WO2021211782A1

WO2021211782A1 - Methods of treating acute lung injury and acute respiratory distress syndrome

Info

Publication number: WO2021211782A1
Application number: PCT/US2021/027388
Authority: WO
Inventors: Wayne Rothbaum; John Byrd
Original assignee: Telios Pharma, Inc.
Priority date: 2020-04-15
Filing date: 2021-04-15
Publication date: 2021-10-21

Abstract

Therapeutic methods and pharmaceutical compositions for treating acute lung injury and acute respiratory distress syndrome in a human subject are described. The therapeutic methods include administering an amount of a compound effective to selectively inhibit Bruton's tyrosine kinase, but not interleukin-2-inducible T-cell kinase, in the human subject.

Description

METHODS OF TREATING ACUTE LUNG INJURY AND ACUTE RESPIRATORY DISTRESS SYNDROME

FIELD OF THE DISCLOSURE

[0001] Methods of treating acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) using a selective Bruton's Tyrosine Kinase (BTK) inhibitor are disclosed herein.

BACKGROUND

[0002] Coronavirus infection presents a significant public health concern. In particular, the SARS- CoV-2 virus, a novel coronavirus, is a serious human to human pathogenic virus and has been designated by the WHO as pandemic pathogen. The clinical syndrome manifested by SARS-CoV-2 is termed COVID- 19 with a common presentation of fever (89%), cough (68%), CT abnormalities (86%) and lymphocytopenia (84%) with nausea (5%) and diarrhea (4%) being less common. SARS-CoV-2 has a variable phenotype ranging from asymptomatic carrier state to rapidly progressive acute respiratory distress syndrome. Severe disease that requires admission to the hospital occurs in 20% of cases and a subset of these patients require ICU care (6%), intubation (2.3%) or die (1.4%). The death rate from COVID-19 in different populations has ranged from 2.4% in China to 7.2% in Italy. The death rate from COVID-19 increases proportionately with older age, being highest among older patients and also those who are immunocompromised or have other co-morbidities or lymphocytopenia. Among hospitalized cancer patients with COVID-19 in China, a 39% frequency of mechanical ventilation or death occurred compared to 8% among patients without cancer. The systemic and pulmonary pathogenesis derived from clinical cases of ICU hospitalized COVID-19 cases and autopsy series demonstrates increased levels of plasma inflammatory cytokines including TNF-alpha, IL-6, and IL-2, and IL-10 and neutrophilic infiltration, macrophages, monocytes, minimal lymphocytes (CD4+ T-cells predominately) and type 2 pneumocytes with electron microscopy (EM) viral particles. Other risk factors for severe COVID-19 illness is the presence of neutrophilia, organ dysfunction (elevated LDH), coagulation abnormalities, thrombocytopenia, and lymphocytopenia suggesting both findings observed in hemophagocytic syndrome, and immune deficiency.

[0003] Current therapies for coronavirus infection, e.g., SARS-CoV-2 infection, that address the rapid progression to acute respiratory distress syndrome are limited. There is therefore a need for effective methods of treating ALI and ARDS caused by a coronavirus. Further, there is a need for effective methods of treating ALI and ARDS caused by infections, including bacterial and viral infections. SUMMARY OF THE DISCLOSURE

[0004] The disclosure relates to methods for selectively inhibiting Bruton's tyrosine kinase (BTK)- associated inflammation in acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), the ALI or ARDS caused by an infection, such as a bacterial infection or a viral infection, in a human subject. The methods comprise administering to the human subject an amount of a compound effective to inhibit BTK, but not interleukin-2-inducible T-cell kinase (ITK) in the human subject, wherein the compound is 1- (4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof. In some embodiments, the ALI or ARDS is caused by a coronavirus in the human subject. In some embodiments, the coronavirus is selected from a HCoV- OC43 virus, a HCoV-HKUl virus, a HCoV-229E virus, a HCoV-NL63 virus, a MERS-CoV virus, a SARS-CoV virus, or a SARS-CoV-2 virus. In some embodiments, the coronavirus is a SARS-CoV-2 virus. In some embodiments, the ALI or ARDS is caused by an influenza virus in the human subject. In some embodiments, the influenza virus is selected from an influenza A virus, an influenza B virus, an influenza C virus, or an influenza D virus. In some embodiments, the influenza virus is an influenza A virus having a serotype selected from H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3, H10N7, H7N9, or H6N1.

[0005] In some embodiments, the human subject has a cancer. In some embodiments, the human subject has a brain cancer, a lung cancer, a colon cancer, an epidermoid cancer, a squamous cell cancer, a bladder cancer, a gastric cancer, a pancreatic cancer, a breast cancer, a head cancer, a neck cancer, a renal cancer, a kidney cancer, a liver cancer, an ovarian cancer, a prostate cancer, a colorectal cancer, a uterine cancer, a rectal cancer, an esophageal cancer, a testicular cancer, a gynecological cancer, a thyroid cancer, a melanoma, or a hematologic malignancy. In some embodiments, the human subject has a cancer precursor disease associated with immune deficiency.

[0006] In some embodiments, the hematologic malignancy is a lymphoid neoplasm selected from B cell lymphoblastic lymphoma, T cell lymphoblastic lymphoma, diffuse large B-cell lymphoma, Burkitt lymphoma, follicular lymphoma, small lymphocytic lymphoma, Waldenstrom macroglobulinemia, mantle cell lymphoma, multiple myeloma, chronic lymphocytic leukemia, acute lymphocytic leukemia, non-Hodgkin lymphoma or Hodgkin lymphoma. In some embodiments, the hematologic malignancy is a myeloid neoplasm selected from acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, myelofibrosis, or myeloproliferative neoplasm. In some embodiments, the myelofibrosis is selected from the group consisting of primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post PV-MF), and post-essential thrombocythemia myelofibrosis (post ET-MF). [0007] In some embodiments, administering is by a route selected from oral, topical, parenteral, pulmonary, or nasal. In some embodiments, administering is by an oral route. In some embodiments, the human subject is in a fasted state when the compound is administered. In some embodiments, the human subject is in a fed state when the compound is administered.

[0008] In some embodiments, the compound is in a dosage form selected from a tablet, a troche, a dispersion, a suspension, a solution, a capsule, or an aerosol. In some embodiments, the compound is in a dosage form selected from a tablet or a powder-in-capsule.

[0009] In some embodiments, the amount is a total daily dose of about 40 mg to about 1500 mg, such as about 50 mg to about 300 mg, about 60 mg to about 250 mg, about 70 mg to about 200 mg, about 80 mg to about 160 mg, about 300 mg to about 1300 mg, about 400 mg to about 1100 mg, about 500 mg to about 1000 mg, about 600 mg to about 900 mg, about 500 mg to about 800 mg, about 400 mg to about 700 mg, about 300 mg to about 600 mg, about 200 mg to about 500 mg, about 100 mg to about 400 mg, about 600 mg, about 400 mg, and/or about 200 mg. In some embodiments, the total daily dose comprises one dose per day, two divided doses per day, three divided doses per day, or four divided doses per day. In some embodiments, the total daily dose comprises one dose per day. In some embodiments, the total daily dose comprises two divided doses per day. In some embodiments, the methods comprise administering the compound in a dose of 300 mg twice daily, 200 mg twice daily, or 100 mg twice daily. In some embodiments, the human subject is in a fasted state when the compound is administered.

[0010] In some embodiments, the methods further comprise inhibiting bone marrow kinase on chromosome X (BMX)-associated inflammation by administering the amount of the compound.

[0011] In some embodiments, BTK is inhibited in a lung of the human subject. In some embodiments, BMX is inhibited in a lung of the human subject.

[0012] In some embodiments, the human subject has (i) a bacterial infection or a viral infection, and (ii) suspected or confirmed pneumonia. In some embodiments, the human subject has a coronavirus infection and suspected or confirmed pneumonia. In some embodiments, the coronavirus infection is COVID-19. In some embodiments, the human subject has an influenza virus infection and suspected or confirmed pneumonia.

[0013] In some embodiments, administering occurs after diagnosing cytokine storm syndrome, diagnosing a coronavirus infection, such as COVID-19, and/or diagnosing an influenza virus infection in the human subject. In some embodiments, administering occurs after detecting a marker for cytokine storm syndrome, detecting a marker for a coronavirus infection, such as COVID-19, and/or detecting a marker for an influenza virus infection in a sample (e.g., a blood sample) from the human subject. In some embodiments, the marker for cytokine storm syndrome, for a coronavirus infection, and/or for an influenza virus infection is an increased level of alanine aminotransferase, lactate dehydrogenase, C- reactive protein, ferritin, D-dimer, a pro- or anti-inflammatory cytokine, or a combination thereof. In some embodiments, the cytokine is IL-6, TNF-alpha, IL-2, IL-lb, IL-10, or a combination thereof.

[0014] In some embodiments, the methods further comprise administering a steroid. In some embodiments, the steroid is a corticosteroid. In some embodiments, the corticosteroid is selected from the group consisting of alclometasone dipropionate, amcinonide, beclometasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone valerate, budesonide, ciclesonide, clobetasol propionate, clobetasone butyrate, cortisone acetate, desonide, dexamethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortolone, fluprednidene acetate, fluticasone furoate, fluticasone propionate, halcinonide, halometasone, hydrocortisone, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, methylprednisolone, mometasone, mometasone furoate, prednicarbate, prednisolone, prednisone, triamcinolone acetonide, tixocortol pivalate, and combinations thereof. In some embodiments, the steroid is administered concurrently with the compound. In some embodiments, the steroid is administered before the compound. In some embodiments, the steroid is administered after the compound. In some embodiments, the steroid is administered in an amount effective to reduce BTK- associated inflammation.

[0015] In some embodiments, the methods further comprise administering an antiviral agent. In some embodiments, the antiviral agent is selected from the group consisting of nucleoside analogs, protease inhibitors, interferons, reverse transcriptase inhibitors, and combinations thereof. In some embodiments, the antiviral agent is selected from the group consisting of acyclovir, favipiravir, ganciclovir, remdesivir, ribavirin, indinavir, lopinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, interferon a-2a, interferon a-2b, interferon a-nl, interferon a-n3, interferon b-la, interferon b-lb, lamivudine, zidovudine, amantadine, foscarnet, nitazoxanide, umifenovir, and combinations thereof. In some embodiments, the antiviral agent is administered concurrently with the compound. In some embodiments, the antiviral agent is administered before the compound. In some embodiments, the antiviral agent is administered after the compound. In some embodiments, the antiviral agent is administered in an amount effective to reduce viral titer.

[0016] In some embodiments, administering is continued until a biomarker of inflammation returns to a normal level. In some embodiments, the biomarker is elevated C-reactive protein (CRP), such as CRP greater than 10 rng/dL In some embodiments, the biomarker is decreased absolute lymphocyte count (ALC), such as ALC less than 1000 cells/pL.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1A provides charts showing relative amounts of various cell populations in a CLL patient receiving treatment for COVID-19.

[0018] FIG. IB provides graphs showing levels of markers of activation in a CLL patient receiving treatment for COVID-19.

[0019] FIG. 1C provides graphs showing levels of markers of adhesion in a CLL patient receiving treatment for COVID-19.

[0020] FIG. ID provides graphs showing the TCR V beta repertoire in a CLL patient receiving treatment for COVID-19.

[0021] FIG. IE provides graphs showing levels of serum cytokines in a CLL patient receiving treatment for COVID-19.

[0022] FIG. IF and FIG. 1G provide graphs showing cell signaling in a CLL patient receiving treatment for COVID-19.

[0023] FIG. 2A provides charts showing relative amounts of various cell populations in a FL patient receiving treatment for COVID-19.

[0024] FIG. 2B provides graphs showing levels of markers of activation in a FL patient receiving treatment for COVID-19.

[0025] FIG. 2C provides graphs showing levels of markers of adhesion in a FL patient receiving treatment for COVID-19.

[0026] FIG. 2D provides graphs showing the TCR V beta repertoire in a FL patient receiving treatment for COVID-19.

[0027] FIG. 2E provides graphs showing levels of serum cytokines in a FL patient receiving treatment for COVID-19.

[0028] FIG. 2F provides graphs showing cell signaling in a FL patient receiving treatment for COVID- 19.

[0029] FIG. 3A provides charts showing relative amounts of various cell populations in a MM patient receiving treatment for COVID-19.

[0030] FIG. 3B provides graphs showing levels of markers of activation in a MM patient receiving treatment for COVID-19. [0031] FIG. 3C provides graphs showing levels of markers of adhesion in a MM patient receiving treatment for COVID-19.

[0032] FIG. 3D provides graphs showing the TCR V beta repertoire in a MM patient receiving treatment for COVID-19.

[0033] FIG. 3E provides graphs showing levels of serum cytokines in a MM patient receiving treatment for COVID-19.

[0034] FIG. 3F and FIG. 3G provide graphs showing cell signaling in a MM patient receiving treatment for COVID-19.

[0035] FIG. 4A provides charts showing relative amounts of various cell populations in a CLL patient receiving treatment for COVID-19.

[0036] FIG. 4B provides graphs showing levels of markers of activation in a CLL patient receiving treatment for COVID-19.

[0037] FIG. 4C provides graphs showing levels of markers of adhesion in a CLL patient receiving treatment for COVID-19.

[0038] FIG. 4D provides graphs showing the TCR V beta repertoire in a CLL patient receiving treatment for COVID-19.

[0039] FIG. 4E provides graphs showing levels of serum cytokines in a CLL patient receiving treatment for COVID-19.

[0040] FIG. 4F and FIG. 4G provide graphs showing cell signaling in a CLL patient receiving treatment for COVID-19.

[0041] FIG. 5A provides charts showing relative amounts of various cell populations in a MM patient receiving treatment for COVID-19.

[0042] FIG. 5B provides graphs showing levels of markers of activation in a MM patient receiving treatment for COVID-19.

[0043] FIG. 5C provides graphs showing levels of markers of adhesion in a MM patient receiving treatment for COVID-19.

[0044] FIG. 5D provides graphs showing the TCR V beta repertoire in a MM patient receiving treatment for COVID-19.

[0045] FIG. 5E provides graphs showing levels of serum cytokines in a MM patient receiving treatment for COVID-19.

[0046] FIG. 6A provides charts showing relative amounts of various cell populations in a CLL patient receiving treatment for COVID-19. [0047] FIG. 6B provides graphs showing levels of markers of activation in a CLL patient receiving treatment for COVID-19.

[0048] FIG. 6C provides graphs showing levels of markers of adhesion in a CLL patient receiving treatment for COVID-19.

[0049] FIG. 6D provides graphs showing the TCR V beta repertoire in a CLL patient receiving treatment for COVID-19.

[0050] FIG. 6E provides graphs showing levels of serum cytokines in a CLL patient receiving treatment for COVID-19.

DETAILED DESCRIPTION

[0051] While preferred embodiments of the disclosure are shown and described herein, such embodiments are provided by way of example only and are not intended to otherwise limit the scope of the disclosure. Various alternatives to the described embodiments may be employed in practicing the disclosed methods.

[0052] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs.

[0053] The term "effective amount" or "an amount of a compound effective to" refers to that amount of an active pharmaceutical ingredient or combination of active pharmaceutical ingredients as described herein that is sufficient to effect the intended application including, but not limited to, disease treatment. A therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated ( e.g ., the weight, age and gender of the subject), the severity of the disease condition, the manner of administration, and other factors which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, (e.g., malignant CD34+ myeloid cells). The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried. [0054] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic, and absorption delaying agents. The use of such media and agents for active pharmaceutical ingredients is well known in the art. Except insofar as any conventional media or agent is incompatible with the active pharmaceutical ingredient, its use in the therapeutic compositions of the disclosure is contemplated. Supplementary active ingredients can also be incorporated into the described compositions.

[0055] The term "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counter ions known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Specific examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In selected embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0056] The terms "QD," "qd," or "q.d." means quaque die, once a day, or once daily. The terms "BID," "bid," or "b.i.d." mean bis in die, twice a day, or twice daily. The terms "TID," "tid," or "t.i.d." mean ter in die, three times a day, or three times daily. The terms "QID," "qid," or "q.i.d." mean quater in die, four times a day, or four times daily.

[0057] The term "acute respiratory distress syndrome" as used herein refers to a severe respiratory impairment characterized by rapid onset of inflammation in the lungs. Acute respiratory distress syndrome generally involves acute inflammation, microvascular damage, and increased pulmonary vascular and epithelial permeability. This impairment can involve a severe immune reaction in which the lung releases too many cytokines into the blood too quickly. Cytokines involved include TNF-alpha, IL-6, and IL-2 and IL-10 followed by neutrophilic infiltration, macrophages, monocytes, minimal lymphocytes (CD4+ T-cells predominately) and type 2 pneumocytes.

[0058] The term "acute lung injury" as used herein refers to a milder form of acute respiratory distress syndrome. [0059] The terms "administered in combination with" and "co-administration" as used herein, encompass administration of two or more active pharmaceutical ingredients to a subject so that both agents and/or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more agents are present.

[0060] The term "combination" or "pharmaceutical combination" is defined herein to refer to a fixed combination in one dosage unit form, a non-fixed combination, or a kit of parts for the combined administration where the therapeutic agents may be administered together, independently at the same time or separately within time intervals, which preferably allows that the combination partners show a cooperative, e.g. synergistic effect. Thus, the single compounds of the pharmaceutical combination could be administered simultaneously or sequentially.

[0061] The term "fixed combination" means that the therapeutic agents, e.g., the single compounds of the combination, are in the form of a single entity or dosage form.

[0062] The term "non-fixed combination" means that the therapeutic agents, e.g., the single compounds of the combination, are administered to a patient as separate entities or dosage forms either simultaneously or sequentially with no specific time limits, wherein preferably such administration provides therapeutically effective levels of the two therapeutic agents in the body of the subject, e.g., a mammal or human in need thereof.

[0063] When ranges are used herein to describe, for example, physical or chemical properties such as molecular weight or chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. Use of the term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary from, for example, between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") includes those embodiments such as, for example, an embodiment of any composition of matter, method or process that "consist of" or "consist essentially of" the described features.

Methods of Treating ALI and ARDS

[0064] The present disclosure relates to the use of a selective BTK inhibitor to treat ALI and ARDS, for example, ALI and/or ARDS resulting from an infection with a bacterium or a virus, such as a coronavirus or an influenza virus. Accordingly, in certain aspects, the disclosure relates to methods of selectively inhibiting BTK-associated inflammation in ALI or ARDS, the ALI or ARDS being caused by an infection, such as a bacterial infection or a viral infection (e.g., a coronavirus infection or an influenza infection), in a human subject. The methods comprise the step of administering to the human subject an amount of a compound effective to inhibit BTK, but not interleukin-2-inducible T-cell kinase (ITK), in the human subject, wherein the compound is l-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4- yl)amino)methyl)-4-fluoropiperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof. [0065] In an embodiment, the disclosure relates to inhibiting bone marrow kinase on chromosome X (BMX)-associated inflammation in ALI or ARDS in a human subject. Thus, in certain embodiments, the disclosure relates to methods of selectively inhibiting BTK- and BMX-associated inflammation in the lungs, but not ITK, in ALI or ARDS in a human subject.

[0066] In an embodiment, the human subject has (i) an infection, such as a bacterial infection or a viral infection, and (ii) suspected or confirmed pneumonia. In an embodiment, the administering occurs after the human subject is diagnosed with the infection and with suspected or confirmed pneumonia. Thus, in an embodiment, administration of an amount of a compound effective to inhibit BTK and optionally BMX, but not ITK, in a human subject begins within 7 days after the human subject is diagnosed with an infection and with suspected or confirmed pneumonia, such as within 6 days, within 5 days, within 4 days, within 3 days, within 2 days, within 1 day, within 12 hours, or within 6 hours after the human subject is diagnosed with the infection and with suspected or confirmed pneumonia.

[0067] In an embodiment, the human subject has a coronavirus infection, such as COVID-19, and suspected or confirmed pneumonia. In an embodiment, the administering occurs after the human subject is diagnosed with a coronavirus infection, such as COVID-19, and with suspected or confirmed pneumonia. Thus, in an embodiment, administration of an amount of a compound effective to inhibit BTK and optionally BMX, but not ITK, in a human subject begins within 7 days after the human subject is diagnosed with a coronavirus infection and with suspected or confirmed pneumonia, such as within 6 days, within 5 days, within 4 days, within 3 days, within 2 days, within 1 day, within 12 hours, or within 6 hours after the human subject is diagnosed with a coronavirus infection and with suspected or confirmed pneumonia. In an embodiment, COVID-19 infection is diagnosed as per World Health Organization (WHO) criteria, including positive nucleic acid test of any specimen including, but not limited to, respiratory, blood, urine, stool, or other bodily fluid. In an embodiment, the pneumonia or suspected pneumonia requires hospitalization and/or oxygen saturation <94% on room air and/or requires supplemental oxygen. [0068] In an embodiment, a symptom of a coronavirus infection, e.g., a SARS-CoV-2 infection, includes fever, cough, CT abnormalities, or lymphocytopenia. In an embodiment, administration of an amount of a compound effective to inhibit BTK and optionally BMX, but not ITK, in a human subject begins within 7 days after the human subject first exhibits one or more symptoms of a coronavirus infection, such as within 6 days, within 5 days, within 4 days, within 3 days, within 2 days, within 1 day, within 12 hours, or within 6 hours after the human subject first exhibits one or more symptoms of a coronavirus infection. In certain embodiments, administration of an amount of a compound effective to inhibit BTK and optionally BMX, but not ITK, in a human subject begins within 7 days after the human subject first exhibits a fever, such as within 6 days, within 5 days, within 4 days, within 3 days, within 2 days, within 1 day, within 12 hours, or within 6 hours after the human subject first exhibits a fever, such as a fever of at least 100°F, at least 100.5°F, at least 101°F, at least 101.5°F, at least 102°F, at least 102.5°F or at least 103°F. In an embodiment, administration of an amount of a compound effective to inhibit BTK and optionally BMX, but not ITK, in a human subject begins within 7 days after the human subject is diagnosed with a coronavirus infection or a probable coronavirus infection, e.g., a SARS-CoV-2 infection, such as within 6 days, within 5 days, within 4 days, within 3 days, within 2 days, within 1 day, within 12 hours, or within 6 hours after the human subject is diagnosed with a coronavirus infection or a probable coronavirus infection.

[0069] In an embodiment, the human subject has an influenza virus infection, and suspected or confirmed pneumonia. In an embodiment, the administering occurs after the human subject is diagnosed with an influenza virus infection, and with suspected or confirmed pneumonia. Thus, in an embodiment, administration of an amount of a compound effective to inhibit BTK and optionally BMX, but not ITK, in a human subject begins within 7 days after the human subject is diagnosed with an influenza virus infection and with suspected or confirmed pneumonia, such as within 6 days, within 5 days, within 4 days, within 3 days, within 2 days, within 1 day, within 12 hours, or within 6 hours after the human subject is diagnosed with an influenza virus infection and with suspected or confirmed pneumonia.

[0070] In an embodiment, administering occurs after detecting a marker for cytokine storm syndrome in a sample, such as a blood sample, from the human subject. Thus, in an embodiment, administration of an amount of a compound effective to inhibit BTK and optionally BMX, but not ITK, in a human subject begins within 7 days after detecting a marker for cytokine storm syndrome in a sample, such as a blood sample, from the human subject, such as within 6 days, within 5 days, within 4 days, within 3 days, within 2 days, within 1 day, within 12 hours, or within 6 hours after detecting a marker for cytokine storm syndrome in a sample, such as a blood sample, from the human subject. In an embodiment administration of an amount of a compound effective to inhibit BTK and optionally BMX, but not ITK, in a human subject begins within 7 days after detecting a marker for a coronavirus infection, such as a COVID-19 infection, in a sample, such as a blood sample, from the human subject, such as within 6 days, within 5 days, within 4 days, within 3 days, within 2 days, within 1 day, within 12 hours, or within 6 hours after detecting a marker for a coronavirus infection in a sample, such as a blood sample, from the human subject. In an embodiment administration of an amount of a compound effective to inhibit BTK and optionally BMX, but not ITK, in a human subject begins within 7 days after detecting a marker for an influenza virus infection in a sample, such as a blood sample, from the human subject, such as within 6 days, within 5 days, within 4 days, within 3 days, within 2 days, within 1 day, within 12 hours, or within 6 hours after detecting a marker for an influenza virus infection in a sample, such as a blood sample, from the human subject. In certain embodiments, the methods disclosed herein involve a step of detecting a marker for cytokine storm syndrome, detecting a marker for a coronavirus infection, such as a COVID-19 infection, and/or detecting a marker for an influenza virus infection in a sample, such as a blood sample, from the human subject.

[0071] In an embodiment, administration of an amount of a compound effective to inhibit BTK and optionally BMX, but not ITK, begins with administration of an initial dose of an amount of the compound, which may occur after the human subject has been diagnosed with a coronavirus infection or a probable coronavirus infection, after the human subject has been diagnosed with an influenza infection or a probable influenza infection, after a marker for cytokine storm syndrome has been detected in a sample, such as a blood sample, from the human subject, after a marker for a coronavirus infection, such as a COVID-19 infection, has been detected in a sample, such as a blood sample, from the human subject, and/or after a marker for an influenza virus infection has been detected in a sample, such as a blood sample, from the human subject. In an embodiment, administration of an initial dose of an amount of the compound occurs a short time after the diagnosis and/or detection of the marker, such as within 7 days after, within 6 days after, within 5 days after, within 4 days after, within 3 days after, within 2 days after, within 1 day after, within 12 hours after, or within 6 hours after the diagnosis and/or detection of the marker.

[0072] In an embodiment, a marker for cytokine storm syndrome and/or coronavirus infection, such as a COVID-19 infection, in a sample, such as a blood sample, of a human subject includes, but is not limited to, an abnormal cytokine level, an abnormal lymphocyte level, abnormal IFN-y expression, abnormal lactate dehydrogenase (LDH) levels, abnormal D-dimer levels, abnormal procalcitonin levels, abnormal C-reactive protein (CRP) levels, abnormal ferritin levels, abnormal soluble IL-2R levels, abnormal NK cells levels, abnormal white blood cell counts, abnormal albumin levels, abnormal alanine aminotransferase levels; or a combination thereof. For example, a marker for cytokine storm syndrome and/or coronavirus infection, such as a COVID-19 infection, includes, but is not limited to, increased cytokine levels (e.g., increased levels of IL-6, IL-10, and TNF-a); lymphopenia (e.g., lymphopenia in CD4⁺ and CD8⁺ T cells); decreased IFN-y expression in CD4⁺ T cells; increased LDH levels, increased D-dimer levels; increased procalcitonin; increased CRP; increased ferritin; increased soluble IL-2R; decreased NK cells; increased white blood cell counts; hypoalbuminemia; increased alanine aminotransferase; or a combination thereof. In an embodiment, a marker for cytokine storm syndrome and/or coronavirus infection in a sample, such as a blood sample, of a human subject includes lymphopenia, hypoalbuminemia, increased alanine aminotransferase, increased LDH, increased CRP, increased ferritin, increased D-dimer, increased IL-2R, increased IL-6, increased IL-10, increased TNF-a, or a combination thereof. In an embodiment, a marker for cytokine storm syndrome and/or coronavirus infection in a sample, such as a blood sample, of a human subject includes increased levels of pro- and anti inflammatory cytokines, such as IFN-y (interferon, IFN), IL-lra (interleukin, IL), IL-2ra, IL-6, IL-10, IL-18, HGF (hepatocyte growth factor), MCP-3 (monocyte chemotactic protein-3), MIG (monokine induced gamma interferon), M-CSF (macrophage colony stimulating factor), G-CSF (granulocyte colony- stimulating factor), MIG-la (macrophage inflammatory protein 1 alpha) CTACK (cutaneous T-cell- attracting chemokine), IP-10 (interferon gamma induced protein 10), or a combination thereof. In an embodiment, a marker for cytokine storm syndrome and/or coronavirus infection in a sample, such as a blood sample, of a human subject includes increased levels of IP-10, MCP-3, IL-lra, or a combination thereof. In an embodiment, a marker for cytokine storm syndrome and/or coronavirus infection in a sample, such as a blood sample, of a human subject includes increased levels of M-CSF, IL-10, IFN-a2, IL- 13, IL-17, IL-4, IP-10, IL-Ib, IL-7, IL-lra, G-CSF, IL-12, IFN-y, IL-la, IL-2, HGF, or a combination thereof. In an embodiment, a marker for cytokine storm syndrome and/or coronavirus infection in a sample, such as a blood sample, of a human subject includes increased levels of IL-2, IL-6, IL-7, IL-10, G-CSF, IP- lO/CXCL-10, MCP-1/CCL2, MIP-la/CCL3, TNF-a, or a combination thereof. In an embodiment, a marker for cytokine storm syndrome and/or coronavirus infection in a sample, such as a blood sample, of a human subject includes abnormal levels of IL-6, TNF-a, IL-2, IL-lb, IL-10, or a combination thereof, such as increased levels of IL-6, TNF-a, IL-2, IL-lb, IL-10, or a combination thereof.

[0073] In an embodiment, increased levels of a marker include levels of the marker greater than the levels typically present in an average human subject that does not have cytokine storm syndrome and/or a coronavirus infection. In an embodiment, increased levels of a marker include levels of the marker that are at least 1.1-fold increased over the normal level, such as at least 1.2-fold increased over the normal level, at least 1.3-fold increased over the normal level, at least 1.4-fold increased over the normal level, at least 1.5-fold increased over the normal level, at least 1.6-fold increased over the normal level, at least 1.7-fold increased over the normal level, at least 1.8-fold increased over the normal level, at least 2-fold increased over the normal level, at least 2.5-fold increased over the normal level, at least 3-fold increased over the normal level, at least 4-fold increased over the normal level, or at least 5-fold increased over the normal level. In an embodiment, decreased levels of a marker include levels of the marker that are less than or equal to 95% of the normal level, such as less than or equal to 90% of the normal level, less than or equal to 85% of the normal level, less than or equal to 80% of the normal level, less than or equal to 75% of the normal level, less than or equal to 70% of the normal level, less than or equal to 65% of the normal level, less than or equal to 60% of the normal level, less than or equal to 55% of the normal level or less than or equal to 50% of the normal level (i.e., half of the normal level).

[0074] In an embodiment, a marker includes a level of ferritin in a blood sample of the human subject greater than 400 pg/L, such as greater than 500 pg/L, greater than 700 pg/L, greater than 800 pg/L, greater than 1000 pg/L, greater than 1200 pg/L, or greater than 1400 pg/L. In an embodiment, a marker includes a level of high-sensitivity CRP in a blood sample of the human subject greater than 10 mg/L, such as greater than 20 mg/L, greater than 30 mg/L, greater than 40 mg/L, greater than 50 mg/L, greater than 60 mg/L, greater than 75 mg/L, or greater than 100 mg/L. In an embodiment, a marker includes a level of D-dimer in a blood sample of the human subject greater than 0.5 pg/L, such as greater than 1 pg/L, greater than 1.5 pg/L, or greater than 2 pg/L. In an embodiment, a marker includes a level of D-dimer in a blood sample of the human subject greater than 0.5 mg/L, such as greater than 1 mg/L, greater than 1.5 mg/L, or greater than 2 mg/L. In an embodiment, a marker includes a level of LDH in a blood sample of the human subject greater than 225 U/L, such as greater than 250 U/L, greater than 300 U/L, greater than 350 U/L, greater than 400 U/L, or greater than 500 pg/L. In an embodiment, a marker includes a level of alanine aminotransferase in a blood sample of the human subject greater than 40 U/L, such as greater than 42 U/L, greater than 45 U/L, or greater than 50 U/L.

[0075] In an embodiment, administering is continued until a biomarker of inflammation returns to a normal level.

[0076] In an embodiment, the biomarker is elevated C-reactive protein (CRP). In an embodiment, administering is continued until CRP returns to a normal level. In an embodiment, administering is continued while CRP remains at an elevated level. In an embodiment, elevated CRP is CRP greater than 10 mg/dL, such as greater than 11 mg/dL, greater than 12 mg/dL, greater than 13 mg/dL, greater than 14 mg/dL, greater than 15 mg/dL, greater than 16 mg/dL, greater than 17 mg/dL, greater than 18 mg/dL, greater than 19 mg/dL, greater than 20 mg/dL, greater than 21 mg/dL, greater than 22 mg/dL, greater than 23 mg/dL, greater than 24 mg/dL, greater than 25 mg/dL, greater than 26 mg/dL, greater than 27 mg/dL, greater than 28 mg/dL, greater than 29 mg/dL, and/or greater than 30 mg/dL. In an embodiment, elevated CRP is CRP greater than 3 mg/dL, such as greater than 4 mg/dL, greater than 5 mg/dL, greater than 6 mg/dL, greater than 7 mg/dL, greater than 8 mg/dL, and/or greater than 9 mg/dL. In an embodiment, normal CRP is CRP less than 3 mg/dL, such as less than 2 mg/dL, less than 1.5 mg/dL, less than 1 mg/dL, less than 0.9 mg/dL, less than 0.8 mg/dL, less than 0.7 mg/dL, less than 0.6 mg/dL, less than 0.5 mg/dL, less than 0.4 mg/dL, less than 0.3 mg/dL, less than 0.2 mg/dL, and/or less than 0.1 mg/dL.

[0077] In an embodiment, the biomarker is decreased absolute lymphocyte count (ALC). In an embodiment, administering is continued until ALC returns to a normal level. In an embodiment, administering is continued while ALC remains at an decreased level. In an embodiment, decreased ALC is ALC less than 1000 cells/pL, such as less than 900 cells/pL, less than 800 cells/pL, less than 700 cells/pL, less than 600 cells/pL, less than 500 cells/pL, less than 400 cells/pL, less than 300 cells/pL, less than 200 cells/pL, and/or less than 100 cells/pL. In an embodiment, normal ALC is ALC greater than 1000 cells/pL, such as greater than 1200 cells/pL, greater than 1400 cells/pL, greater than 1600 cells/pL, greater than 1800 cells/pL, greater than 2000 cells/pL, greater than 2200 cells/pL, greater than 2400 cells/pL, greater than 2600 cells/pL, greater than 2800 cells/pL, greater than 3000 cells/pL, greater than 3200 cells/pL, greater than 3400 cells/pL, greater than 3600 cells/pL, greater than 3800 cells/pL, and/or greater than 4000 cells/pL.

[0078] In an embodiment, the coronavirus is selected from the group consisting of a HCoV-OC43 virus, a HCoV-HKUl virus, a HCoV-229E virus, a HCoV-NL63 virus, a MERS-CoV virus, a SARS-CoV virus, and a SARS-CoV-2 virus.

[0079] In an embodiment, the influenza virus is selected from the group consisting of an influenza A virus, an influenza B virus, an influenza C virus, or an influenza D virus. In an embodiment, the influenza virus is an influenza A virus having a serotype selected from H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3, H10N7, H7N9, or H6N1.

[0080] In an embodiment, the human subject has a cancer. In an embodiment, the human subject has a brain cancer, a lung cancer, a colon cancer, an epidermoid cancer, a squamous cell cancer, a bladder cancer, a gastric cancer, a pancreatic cancer, a breast cancer, a head cancer, a neck cancer, a renal cancer, a kidney cancer, a liver cancer, an ovarian cancer, a prostate cancer, a colorectal cancer, a uterine cancer, a rectal cancer, an esophageal cancer, a testicular cancer, a gynecological cancer, a thyroid cancer, a melanoma, or a hematologic malignancy. In an embodiment, the hematologic malignancy is a lymphoid neoplasm selected from B cell lymphoblastic lymphoma, T cell lymphoblastic lymphoma, diffuse large B-cell lymphoma, Burkitt lymphoma, follicular lymphoma, small lymphocytic lymphoma, Waldenstrom macroglobulinemia, mantle cell lymphoma, multiple myeloma, chronic lymphocytic leukemia, acute lymphocytic leukemia, non-Hodgkin lymphoma or Hodgkin lymphoma. In an embodiment, the hematologic malignancy is a myeloid neoplasm selected from acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, myelofibrosis, or myeloproliferative neoplasm. In an embodiment, in the myelofibrosis is selected from the group consisting of primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post PV-MF), and post-essential thrombocythemia myelofibrosis (post ET-MF). In an embodiment, the human subject has a cancer precursor disease associated with immune deficiency.

[0081] In an embodiment, BTK is inhibited in a lung of the human subject. In an embodiment, BMX is inhibited in a lung of the human subject. In an embodiment, both BTK and BMX are inhibited in a lung of the human subject.

Mechanism of Action

[0082] Without wishing to be bound by theory, it is believed that selective inhibition of BTK- associated inflammation in ALI and ARDS can diminish the lung pathology mediated by a bacterial infection or a viral infection, e.g., a coronavirus infection, such as infection caused by the SARS-CoV-2 virus, while also avoiding undesirable side effects. Ibrutinib, is an irreversible inhibitor of BTK that was approved for marketing for treatment of chronic lymphocytic leukemia (CLL), Waldenstrom's macroglobulinemia, marginal zone lymphoma, and mantle cell lymphoma. Ibrutinib has several alternative irreversible targets with close potency (BLK, TEC, BMX, ErbB4) in the <1 nM range and between 10-22 nM (ErbB2, EGFR, and ITK). These alternative kinases provide different avenues for therapeutic benefit of ibrutinib as an immune modulating agent and also directed at select solid tumors. However, they also represent a significant liability toward adverse events such as rash and diarrhea (EGFR), NK cell function loss relative to antibody dependent cellular cytotoxicity (ITK), cardiac arrhythmias, and bleeding. [0083] Without wishing to be bound by theory, it is believed that that selective inhibition of BTK- associated inflammation in ALI and ARDS using l-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4- yl)amino)methyl)-4-fluoropiperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof, may result in more favorable safety and tolerability compared to currently approved BTK inhibitors. 1- (4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-l-yl)prop-2-en-l-one targets only BTK with 10 fold or more selectivity to other kinases including BLK, BMX, and TXK. l-(4-(((6- amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-l-yl)prop-2-en-l-one binds irreversibly to BTK, and therefore results in prolonged inhibition of BTK. Restoration of BTK activity is dependent on de-novo protein synthesis of BTK.

Combination Therapies

[0084] In some embodiments, the present disclosure relates to combination therapies and related methods to treat ALI and ARDS, for example, ALI and/or ARDS resulting from an infection with a bacterium or a virus, such as a coronavirus or an influenza virus.

[0085] In some embodiments, the methods include the use of a selective BTK inhibitor in combination with a steroid to treat ALI and ARDS, for example, ALI and/or ARDS resulting from an infection with a bacterium or a virus, such as a coronavirus or an influenza virus. In some embodiments, the methods include selectively inhibiting BTK-associated inflammation in ALI or ARDS, the ALI or ARDS being caused by an infection, such as a bacterial infection or a viral infection (e.g., a coronavirus infection or an influenza infection), in a human subject. The methods comprise the step of co administering to the human subject an amount of a compound effective to inhibit BTK, but not interleukin-2-inducible T-cell kinase (ITK), in the human subject, and an amount of a steroid, wherein the compound is l-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-l- yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, the steroid is a corticosteroid. In some embodiments, the corticosteroid is selected from the group consisting of alclometasone dipropionate, amcinonide, beclometasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone valerate, budesonide, ciclesonide, clobetasol propionate, clobetasone butyrate, cortisone acetate, desonide, dexamethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortolone, fluprednidene acetate, fluticasone furoate, fluticasone propionate, halcinonide, halometasone, hydrocortisone, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, methylprednisolone, mometasone, mometasone furoate, prednicarbate, prednisolone, prednisone, triamcinolone acetonide, tixocortol pivalate, and combinations thereof.

[0087] In some embodiments, the steroid is administered concurrently with the selective BTK inhibitor. As used herein, the administration is considered concurrent if the time between administration of the steroid and administration of the selective BTK inhibitor is less than 30 minutes, such as less than 20 minutes, less than 15 minutes, less than 10 minutes, less than 5 minutes, less than 3 minutes, less than 2 minutes, or less than 1 minute.

[0088] In some embodiments, the steroid is administered before the selective BTK inhibitor. In some embodiments, the steroid is administered about 0.5 to about 12 hours before the selective BTK inhibitor is administered, such as about 1 to about 12 hours before, about 2 to about 10 hours before, about 3 to about 9 hours before, about 4 to about 6 hours before, about 0.5 to about 1 hours before, about 1 to about 2 hours before, about 2 to about 3 hours before, about 3 to about 4 hours before, about 4 to about 5 hours before, about 5 to about 6 hours before, about 6 to about 7 hours before, about 7 to about 8 hours before, about 8 to about 9 hours before, about 9 to about 10 hours before, about 10 to about 11 hours before, and/or about 11 to about 12 hours before the selective BTK inhibitor is administered.

[0089] In some embodiments, the steroid is administered after the selective BTK inhibitor. In some embodiments, the steroid is administered about 0.5 to about 12 hours after the selective BTK inhibitor is administered, such as about 1 to about 12 hours after, about 2 to about 10 hours after, about 3 to about 9 hours after, about 4 to about 6 hours after, about 0.5 to about 1 hours after, about 1 to about 2 hours after, about 2 to about 3 hours after, about 3 to about 4 hours after, about 4 to about 5 hours after, about 5 to about 6 hours after, about 6 to about 7 hours after, about 7 to about 8 hours after, about 8 to about 9 hours after, about 9 to about 10 hours after, about 10 to about 11 hours after, and/or about 11 to about 12 hours after the selective BTK inhibitor is administered.

[0090] In some embodiments, the steroid is administered in an amount effective to reduce BTK- associated inflammation.

[0091] In an embodiment, the present disclosure relates to a combination comprising a selective BTK inhibitor and a steroid, or pharmaceutically acceptable salts thereof.

[0092] In an embodiment, the combination is in the form of a pharmaceutical composition.

[0093] In an embodiment, the combination is in the form of a kit comprising two or more pharmaceutical compositions and optionally a package insert or label providing directions for administering the pharmaceutical compositions simultaneously, separately, or sequentially, wherein the two or more pharmaceutical compositions together comprise a steroid and the selective BTK inhibitor or pharmaceutically acceptable salt thereof.

[0094] In some embodiments, the methods include the use of a selective BTK inhibitor in combination with an antiviral agent to treat ALI and ARDS, for example, ALI and/or ARDS resulting from an infection with a bacterium or a virus, such as a coronavirus or an influenza virus. In some embodiments, the methods include selectively inhibiting BTK-associated inflammation in ALI or ARDS, the ALI or ARDS being caused by an infection, such as a bacterial infection or a viral infection (e.g., a coronavirus infection or an influenza infection), in a human subject. The methods comprise the step of co-administering to the human subject an amount of a compound effective to inhibit BTK, but not interleukin-2-inducible T-cell kinase (ITK), in the human subject, and an amount of an antiviral agent, wherein the compound is l-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4- fluoropiperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments, the methods further comprise administering an antiviral agent. In some embodiments, the antiviral agent is selected from the group consisting of nucleoside analogs, protease inhibitors, interferons, reverse transcriptase inhibitors, and combinations thereof. In some embodiments, the antiviral agent is selected from the group consisting of acyclovir, favipiravir, ganciclovir, remdesivir, ribavirin, indinavir, lopinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, interferon a-2a, interferon a-2b, interferon a-nl, interferon a-n3, interferon b-la, interferon b-lb, lamivudine, zidovudine, amantadine, foscarnet, nitazoxanide, umifenovir, and combinations thereof. [0096] In some embodiments, the antiviral agent is administered concurrently with the selective BTK inhibitor. As used herein, the administration is considered concurrent if the time between administration of the antiviral agent and administration of the selective BTK inhibitor is less than 30 minutes, such as less than 20 minutes, less than 15 minutes, less than 10 minutes, less than 5 minutes, less than 3 minutes, less than 2 minutes, or less than 1 minute.

[0097] In some embodiments, the antiviral agent is administered before the selective BTK inhibitor. In some embodiments, the antiviral agent is administered about 0.5 to about 12 hours before the selective BTK inhibitor is administered, such as about 1 to about 12 hours before, about 2 to about 10 hours before, about 3 to about 9 hours before, about 4 to about 6 hours before, about 0.5 to about 1 hours before, about 1 to about 2 hours before, about 2 to about 3 hours before, about 3 to about 4 hours before, about 4 to about 5 hours before, about 5 to about 6 hours before, about 6 to about 7 hours before, about 7 to about 8 hours before, about 8 to about 9 hours before, about 9 to about 10 hours before, about 10 to about 11 hours before, and/or about 11 to about 12 hours before the selective BTK inhibitor is administered.

[0098] In some embodiments, the antiviral agent is administered after the selective BTK inhibitor.

In some embodiments, the antiviral agent is administered about 0.5 to about 12 hours after the selective BTK inhibitor is administered, such as about 1 to about 12 hours after, about 2 to about 10 hours after, about 3 to about 9 hours after, about 4 to about 6 hours after, about 0.5 to about 1 hours after, about 1 to about 2 hours after, about 2 to about 3 hours after, about 3 to about 4 hours after, about 4 to about 5 hours after, about 5 to about 6 hours after, about 6 to about 7 hours after, about 7 to about 8 hours after, about 8 to about 9 hours after, about 9 to about 10 hours after, about 10 to about 11 hours after, and/or about 11 to about 12 hours after the selective BTK inhibitor is administered. [0099] In some embodiments, the antiviral agent is administered in an amount effective to reduce viral titer.

[00100] In an embodiment, the present disclosure relates to a combination comprising a selective BTK inhibitor and an antiviral agent, or pharmaceutically acceptable salts thereof.

[00101] In an embodiment, the combination is in the form of a pharmaceutical composition.

[00102] In an embodiment, the combination is in the form of a kit comprising two or more pharmaceutical compositions and optionally a package insert or label providing directions for administering the pharmaceutical compositions simultaneously, separately, or sequentially, wherein the two or more pharmaceutical compositions together comprise an antiviral agent and the selective BTK inhibitor or pharmaceutically acceptable salt thereof.

Pharmaceutical Compositions

[00103] In some embodiments, the disclosure provides pharmaceutical compositions comprising a selective BTK inhibitor such as is l-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4- fluoropiperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof for inhibiting BTK- associated inflammation in ALI or ARDS.

[00104] The pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of the selective BTK inhibitor or a pharmaceutically acceptable salt thereof. Where desired, the pharmaceutical compositions contain a pharmaceutically acceptable salt and/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Where desired, other ingredients in addition to the selective BTK inhibitor or a pharmaceutically acceptable salt thereof may be mixed into a preparation or both components may be formulated into separate preparations for use in combination separately or at the same time.

[00105] In selected embodiments, the concentration of the selective BTK inhibitor or a pharmaceutically acceptable salt thereof provided in the pharmaceutical compositions of the disclosure is less than, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/v or v/v.

[00106] In selected embodiments, the concentration of the selective BTK inhibitor or a pharmaceutically acceptable salt thereof provided in the pharmaceutical compositions of the disclosure is independently greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/v, or v/v.

[00107] In selected embodiments, the concentration of the selective BTK inhibitor or a pharmaceutically acceptable salt thereof is independently in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12% or approximately 1% to approximately 10% w/w, w/v or v/v.

[00108] In selected embodiments, the concentration of the selective BTK inhibitor or a pharmaceutically acceptable salt thereof is independently in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v or v/v.

[00109] In selected embodiments, the amount of the selective BTK inhibitor or a pharmaceutically acceptable salt thereof is independently equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g or 0.0001 g.

[00110] In selected embodiments, the amount of the selective BTK inhibitor or a pharmaceutically acceptable salt thereof is independently more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g or 10 g.

[00111] Described below are non-limiting exemplary pharmaceutical compositions and methods for preparing the same.

Pharmaceutical Compositions for Oral Administration

[00112] In selected embodiments, the disclosure provides a pharmaceutical composition for oral administration comprising the selective BTK inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient suitable for oral administration. [00113] In selected embodiments, the disclosure provides a solid pharmaceutical composition for oral administration containing: (i) an effective amount of the selective BTK inhibitor or a pharmaceutically acceptable salt thereof, in combination and (ii) a pharmaceutical excipient suitable for oral administration.

[00114] In selected embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions of the disclosure suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such dosage forms can be prepared by any of the methods, but all methods include the step of bringing the active ingredient(s) into association with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient(s) with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[00115] The disclosure further encompasses anhydrous pharmaceutical compositions and dosage forms since water can facilitate the degradation of some compounds. For example, water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. Anhydrous pharmaceutical compositions and dosage forms of the disclosure can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms of the disclosure which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.

[00116] The selective BTK inhibitor or a pharmaceutically acceptable salt thereof can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.

[00117] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.

[00118] Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

[00119] Disintegrants may be used in the compositions of the disclosure to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which disintegrate in the bottle. Too little may be insufficient for disintegration to occur, thus altering the rate and extent of release of the active ingredients from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.

[00120] Lubricants which can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil ( e.g ., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof. A lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.

[00121] When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

[00122] The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

[00123] Surfactants which can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.

[00124] A suitable hydrophilic surfactant may generally have an H LB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable.

Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.

[00125] Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[00126] Within the aforementioned group, ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[00127] Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof.

[00128] Hydrophilic non-ionic surfactants may include, but not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

[00129] Other hydrophilic-non-ionic surfactants include, without limitation, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers.

[00130] Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[00131] In an embodiment, the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present disclosure and to minimize precipitation of the compound of the present disclosure. This can be especially important for compositions for non-oral use, such as for compositions for injection. A solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[00132] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds such as 2- pyrrolidone, 2-piperidone, E-caprolactam, A/-alkylpyrrolidone, A/-hydroxyalkylpyrrolidone, N- alkylpiperidone, /V-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, epsilon- caprolactone and isomers thereof, d-valerolactone and isomers thereof, b-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N- methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water.

[00133] Mixtures of solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N- hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol. [00134] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to providing the composition to a patient using conventional techniques, such as distillation or evaporation. Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer may also be used, such as 5%, 2%, 1% or even less.

Typically, the solubilizer may be present in an amount of about 1% to about 100%, more typically about 5% to about 25% by weight.

[00135] The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[00136] In addition, an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable are bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of polyprotic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals and alkaline earth metals. Examples may include, but are not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium. [00137] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid and uric acid.

Pharmaceutical Compositions for Injection

[00138] In selected embodiments, the disclosure provides a pharmaceutical composition for injection comprising the selective BTK inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient suitable for injection. Components and amounts of agents in the compositions are as described herein.

[00139] The forms in which the compositions of the present disclosure may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[00140] Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol and liquid polyethylene glycol (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid and thimerosal.

[00141] Sterile injectable solutions are prepared by incorporating the selective BTK inhibitor or a pharmaceutically acceptable salt thereof in the required amounts in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.

Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desirable methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[00142] Exemplary parenteral administration forms include solutions or suspensions of active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.

[00143] The disclosure also provides kits. The kits include a selective BTK inhibitor or a pharmaceutically acceptable salt thereof, either alone or in combination in suitable packaging, and written material that can include instructions for use, discussion of clinical studies and listing of side effects. Such kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider. Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials. Suitable packaging and additional articles for use (e.g., measuring cup for liquid preparations, foil wrapping to minimize exposure to air, and the like) are known in the art and may be included in the kit. Kits described herein can be provided, marketed and/or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may also, in selected embodiments, be marketed directly to the consumer. In an embodiment, the disclosure provides a kit comprising the selective BTK inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of BTK-associated inflammation as described herein.

Dosages and Dosing Regimens

[00144] The amount of the selective BTK inhibitor or a pharmaceutically acceptable salt thereof administered will be dependent on the human being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compounds and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, such as about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, such as about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect - e.g., by dividing such larger doses into several small doses for administration throughout the day. [00145] In some embodiments, the selective BTK inhibitor or a pharmaceutically acceptable salt thereof is administered in a single dose. Mutiple daily doses are also embodied, for example, twice daily. Typically, such administration will be oral. However, other routes may be used as appropriate.

[00146] In some embodiments, the selective BTK inhibitor or a pharmaceutically acceptable salt thereof is administered in multiple doses for treating BTK-associated inflammation in ALI or ARDS. In an embodiment, the selective BTK inhibitor or a pharmaceutically acceptable salt thereof is administered in multiple doses. In an embodiment, dosing may be once, twice, three times, or four times per day. In an embodiment, dosing may be selected from the group consisting of once a day, twice a day, three times a day, or four times a day, once every other day, once weekly, twice weekly, three times weekly, four times weekly, biweekly, and monthly. In other embodiments, the selective BTK inhibitor or a pharmaceutically acceptable salt thereof is administered about once per day to about four times per day. In some embodiments the selective BTK inhibitor or a pharmaceutically acceptable salt thereof is administered once daily, while in other embodiments the selective BTK inhibitor or a pharmaceutically acceptable salt thereof is administered twice daily, and in other embodiments the selective BTK inhibitor or a pharmaceutically acceptable salt thereof is administered three times daily. In some embodiments the selective BTK inhibitor or a pharmaceutically acceptable salt thereof is administered three times a week, including every Monday, Wednesday, and Friday.

[00147] Administration of the selective BTK inhibitor or a pharmaceutically acceptable salts thereof may continue as long as necessary. In some embodiments, the selective BTK inhibitor or a pharmaceutically acceptable salt thereof is administered for more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or more days. In some embodiments, the selective BTK inhibitor or a pharmaceutically acceptable salt thereof is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the selective BTK inhibitor or a pharmaceutically acceptable salt thereof is administered for about 14 days, about 21 days, about 28 days, about 35 days, about 42 days, about 49 days, or about 56 days. In some embodiments, the selective BTK inhibitor or a pharmaceutically acceptable salt thereof is administered chronically on an ongoing basis - e.g., for the treatment of chronic effects. In another embodiment the administration of the selective BTK inhibitor or a pharmaceutically acceptable salt thereof continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months or one year. In some embodiments, the administration continues for more than about one year, two years, three years, four years, or five years. In some embodiments, continuous dosing is achieved and maintained as long as necessary.

[00148] In some embodiments, an effective dosage of the selective BTK inhibitor or a pharmaceutically acceptable salt thereof is in the range of about 1 mg to about 600 mg, about 10 mg to about 500 mg, about 20 mg to about 450 mg, about 25 mg to about 200 mg, about 10 mg to about 200 mg, about 20 mg to about 150 mg, about 30 mg to about 120 mg, about 10 mg to about 90 mg, about 20 mg to about 80 mg, about 30 mg to about 70 mg, about 40 mg to about 60 mg, about 45 mg to about 55 mg, about 48 mg to about 52 mg, about 50 mg to about 150 mg, about 60 mg to about 140 mg, about 70 mg to about 130 mg, about 80 mg to about 120 mg, about 90 mg to about 110 mg, about 95 mg to about 105 mg, about 150 mg to about 250 mg, about 160 mg to about 240 mg, about 170 mg to about 230 mg, about 180 mg to about 220 mg, about 190 mg to about 210 mg, about 195 mg to about 205 mg, or about 198 to about 202 mg. In some embodiments, an effective dosage of the selective BTK inhibitor or a pharmaceutically acceptable salt thereof is about 15 mg, about 25 mg, about 30 mg, about 50 mg, about 50 mg, about 75 mg, about 90 mg, about 100 mg, about 120 mg, about 125 mg, about 150 mg, about 175 mg, about 180 mg, about 200 mg, about 225 mg, about 240 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 360 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 480 mg, or about 500 mg. In some embodiments, an effective dosage of the selective BTK inhibitor or a pharmaceutically acceptable salt thereof is 15 mg, 25 mg, 30 mg, 50 mg, 60 mg, 75 mg, 90 mg, 100 mg, 120 mg, 150 mg, 175 mg, 180 mg, 200 mg, 225 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 360 mg, 375 mg, and 480 mg.

[00149] In some embodiments, an effective dosage of the selective BTK inhibitor or a pharmaceutically acceptable salt thereof is in the range of about 0.01 mg/kg to about 4.3 mg/kg, about 0.15 mg/kg to about 3.6 mg/kg, about 0.3 mg/kg to about 3.2 mg/kg, about 0.35 mg/kg to about 2.85 mg/kg, about 0.15 mg/kg to about 2.85 mg/kg, about 0.3 mg to about 2.15 mg/kg, about 0.45 mg/kg to about 1.7 mg/kg, about 0.15 mg/kg to about 1.3 mg/kg, about 0.3 mg/kg to about 1.15 mg/kg, about 0.45 mg/kg to about 1 mg/kg, about 0.55 mg/kg to about 0.85 mg/kg, about 0.65 mg/kg to about 0.8 mg/kg, about 0.7 mg/kg to about 0.75 mg/kg, about 0.7 mg/kg to about 2.15 mg/kg, about 0.85 mg/kg to about 2 mg/kg, about 1 mg/kg to about 1.85 mg/kg, about 1.15 mg/kg to about 1.7 mg/kg, about 1.3 mg/kg mg to about 1.6 mg/kg, about 1.35 mg/kg to about 1.5 mg/kg, about 2.15 mg/kg to about 3.6 mg/kg, about 2.3 mg/kg to about 3.4 mg/kg, about 2.4 mg/kg to about 3.3 mg/kg, about 2.6 mg/kg to about 3.15 mg/kg, about 2.7 mg/kg to about 3 mg/kg, about 2.8 mg/kg to about 3 mg/kg, or about 2.85 mg/kg to about 2.95 mg/kg. In some embodiments, an effective dosage of the BTK inhibitor or a pharmaceutically acceptable salt thereof is about 0.35 mg/kg, about 0.7 mg/kg, about 1 mg/kg, about 1.4 mg/kg, about 1.8 mg/kg, about 2.1 mg/kg, about 2.5 mg/kg, about 2.85 mg/kg, about 3.2 mg/kg, or about 3.6 mg/kg.

[00150] In some embodiments, the selective BTK inhibitor or a pharmaceutically acceptable salt thereof is administered at a dosage of 10 to 500 mg BID, including a dosage of 15 mg, 25 mg, 30 mg, 50 mg, 60 mg, 75 mg, 90 mg, 100 mg, 120 mg, 150 mg, 175 mg, 180 mg, 200 mg, 225 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 360 mg, 375 mg, and 480 mg BID.

[00151] In some embodiments, the selective BTK inhibitor or a pharmaceutically acceptable salt thereof is administered at a dosage of 10 to 600 mg QD, including a dosage of 15 mg, 25 mg, 30 mg, 50 mg, 60 mg, 75 mg, 90 mg, 100 mg, 120 mg, 150 mg, 175 mg, 180 mg, 200 mg, 225 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 360 mg, 375 mg, and 480 mg QD.

[00152] In some embodiments, the amount administered is a total daily dose of about 40 mg to about 1500 mg, such as about 50 mg to about 300 mg, about 60 mg to about 250 mg, about 70 mg to about 200 mg, about 80 mg to about 160 mg, about 300 mg to about 1300 mg, about 400 mg to about 1100 mg, about 500 mg to about 1000 mg, about 600 mg to about 900 mg, about 600 mg, about 400 mg, and/or about 200 mg. In some embodiments, the total daily dose comprises one dose per day, two divided doses per day, three divided doses per day, or four divided doses per day. In selected embodiments, the selective BTK inhibitor compound is administered in a dose of 300 mg twice daily, 200 mg twice daily, or 100 mg twice daily.

[00153] An effective amount of the selective BTK inhibitor or a pharmaceutically acceptable salt thereof may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including oral, topical, parenteral, pulmonary, or nasal.

In some embodiments, the human subject is in a fasted state when the selective BTK inhibitor is administered. In some embodiments, the selective BTK inhibitor is administered orally and the human subject is in a fasted state when the selective BTK inhibitor is administered. In some embodiments, the human subject is in a fed state when the selective BTK inhibitor is administered. In some embodiments, the selective BTK inhibitor is administered orally and the human subject is in a fed state when the selective BTK inhibitor is administered.

EXAMPLES

[00154] The embodiments encompassed herein are now described with reference to the following examples. These examples are provided for the purpose of illustration only and the disclosure encompassed herein should in no way be construed as being limited to these examples, but rather should be construed to encompass any and all variations which become evident as a result of the teachings provided herein.

Example 1: Randomized Phase lb/2 Study of Compound A in Blood Cancer Patients [00155] There is a significant unmet need for therapies in patients with COVID-19 with a history of blood cancers. Clinical trials for treatment of SARS-CoV-2 often exclude patients with low blood counts typical of patients with hematologic malignancies. Use of Compound A (l-(4-(((6-amino-5-(4- phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-l-yl)prop-2-en-l-one) advantageously reduces risk of myelosuppression.

Study Design

[00156] This study is a novel Phase lb/2 randomized trial of Compound A with an adaptive group sequential design directed at moving a highly effective therapy forward in sequential steps with adaptation based upon observed frequency of the primary endpoint events in the control population, and efficacy and toxicity in the experimental arm.

[00157] Phase lb: This study will begin with a 6 patient run-in phase lb portion to evaluate toxicity. The initial dose is chosen for in view of safety and selectivity of Compound A, and to minimize patient exposure to what may be a sub-therapeutic dose. In this phase of the study, 6 patients will be enrolled and will all receive Compound A at a dose of 300 mg twice daily (BID) in the fasted state (1 hour before or 2 hours after meals). Dose limiting toxicity (DLT) will be evaluated at day 7. At this time, DLT would be considered to be any of the following: (1) Grade 3 or higher non-hematologic toxicity that are considered at least possibly related to Compound A with the exception of nausea, vomiting, diarrhea, or electrolyte abnormality, unless these persist for at least 3 days despite maximal supportive care; or (2) Any grade 3 or higher new fungal or bacterial infection (excluding line infection or C difficile infection), cardiac toxicity (with the exception of hypertension) or bleeding regardless of the attribution [00158] If zero or one patients in the first 6 have a DLT, the study will proceed to phase 2 and 300 mg BID (twice daily) of Compound A will be considered the RP2D. If two or more have a DLT, Compound A will be dose reduced to 200 mg BID and an additional 6 patients will be accrued and assessed for safety using the same DLT rules. If zero or one patients in these 6 have a DLT, the study will proceed to phase 2 with 200 mg BID as the dose and will be considered the RP2D. If two or more have a DLT, the dose will be reduced to 100 mg BID. Tolerability will be assessed in the same manner. If two or more have a DLT, the study will stop. Patients who do not receive 7 days of Compound A for reasons other than toxicity or DLT will be replaced.

[00159] Patients enrolled to the phase lb portion of the study will then continue to receive Compound A in the same manner as outlined for the phase 2 study.

[00160] Randomized Phase 2 Study: Following completion of the phase lb portion, patients in the phase 2 portion will be randomized in a 2:1 fashion to receive Compound A or standard treatment for COVID-19. The study is non-blinded, and no placebo will be given. Patients on Arm A (the Compound A arm) may receive any additional therapies that are not prohibited concomitant medications. Compound A will be administered in the fasting state (1 hour before or 2 hours after meals). Patients on Arm B (the standard arm) will be followed in exactly the same manner as those on the Compound A arm, with the exception that none of the concomitant medication rules are applicable.

[00161] In this trial, cycles will be 7 days in length. Compound A therapy will continue for 2 cycles (14 days) if hospitalization is complete by this time. If they are discharged before 14 days they will be discharged with sufficient medicine to complete this. Patients who remain hospitalized at 14 days may receive up to 2 additional cycles. Additionally, as it is possible that patients may develop recurrent pulmonary symptoms due to continued lung inflammation when Compound A is discontinued, in such settings Compound A may be given for an additional 4 cycles after consultation with the medical monitor.

Study Objectives

Inclusion Criteria

[00162] Patients in both Arm A and Arm B must meet all of the following criteria to be eligible for the study: (1) Known prior diagnosis of hematologic cancer or precursor disease (myelodysplastic syndromes (MDS), aplastic anemia, monoclonal gammopathy of undetermined significance (MGUS), or monoclonal B-Cell Lymphocytosis (MBL)) associated with immune deficiency; (2) Hospitalization for confirmed PCR+ COVID-19 infection (to be confirmed by a second reference lab centrally but not used for clinical decisions or eligibility determination here); (3) Age > 18; (4) Adequate renal function: creatinine clearance > 30 mg/min by Cockcroft-Gault equation; (5) Adequate hepatic function: bilirubin < 1.5 x upper limit of normal [ULN] (unless due to Gilbert's disease) at screening and ALT/AST <3 x ULN at screening; (6) Adequate bone marrow function: absolute neutrophil count (ANC) >1000 cells/pL unless due to bone marrow involvement by disease, platelet count > 100 x 10⁹/L unless due to bone marrow involvement by disease or attributed to COVID-19 (these patients may enroll without limitations of neutrophil or platelet count provided platelets can be transfused to be maintained above 20 x 10⁹/L; this lower platelet count and absence of absolute neutrophil requirement is provided as MDS, AML, aplastic anemia, and other blood cancer patients often have low blood counts as a consequence of their disease); (7) Ability to swallow and absorb oral medications; (8) Ability to obtain informed consent; (9) Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials; men must agree to not donate sperm during and after the study; for females, these restrictions apply for 1 month after the last dose of study drug and for males, these restrictions apply for 3 months after the last dose of study drug.

Exclusion Criteria

[00163] Subjects in both Arm A and Arm B who meet any of the following criteria will not be eligible for the study: (1) Therapeutic anticoagulation at study entry; (2) Currently receiving BTK inhibitor therapy; (3) Myocardial infarct within 6 months, uncontrolled cardiac arrhythmia, or NYHA class 3/4 heart failure; (4) Requirement for artificial ventilation at screening; (5) Known bleeding disorders (e.g., Von Willebrand's disease, platelet storage pool disorders, or hemophilia); (6) Stroke or intracranial hemorrhage within 6 months of enrollment; (7) Pregnancy or breastfeeding; (8) Concomitant administration of prohibited medications which include Proton Pump Inhibitors (PPIs) and also CYP3A4 strong inducers; H2 blockade is allowed for prophylaxis if dosed 2 hours after Compound A; if this is ineffective, PPIs may then be used but must be approved by the medical monitor; (9) Known active HIV, hepatitis B or C as defined by detectable viral load; (10) QTc prolongation > 480 ms or history of prolonged QT congenital syndrome; Patients with prolonged QTc interval in the setting of bundle branch block or pacemaker may participate in the study with approval of the medical monitor; (11) Disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption (malabsorption syndrome, resection of the small bowel, poorly controlled inflammatory bowel disease, etc.)

Treatment Algorithm

[00164] Patients on phase 2 will be randomized 2:1 to Compound A (Arm A) versus standard treatment (Arm B) with stratification based upon age < 60 or > 60 years.

Dose, Route of Administration, and Dosing Regimen [00165] Compound A is administered orally.

[00166] For phase lb: 300 mg BID or 200 mg or 100 mg BID will be given for 2 cycles (14 days) and up to 2 additional cycles (total of 28 days) and if recurrent pneumonia is suspected up to additional 4 cycles can be given.

[00167] For phase 2: RP2D from phase lb will be given for 2 cycles (14 days) and up to 2 additional cycles (total of 28 days) and if recurrent pneumonia is suspected up to additional 4 cycles can be given. Study Assessments

[00168] The following biological specimens will be collected in this study and will be used to evaluate the association of exploratory systemic and/or tissue specific biomarkers with study drug response including efficacy and/or adverse events. Biomarker samples may be used for potential assay development of companion diagnostics. Tests will include: (1) Measurement of viral clearance in each treatment arm; (2) Measurement of immune cell subsets for absolute number, activation, exhaustion markers, and presence of maturation arrest (NK cells) at baseline and over time among patients treated with Compound A (Arm A) versus control (Arm B) treatment; (3) Measurement of IgM, IgA, and IgG response to SARS-CoV-2 over time among patients treated with Compound A (Arm A) versus control (Arm B) treatment; (4) Measurement of serial change cytokines including (but not limited to) IL6, IL1B, TNF-alpha over time among patients treated with Compound A (Arm A) versus control (Arm B) treatment; (5) Measurement of epigenetic age and clonal hematopoiesis among patients treated with Compound A (Arm A) versus control (Arm B) treatment; (6) Pharmacokinetics and pharmacodynamics of Compound A.

Statistical Analysis [00169] In phase lb, 6 patients will be treated with Compound A to establish tolerability. As long as less than two patients have DLT, the study will proceed with the phase 2. In phase 2, we propose a two- arm randomized trial of Compound A for patients with hematological cancers and selected precursor diseases. These patients are at high risk from COVID-19 syndrome, intubation, and death. The primary endpoint of this study is need for artificial ventilation and death. Based on incidence in China, we assume that the event rate is 40% and that it can be reduced to 15% when Compound A is given. We plan to randomize a total of 60 patients in a 2:1 ratio to the two arms of the study. There will be an interim analysis after the first 30 patients [information fraction = 0.50; 20 on Compound A arm (Arm A) and 10 on control arm (Arm B)]. The study will be stopped early if at the interim analysis the observed event rate is higher in the Compound A arm than in the control arm. Using a standard group sequential design, there will be sufficient evidence to claim a promising signal with Compound A if the z score is less than -0.84162. This design constrains the one-sided type I error to 20% and has at least 85% power to detect a reduction in the event rate under the alternative hypothesis (z-test for difference in two proportions using pooled variance). At the final analysis, data will be analyzed using a one-sided test for a difference in proportions. All eligible patients who are randomized will be considered evaluable for the primary endpoint.

Example 2: Double-Blind, Randomized Phase 1/2 Study of Compound A for Treatment of COVID-19 in Blood Cancer Patients

[00170] There is a significant unmet need for therapies in patients with COVID-19 with a history of blood cancers. Clinical trials for treatment of SARS-CoV-2 often exclude patients with low blood counts typical of patients with hematologic malignancies. Use of Compound A (l-(4-(((6-amino-5-(4- phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-l-yl)prop-2-en-l-one) advantageously reduces risk of myelosuppression.

Dosing Regimen/Mode of Administration

[00171] Compound A will be administered orally BID with water in a fasted state at least 2 hours prior to a meal or 2 hours after a meal continuously in 7-day cycles for 2 cycles. Up to 4 cycles (4 weeks) of dosing will be allowed.

[00172] For subjects that have a nasogastric (NG) tube, Compound A or placebo tablets will be crushed and suspended in a suitable low pH diluent for administration via the NG tube. Doses will be given orally BID in a fasted state at least 2 hours before administration of liquid nutrition formula or at least 2 hours afterwards. Up to 4 cycles of dosing will be allowed. Study Design

[00173] This study is a Phase 1/2 randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of adding Compound A treatment to standard available therapy (SAT) in subjects with cancer hospitalized for COVID-19. This is a 2-part study comprising a Phase 1 safety lead-in (Part 1) that will determine the recommended phase 2 dose (RP2D) to be used in all subsequent eligible subjects in Phase 2 (Part 2).

[00174] Part 1 (Phase 1 safety lead-in) comprises a 6 subject run-in to evaluate the safety and tolerability of Compound A in patients with cancer in the COVID-19 setting. Compound A will be administered orally at 300 mg BID continuously in 7-day cycles for 2 cycles and subjects will be evaluated for dose limiting toxicities (DLTs). If at the 300 mg BID dose level <1 of 6 subjects experience a DLT, then 300 mg BID will be considered the recommended phase 2 dose (RP2D). If >2 of 6 subjects experience a DLT then the next lower Compound A dose level (200 mg BID) will be opened for enrollment, and an additional 6 subjects will be enrolled and will follow the same DLT rules until the RP2D is determined. At the lowest dose level (100 mg BID), if >2 of 6 subjects experience a DLT then the study will stop.

[00175] Part 2 comprises a Phase 2, randomized, double-blind, placebo-controlled study. In Part 2, eligible subjects will be randomized in a 1:1 ratio to Arm 1 (Compound A in addition to standard available therapy [SAT]) or Arm 2 (placebo in addition to SAT) with stratifications based on age <65 or >65 years old and whether they are receiving therapies for COVID-19. Investigators and Sponsor will be blinded to each subject's assigned study intervention throughout the course of the study.

[00176] Subjects in Arm 1 will receive Compound A orally BID at the RP2D continuously in 7-day cycles for 2 cycles in addition to SAT for COVID-19. Up to 4 cycles of dosing will be allowed. Subjects in Arm 2 will receive placebo at the RP2D orally BID continuously in 7-day cycles for 2 cycles in addition to standard available treatment for COVID-19. Up to 4 cycles of dosing will be allowed.

Study Objectives and Endpoints

Inclusion Criteria

[00177] Patients must meet all of the following criteria to be eligible for the study: (1) Age > 18; (2) known diagnosis of cancer that has not been considered cured or disease free for more than 3 years; (3) confirmed COVID-19 infection as per World Health Organization (WHO) criteria (including positive nucleic acid test of any specimen [e.g., respiratory, blood, urine, stool, or other bodily fluid] within 3 weeks of Cycle 1 Day 1) with suspected pneumonia requiring hospitalization and oxygen saturation <94% on room air or requires supplemental oxygen; (4) adequate hematological function; (5) adequate hepatic function; (6) adequate renal function; (7) ability to swallow and absorb oral medications; (8) use of effective birth control.

Exclusion Criteria

[00178] Subjects who meet any of the following criteria will not be eligible for the study:

[00179] (1) life expectancy of less than 6 months; (2) no remaining available therapies for advanced or metastatic malignancies; (3) subjects who are not committed to aggressive management; (4) active treatment with a BTK, BMX, PI3k or JAK inhibitor; (5) subjects who require chemotherapy due to active oncologic disease that cannot be suspended while receiving study treatment; (6) subjects who received systemic chemotherapy resulting in immunosuppression within 14 days of Cycle 1 Day 1; (7) active treatment with immunomodulator medications including immune checkpoint inhibitors (PD-1, PD-L1, CTLA4 blockers) that could not be suspended for the duration of the study; (8) subjects who received prior anti-cytokine therapy (anti-IL-6) within 5 half-lives of the drug from Cycle 1 Day 1; (9) participation in another clinical study with therapeutic intent for COVID-19, except that patients participating in clinical trials receiving hydroxychloroquine or chloroquine and/or azithromycin and/or remdesivir will be allowed; (10) patients on warfarin at study entry; (11) myocardial infarct within 6 months, unstable angina, uncontrolled cardiac arrhythmia, or New York Heart Association (NYHA) class 3/4 heart failure; (12) requirement for artificial ventilation (HFNC, NiPPV, ECMO, or intubation and MV) at screening; (13) known bleeding disorders (e.g., Von Willebrand's disease, platelet storage pool disorders, or hemophilia); (14) stroke or intracranial hemorrhage within 6 months of Cycle 1 Day 1; (15) women who are pregnant or breastfeeding; (16) requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole); (17) subjects with active hepatitis B virus (HBV) or hepatitis C virus (HCV); (18) subjects with known history of human immunodeficiency virus (HIV); (19) Grade 2 or higher QTc prolongation; (20) disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption; (21) untreated or actively progressing known central nervous system (CNS) lesions (carcinomatous meningitis).

Example 3: Administration of Compound A for Treatment of COVID-19 in a Chronic Lymphocytic Leukemia (CLL) Patient

[00180] A CLL patient was treated for COVID-19 with covalescent plasma, dexamethasone, remdesivir, and Compound A. The treatments were administered according to the following dosing regimen: 200 mg remdesivir IV (day -2); 200 mg Compound A, 100 mg remdesivir IV, 6 mg dexamethasone PO (day 1); 400 mg Compound A, 300 mg covalescent plasma, 100 mg remdesivir IV, 6 mg dexamethasone PO (day 2); 400 mg Compound A, 100 mg remdesivir IV, 6 mg dexamethasone PO (day 3 and day 4); 400 mg Compound A, 6 mg dexamethasone PO (day 5, day 6, and day 7); 200 mg Compound A, 6 mg dexamethasone PO (day 8); 400 mg Compound A, 6 mg dexamethasone PO (day 9 and day 10); 400 mg Compound A (day 11, day 12, day 13, and day 14); 200 mg Compound A (day 15). Day 1 immediately followed day minus 1 (no day 0).

[00181] At day 1, day 3, day 8, and 27 days from the last Compound A dose ("EOT"), whole blood from the patient was sampled and the relative amounts of various cell populations were determined. From the population of live cells, the relative amounts of lymphocytes, monocytes, and granulocytes were determined. From the population of lymphocytes, the relative amounts of B cells (CD19+), T cells (CD3+), and NK cells were determined. From the population of T cells, the relative amounts of helper T cells (CD4+), cytotoxic T cells (CD8+), CD4-CD8-, and CD4+CD8+ were determined. The results are shown in FIG. 1A.

[00182] The samples were also assessed for markers of activation (CD69, CD86, CD40, and CD25) and markers of adhesion (CDlla, CD47, CD62L, CD49d, and CXCR4) present on B cells (CD19+), T cells (CD3+), monocytes (CD14+), and granulocytes. The results are shown in FIG. IB and FIG. 1C, respectively.

[00183] The T-cell receptor V beta repertoire (Vb 1, Vb 2, Vb 3, Vb 4, Vb 5.1, Vb 5.2, Vb 5.3, Vb 7.1, Vb 7.2, Vb 8, Vb 9, Vb 11, Vb 12, Vb 13.1, Vb 13.2, Vb 13.6, Vb 14, Vb 16, Vb 17, Vb 18, Vb 20, Vb 21.3, Vb 22, and Vb 23) of the samples was determined for the following parent cell types: T cells (CD3+), helper T cells (CD4+), and cytotoxic T cells (CD8+). The results are shown in FIG. ID.

[00184] The serum levels of various cytokines (IL-6, IL-8, IL-10, MCP-1, MIP-la, IL-lb, IL-12p70, IFNa, and TNF) in the samples were also determined. The results are shown in FIG. IE, where the solid gray line shows the cutoff for the limit of detection (LOD) and the dashed gray line shows the average level in healthy donor plasma (N=3).

[00185] Cell signaling for the samples was assessed by determining levels of total BTK, pBTK, pSYK, pPLCgl, pCREB, pERK, Ki67, pNFkBp65, pP38, pAKT, pS6, pSTATl, pSTAT3, pSTAT4, and pSTAT5 for T cells (CD3+), B cells (CD20+), monocytes (CD14+), and granulocytes (CD14-). The results are shown in

FIG. IF and FIG. 1G.

Example 4: Administration of Compound A for Treatment of COVID-19 in a Follicular lymphoma (FL) Patient

[00186] A FL patient was treated for COVID-19 with covalescent plasma, dexamethasone, remdesivir, and Compound A. The treatments were administered according to the following dosing regimen: 200 mg remdesivir IV, 6 mg dexamethasone IV (day -1); 300 mg covalescent plasma, 200 mg Compound A, 100 mg remdesivir IV, 6 mg dexamethasone IV (day 1); 400 mg Compound A, 100 mg remdesivir IV, 6 mg dexamethasone IV (day 2, day 3, day 4, day 5, day 6, day 7, and day 8); 400 mg Compound A, 100 mg remdesivir IV (day 9); 400 mg Compound A (day 10, day 11, day 12, day 13, and day 14); 200 mg Compound A (day 15). Day 1 immediately followed day minus 1 (no day 0).

[00187] At day 3, day 8, and 35 days from the last Compound A dose ("EOT"), whole blood from the patient was sampled and the relative amounts of various cell populations were determined. From the population of live cells, the relative amounts of lymphocytes, monocytes, and granulocytes were determined. From the population of lymphocytes, the relative amounts of B cells (CD19+), T cells (CD3+), and NK cells were determined. From the population of T cells, the relative amounts of helper T cells (CD4+), cytotoxic T cells (CD8+), CD4-CD8-, and CD4+CD8+ were determined. The results are shown in FIG. 2A.

[00188] The samples were also assessed for markers of activation (CD69, CD86, CD40, and CD25) and markers of adhesion (CDlla, CD47, CD62L, CD49d, and CXCR4) present on B cells (CD19+), T cells (CD3+), NK cells, monocytes (CD14+), and granulocytes. The results are shown in FIG. 2B and FIG. 2C, respectively.

[00189] The T-cell receptor V beta repertoire (Vb 1, Vb 2, Vb 3, Vb 4, Vb 5.1, Vb 5.2, Vb 5.3, Vb 7.1, Vb 7.2, Vb 8, Vb 9, Vb 11, Vb 12, Vb 13.1, Vb 13.2, Vb 13.6, Vb 14, Vb 16, Vb 17, Vb 18, Vb 20, Vb 21.3, Vb 22, and Vb 23) of the samples was determined for the following parent cell types: T cells (CD3+), helper T cells (CD4+), and cytotoxic T cells (CD8+). The results are shown in FIG. 2D.

[00190] The serum levels of various cytokines (IL-6, IL-8, IL-10, MCP-1, MIP-la, IL-lb, IL-12p70, IFNa, and TNF) in the samples were also determined. The results are shown in FIG. 2E, where the solid gray line shows the cutoff for the limit of detection (LOD) and the dashed gray line shows the average level in healthy donor plasma (N=3).

[00191] Cell signaling for the samples was assessed by determining levels of total BTK, pBTK, pSYK, pPLCgl, pCREB, pERK, Ki67, pNFkBp65, pP38, pAKT, pS6, pSTATl, pSTAT3, pSTAT4, and pSTAT5 for T cells (CD3+), B cells (CD20+), monocytes (CD14+), and granulocytes (CD14-). The results are shown in

FIG. 2F.

Example 5: Administration of Compound A for Treatment of COVID-19 in a Multiple Myeloma (MM) Patient

[00192] A MM patient was treated for COVID-19 with covalescent plasma, dexamethasone, remdesivir, acyclovir, and Compound A. The treatments were administered according to the following dosing regimen: 1600 mg acyclovir PO (day -8, day -7, day -6, day -5, day -4, and day -3); 1600 mg acyclovir PO, 200 mg remdesivir IV (day -2); 1600 mg acyclovir PO, 100 mg remdesivir IV (day -1); 1600 mg acyclovir PO, 400 mg Compound A, 100 mg remdesivir IV, 6 mg dexamethasone PO (day 1) (dexamethasone PO stop date unknown); 1600 mg acyclovir PO, 400 mg Compound A, 100 mg remdesivir IV (day 2, day 3, and day 4); 1600 mg acyclovir PO, 200 mg Compound A, 100 mg remdesivir IV, 6 mg dexamethasone IV (day 5); 500 mg acyclovir IV, 400 mg Compound A, 300 mg covalescent plasma, 100 mg remdesivir IV (day 6); 500 mg acyclovir IV, 400 mg Compound A, 100 mg remdesivir IV (day 7 and day 8); 500 mg acyclovir IV, 400 mg Compound A (day 9); 800 mg acyclovir PO, 400 mg Compound A (day 10) (acyclovir PO stop date unknown); 400 mg Compound A (day 11, day 12, day 13, day 14, day 15, day 16, day 17, day 18, and day 19). Day 1 immediately followed day minus 1 (no day 0). [00193] At day 1, day 3, day 8, and day 15, whole blood from the patient was sampled and the relative amounts of various cell populations were determined. From the population of live cells, the relative amounts of lymphocytes, monocytes, and granulocytes were determined. From the population of lymphocytes, the relative amounts of B cells (CD19+), T cells (CD3+), and NK cells were determined. From the population of T cells, the relative amounts of helper T cells (CD4+), cytotoxic T cells (CD8+), CD4-CD8-, and CD4+CD8+ were determined. The results are shown in FIG. 3A.

[00194] The samples were also assessed for markers of activation (CD69, CD86, CD40, and CD25) and markers of adhesion (CDlla, CD47, CD62L, CD49d, and CXCR4) present on B cells (CD19+), T cells (CD3+), NK cells, monocytes (CD14+), and granulocytes. The results are shown in FIG. 3B and FIG. 3C, respectively.

[00195] The T-cell receptor V beta repertoire (Vb 1, Vb 2, Vb 3, Vb 4, Vb 5.1, Vb 5.2, Vb 5.3, Vb 7.1, Vb 7.2, Vb 8, Vb 9, Vb 11, Vb 12, Vb 13.1, Vb 13.2, Vb 13.6, Vb 14, Vb 16, Vb 17, Vb 18, Vb 20, Vb 21.3, Vb 22, and Vb 23) of the samples was determined for the following parent cell types: T cells (CD3+), helper T cells (CD4+), and cytotoxic T cells (CD8+). The results are shown in FIG. 3D.

[00196] The serum levels of various cytokines (IL-6, IL-8, IL-10, MCP-1, MIP-la, IL-lb, IL-12p70, IFNa, and TNF) in the samples were also determined. The results are shown in FIG. 3E, where the solid gray line shows the cutoff for the limit of detection (LOD) and the dashed gray line shows the average level in healthy donor plasma (N=3).

[00197] Cell signaling for the samples was assessed by determining levels of total BTK, pBTK, pSYK, pPLCgl, pCREB, pERK, Ki67, pNFkBp65, pP38, pAKT, pS6, pSTATl, pSTAT3, pSTAT4, and pSTAT5 for T cells (CD3+), B cells (CD20+), monocytes (CD14+), and granulocytes (CD14-). The results are shown in

FIG. 3F and FIG. 3G.

Example 6: Administration of Compound A for Treatment of COVID-19 in a Chronic Lymphocytic Leukemia (CLL) Patient

[00198] A CLL patient was treated for COVID-19 with covalescent plasma, dexamethasone, remdesivir, valacyclovir, and Compound A. The treatments were administered according to the following dosing regimen: 1000 mg valacyclovir PO, 6 mg dexamethasone IV (day -2); 1000 mg valacyclovir PO, 100 mg remdesivir IV, 6 mg dexamethasone IV (day -1); 1000 mg valacyclovir PO, 400 mg Compound A, 300 mg covalescent plasma, 100 mg remdesivir IV, 6 mg dexamethasone IV (day 1); 1000 mg valacyclovir PO, 400 mg Compound A, 100 mg remdesivir IV, 6 mg dexamethasone IV (day 2 and day 3) (remdesivir IV stop date unknown); 1000 mg valacyclovir PO, 200 mg Compound A, 6 mg dexamethasone PO (day 4); 1000 mg valacyclovir PO, 6 mg dexamethasone PO (day 5); 6 mg dexamethasone PO (day 6, day 7, day 8, and day 9). Day 1 immediately followed day minus 1 (no day 0). [00199] At day 1 and day 3, whole blood from the patient was sampled and the relative amounts of various cell populations were determined. From the population of live cells, the relative amounts of lymphocytes, monocytes, and granulocytes were determined. From the population of lymphocytes, the relative amounts of B cells (CD19+), T cells (CD3+), and NK cells were determined. From the population of T cells, the relative amounts of helper T cells (CD4+), cytotoxic T cells (CD8+), CD4-CD8-, and CD4+CD8+ were determined. The results are shown in FIG. 4A.

[00200] The samples were also assessed for markers of activation (CD69, CD86, CD40, and CD25) and markers of adhesion (CDlla, CD47, CD62L, CD49d, and CXCR4) present on B cells (CD19+), T cells (CD3+), NK cells, monocytes (CD14+), and granulocytes. The results are shown in FIG. 4B and FIG. 4C, respectively.

[00201] The T-cell receptor V beta repertoire (Vb 1, Vb 2, Vb 3, Vb 4, Vb 5.1, Vb 5.2, Vb 5.3, Vb 7.1, Vb 7.2, Vb 8, Vb 9, Vb 11, Vb 12, Vb 13.1, Vb 13.2, Vb 13.6, Vb 14, Vb 16, Vb 17, Vb 18, Vb 20, Vb 21.3, Vb 22, and Vb 23) of the samples was determined for the following parent cell types: T cells (CD3+), helper T cells (CD4+), and cytotoxic T cells (CD8+). The results are shown in FIG. 4D.

[00202] The serum levels of various cytokines (IL-6, IL-8, IL-10, MCP-1, MIP-la, IL-lb, IL-12p70, IFNa, and TNF) in the samples were also determined. The results are shown in FIG. 4E, where the solid gray line shows the cutoff for the limit of detection (LOD) and the dashed gray line shows the average level in healthy donor plasma (N=3).

[00203] Cell signaling for the samples was assessed by determining levels of total BTK, pBTK, pSYK, pPLCgl, pCREB, pERK, Ki67, pNFkBp65, pP38, pAKT, pS6, pSTATl, pSTAT3, pSTAT4, and pSTAT5 for T cells (CD3+), B cells (CD20+), monocytes (CD14+), and granulocytes (CD14-). The results are shown in

FIG. 4F and FIG.4G.

Example 7: Administration of Compound A for Treatment of COVID-19 in a Multiple Myeloma (MM) Patient

[00204] A MM patient was treated for COVID-19 with dexamethasone, remdesivir, acyclovir, and Compound A. The treatments were administered according to the following dosing regimen: 400 mg acyclovir PO, 100 mg remdesivir IV, 6 mg dexamethasone IV (day -2) (acyclovir PO stop date unknown); 100 mg remdesivir IV, 6 mg dexamethasone IV (day -1); 400 mg Compound A, 100 mg remdesivir IV, 6 mg dexamethasone IV (day 1); 400 mg Compound A, 100 mg remdesivir IV (day 2); 400 mg Compound A (day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 13, and day 14). Day 1 immediately followed day minus 1 (no day 0).

[00205] At day 1, whole blood from the patient was sampled and the relative amounts of various cell populations were determined. From the population of live cells, the relative amounts of lymphocytes, monocytes, and granulocytes were determined. From the population of lymphocytes, the relative amounts of B cells (CD19+), T cells (CD3+), and NK cells were determined. From the population of T cells, the relative amounts of helper T cells (CD4+), cytotoxic T cells (CD8+), CD4-CD8-, and CD4+CD8+ were determined. The results are shown in FIG. 5A.

[00206] The samples were also assessed for markers of activation (CD69, CD86, CD40, and CD25) and markers of adhesion (CDlla, CD47, CD62L, CD49d, and CXCR4) present on B cells (CD19+), T cells (CD3+), NK cells, monocytes (CD14+), and granulocytes. The results are shown in FIG. 5B and FIG. 5C, respectively.

[00207] The T-cell receptor V beta repertoire (Vb 1, Vb 2, Vb 3, Vb 4, Vb 5.1, Vb 5.2, Vb 5.3, Vb 7.1, Vb 7.2, Vb 8, Vb 9, Vb 11, Vb 12, Vb 13.1, Vb 13.2, Vb 13.6, Vb 14, Vb 16, Vb 17, Vb 18, Vb 20, Vb 21.3,

Vb 22, and Vb 23) of the samples was determined for the following parent cell types: T cells (CD3+), helper T cells (CD4+), and cytotoxic T cells (CD8+). The results are shown in FIG. 5D.

[00208] The serum levels of various cytokines (IL-6, IL-8, IL-10, MCP-1, MIP-la, IL-lb, IL-12p70, IFNa, and TNF) in the samples were also determined. The results are shown in FIG. 5E, where the solid gray line shows the cutoff for the limit of detection (LOD) and the dashed gray line shows the average level in healthy donor plasma (N=3).

Example 8: Administration of Compound A for Treatment of COVID-19 in a Chronic Lymphocytic Leukemia (CLL) Patient

[00209] A CLL patient was treated for COVID-19 with covalescent plasma, dexamethasone, remdesivir, valacyclovir, and Compound A. The treatments were administered according to the following dosing regimen: 1000 mg valacyclovir PO (day -7) (valacyclovir stop date unknown); 6 mg dexamethasone IV (day -6 and day -5); 300 mg covalescent plasma, 6 mg dexamethasone IV (day -4); 6 mg dexamethasone IV (day -3 and day -2); 200 mg remdesivir IV, 6 mg dexamethasone IV (day -1); 400 mg Compound A, 100 mg remdesivir IV, 6 mg dexamethasone IV (day 1, day 2, and day 3); 400 mg Compound A, 6 mg dexamethasone IV (day 4); 400 mg Compound A (day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 13, and day 14). Day 1 immediately followed day minus 1 (no day 0).

[00210] At day 1 and day 3, whole blood from the patient was sampled and the relative amounts of various cell populations were determined. From the population of live cells, the relative amounts of lymphocytes, monocytes, and granulocytes were determined. From the population of lymphocytes, the relative amounts of B cells (CD19+), T cells (CD3+), and NK cells were determined. From the population of T cells, the relative amounts of helper T cells (CD4+), cytotoxic T cells (CD8+), CD4-CD8-, and CD4+CD8+ were determined. The results are shown in FIG. 6A.

[00211] The samples were also assessed for markers of activation (CD69, CD86, CD40, and CD25) and markers of adhesion (CDlla, CD47, CD62L, CD49d, and CXCR4) present on B cells (CD19+), T cells (CD3+), NK cells, monocytes (CD14+), and granulocytes. The results are shown in FIG. 6B and FIG. 6C, respectively.

[00212] The T-cell receptor V beta repertoire (Vb 1, Vb 2, Vb 3, Vb 4, Vb 5.1, Vb 5.2, Vb 5.3, Vb 7.1, Vb 7.2, Vb 8, Vb 9, Vb 11, Vb 12, Vb 13.1, Vb 13.2, Vb 13.6, Vb 14, Vb 16, Vb 17, Vb 18, Vb 20, Vb 21.3, Vb 22, and Vb 23) of the samples was determined for the following parent cell types: T cells (CD3+), helper T cells (CD4+), and cytotoxic T cells (CD8+). The results are shown in FIG. 6D.

[00213] The serum levels of various cytokines (IL-6, IL-8, IL-10, MCP-1, MIP-la, IL-lb, IL-12p70, IFNa, and TNF) in the samples were also determined. The results are shown in FIG. 6E, where the solid gray line shows the cutoff for the limit of detection (LOD) and the dashed gray line shows the average level in healthy donor plasma (N=3).

Claims

1. A method for selectively inhibiting Bruton's tyrosine kinase (BTK)-associated inflammation in acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), the ALI or ARDS caused by a bacterium or a virus, in a human subject comprising: administering to the human subject an amount of a compound effective to inhibit BTK, but not interleukin-2-inducible T-cell kinase (ITK) in the human subject, wherein the compound is l-(4-(((6-amino-5-(4- phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the ALI or ARDS is caused by a coronavirus.

3. The method of claim 2, wherein the coronavirus is selected from the group consisting of a HCoV-OC43 virus, a HCoV-HKUl virus, a HCoV-229E virus, a HCoV-NL63 virus, a MERS-CoV virus, a SARS-CoV virus, and a SARS-CoV-2 virus.

4. The method of claim 2, wherein the coronavirus is a SARS-CoV-2 virus.

5. The method of claim 1, wherein the ALI or ARDS is caused by an influenza virus.

6. The method of any one of claims 1, 2, 3, 4, or 5, wherein the human subject has a cancer.

7. The method of any one of claims 1, 2, 3, 4, or 5, wherein the human subject has a brain cancer, a lung cancer, a colon cancer, an epidermoid cancer, a squamous cell cancer, a bladder cancer, a gastric cancer, a pancreatic cancer, a breast cancer, a head cancer, a neck cancer, a renal cancer, a kidney cancer, a liver cancer, an ovarian cancer, a prostate cancer, a colorectal cancer, a uterine cancer, a rectal cancer, an esophageal cancer, a testicular cancer, a gynecological cancer, a thyroid cancer, a melanoma, or a hematologic malignancy.

8. The method of claim 7, wherein the hematologic malignancy is a lymphoproliferative neoplasm selected from B cell lymphoblastic lymphoma, T cell lymphoblastic lymphoma, diffuse large B-cell lymphoma, Burkitt lymphoma, follicular lymphoma, small lymphocytic lymphoma, Waldenstrom macroglobulinemia, mantle cell lymphoma, multiple myeloma, chronic lymphocytic leukemia, acute lymphocytic leukemia, non-Hodgkin lymphoma or Hodgkin lymphoma.

9. The method of claim 7, wherein the hematologic malignancy is a myeloproliferative neoplasm selected from acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, myelofibrosis, or myeloproliferative neoplasm.

10. The method of claim 9, wherein the myelofibrosis is selected from the group consisting of primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post PV-MF), and post essential thrombocythemia myelofibrosis (post ET-MF).

11. The method of any one of claims 1, 2, 3, 4, or 5, wherein the human subject has a cancer precursor disease associated with immune deficiency.

12. The method of any one of the preceding claims, wherein administering is by a route selected from oral, topical, parenteral, pulmonary, or nasal.

13. The method of any one of the preceding claims, wherein administering is by an oral route.

14. The method of claim 13, wherein the human subject is in a fasted state when the compound is administered.

15. The method of claim 13, wherein the human subject is in a fed state when the compound is administered.

16. The method of any one of the preceding claims, wherein the compound is in a dosage form selected from a tablet, a troche, a dispersion, a suspension, a solution, a capsule, or an aerosol.

17. The method of any one of the preceding claims, wherein the compound is in a dosage form selected from a tablet or a powder-in-capsule.

18. The method of any one of the preceding claims, wherein the amount is a total daily dose of about 40 mg to about 1500 mg, such as about 50 mg to about 300 mg, about 60 mg to about 250 mg, about 70 mg to about 200 mg, about 80 mg to about 160 mg, about 300 mg to about 1300 mg, about 400 mg to about 1100 mg, about 500 mg to about 1000 mg, about 600 mg to about 900 mg, about 500 mg to about 800 mg, about 400 mg to about 700 mg, about 300 mg to about 600 mg, about 200 mg to about 500 mg, about 100 mg to about 400 mg, about 600 mg, about 400 mg, and/or about 200 mg.

19. The method of claim 18, wherein the total daily dose comprises one dose per day, two divided doses per day, three divided doses per day, or four divided doses per day.

20. The method of claim 18, wherein the total daily dose comprises one dose per day.

21. The method of claim 18, wherein the total daily dose comprises two divided doses per day.

22. The method of claim 21, comprising administering the compound in a dose of 300 mg twice daily, 200 mg twice daily, or 100 mg twice daily.

23. The method of claim 22, wherein the human subject is in a fasted state when the compound is administered.

24. The method of any one of the preceding claims, further comprising inhibiting bone marrow kinase on chromosome X (BMX)-associated inflammation by administering the amount of the compound.

25. The method of any one of the preceding claims, wherein BTK is inhibited in a lung of the human subject.

26. The method of any one of the preceding claims, wherein BMX is inhibited in a lung of the human subject.

27. The method of any one of the preceding claims, wherein the human subject has (i) a bacterial infection or a viral infection, and (ii) suspected or confirmed pneumonia.

28. The method of claim 27, wherein the viral infection is a coronavirus infection.

29. The method of claim 28, wherein the coronavirus infection is COVID-19.

30. The method of any one of the preceding claims, wherein administering occurs after diagnosing cytokine storm syndrome, a coronavirus infection, or an influenza infection in the human subject.

31. The method of claim 30, wherein administering occurs after diagnosing cytokine storm syndrome and a coronavirus infection in the human subject.

32. The method of claim 30, wherein administering occurs after diagnosing cytokine storm syndrome and an influenza infection in the human subject.

33. The method of any one of the preceding claims, wherein administering occurs after detecting a marker for cytokine storm syndrome, a coronavirus infection, or an influenza virus infection in a sample from the human subject.

34. The method of any claim 33, wherein administering occurs after detecting a marker for cytokine storm syndrome and a coronavirus infection in a sample from the human subject.

35. The method of any claim 33, wherein administering occurs after detecting a marker for cytokine storm syndrome and an influenza infection in a sample from the human subject.

36. The method of claim 33, wherein the marker for cytokine storm syndrome, coronavirus infection, or influenza virus infection is an increased level of alanine aminotransferase, lactate dehydrogenase, C-reactive protein, ferritin, D-dimer, a pro- or anti-inflammatory cytokine, or a combination thereof.

37. The method of claim 36, wherein the cytokine is IL-6, TNF-alpha, IL-2, IL-lb, IL-10, or a combination thereof.

38. The method of any one of the preceding claims, further comprising administering a steroid.

39. The method of claim 38, wherein the steroid is a corticosteroid.

40. The method of claim 39, wherein the corticosteroid is selected from the group consisting of alclometasone dipropionate, amcinonide, beclometasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone valerate, budesonide, ciclesonide, clobetasol propionate, clobetasone butyrate, cortisone acetate, desonide, dexamethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortolone, fluprednidene acetate, fluticasone furoate, fluticasone propionate, halcinonide, halometasone, hydrocortisone, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, methylprednisolone, mometasone, mometasone furoate, prednicarbate, prednisolone, prednisone, triamcinolone acetonide, tixocortol pivalate, and combinations thereof.

41. The method of any one of claims 38 to 40, wherein the steroid is administered concurrently with the compound.

42. The method of any one of claims 38 to 40, wherein the steroid is administered before the compound.

43. The method of any one of claims 38 to 40, wherein the steroid is administered after the compound.

44. The method of any one of claims 38 to 43, wherein the steroid is administered in an amount effective to reduce BTK-associated inflammation.

45. The method of any one of the preceding claims, further comprising administering an antiviral agent.

46. The method of claim 45, wherein the antiviral agent is selected from the group consisting of nucleoside analogs, protease inhibitors, interferons, reverse transcriptase inhibitors, and combinations thereof.

47. The method of claim 45, wherein the antiviral agent is selected from the group consisting of acyclovir, favipiravir, ganciclovir, remdesivir, ribavirin, indinavir, lopinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, interferon a-2a, interferon a-2b, interferon a-nl, interferon a- n3, interferon b-la, interferon b-lb, lamivudine, zidovudine, amantadine, foscarnet, nitazoxanide, umifenovir, and combinations thereof.

48. The method of any one of claims 45 to 47, wherein the antiviral agent is administered concurrently with the compound.

49. The method of any one of claims 45 to 47, wherein the antiviral agent is administered before the compound.

50. The method of any one of claims 45 to 47, wherein the antiviral agent is administered after the compound.

51. The method of any one of claims 45 to 47, wherein the antiviral agent is administered in an amount effective to reduce viral titer.

52. The method of any one of the preceding claims, wherein administering is continued until a biomarker of inflammation returns to a normal level.

53. The method of claim 52, wherein the biomarker is elevated C-reactive protein (CRP), such as CRP greater than 10 mg/dL.

54. The method of claim 52, wherein the biomarker is decreased absolute lymphocyte count (ALC), such as ALC less than 1000 cells/pL.