to about 8 scopes.In certain embodiments, the pharmaceutical composition that is used for the nebulizer has the pH in about 3.5 to about 4.5 scopes.In certain embodiments, the pharmaceutical composition that is used for the nebulizer has the pH of about 4.0.

[0127] In some embodiments, the pharmaceutical composition for use in a nebulizer inhaler further comprises a buffer. In some embodiments, the buffer is citric acid.

[0128] In some embodiments, the pharmaceutical composition for use in a nebulizer inhaler further comprises a tonicity agent. In some embodiments, the tonicity agent is sodium chloride.

[0129] Provided herein is a method for treating a respiratory condition in a subject in need thereof who is receiving high-flow supplemental oxygen via a nasal cannula, comprising administering to the subject a pharmaceutical composition comprising nezucitinib or a pharmaceutically acceptable salt thereof by oral aerosol inhalation, wherein the flow of supplemental oxygen to the subject is not reduced or suspended throughout the administration of the pharmaceutical composition.

[0130] The following non-limiting examples illustrate representative pharmaceutical compositions of the present disclosure.

[0131] Nebulizer composition

[0132] Compound 1 (25 mg) was dissolved in a solution containing 1.5 to 2.5 equivalents of hydrochloric acid, followed by addition of sodium hydroxide to adjust the pH to 3.5 to 5.5, and 3% by weight of glycerol. The solution was stirred thoroughly until all components were dissolved. The solution was administered using a nebulizer device that provided approximately 0.1 to approximately 4 mg of Compound 1 per dose.

[0133] Compound 1 or a pharmaceutically acceptable salt thereof is typically administered in a single daily dose or multiple daily doses, but other administration forms may also be used. The amount of active agent administered per dose or the total amount administered per day will typically be determined by a physician based on the relevant circumstances, including the condition to be treated; the route of administration selected; 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.

[0134] utility

[0135] In some embodiments of the methods provided herein, the therapeutic agent is a JAK inhibitor. In certain embodiments, JAK inhibitors are designed to treat respiratory inflammation and fibrotic diseases. In certain embodiments, the compound is designed to deliver effective anti-cytokine drugs directly to the site of action of pulmonary respiratory diseases while limiting systemic exposure. Such lung-selective JAK inhibitors are known in the art and include, for example, TD-8236 (which is disclosed in U.S. Patent No. 10,100,049).

[0136] Compound 1 is designed for the treatment of airway inflammatory and fibrotic diseases. Specifically, the compound is designed to deliver a potent anti-cytokine drug directly to the site of action in respiratory diseases of the lungs while limiting systemic exposure.

[0137] Compound 1 is a potent inhibitor of the JAK enzyme family: JAK1, JAK2, JAK3, and TYK2, and is a potent inhibitor of pro-inflammatory and pro-fibrotic cytokines. It is recognized that the broad anti-inflammatory effects of systemically available JAK inhibitors may suppress normal immune cell function, potentially leading to an increased risk of infection. In contrast, Compound 1 is able to deliver potent anti-cytokine drugs directly to the site of action of respiratory conditions in the lungs while limiting systemic exposure.

[0138] Compound 1 was evaluated in a Phase 1 clinical trial and administered to humans at doses of 1 mg, 3 mg, and 10 mg by nebulized inhalation for up to 7 days. 最大 (maximum plasma concentration) values ​​are much lower than the binding-corrected JAKIC 50 , which is the plasma concentration required to inhibit Janus kinase by 50%. The pharmacokinetics of inhaled compound 1 are consistent with the low plasma exposure after inhaled administration. At the 3 mg and 10 mg dose levels, the maximum plasma exposure of compound 1 was the protein-adjusted JAK IC 50About 20 times lower and about 7 times lower. In addition, absolute NK cell counts were assessed after multiple doses to assess the potential for systemic pharmacological effects associated with JAK inhibition of compound 1. In participants receiving placebo or compound 1 at any dose level (1 mg, 3 mg or 10 mg) explored in the study, no NK cell reduction was observed relative to baseline. The lack of a reduction in NK cell counts is also consistent with the lack of systemic JAK inhibition. In contrast, a significant reduction in NK cell counts was observed using 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 systemic mediated hematological changes associated with JAK inhibition, including neutrophil and hemoglobin reduction and lipid changes, were not observed when compound 1 was administered by inhalation. These results support a good safety and tolerability curve, and PK is lower than the level expected to produce systemic effects.

[0139] The anti-inflammatory activity of JAK inhibitors has been strongly 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.

[0140] Asthma inflammation-related cytokines signaled by 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). Therefore, compound 1 is expected to be useful for treating inflammatory respiratory conditions, particularly asthma. Asthma has been classified into Th2 low subtype and Th2 high subtype (Simpson et al., Respirology, 2006, 11, 54-61). IL-4, IL-13, IL-5 and TSLP are associated with Th2 high asthma, while IL-23 / IL-12, IL-6, IL-27 and IFNγ are associated with Th2 low asthma. Based on its pan-JAK inhibitory properties, compound 1 can effectively inhibit the mediators of Th2 high asthma and Th2 low asthma. Therefore, it is expected that Compound 1 will be useful in treating both Th2 high and Th2 low asthma.

[0141] Lung inflammation and fibrosis are characteristics of other respiratory diseases besides asthma, 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. Therefore, JAK inhibitors, such as the lung-selective JAK inhibitors described herein and 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.

[0142] When compared to its corresponding fluorinated analog, compound 1 has been shown to have similar JAK activity. However, as shown in the assay section, it has the advantage of producing significantly less sulfation metabolism. This is important because sulfation metabolism occurs in the lungs, which could result in a rapid reduction in exposure to the active parent compound.

[0143] Compound 1 has been shown to inhibit cytokines associated with inflammation. Therefore, Compound 1 may be useful in treating certain respiratory diseases and conditions, as detailed below.

[0144] Eosinophilic airway inflammation is a characteristic of a group of diseases collectively known 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 pneumonia (e.g., caused by therapeutic drugs such as antibiotics, phenytoin, or l-tryptophan), fungal-induced pneumonia (e.g., allergic bronchopulmonary aspergillosis), hypersensitivity pneumonitis, and eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome). Eosinophilic lung diseases of unknown etiology include idiopathic acute eosinophilic pneumonia, idiopathic chronic eosinophilic pneumonia, hypereosinophilic syndrome, and Loeffler syndrome.

[0145] Polymorphisms in the IL-6 gene are associated with elevated IL-6 levels and an increased risk of developing pulmonary arterial hypertension (PAH) (Fang et al., J. Am. Soc. Hypertens., 2017, 11(3), 171-177). A role for IL-6 in PAH has been confirmed, and inhibition of the IL-6 receptor chain gp130 can ameliorate disease in a PAH rat model (Huang et al., Can. J. Cardiol., 2016, 32(11), 1356.e1-1356.e10).

[0146] Cytokines such as IFNγ, IL-12, and IL-6 are associated with a range of 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). The compounds of the present disclosure have also been shown to inhibit IL-6 and IFNγ signaling.

[0147] Bronchiectasis and infiltrative lung disease are diseases associated with chronic neutrophilic inflammation.

[0148] Pathological T cell activation is crucial in the etiology of several respiratory diseases. Autoreactive T cells play a role in bronchiolitis obliterans with organizing pneumonia (also known as COS). Similar to COS, the etiology of lung transplant rejection is related to aberrant T cell activation of recipient T cells by the donor lung. Lung transplant rejection may occur early in the course of primary graft dysfunction (PGD), organizing pneumonia (OP), acute rejection (AR), or lymphocytic bronchiolitis (LB), or they may develop years after lung transplantation as in chronic allograft dysfunction (CLAD). CLAD was previously known as bronchiolitis obliterans (BO) but is now recognized as a syndrome with distinct pathological manifestations, including BO, restrictive CLAD (rCLAD or RAS), and neutrophilic allograft dysfunction. Chronic lung allograft dysfunction (CLAD) is a major challenge in the long-term management of lung transplant recipients as it leads to a gradual loss of function of the transplanted lung (Gauthier et al., Curr Transplant Rep., 2016, 3(3), 185–191). CLAD responds poorly to treatment, and there remains 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., Clin. Transplant. 2017, 31, e12898). In addition, high levels of CXCR3 chemokines, such as CXCL9 and CXCL10, which are downstream of JAK-dependent IFN signaling, in the lungs are associated with poor outcomes in lung transplant patients (Shino et al., PLOS One, 2017, 12(7), e0180281). Systemic JAK inhibition has been shown to be effective for renal transplant rejection (Vicenti et al., American Journal of Transplantation, 2012, 12, 2446-56). Therefore, JAK inhibitors are likely to effectively prevent or delay lung transplant rejection and CLAD. Similar T cell activation events described as the basis for lung transplant rejection are also considered to be the main driving factors for pulmonary graft-versus-host disease (GVHD) that may occur after hematopoietic stem cell transplantation. Similar to CLAD, pulmonary GVHD is a chronic progressive condition with a very poor prognosis, and there is currently no approved treatment. A retrospective, multicenter investigation of 95 patients with steroid-refractory acute or chronic GVHD who received systemic JAK inhibitor ruxolitinib as salvage therapy showed that most patients (including patients with pulmonary GVHD) had a complete or partial response to ruxolitinib (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, non-systemic JAK inhibitors to prevent or delay lung transplant rejection or pulmonary GVHD. Compound 1 possesses the properties necessary to address this need. Recently, with the increased use of immune checkpoint inhibitors, immune checkpoint inhibitor-induced pneumonitis, another T cell-mediated lung disease, has emerged. In cancer patients treated with these T cell stimulators, life-threatening pneumonitis can develop.

[0149] The mixed lymphocyte reaction assay is an in vitro assay that simulates transplant rejection. Compound 1 was shown to effectively inhibit IFNγ secretion.

[0150] Thus, in some embodiments, the present disclosure provides a method for treating a respiratory condition in a subject in need thereof while the subject receives high-flow oxygen through a nasal cannula, the method comprising administering a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof to the subject by oral aerosol inhalation while the subject receives high-flow oxygen through a nasal cannula at a rate of greater than or equal to about 30 L / min.

[0151] In some embodiments, respiratory disorders are 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 diseases, helminthic infections, pulmonary hypertension, lymphangioleiomyomatosis, bronchiectasis, infiltrative lung disease, drug-induced pneumonia, fungal-induced pneumonia, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, eosinophilic granulomatosis with polyangiitis, idiopathic acute eosinophilic pneumonia, idiopathic chronic eosinophilic pneumonia, eosinophilic syndrome, Loeffler syndrome, bronchiolitis obliterans with organizing pneumonia, pulmonary graft-versus-host disease, and immune checkpoint inhibitor-induced pneumonia. In some embodiments, respiratory disorders are asthma or chronic obstructive pulmonary disease. In some embodiments, respiratory disorders are asthma. In some embodiments, 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 condition is chronic obstructive pulmonary disease. In some embodiments, the respiratory condition is lung transplant rejection. In some embodiments, the respiratory condition is coronavirus infection.

[0152] In some embodiments, the present disclosure provides a method for preventing or delaying lung transplant rejection in a subject in need thereof when the subject receives high-flow oxygen through a nasal cannula, the method comprising administering a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof to the subject by oral atomization inhalation while the subject receives high-flow oxygen through a nasal cannula at a rate greater than or equal to about 30 L / min. In some embodiments, lung transplant rejection is selected from the group consisting of: primary graft dysfunction, organizing pneumonia, acute rejection, lymphocytic bronchiolitis, and chronic lung allograft dysfunction. In some embodiments, lung transplant rejection is acute lung transplant rejection. In some embodiments, lung transplant rejection is chronic lung allograft dysfunction. In some embodiments, lung transplant rejection is selected from the group consisting of: obliterative bronchiolitis, restrictive chronic lung allograft dysfunction, and neutrophil allograft dysfunction. In some embodiments, the pharmaceutical composition is administered by inhalation.

[0153] The present disclosure also provides a method for treating asthma in a subject in need thereof when the subject receives high-flow oxygen through a nasal cannula, the method comprising administering a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof to the subject by oral aerosol inhalation while the subject receives high-flow oxygen through a nasal cannula at a rate of greater than or equal to about 30 L / min.

[0154] When used to treat asthma, Compound 1 is typically administered in a single daily dose or multiple daily doses, but other administration forms may also be used. The amount of active agent administered per dose or the total amount administered per day will typically be determined by a physician based on the relevant circumstances, including the condition to be treated; the route of administration selected; the age, weight, and response of the individual subject; the severity of the subject's symptoms, etc.

[0155] The present disclosure also provides a method for treating a respiratory condition (including but not limited to the conditions described herein) in a subject in need thereof when the subject receives high-flow oxygen through a nasal cannula, the method comprising administering a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof to the subject by oral aerosol inhalation while the subject receives high-flow oxygen through a nasal cannula at a rate of greater than or equal to about 30 L / min.

[0156] When used to treat respiratory disorders (including but not limited to the disorders described herein), Compound 1 is typically administered in a single dose per day or multiple doses per day, but other forms of administration may also be used. The amount of active agent administered per dose or the total amount administered per day will typically be determined by a physician in view of the relevant circumstances, including the condition to be treated; the route of administration selected; the age, weight, and response of the individual subject; the severity of the subject's symptoms, etc.

[0157] Human coronaviruses are common respiratory pathogens and typically cause mild upper respiratory tract illness. Severe acute respiratory syndrome-related coronavirus (SARS-CoV-1) and Middle East respiratory syndrome-related coronavirus (MERS-CoV) are two highly pathogenic viruses that can cause 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 related pandemic has triggered a global healthcare emergency. Similar to SARS-CoV-1 and MERS-CoV, a portion of patients (approximately 16%) may develop severe respiratory symptoms manifested as acute lung injury (ALI), leading to ICU admission (approximately 5%), respiratory failure (approximately 6.1%), and death (Wang et al., JAMA, 2020, 323, 11, 1061-1069; Guan et al., NEngl 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 portion of COVID-19 patients appear to suffer from an excessively inflammatory “cytokine storm,” leading to acute lung injury and acute respiratory distress syndrome (ARDS). This cytokine storm may also spread to the systemic circulation and produce sepsis, and ultimately lead to multiple organ dysfunction syndrome. The dysregulated cytokine signaling seen in COVID-19 is characterized by increased expression of interferons (IFNs), interleukins (ILs), and chemokines, leading to ALI and associated mortality.

[0158] 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, showed elevation of JAK-dependent cytokines, such as IFNγ, IL-6, and IL-12, and downstream chemokines, such as chemokine (C-C 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., Virology. 2009, 395(2), 210–22. It has recently been shown that, similar to SARS-CoV-1 and MERS-CoV, patients with severe COVID-19 have elevated Th17 levels, which can be driven by IL-6 and IL-23 through signal transducer and activator of transcription 3 and 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 by JAK inhibitors (Wu et al., J Microbiol Immunol Infect., 2020, S1684118220300657). Although IFN responses may have a protective role in viral infection, there is evidence that delayed responses in humans can lead to viral-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).

[0159] There is also concern that systemic JAK inhibitors may increase the risk of thromboembolism, which is particularly concerning given the observation of severe hypercoagulability in patients with COVID-19.

[0160] Compound 1 is a lung-selective inhaled pan-JAK inhibitor that addresses the shortcomings of oral JAK inhibitors by avoiding systemic immunosuppression, thromboembolism, and other infections that worsen mortality.

[0161] Additionally, Compound 1 has been used and can be used alone or in combination with standard of care, which includes remdesivir and corticosteroids such as dexamethasone.

[0162] Compound 1 works through a mechanism of action that can inhibit the cytokine storm associated with coronavirus infection.

[0163] Compound 1 has been studied in a Phase 2 clinical study in subjects infected with COVID. Although there was no statistically significant difference in RFD between Compound 1 and placebo in the ITT from randomization to day 28 (median: 21 days vs. 21 days; p = 0.61), and the SaO2 / FiO2 ratio on day 7, 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 on day 28 did not change compared with baseline, Compound 1 showed a favorable trend towards improvement in 28-day all-cause mortality (total deaths: 6 vs. 13, HR: 0.42, p = 0.08) and recovery time (median: 10 days vs. 11 days, HR: 1.27, p = 0.12) when compared with placebo.

[0164] Importantly, in a post hoc analysis of subjects with baseline CRP (n=201), among subjects with CRP <150 mg / L (n=171), those treated with Compound 1 had improvements when compared to placebo:

[0165] - 28-day all-cause mortality (total deaths: 1 vs. 9, HR: 0.097, p=0.009).

[0166] - Recovery time (median: 10 days vs. 11 days, HR: 1.48, p=0.02).

[0167] Among 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.

[0168] Therefore, Compound 1 is particularly suitable for treating a subpopulation of subjects whose baseline CRP (C-reactive protein) level is less than 150 mg / L. In some embodiments, the subject has a baseline C-reactive protein level of less than or equal to about 150 mg / L.

[0169] C-reactive protein (CRP) is a protein found in plasma whose circulating concentration increases in response to inflammation. It is an acute phase protein originating from the liver and increases following the secretion of interleukin-6 by macrophages and T cells. In healthy adults, normal CRP concentrations vary between 0.8 mg / L and 3.0 mg / L. However, some healthy adults have elevated CRP levels up to 10 mg / L.

[0170] Compound 1 was well tolerated. Adverse events and serious adverse events occurred in 34.0% and 9.7% of subjects treated with Compound 1, respectively, and in 41.2% and 15.7% of subjects treated with placebo, respectively. Adverse events of liver abnormalities or diseases 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 no subjects treated with Compound 1, respectively, and in 2.0% and 4.9% of subjects treated with placebo, respectively.

[0171] Plasma exposure of compound 1 was low and consistent with expectations for a lung-selective drug.

[0172] In addition, coronavirus enters the host cell by fusing with the cell membrane, which is a step required for viral replication. It is reported that Abelson kinase inhibitors are effective inhibitors (Coleman et al., Journal of Virology, 2016, 90, 19, 8924-8933 of SARS-CoV-1 and MERS-CoV fusion; Sisk et al., Journal of General Virology, 2018, 99, 619-630), supporting the fact that Abelson kinase inhibitors can be used to treat patients infected with coronavirus by reducing the viral load of the patient. Compound 1 has been shown to effectively inhibit Abl2.

[0173] Therefore, without being limited by this theory, compound 1 may be particularly suitable for treating coronavirus because it is a compound that can be selectively delivered to the lungs, has pan-JAK inhibitory activity that can suppress the cytokine storm associated with COVID-19, and has Abelson kinase inhibitory activity that can reduce the viral load of coronavirus in subjects.

[0174] In some embodiments, the present disclosure provides a method for treating SARS-CoV-2 lung infection in a subject in need thereof while the subject is receiving high-flow oxygen through a nasal cannula, the method comprising administering a pharmaceutical composition comprising nezumitinib or a pharmaceutically acceptable salt thereof to the subject by oral aerosol inhalation while the subject is receiving high-flow oxygen through a nasal cannula at a rate of greater than or equal to about 30 L / min.

[0175] 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 a pharmaceutically acceptable salt thereof may also act by strengthening endothelial cell-cell contacts and promoting endothelial cell-extracellular matrix adhesion.

[0176] According to another theory, the potential ability of compound 1 to directly affect coronaviruses may offset or mitigate the possible increase in local viral replication caused by the use of compounds that cause immunosuppression.

[0177] It has also been reported that the ability of neutrophils to form neutrophil extracellular traps (NETs) may promote organ damage and death in COVID-19 patients (Barnes et al., J. Exp. Med., 2020, 217, 6, e20200652, 1-7). Abnormal NET formation is associated with lung disease, thrombosis, airway mucus secretion, and cytokine production. Therefore, compound 1 or a pharmaceutically acceptable salt thereof can be used to (a) block or inhibit neutrophil leukocytosis and / or neutrophil extracellular trap (NET) formation in subjects infected with coronavirus, (b) reduce the risk of thrombosis in subjects infected with coronavirus, and / or (c) reduce the incidence of thrombosis in a population of subjects infected with coronavirus.

[0178] Multisystem inflammatory syndrome in children (MIS-C) is a condition in which different parts of the body become inflamed, including the heart, lungs, kidneys, brain, skin, eyes, or gastrointestinal organs. MIS-C has been associated with exposure to COVID-19 and appears to be a rare but serious complication associated with COVID-19. MIS-C is associated with lung inflammation. Therefore, Compound 1 is expected to be useful in preventing or treating MIS-C.

[0179] In addition, the death of respiratory epithelial cells caused by influenza virus infection is the cause of inducing inflammatory response. It has been shown that influenza A virus infection triggers pyroptosis and apoptosis of respiratory epithelial cells through the type I interferon signaling pathway (Lee et al., Journal of Virology, 2018, 92, 14, e00396-18). The JAK-STAT signaling pathway mediated by type I interferon (IFN) may inhibit apoptosis by inducing expression of Bcl-xL anti-apoptotic genes, thereby promoting the transition of apoptosis to pyroptosis. In addition, inhibition of JAK-STAT signaling can inhibit pyroptosis, but enhances the apoptosis of infected PL16T cells. This shows that the type I IFN signaling pathway plays an important role in inducing pyroptosis, but inhibits the apoptosis of respiratory epithelial cells, thereby inducing a pro-inflammatory response to influenza virus infection. Therefore, it is expected that the compound of Formula 1 or a pharmaceutically acceptable salt thereof can be used to treat subjects infected with influenza. Based on its mechanism of action, the compound of Formula 1 or a pharmaceutically acceptable salt thereof is expected to prevent or treat lung inflammation and / or ALI and / or ARDS in subjects infected with influenza.

[0180] Also provided herein is the use of Compound 1 in medical therapy and in the preparation of a formulation or medicament for treating, preventing, delaying or ameliorating diseases and conditions suitable for treatment with JAK inhibitors, particularly respiratory disorders, lung transplant rejection and coronavirus infection.

[0181] Combination therapy

[0182] In some embodiments, the methods described herein include administering one or more additional therapeutic agents or treatments to a subject. Compound 1, or a pharmaceutically acceptable salt thereof, can be used in combination with one or more additional therapeutic agents or treatments that act by the same mechanism or by a different mechanism to treat a disease. Different therapeutic agents or treatments can be administered sequentially or simultaneously in separate compositions or in the same composition. Useful classes of therapeutic agents for combination therapy include, but are not limited to, IL-6 inhibitors, IL-6 receptor antagonists, IL-6 receptor agonists, IL-2 inhibitors, antivirals, anti-inflammatory drugs, sodium-glucose co-transporter 2 inhibitors, vaccines, ACE2 inhibitors, antibiotics, antiparasitics, sphingosine 1-phosphate receptor modulators, TMPRSS2 inhibitors, TNFα inhibitors, anti-TNF, membrane hemagglutinin fusion inhibitors, ACE2 terminal glycosylation inhibitors, 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 inhibitory factors, multipotent adult progenitor cell therapy, antiviral porins, 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, cell Cytotoxic T-lymphocyte protein-4 inhibitors, pulmonary surfactant-associated protein D regulators, protease inhibitors, nuclear factor-κB inhibitors, xanthine oxidase inhibitors, endoplasmic reticulum regulators, CCL26 gene inhibitors, TLR regulators, 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 regulators, MEK protein kinase inhibitors, CD40 ligand receptor agonists, CD70 antigen modulators, amyloid 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 1α2 regulators, VEGF-1 receptor modulators, angiotensin II AT-2 receptor agonists, basic immunoglobulin (basigin) inhibitors, viral envelope glycoprotein inhibitors, gelsolin stimulators, trypsin inhibitors, GM-CSF ligand inhibitors, urokinase plasminogen activator inhibitors, serine protease inhibitors, PDE 3 inhibitors, PDE 4 inhibitors, C-reactive protein inhibitors,Chemokine CC22 ligand inhibitors, GM-CSF receptor antagonists, hemoglobin scavenger receptor antagonists, metalloproteinase-1 inhibitors, metalloproteinase-3 inhibitors, metalloproteinase inhibitors, small inducible cytokine A17 ligand inhibitors, VEGF gene inhibitors, coronavirus spike glycoprotein inhibitors, nucleoprotein inhibitors, ATP-binding cassette transporter B5 modulators, vimentin modulators, stem cell antigen-1 inhibitors, casein kinase II inhibitors, complement factor C5a 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-1β 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 κB gene modulators, Grp78 calcium-binding protein inhibitors, Jun N-terminal kinase inhibitors, transferrin modulators, p38 MAP kinase regulators, 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 regulators, human papillomavirus E7 protein regulators, Ca2+ release-activated Ca2+ channel 1 inhibitors, amyloid deposition inhibitors, γ-secretase inhibitors, 2,5-oligoadenylate synthetase stimulators, interferon type I receptor agonists, ribonuclease stimulators, S phase kinase-associated protein 2 inhibitors, dehydropeptidase-1 regulators, calcium channel regulators, signal transduction factor CD24 regulators, 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-α-sialidase modulators, muscarinic receptor antagonists, IL-8 receptor antagonists, vitamin D3 receptor agonists, high-mobility group protein B1 inhibitors, CASP8-FADD-like regulatory factor inhibitors, exo-NOX disulfide-thiol exchange factor 2 inhibitors, sphingosine kinase inhibitors, sphingosine-1-phosphate receptor-1 antagonists, interferon gene stimulator protein stimulators, topoisomerase inhibitors, X-linked inhibitor of apoptosis protein inhibitors, angiopoietin ligand-2 inhibitors, neuropilin 2 inhibitors,Listeriolysin stimulators, interferon gamma receptor agonists, MAPK gene modulators, GM-CSF ligand inhibitors, immunoglobulin G1 modulators, immunoglobulin kappa modulators, kallikrein modulators, mannan-binding lectin serine protease inhibitors, ubiquitin modulators, IL-12 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 receptors antagonists, exportin 1 inhibitors, hyaluronidase inhibitors, sodium glucose transporter-2 inhibitors, dihydroceramide δ4 desaturase inhibitors, sphingosine kinase 2 inhibitors, interferon beta ligands, ICAM-1 stimulators, TNF antagonists, vascular cell adhesion protein 1 agonists, COVID19 spike glycoprotein modulators, complement C1s subcomponent inhibitors, NMDA receptor ε2 subunit inhibitors, tankyrase-1 inhibitors, protein translation initiation inhibitors, σ receptor modulators, σR1 receptor modulators, σR2 receptor modulators, antihistamines, anti-C5aR, RNAi, corticosteroids, BC R-ABL, tyrosine kinase inhibitors, colony-stimulating factors, tissue factor (TF) inhibitors, recombinant granulocyte macrophage colony-stimulating factor (GM-CSF), Gardos channel blockers, heat shock protein 90 (Hsp90) inhibitors, alpha blockers, cap binding complex 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, PDE4 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 CD6l receptor modulators, factor XIIa antagonists, oral spleen tyrosine kinase (SYK) inhibitors, CK2 inhibitors, NMDA receptor antagonists, SK2 inhibitors, antiandrogens and tankyrase-2 inhibitors.

[0183] Specific therapeutic agents that can be used in combination with Compound 1 include, but are not limited to, cidofovir triphosphate, cidofovir, abacavir, ganciclovir, stavudine triphosphate, 2'-O-methylated UTP, desidustat, ampion, trans-sodium crocetin, CT-P59, Ab8, heparin, apixaban, GC373, GC376, oleandrin, GS-441524, sertraline, Lanadelumab, zilucoplan, abatacept, CLBS119, ranitidine, risankizumab, AR-711, AR-701, MP0423, bempegalde sleukin), melatonin, carvedilol, mercaptopurine, paroxetine, casirivimab, imdevimab, ADG20, emricasan, dapansutrile, cisevir / infliximab, DWRX2003, AZD7442, MAN-19, LAU-7b, niclosamide, ANA001, fluvoxamine, narsoplimab, Sarconeos, GIGA-2050, VERU-111, REGN-COV2, icatibant, cisenikvir / infliximab, NTR-441, LAM-002 A, oseltamivir, VHH72-Fc, MK-4482, EB05, OB-002, CM-4620-IE, IMU-838, SNG001, NT-17, BOLD-100, WP1122, itozuzumab, PB1046, fostamatinib, colchicine, M5049, EDP1815, ABX464, CPI-006, azelastine, galadacimab, cimetidine, lopinavir, ritonavir, remdesivir, chloroquine, hydrochloroquine, convalescent plasma transfusion, azithromycin, tocilizumab, famotidine, salicylumab, interferon beta, interferon beta-1a, interferon beta-1b, pegylated interferon lambda-1a, favipiravir, ASDC -09, dapagliflozin, CD24Fc, ribavirin, ufenovir, nitric oxide, APN01, teicoplanin, oritavancin, dalbavancin, monensin, ivermectin, darunavir, cobicistat, fingolimod, camostat, gadecivir, salomide, leronlimab, remestemcel-L, canakinumab, TAK-888, azvudine, BPI-002, AT-100, T-89, Neumifil, GreMERSfi, liposomal curcumin, OYA-1, oxypurinol, mosetimod, PUL-042, naltrexone, metikerin, 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, meplazumab, pathogen-specific aAPC, LV-SMENP-DC, ARMS-I, rhu-pGSN, PRTX-007, CK-0802, Nafamostat, upamostat, NI-007, COVID-HIG, CYNK-001, Nafamostat, 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-hydroxy Ecdysone, IFX-1, elsuvirine, emapalumab, CEL-1000, trabedersen, VBI-2901, ASC-09, TJM-2, RPH-104, tranexamic acid, WP-1122, olokizumab, APN-01, danoprevir, piclidenoson, FW-1022, CORAVAX, laminaria COVID-19, COVID-19XWG-03, EIDD-2801, AVM-0703, DC-661, acalabrutinib, spiramycin (bitspiramycin), Allocetra, tradipitant, bacTRL-Tri, Ad5-nCoV, EPV-CoV19, ADX-629, vazegepant, thiolamine, sonlicromanol, aviptail, fenretinide, IT-139, nitazoxanide, apatalone, lucinactant, bacTRL-Spike, SAB-185, NVX-CoV2373, CM-4620, INO-4800, eicosapentaenoic acid,itanapraced, rintatolimod, XAV-19, niclosamide, ciclesonide, DAS181, ORBCEL-C, Metablok, dantrolene, CD24-IgFc, fadraciclib, gimsilumab, seliciclib, Cyto-MSC, ST-266, MRx-0004, ravulizumab, tafoxiparin, DAS-181, BMS-986253, cholecalciferol, nafamostat, ChAdOx1 nCoV-19, idronoxil, LY-3127804, ATYR-1923, VPM-1002, Mycobacterium w, renzilumab, Polyoxidonium, conestat α, ubiquitin proteasome modulator, COVID-19 virus main protease Mpro inhibitor, mRNA-1273, clavudine, bucillamine, sodium metaarsenite, vidofludimus, DARPin, COV-ENT-1, KTH-222, mefuparib, brensocatib, zanubrutinib, anakinra, selinexor, salicylumab (s arilumab), astodrimer, dapagliflozin propylene glycol, opaganib, BNT-162c2, BNT-162b2, BNT-162b1, BNT-162a1, ifenprodil, PIC1-01, 2X-121, zotatifin, aplidin, cloperidin, clematin, dociparstat, avdoralimab, VIR-2703, ALN-COV, intravenous immunoglobulin (IVIg), apremilast, vicromax, baloxavir marboxil), emtricitabine, tenofovir, novaferon, secukinumab, valsartan, imatinib, omalizumab, leucine, sofosbuvir, alovudine, zidovudine, R-107, AB-201, sargramostim, LYT-100, senecarpol, fluvoxamine, aspirin, losartan, ADX-1612, ADX-629, sirukumab, otilimab, STI-1499, TR-C19, ABX-464, interferon α2b, arbidol, S309, vafidemstat, AT-527, ibudilast, auxora, bemcentinib, eculizumab, JS016, FSD-201, LY-CoV555,Avifavir, OP-101, RLF-100, DMX-200, 47D11, remsima, TYR1923, dexamethasone, EDP-1815, PTC29, rabeximod, foralumab, budesonide, molnupiravir, ensovibep, dalcetrapib, FSD201, pralatrexate, paxlovid, clofazimine, and merimepodib.

[0184] In some embodiments, a 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 Monoupravir. In some embodiments, the antiviral agent is Nirmatrelvir enhanced with Ritonavir. In some embodiments, the corticosteroid is Dexamethasone.

[0185] Also provided herein are pharmaceutical compositions comprising a JAK inhibitor or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents. Also provided herein are pharmaceutical compositions comprising: Compound 1 or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents. The therapeutic agent can be selected from the class of agents specified above and from the list of specific agents described above. In some embodiments, the pharmaceutical composition is suitable for delivery to the lungs. In some embodiments, the pharmaceutical composition is suitable for inhalation or aerosol administration. In some embodiments, the pharmaceutical composition is a dry powder or liquid composition.

[0186] For all methods disclosed herein, the method comprises administering to the subject a JAK inhibitor or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents. In addition, for all methods disclosed herein, the method comprises administering subject compound 1 or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents.

[0187] When used in combination therapy, the agents can be formulated in a single pharmaceutical composition, or the agents can be provided in separate compositions that are administered simultaneously or at separate times by the same or different routes of administration. Such compositions can be packaged separately or can be packaged together as a kit. The two or more therapeutic agents in the kit can be administered by the same route of administration or by different routes of administration.

[0188] Examples

[0189] Example 1 - Clinical Study: A Phase 1, open-label study to evaluate the pharmacokinetics and safety of inhaled nezumibinib administered in a supplemental oxygenation setting in healthy participants

[0190] Research objectives

[0191] Part A: Evaluation of the plasma PK of nezumibinib in healthy participants following a single inhaled dose in the setting of various supplemental oxygenation scenarios.

[0192] Part B: To assess the safety and tolerability of nezumibinib following a single inhaled dose in healthy participants in the setting of various supplemental oxygenation scenarios.

[0193] This is a phase 1, open-label, fixed-sequence, 4-period study designed to evaluate the PK and safety of a single inhaled dose of nezumitinib administered in different supplemental oxygenation settings.

[0194] Supplemental oxygenation is commonly used in hospitalized subjects with ALI due to COVID-19 and may be co-administered with nezumab in the clinical setting. High-flow supplemental oxygen is known to reduce the delivered dose of inhaled medications. Therefore, it is important to evaluate the safety and PK of inhaled nezumab administered in healthy participants in the context of various supplemental oxygenation scenarios to inform possible dose adjustments and guide dosing instructions in future studies.

[0195] Study participants

[0196] Fourteen healthy adult male and female participants were recruited. Participants met all of the following inclusion criteria:

[0197] Healthy adults, male or female, aged 18 to 65 years (inclusive) at the screening visit.

[0198] Pregnancy problems:

[0199] o Female subjects must be of non-childbearing potential, or if of childbearing potential, must not be pregnant or breastfeeding and must agree to use a highly effective method of birth control during the study and for 30 days after the last dose of nezumibinib.

[0200] o Male subjects must agree to use condoms to prevent potential exposure of the fetus or partner through semen, in addition to using highly effective pregnancy prevention measures with their female partners of reproductive potential during the study and for 30 days after the last dose of nezumibinib.

[0201] Body mass index (BMI) ≥18.0 and ≤35.0 kg / m2 at the screening visit 2 , and weighed at least 50 kg at the screening visit.

[0202] In the opinion of the Investigator or designee, at Screening and prior to dosing of Cycle 1, the patient is in good health with no significant clinical history, physical examination, spirometry, laboratory data, vital signs, or ECG, including the following:

[0203] o Liver function tests (i.e., alanine transaminase [ALT], aspartate transaminase [AST], alkaline phosphatase [ALP], gamma-glutamyl transferase [GGT], and bilirubin) ≤ upper limit of normal or as judged by the investigator and the sponsor's medical monitor as medically acceptable.

[0204] o Absolute lymphocyte counts should be within the normal range or should be considered medically acceptable by the investigator and the sponsor's medical monitor.

[0205] Participants at screening The test result must be negative.

[0206] Forced expiratory volume in 1 second (FEV1) ≥ 80% of the predicted value at screening.

[0207] Able to understand and accept the use of a nebulizer device and breathing through the necessary procedures for supplemental oxygenation at the Screening Visit and Cycle 1 Day -1.

[0208] Understand the study procedures in the Informed Consent Form (ICF) and be willing and able to comply with the protocol.

[0209] Participants may withdraw from the study at any time for any reason and may be withdrawn by the investigator following an adverse event or failure to comply with study criteria (i.e., pregnancy, drug or alcohol abuse, etc.).

[0210] Participant's participation period

[0211] The length of study participation for each participant was approximately 50 days, as follows: a screening period of up to 28 days before the first dose, followed by up to 4 cycles consisting of a single dose on day 1 of each cycle, a washout period of at least 5 days between each nezumibinib dose, and a follow-up period of 7 (± 2) days after the last dose of nezumibinib.

[0212] The washout period was based on the PK of nezumibinib rather than oxygen supplementation, as any effects of supplemental oxygen (i.e., changes in pulse oximetry, respiratory rate, and blood pH) were expected to return to normal within minutes after discontinuation of supplemental oxygen in healthy participants. The washout between doses was considered sufficient to prevent carryover effects from prior nezumibinib administration.

[0213] Research Products

[0214] The drug product (nezucitinib inhalation solution) consists of 3 mg of nezucitinib in a sterile aqueous solution containing 10 mM citrate buffer and 150 mM sodium chloride (pH 4.0). It is a clear, colorless to yellow solution. The drug product is manufactured at a strength of 3 mg / mL (as free base equivalent). It is supplied in unit-dose low-density polyethylene (LDPE) vials manufactured by blow-fill-seal (BFS) technology and individually packaged in sealed aluminum foil laminated bags. An Aerogen Solo nebulizer system (manufactured by Aerogen Limited, Ireland) is used to administer the drug product. The unit dose composition of the drug product formulation (3 mg / 1 mL) is given in Table 1.

[0215] Table 1: Composition of Nezucitinib Inhalation Solution, 3 mg / 1 mL

[0216] Material grade Function Amount (mg / 1mL) Nezucitinib N / A Drug substances 3 (free base equivalent) Citric acid, monohydrate USP, Ph.Eur buffer 2.1 Sodium chloride USP, Ph.Eur Tonicity agents 8.8 hydrochloric acid NF, Ph.Eur pH adjustment Adjust to pH 4.0±0.5 Sodium hydroxide NF, Ph.Eur pH adjustment Adjust to pH 4.0±0.5 Water for injection USP solvent Appropriate amount up to 1mL

[0217] Dosage, dosage form, route, and dosage regimen

[0218] Participants received a single inhaled dose of nezumibinib using a nebulizer device on day 1 of each administration cycle, under different supplemental oxygenation conditions and under fasting conditions.

[0219] Apply as follows:

[0220] • Administration A (Test): 3 mg of nezumibinib was delivered by nasal inhalation via the Aerogen Solo, which has an integrated high-flow nasal cannula circuit delivering supplemental oxygen at a flow rate of 30 L / min.

[0221] Administration B (reference): 3 L / min of nasal sedation was delivered by oral inhalation via the Aerogen Solo coupled to the Aerogen Ultra handheld device in the presence of 6 L / min of supplemental oxygen delivered via a low-flow nasal cannula.

[0222] mg nelzurinib.

[0223] • Administration C (Test): 3 mg of nezucitinib was delivered by oral inhalation via the Aerogen Solo coupled to the Aerogen Ultra handheld device in the presence of supplemental oxygen delivered at a flow rate of 30 L / min via a high-flow nasal cannula.

[0224] • Administration D1 (Test): 3 mg of nezucitinib was delivered by oral inhalation via the Aerogen Solo coupled to the Aerogen Ultra handheld device in the presence of supplemental oxygen delivered at a flow rate of 50 L / min via a high-flow nasal cannula.

[0225] • Administration D2 (Test): 9 mg of nezucitinib was delivered by oral inhalation via the Aerogen Solo coupled to the Aerogen Ultra handheld device in the presence of supplemental oxygen delivered at a flow rate of 50 L / min via a high-flow nasal cannula.

[0226] Hour 0 was defined as the start of the inhaled nezumibinib segment for each dose administration.

[0227] Supplemental oxygen was administered for approximately 5 minutes prior to dosing to allow participants to acclimate to the method of oxygen delivery corresponding to the administration period for which they were about to receive the dose.

[0228] The CRU's pharmacy provided each dose in separate unit-dose containers for each participant and each study period.

[0229] It was found that single and multiple doses of 1 mg, 3 mg and 10 mg of nab were safe and well tolerated in healthy adult participants. After single and multiple doses in the range of 1 mg to 10 mg of nab, systemic exposure (AUC0-24) and Cmax increased in a dose-proportional manner. The 3 mg dose selected in this study is consistent with the dose in the recently completed Phase 2 study. In addition, the 3 mg dose ensures the full characterization of the nab PK profile. Dose levels of up to 9 mg of nab were also evaluated (administered on D2). This dose level is within the dose range (up to 10 mg of nab) previously tested in healthy subjects and those with COVID-19 in previous clinical studies.

[0230] Several factors are known to influence the delivery of inhaled medications administered in the presence of high-flow oxygen therapy, including gas flow rate and the position of the nebulizer device within the high-flow circuit. Previous in vitro studies have shown that to maximize the amount of drug delivered during high-flow oxygen therapy, the gas flow rate should be low and the nebulizer should be placed immediately before or after the humidification chamber. This scenario was evaluated in Administration A.

[0231] A flow rate of 30 L / min for both Administrations A and C was chosen as the lower end of the clinically relevant range in order to maximize drug delivery. Although oral inhalation in the presence of high-flow nasal oxygen therapy (Administration C) has been shown to be suboptimal, this scenario will be the most prevalent as it can be performed without regard to the limitations of the nebulizer device incorporating the various high-flow systems available and used in clinical settings worldwide.

[0232] The reference condition of oral inhalation in the presence of low-flow nasal oxygen therapy (Administration B) was selected based on prior experience from a Phase 2 study in COVID-19. Most subjects in that study received nezucitinib under this condition. Furthermore, plasma concentrations of nezucitinib under this condition were found to be similar to those in healthy subjects when nezucitinib was administered by oral inhalation without supplemental oxygen therapy.

[0233] Pharmacokinetic sample collection

[0234] Serial blood samples were collected before and up to 48 hours after dosing on Day 1 of each cycle to determine plasma nezumibinib concentrations.

[0235] Pharmacokinetic parameters and analysis

[0236] The following non-compartmental PK parameters of nezumibinib were calculated as appropriate:

[0237] plasma:

[0238] AUC0-t: The area under the concentration-time curve, from time 0 to the last observed non-zero concentration, calculated by the linear trapezoidal method.

[0239] AUC0-24: Area under the concentration-time curve, from time 0 to the 24-hour time point, calculated by the linear trapezoidal method.

[0240] AUC0-infinity: The area under the concentration-time curve extrapolated from time 0 to infinity. AUC0-infinity is calculated as the sum of AUC0-t plus the ratio of the last measurable plasma concentration to the elimination rate constant.

[0241] AUC% extrapolation: The percentage of AUC0-infinity extrapolation, expressed as (1–AUC0-t / AUC0-infinity)*100.

[0242] CL / F: Apparent total plasma clearance after oral (extravascular) administration, calculated as dose / AUC0-infinity.

[0243] Cmax: Maximum observed concentration.

[0244] Tmax: The time at which Cmax is reached. If the maximum value occurs at multiple time points, Tmax is defined as the first time point with this value.

[0245] Kel: Apparent first-order terminal elimination rate constant calculated from a semi-logarithmic plot of the plasma concentration versus time curve. This parameter is calculated by linear least squares regression analysis using the maximum number of points in the terminal log-linear phase (e.g., three or more non-zero plasma concentrations).

[0246] ·t1 / 2: The apparent first-order terminal elimination half-life is calculated to be 0.693 / Kel.

[0247] Vz / F: Apparent volume of distribution during the terminal elimination phase following oral (extravascular) administration, calculated as dose / (AUC0-infinity*Kel).

[0248] Table 2 provides the calculated non-compartmental PK parameters for various nezumibinib administrations.

[0249] Table 2: Summary of plasma nezumibinib pharmacokinetic parameters following a single inhaled dose

[0250]

[0251]

[0252] For cases that did not exhibit a terminal log-linear phase in the concentration-time curve, Kel, AUC0-infinity, AUC% extrapolation, CL / F, Vz / F, or t were not reported. 1 The value of / 2.

[0253] PK parameters were not calculated for participants with fewer than three consecutive time points with detectable concentrations.

[0254] PK parameters were summarized by administration using descriptive statistics.

[0255] Analysis of variance (ANOVA) was performed on the natural logarithm (ln) transformed AUC0-t, AUC0-24, AUC0-infinity and Cmax using an appropriate statistical program.

[0256] It was estimated that twelve (12) participants provided 90% power to detect a 2-fold difference between the geometric mean of the PK parameter AUC0-infinity for the test (A, C, or D) and the reference administration (B). Therefore, similarity was concluded if the 90% confidence interval (CI) for the ratio of the geometric least square means (LSM) of AUC0-t, AUC0-infinity, and Cmax for nezucitinib fell between 0.50 and 2.00.

[0257] Safety Assessment

[0258] Safety was monitored by physical examination, including at least the respiratory, cardiovascular, and gastrointestinal systems, with further focused examinations of other systems as necessary based on 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 AEs.

[0259] Security Analysis

[0260] The following analyses were performed; however, no formal inferential statistics were performed on the safety assessments.

[0261] Descriptive statistics were calculated for quantitative safety data, and frequency counts were compiled to categorize qualitative safety data.

[0262] Adverse events

[0263] AE uses the latest version of the Medical Dictionary for Regulatory Activities to encode.

[0264] A list of AE data by participant is provided, including verbatim term, preferred term, system organ class (SOC), administration, severity, and relationship to drug.

[0265] A summary of adverse events (AEAEs) arising from administration is presented by SOC, preferred term, and the frequency and percentage of participants reporting each observed event. The frequency of participants experiencing AEAEs is summarized overall and by study part and administration. AEs are also summarized based on their relationship to administration (study drug) and severity.

[0266] Medical history and physical examination

[0267] Medical histories were listed by participant.

[0268] Clinically significant changes in physical examination were captured as AEs.

[0269] Clinical laboratory results, electrocardiogram, spirometry, pulse oximetry, and vital sign measurements

[0270] All clinical laboratory results, 12-lead safety ECG, spirometry, pulse oximetry, vital sign measurements, and their changes from baseline were summarized by study part, administration, and collection time point.

[0271] Concomitant medication

[0272] Concomitant medications were coded using the latest World Health Organization (WHO) drug dictionary and listed by participant.

[0273] Study Design

[0274] This is a phase 1, open-label, fixed-sequence, 4-period study designed to evaluate the PK and safety of a single inhaled dose of nelzumab in different supplemental oxygenation scenarios.

[0275] Fourteen healthy adult male and female participants were recruited and screened within 28 days before the first dose.

[0276] On day 1 of each cycle, participants received a single inhaled dose of nezumab under one of the supplemental oxygenation settings. Blood samples were collected before and 48 hours after each nezumab administration for assessment of plasma nezumab concentrations. A washout period of at least 5 days was allowed between each nezumab dose.

[0277] Safety was assessed throughout the study (i.e., physical examination, vital signs, 12-lead safety ECG, spirometry, clinical laboratory tests, and adverse events); blood, urine, and expired breath samples were collected for safety assessments. Blood oxygen levels were monitored by pulse oximetry before and during the administration of supplemental oxygen. Participants who discontinued were not replaced.

[0278] Residency and Follow-up

[0279] Participants were admitted to the Clinical Research Unit (CRU) on Day -1 of each study cycle and remained there after completion of study assessments until 48 hours after Day 3 of each study cycle. Participants were admitted to the CRU prior to Day -1 for COVID-19 testing unrelated to the study protocol, as required by the CRU. Participants may be required to remain in the CRU for longer periods of time at the discretion of the Investigator or designee. Participants were confined throughout the study (i.e., washout period) based on site preference.

[0280] All participants who received at least one dose of nezumab (including those who discontinued the study early) returned to the CRU 7 (± 2) days after the last nezumab administration for follow-up procedures and to determine whether any AEs had occurred since the last study visit.

[0281] Study end was defined as the date of the last scheduled study procedure.

[0282] Study endpoints

[0283] The study endpoints in Part A were: AUC0-t, AUC0-24, AUC0-infinity, AUC% extrapolation, Cmax, Tmax, CL / F, Vz / F, Kel, and t of nezumibinib. 1 Similarity was concluded if the 90% confidence interval for the ratio of the geometric least squares means of AUC0-t, AUC0-infinity, and Cmax for nezumibinib fell between 0.50 and 2.00.

[0284] Study endpoints for Part B were: administration-emergent adverse events, physical examination, vital signs, 12-lead safety ECG, spirometry, pulse oximetry, and clinical laboratory tests.

[0285] result

[0286] All 14 subjects completed 3 cycles (treatment), with 13 subjects completing all 4 cycles (1 subject withdrew consent after cycle 3 due to personal scheduling reasons).

[0287] Seven subjects completed treatment D1 (a 3 mg dose of nezucitinib via nebulized oral inhalation using a high-flow nasal cannula at a flow rate of 50 L / min), and six subjects completed treatment D2 (a 9 mg dose of nezucitinib via nebulized oral inhalation using a high-flow nasal cannula at a flow rate of 50 L / min).

[0288] Two subjects (14.3%) experienced adverse events: one subject experienced two episodes of nasal congestion, and the other subject experienced one episode of epistaxis. All adverse events were mild in severity and considered unrelated to the study medication. Furthermore, all adverse events resolved during the study, and no adverse event led to dosing discontinuation or withdrawal from the study.

[0289] No clinically relevant changes were seen in the following other subject safety assessments: safety laboratory measurements (clinical chemistry and hematology parameters), safety electrocardiogram, vital sign assessments, pulse oximetry, or spirometry.

[0290] Plasma concentrations of nezumibinib in subjects according to time are shown in Figures 1 to 6 Surprisingly, administration of 3 mg of nezucitinib via nebulized oral inhalation in the presence of high-flow nasal oxygen at a flow rate of 30 L / min (Administration C, Test) provided sustained increases in plasma concentrations compared to 3 mg of nezucitinib administered nasally through a high-flow circuit at a flow rate of 30 L / min (Administration A, Test), and resulted in similar plasma concentrations compared to 3 mg of nezucitinib administered nebulized oral inhalation in the presence of low-flow nasal oxygen at a flow rate of 6 L / min (Administration B, Reference), as shown in Table 1. Figure 3 Visible in.

[0291] Increasing the flow rate through the high-flow nasal cannula from 30 L / min (administration C, test) to 50 L / min (administration D1, test) did not affect the plasma concentration associated with administration of 3 mg nezucitinib via nebulized oral inhalation. In addition, increasing the nebulized oral inhalation dose from 3 mg nezucitinib (administration D1, test) to 9 mg nezucitinib (administration D2, test) at a high-flow nasal cannula flow rate of 50 L / min resulted in an approximately dose-proportional increase in plasma concentrations, as shown in Table 1. Figure 6 Visible in.

[0292] like Figure 4As can be seen in the Figure 3, subjects who received a 3 mg dose of nezucinib via oral nebulization while also 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 the active agent compared to subjects who received a similar 3 mg dose of nezucinib via oral nebulization while only receiving low-flow supplemental oxygen at a rate of 6 L / min (administration B, reference), indicating that nezucinib administered via oral nebulization can provide sufficient active agent to the subject's respiratory system regardless of the rate of concurrently administered nasal supplemental oxygen. This result is in Figure 5 This is further supported by the finding that subjects who were administered a 3 mg dose of nezumab via 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 nezumab to those who received Administration B or Administration C.

[0293] In summary, it was found that administering a pharmaceutical composition comprising nezucitinib or a pharmaceutically acceptable salt thereof to a subject by oral nebulization while the subject was receiving high-flow oxygen at a rate of greater than or equal to about 30 L / min via a nasal cannula was unexpectedly superior to administration via a series high-flow circuit, contrary to current recommendations in the art. Furthermore, administration via oral nebulization to subjects receiving both high-flow and low-flow oxygen surprisingly resulted in similar exposures. Thus, it has now been discovered that administering a pharmaceutical composition comprising nezucitinib or a pharmaceutically acceptable salt thereof to a subject in need thereof via a high-flow nasal circuit is unnecessary and inferior to oral nebulization; and that there is no need to reduce the flow of oxygen when administering the pharmaceutical composition to a subject.

[0294] Example 2 - Administration of Nezucitinib Inhalation Solution to Subjects Receiving Oxygen via High Flow Nasal Cannula (HFNC)

[0295] The nezumigestinib solution for inhalation used in this example is a clear, colorless to yellow solution consisting of 3 mg of nezumigestinib in a sterile aqueous solution containing 10 mM citrate buffer and 150 mM sodium chloride, pH 4.0. The nezumigestinib inhalation solution is provided in unit-dose, low-density polyethylene (LDPE) vials manufactured using blow-fill-seal (BFS) technology and individually packaged in sealed foil laminated bags. Each pouch contains a unit vial containing 1 mL of nezumigestinib inhalation solution at a concentration of 3 mg / mL. The nezumigestinib inhalation solution bags should be stored at a temperature between 2°C and 8°C.

[0296] Nezucitinib inhalation solution can be administered by oral inhalation using the Aerogen Solo+ Ultra nebulizer system to subjects receiving supplemental oxygen via HFNC. The following representative procedure can be followed to administer the nezucitinib inhalation solution.

[0297] 1. If the oxygen flow rate is greater than 50 L / min, reduce the flow rate to 50 L / min and adjust the FiO2 as needed, allowing the subject to acclimate to the adjustments while the equipment is prepared.

[0298] 2. Ensure all needed supplies are available, including:

[0299] (i) Aerogen Controller (can be used for multiple subjects)

[0300] (ii) Aerogen Solo nebulizer (used by each subject for up to one week)

[0301] (iii) New Aerogen Ultra handle and filter (single-use, daily disposal)

[0302] (iv) 3 bottles of nezumibinib inhalation solution (3 mg nezumibinib per bottle, total dose 9 mg)

[0303] 3. Confirm that the subject ID number written on the pouch label matches the subject ID of the subject who received the dose and record the batch number, dose, and dose volume in the subject's source record.

[0304] 4. Assemble the Aerogen Solo nebulizer system according to the product instructions, leaving the medication reservoir open, and connect it to a clean Aerogen controller.

[0305] 5. Open each bag of Nezucitinib Inhalation Solution and remove the vial. Open and remove one vial and squeeze the entire contents into the reservoir cup of the Aerogen Solo; the subject will then nebulize the contents of the vial (approximately 3 minutes), and this will be repeated 3 times for each of the 3 vials, with a 1-minute interval between each vial (see step 10 below).

[0306] Important: To avoid irritation from inhalation of aerosols when too cold, do not use nezumibinib inhalation solution directly from the refrigerator. Warm in your hands if needed.

[0307] 6. Close the nebulizer reservoir.

[0308] 7. After placing the nezumibinib inhalation solution into the reservoir, do not tilt the nebulizer handle more than 45 degrees (upward, downward, or sideways).

[0309] 8. Check whether all parts of the nebulizer are tightly connected and whether the liquid reservoir is closed.

[0310] 9. Hand the Aerogen Ultra handle to the subject and, if possible, ensure they are sitting upright (greater than 45 degrees) with their elbows resting on a tray or sturdy support and holding the device in the appropriate orientation. If the subject is unable to hold the nebulizer device for dosing, staff can provide assistance. Instruct the subject to form a seal around the mouthpiece with their lips and practice breathing normally through the mouthpiece of the device for a few minutes to adapt to mouth breathing in the presence of high-flow nasal oxygen. It is important that the subject can breathe comfortably through their mouth during the dosing procedure.

[0311] 10. Press the Off / On button to begin administration of the study drug. Instruct the subject to breathe normally through the mouthpiece during dosing. The start and end times of inhalation should be recorded in the subject source notes. Nebulization time for each 1 mL vial takes approximately 3 minutes. With a 1 minute interval between vials, dosing should be completed within approximately 15 minutes of the start of nebulization. If an extended rest period is required for reoxygenation, the dosing time will be increased. Subjects will receive three 1 mL vials of nezumibinib inhalation solution for a total dose of 9 mg. The contents of each vial should be squeezed into the nebulizer (Aerogen Solo) and administered as follows:

[0312] (a) Nebulize the entire 1 mL volume of bottle 1 (approximately 3 min).

[0313] NOTE: Foam may form in the Aerogen Solo reservoir cup during dosing. Medication will continue to be delivered despite the foaming. When the nebulizer cup is empty and no more mist is visible from the nebulizer,

[0314] Stop the controller (approximately 3 minutes after the start of each bottle dose).

[0315] (b) The nebulizer should be turned off, and the subject should then remove the nebulizer mouthpiece from their mouth and pause for approximately 1 minute or longer, resting and re-oxygenating as needed.

[0316] During the pause, if saliva accumulates during oral inhalation, the subject should be instructed to spit or swallow. In addition, during the pause, another 1 mL vial should be added to the nebulizer.

[0317] (c) After approximately 1 minute, the subject should place the nebulizer mouthpiece back into their mouth and the nebulizer should be activated to resume dosing until the entire contents of the vial have been administered (approximately 3 minutes).

[0318] (d) Once the second bottle is complete, complete steps (b) and (c) again to administer the third bottle.

[0319] 11. Once the administration of nezumibinib inhalation solution is completed, the Aerogen Solo nebulizer should be removed from the Ultra handle and stored for reuse with the same subject for up to 7 days. The Ultra handle and filter should be discarded after each use.

[0320] 12. The Aerogen USB Controller can be used on multiple subjects and should be cleaned between applications using alcohol-based disinfectant wipes or quaternary ammonium compound disinfectant wipes. Do not (i) spray liquids directly onto the Aerogen USB Controller; (ii) immerse the Aerogen USB Controller in liquid; or (iii) sterilize (autoclave) the Aerogen USB Controller.

[0321] Although the present disclosure has been described with reference to specific aspects or embodiments thereof, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the present disclosure. In addition, to the extent permitted by applicable patent statutes 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 were individually incorporated by reference.

Claims

1. A method for treating a respiratory condition in a subject in need thereof while the subject is receiving high-flow oxygen through a nasal cannula, the method comprising administering a pharmaceutical composition comprising nezumitinib or a pharmaceutically acceptable salt thereof to the subject by oral atomization inhalation while the subject is receiving high-flow oxygen through a nasal cannula at a rate of greater than or equal to about 30 L / min.

2. The method of claim 1, wherein the subject receives high flow oxygen via 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 nezumitinib or a pharmaceutically acceptable salt thereof.

4. The method according to any one of claims 1 to 3, wherein the pharmaceutical composition comprises about 3 mg of nezumitinib or a pharmaceutically acceptable salt thereof.

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

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

0.

8. The method according to any one of claims 1 to 7, wherein the pharmaceutical composition further comprises a buffer.

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

10. The method according to any one of claims 1 to 9, wherein the pharmaceutical composition further comprises a tonicity agent.

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

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

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 diseases, helminthic infections, pulmonary hypertension, lymphangioleiomyomatosis, bronchiectasis, infiltrative lung disease, drug-induced pneumonia, fungal-induced pneumonia, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, eosinophilic granulomatosis with polyangiitis, idiopathic acute eosinophilic pneumonia, idiopathic chronic eosinophilic pneumonia, hypereosinophilic syndrome, Loeffler syndrome, bronchiolitis obliterans organizing pneumonia, pulmonary graft-versus-host disease, and immune checkpoint inhibitor-induced pneumonia.

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

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

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

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

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

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

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

21. A method for treating SARS-CoV-2 lung infection in a subject in need thereof while the subject is receiving high-flow oxygen via nasal cannula, the method comprising administering a pharmaceutical composition comprising nezumitinib or a pharmaceutically acceptable salt thereof to the subject by oral aerosol inhalation while the subject is receiving high-flow oxygen via nasal cannula at a rate of greater than or equal to about 30 L / min.

22. The method of claim 21, wherein the subject receives high flow oxygen via 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 about 1 mg to about 10 mg of nezucitinib or a pharmaceutically acceptable salt thereof.

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

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 nezucitinib or a pharmaceutically acceptable salt thereof.

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

0.

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

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

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

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

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

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

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

35. A method of treating a pulmonary disease, disorder or condition in a subject in need thereof while the subject is receiving high flow oxygen via nasal cannula, the method comprising administering to the subject by oral nebulization inhalation a pharmaceutical composition comprising a therapeutic agent or a pharmaceutically acceptable salt thereof while the subject is receiving high flow oxygen via nasal cannula at a rate of greater than or equal to about 30 L / min.

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

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

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

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

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 diseases, helminthic infections, pulmonary hypertension, lymphangioleiomyomatosis, bronchiectasis, infiltrative lung disease, drug-induced pneumonia, fungal-induced pneumonia, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, eosinophilic granulomatosis with polyangiitis, idiopathic acute eosinophilic pneumonia, idiopathic chronic eosinophilic pneumonia, hypereosinophilic syndrome, Loeffler's syndrome, bronchiolitis obliterans organizing pneumonia, pulmonary graft-versus-host disease, and immune checkpoint inhibitor-induced pneumonia.

41. The method of any preceding claim, wherein the nebulizer is a mesh nebulizer.

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

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