Method of treating respiratory conditions in chronic obstructive pulmonary disease patients

Abstract

The present disclosure describes a method of treating a respiratory condition, wherein the respiratory condition is a respiratory enterovirus infection, an upper respiratory infection, a common cold, or a combination thereof, in a human subject with COPD which includes administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof, thereby treating the respiratory condition in the subject. Pharmaceutical formulations of vapendavir and pharmaceutically acceptable salts thereof are also disclosed.

Description

Attorney Docket No. 433899-001802METHOD OF TREATING RESPIRATORY CONDITIONS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE PATIENTSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application Nos. 63 / 684,652 filed on August 19, 2024, 63 / 715,272 filed on November 1, 2024, 63 / 804,845 filed on May 13, 2025, 63 / 715,172 filed onNovember 1, 2024, 63 / 684,655 filed on August 19, 2024, 63 / 715,299 filed on November 1, 2024, 63 / 694,305 filed on September 13, 2024, 63 / 684,661 filed on August 19, 2024, 63 / 814,168 filed on May 29, 2025, 63 / 715,323 filed on November 1, 2024, and 63 / 743,420 filed on January 9, 2025, which are hereby incorporated by reference herein in their entirety.BACKGROUND

[0002] Rhinoviruses (RVs) are small RNA viruses that represent significant diversity within the Enterovirus (EV) genus, with over 180 distinct serotypes. RVs are the most common cause of upper respiratory tract infections (UTRI) and a frequent cause of community-acquired pneumonia in adults. While RVs are normally associated with mild and self-limiting cold-like symptoms, RVs can cause significant morbidity and mortality via the exacerbation of chronic respiratory diseases such as asthma, cystic fibrosis, primary ciliary dyskinesia, or COPD.

[0003] Acute exacerbations are the primary contributors to the morbidity and mortality associated with COPD. These exacerbations are associated with an impaired quality of life and accelerated deterioration of lung function. Approximately 40-50% of COPD exacerbations are linked to RV infection. However, current therapies for managing COPD and treating acute exacerbations are aimed at palliating the symptoms and, in many cases, have significant side effects. Current therapies such as long-acting muscarinic receptor antagonists (LAMAs), long acting P2 receptor agonists (LABAs), inhaled corticosteroids (ICS), and antibacterial drugs are only partially effective and fail to address the underlying mechanisms of disease or triggers of exacerbation.

[0004] Vapendavir (VPV) is a potent, broad spectrum antiviral drug active against a majority of RV serotypes and other enteroviruses evaluated in cell-based assay systems and human clinical trials. Vapendavir has been tested in humans with no appreciable safety concerns noted following single and multiple doses. There remains a need for an effective treatment for RV infection, particularly in patients having chronic respiratory conditions such as COPD.Attorney Docket No. 433899-001802SUMMARY

[0005] In some aspects, the techniques described herein relate to a method of treating a respiratory condition, wherein the respiratory condition is a respiratory enterovirus infection, an upper respiratory infection, a common cold, or a combination thereof, in a subject with COPD including orally administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof, thereby treating the respiratory condition in the subject.

[0006] In some aspects, the techniques described herein relate to a method, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is between about 250 mg and about 2,000 mg per day.

[0007] In some aspects, the techniques described herein relate to a method, wherein the respiratory condition is a respiratory enterovirus infection, and the respiratory enterovirus infection is selected from a rhinovirus, echovirus, EV-68, EV-71, coxsackie virus, a non-polio enterovirus and combinations thereof.

[0008] In some aspects, the techniques described herein relate to a method, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg to about 1000 mg daily for about 4 to about 10 days.

[0009] In some aspects, the techniques described herein relate to a method, wherein the loading dose and maintenance dose are administered within about 30 minutes of the subject consuming a meal with solid food.

[0010] In some aspects, the techniques described herein relate to a method, wherein the subject is in a fed state when administering the loading dose and the maintenance doses.

[0011] In some aspects, the techniques described herein relate to a method, wherein the subject is in a fasted state when administering the loading dose and the maintenance doses.

[0012] In some aspects, the techniques described herein relate to a method, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / mL.Attorney Docket No. 433899-001802

[0013] In some aspects, the techniques described herein relate to a method, wherein the vapendavir or a pharmaceutically acceptable salt thereof includes vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof.

[0014] In some aspects, the techniques described herein relate to a method, wherein the subject been diagnosed with GOLD stage 1 COPD, GOLD stage 2 COPD, GOLD stage 3 COPD, or GOLD stage 4 COPD.

[0015] In some aspects, the techniques described herein relate to a method, wherein the subject is receiving stable maintenance therapy for COPD.

[0016] In some aspects, the techniques described herein relate to a method, wherein treating the respiratory enterovirus in the subject includes preventing a decrease in the subject's lung function compared to the subject's lung function prior to treatment.

[0017] In some aspects, the techniques described herein relate to a method, wherein the subject's lung function is measured by Forced Expiratory Volume -1 (FEV-1; in liters and % predicted), Forced Vital Capacity (FVC; in liters and % predicted) FEV1 / FVC ratio and peak expiratory flow (PEF) or any combination thereof.

[0018] In some aspects, the techniques described herein relate to a method, wherein treating the respiratory condition in the subject includes decreasing a viral load in the sputum, nasal passages, or a combination thereof in the subject compared with a viral load in the sputum, nasal passages, or a combination thereof of the subject prior to treatment.

[0019] In some aspects, the techniques described herein relate to a method, wherein treating the respiratory condition in the subject results in a time to resolution of less than about 3.5 days.

[0020] In some aspects, the techniques described herein relate to a method, wherein treating the respiratory condition in the subject results in less than about 2 days with clinically significant deterioration.

[0021] In some aspects, the techniques described herein relate to a method, wherein treating the respiratory condition in the subject minimizes a Type 2 immune response phenotype in the subject.Attorney Docket No. 433899-001802

[0022] In some aspects, the techniques described herein relate to a method, wherein treating the respiratory condition in the subject does not include administering a chronic immune therapy to the subject.

[0023] In some aspects, the techniques described herein relate to a method, further including administering to the subject a therapeutically effective amount of pleconaril to the subject.

[0024] In some aspects, the techniques described herein relate to a method of treating a respiratory condition, wherein the respiratory condition is a respiratory enterovirus infection, an upper respiratory infection, a common cold, or a combination thereof, in a subject with asthma including orally administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof, thereby treating the respiratory condition in the subject.

[0025] In some aspects, the techniques described herein relate to a method, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is between about 250 mg and about 2,000 mg per day.

[0026] In some aspects, the techniques described herein relate to a method, wherein the respiratory condition is a respiratory enterovirus infection, and the respiratory enterovirus infection is selected from a rhinovirus, echovirus, EV-68, EV-71, coxsackie virus, a non-polio enterovirus and combinations thereof.

[0027] In some aspects, the techniques described herein relate to a method, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg to about 1000 mg daily for about 4 to about 10 days.

[0028] In some aspects, the techniques described herein relate to a method, wherein the loading dose and maintenance dose are administered within about 30 minutes of the subject consuming a meal with solid food.

[0029] In some aspects, the techniques described herein relate to a method, wherein the subject is in a fed state when administering the loading dose and the maintenance doses.Attorney Docket No. 433899-001802

[0030] In some aspects, the techniques described herein relate to a method, wherein the subject is in a fasted state when administering the loading dose and the maintenance doses.

[0031] In some aspects, the techniques described herein relate to a method, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / mL.

[0032] In some aspects, the techniques described herein relate to a method, wherein the vapendavir or a pharmaceutically acceptable salt thereof includes vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof.

[0033] In some aspects, the techniques described herein relate to a method, wherein treating the respiratory enterovirus in the subject includes preventing a decrease in the subject's lung function compared to the subject's lung function prior to treatment.

[0034] In some aspects, the techniques described herein relate to a method, wherein the subject's lung function is measured by Forced Expiratory Volume -1 (FEV-1; in liters and % predicted), Forced Vital Capacity (FVC; in liters and % predicted) FEV1 / FVC ratio and peak expiratory flow (PEF) or any combination thereof.DRAWINGS

[0035] Aspects, features, benefits, and advantages of the embodiments described herein will be apparent with regard to the following description, appended claims, and accompanying drawings where:

[0036] FIG. 1 is an XRPD diffractogram of Crystalline Form A of vapendavir chloride.

[0037] FIG. 2 is an XRPD diffractogram of Crystalline Form B of vapendavir chloride.

[0038] FIG. 3 is an XRPD diffractogram of Crystalline Form C of vapendavir chloride.

[0039] FIG. 4 is an XRPD diffractogram of Crystalline Form D of vapendavir chloride.

[0040] FIG. 5 is an XRPD diffractogram of Crystalline Form G of vapendavir chloride.

[0041] FIG. 6 is an XRPD diffractogram of Crystalline Form H of vapendavir chloride.Attorney Docket No. 433899-001802

[0042] FIG. 7A is an overlay of the DSC results for Crystalline Form A, Crystalline Form B, Crystalline Form D, Crystalline Form G, and Crystalline Form H of vapendavir chloride, according to embodiments the present disclosure. FIG. 7B shows further detail on the thermal events of Crystalline Form H of vapendavir chloride, according to embodiments the present disclosure.

[0043] FIG. 8 is an overlay the XRPD diffractograms for each of the evaporation experiments 1-12 and the reference patterns for Crystalline Forms A and B of vapendavir chloride, according to an embodiment of the present disclosure.

[0044] FIG. 9 is an overlay the XRPD diffractograms for each of the evaporation experiments 13-24 and the reference patterns for Crystalline Forms A and B of vapendavir chloride, according to an embodiment of the present disclosure.

[0045] FIG. 10 is an overlay the XRPD diffractograms for the mixtures of crystalline forms observed in cooling experiments 1, 6, 7, and 11, and the reference patterns for Crystalline Forms A and B of vapendavir chloride, according to an embodiment of the present disclosure.

[0046] FIG. 11 is an overlay the XRPD diffractograms for the mixtures of crystalline forms observed in slurry experiments 1-12, and the reference patterns for Crystalline Forms A and B of vapendavir chloride, according to an embodiment of the present disclosure.

[0047] FIG. 12 is an overlay the XRPD diffractograms for the mixtures of crystalline forms observed in slurry experiments 13-24, and the reference patterns for Crystalline Forms A and B of vapendavir chloride, according to an embodiment of the present disclosure.

[0048] FIG. 13 is an XRPD diffractogram of a crystalline form of vapendavir oxalate, according to an embodiment the present disclosure.

[0049] FIG. 14 is an image of crystals of vapendavir oxalate, according to an embodiment the present disclosure.

[0050] FIG. 15 is an XRPD diffractogram of a crystalline form of vapendavir maleate, according to an embodiment the present disclosure.

[0051] FIG. 16 shows the DSC of vapendavir maleate, according to an embodiment of the present disclosure.Attorney Docket No. 433899-001802

[0052] FIG. 17 is an XRPD diffractogram of a crystalline form of vapendavir tartrate, according to an embodiment the present disclosure.

[0053] FIG. 18 shows the DSC of vapendavir tartrate, according to an embodiment the present disclosure.

[0054] FIG. 19 is an XRPD diffractogram of Crystalline Form 1 of vapendavir mesylate obtained from a slurry in methanol, according to embodiments of the present disclosure.

[0055] FIG. 20 is an XRPD diffractogram of Crystalline Form 1 of vapendavir mesylate obtained from a slurry in acetonitrile, according to embodiments of the present disclosure.

[0056] FIG. 21 is an XRPD diffractogram of Crystalline Form 2 of vapendavir mesylate obtained from a slurry in acetone, according to embodiments of the present disclosure.

[0057] FIG. 22 is an XRPD diffractogram of Crystalline Form 2 of vapendavir mesylate obtained from a slurry in tetrahydrofuran, according to embodiments of the present disclosure.

[0058] FIG. 23 is a DSC / TGA trace of Crystalline Form 2 of vapendavir mesylate, according to embodiments of the present disclosure.

[0059] FIG. 24 is a DVS isotherm plot of Crystalline Form 2 of vapendavir mesylate, according to embodiments of the present disclosure.

[0060] FIG. 25A shows the heat flow by DSC for 25 / 75 VPV / HPMAC-M from 80 / 20 DCM / MeOH. FIG. 25B shows the heat flow by DSC for 25 / 6.3 / 68.7 VPV / MSA / HPMAC- M from MeOH. FIG. 25C shows the heat flow by DSC for 25 / 75 VPV / Hydroxypropyl-beta- cyclodextrin. FIG. 25D shows the heat flow by DSC for 25 / 75 VPV / HPMAC-M from 80 / 20 MeOH / Acetic acid. FIG. 25E shows the heat flow by DSC for 15 / 85 VPV / HPMAC-M from 80 / 20 DCM / MeOH.

[0061] FIG. 26A shows the reversing heat flow by DSC for 25 / 75 VPV / HPMAC-M from 80 / 20 DCM / MeOH. FIG. 26B shows the reversing heat flow by DSC for 25 / 6.3 / 68.7 VPV / MSA / HPMAC-M from MeOH. FIG. 26C shows the reversing heat flow by DSC for 25 / 75 VPV / Hydroxypropyl-beta-cyclodextrin. FIG. 26D shows the reversing heat flow by DSC for 25 / 75 VPV / HPMAC-M from 80 / 20 MeOH / Acetic acid. FIG. 26E shows the reversing heat flow by DSC for 15 / 85 VPV / HPMAC-M from 80 / 20 DCM / MeOH.Attorney Docket No. 433899-001802

[0062] FIG. 27 is an overlay of the diffractograms of crystalline VPV with spray-dried dispersion formulations 6, 7, and 9, according to an embodiment of the present disclosure.

[0063] FIG. 28 shows non-sink dissolution under fasted conditions showing concentration after ultracentrifugation (indicative of dissolved drug concentration), according to an embodiment of the present disclosure.

[0064] FIG. 29 shows non-sink dissolution under fasted conditions showing concentration after microcentrifugation (indicated by circular points) and ultracentrifugation (indicated by Xs), according to an embodiment of the present disclosure.

[0065] FIG. 30 shows non-sink dissolution under PPI fasted conditions showing concentration after ultracentrifugation (indicative of dissolved drug concentration), according to an embodiment of the present disclosure.

[0066] FIG. 31 shows non-sink dissolution under PPI fasted conditions showing concentration after microcentrifugation (indicated by circular points) and ultracentrifugation (indicated by Xs), according to an embodiment of the present disclosure.

[0067] FIG. 32 shows non-sink dissolution under fed conditions showing concentration after ultracentrifugation (indicative of dissolved drug concentration), according to an embodiment of the present disclosure.

[0068] FIG. 33 shows non-sink dissolution under fed conditions showing concentration after microcentrifugation (indicated by circular points) and ultracentrifugation (indicated by Xs), according to an embodiment of the present disclosure.

[0069] FIG. 34A is a graph (time vs individual concentration) of micronized free base vapendavir when co-administered with famotidine or pentagastrin. FIG. 34B is a graph (time vs individual concentration) of 25% vapendavir / HPMCAS-M spray dried dispersion when coadministered with famotidine or pentagastrin. FIG. 34C shows the maximum absorption (Cmax) of free base or spray dried dispersion when co-administered with famotidine compared to co-administration with pentagastrin. FIG. 34D shows AUC for both formulations coadministered with either pentagastrin or famotidine.

[0070] FIG. 35A shows time vs. concentration for VPV phosphate salt and FIG. 35B shows Cmax and AUC for VPV phosphate salt, as a comparison.Attorney Docket No. 433899-001802

[0071] FIG. 36A shows the time vs. concentration for Formulation 1, FIG. 36B shows the time vs. concentration for Formulation 2, FIG. 36C shows the time vs. concentration for Formulation 3, and FIG. 36D shows the time vs. concentration for Formulation 4.

[0072] FIG. 37A shows the time vs. concentration for Formulation 1, FIG. 37B shows the time vs. concentration for Formulation 2, FIG. 37C shows the time vs. concentration for Formulation 3, and FIG. 37D shows the time vs. concentration for Formulation 4.

[0073] FIG. 38A shows Cmax evaluated in the four formulations and FIG. 38B shows Cmax / D.

[0074] FIG. 39A shows AUC evaluated in the four formulations and FIG. 39B shows AUC / D.

[0075] FIG. 40A shows the XRPD of Formulation 2 over the stability study. FIG. 40B shows the XRPD of Formulation 3 over the stability study. FIG. 40C shows the XRPD of Formulation 4 over the stability study.

[0076] FIG. 41 shows the XRPD for the formulations of TABLE 30.

[0077] FIG. 42 shows the reversing and non-reversing thermograms corresponding to TABLE 32

[0078] FIG. 43 shows non-sink dissolution under fasted conditions showing concentration after ultracentrifugation (indicative of dissolved drug concentration).

[0079] FIG. 44 shows non-sink dissolution under fasted conditions showing concentration after microcentrifugation (indicated by circular points) and ultracentrifugation (indicated by Xs).

[0080] FIG. 45 shows non-sink dissolution under PPI fasted conditions showing concentration after ultracentrifugation (indicative of dissolved drug concentration).

[0081] FIG. 46 shows non-sink dissolution under PPI fasted conditions showing concentration after microcentrifugation (indicated by circular points) and ultracentrifugation (indicated by Xs).Attorney Docket No. 433899-001802

[0082] FIG. 47 shows non-sink dissolution under fed conditions showing concentration after ultracentrifugation (indicative of dissolved drug concentration).

[0083] FIG. 48 shows non-sink dissolution under fed conditions showing concentration after microcentrifugation (indicated by circular points) and ultracentrifugation (indicated by Xs).

[0084] FIG. 49A shows the non-sink dissolution of 25% Vapendavir / HPMCAS-M, FIG. 49B shows the non-sink dissolution of 40 / 10.3 / 49.7 Vapendavir / IUSCWEudragit, and FIG. 49C shows the non-sink dissolution of 40% Vapendavir / Eudragit.DETAILED DESCRIPTION

[0085] Before compounds, compositions and methods are described in detail, it is to be understood that this disclosure is not limited to the particular processes, compositions, or methodologies described, as these may vary. It is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of the disclosure which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the disclosure, the preferred methods, devices, and materials are now described.

[0086] It is further appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the disclosure which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0087] As used in this document, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Nothing in this disclosure is to be construed as an admission that the embodiments described in this disclosure are not entitled to antedate such disclosure by virtueAttorney Docket No. 433899-001802 of prior invention. As used in this document, the term “comprising” means “including, but not limited to.”

[0088] As used herein, the term “about” means plus or minus up to 20% of the numerical value of the number with which it is being used. For example, “about 50%” means in the range of 40-60% and includes exactly 50%. The term “about” may refer to plus or minus 1%, 5%, 10%, 15%, or 20% of the numerical value of the number with which it is being used.

[0089] "Administering," when used in conjunction with the compounds of the disclosure, means to administer a compound directly into or onto a target tissue or to administer a compound systemically or locally to a patient or other subject.

[0090] The term "animal" as used herein includes, but is not limited to, humans and nonhuman vertebrates such as wild, experimental, domestic, and farm animals, and pets. As used herein, the terms "subject," "individual," and "patient," are used interchangeably and refer to any animal, including mammals, mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, non-human primates, humans, and the like.

[0091] The term "improves" is used to convey that the disclosure changes either the characteristics and / or the physical attributes of the tissue to which it is being provided, applied, or administered. The term "improves" may also be used in conjunction with a disease state such that when a disease state is "improved" the symptoms or physical characteristics associated with the disease state are diminished, reduced, eliminated, delayed, or averted.

[0092] The term "inhibiting" includes the blockade, aversion of a certain result or process, or the restoration of the converse result or process. In terms of treatment by administration of a compound of the disclosure, "inhibiting" includes protecting against (partially or wholly) or delaying the onset of symptoms, alleviating symptoms, or protecting against, diminishing, or eliminating a disease, condition, or disorder.

[0093] As used herein, the term “free base” refers to a non-salt form of a compound as described herein.

[0094] The term “salts” can include acid addition salts or addition salts of free bases. The salts as described herein may be pharmaceutically acceptable. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include but are not limited to salts derived from nontoxic inorganic acids such as nitric, phosphoric, sulfuric, hydrobromic,Attorney Docket No. 433899-001802 hydroiodic, hydrofluoric, or phosphorus acids, as well as salts derived from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyl alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and acetic, maleic, succinic, or citric acids. Non-limiting examples of such salts include napadisylate, besylate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, hydrochloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Salts of amino acids are also contemplated, such as arginate, gluconate, galacturonate, and the like.

[0095] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. For example, a complex with water is known as a “hydrate.” Solvates of the compounds of the present disclosure are within the scope of this disclosure. The salts of the compound of any of the formulae described herein may form solvates (e.g., hydrates) and the present disclosure includes all such solvates. The meaning of the word “solvates” is well known to those skilled in the art as a compound formed by interaction of a solvent and a solute (i.e., solvation). Techniques for the preparation of solvates are well established in the art.

[0096] As used herein, unless specifically indicated, the term “active ingredient” refers to a compound of any of the formulae as described herein.

[0097] The phrase “pharmaceutically acceptable” refers to molecular entities and compositions that are generally regarded as safe and nontoxic. In particular, pharmaceutically acceptable carriers, diluents or other excipients used in the pharmaceutical compositions of this disclosure are physiologically tolerable, compatible with other ingredients, and do not typically produce an allergic or similar untoward reaction (for example, gastric upset, dizziness and the like) when administered to a subject. In some embodiments, as used herein, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans. The phrase “pharmaceutically acceptableAttorney Docket No. 433899-001802 salt(s)”, as used herein, includes those salts of compounds of the disclosure that are safe and effective for use in mammals and that possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in compounds of the disclosure or in compounds identified pursuant to the methods of the disclosure. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate, and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compounds of the disclosure can form pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, iron and diethanolamine salts. Pharmaceutically acceptable base addition salts are also formed with amines, such as organic amines. Examples of suitable amines are N,N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.

[0098] As used herein, the term "therapeutic" means an agent utilized to treat, combat, ameliorate, protect against, or improve an unwanted condition or disease of a subject.

[0099] A "therapeutically effective amount" or "effective amount" of a compound, such as vapendavir, or composition of the disclosure is a predetermined amount which confers a therapeutic effect on the treated subject, at a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect or physician observes a change). The effect contemplated herein includes medical therapeutic treatment, as appropriate. The specific dose of a compound administered according to this disclosure to obtain therapeutic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, the co-administration of other active ingredients, the condition being treated, the activity of the specific compound employed, the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed and the duration of the treatment. The effective amount administered will be determined by the physician in theAttorney Docket No. 433899-001802 light of the foregoing relevant circumstances and the exercise of sound medical judgment. A therapeutically effective amount of a compound of this disclosure, such as vapendavir, is typically an amount such that when it is administered in a physiologically tolerable excipient composition, it is sufficient to achieve an effective systemic concentration or local concentration in the tissue.

[0100] The terms "treat", "treated", or "treating" as used herein refers to therapeutic treatment measures, wherein the object is to protect against (partially or wholly) or slow down (e.g., lessen or postpone the onset of) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results such as partial or total restoration or inhibition in decline of a parameter, value, function or result that had or would become abnormal. For the purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent or vigor or rate of development of the condition, disorder or disease; stabilization (z.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether or not it translates to immediate lessening of actual clinical symptoms, or enhancement or improvement of the condition, disorder or disease. Treatment seeks to elicit a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.

[0101] As used herein, the term “adverse event” refers to any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. The abbreviation “AE” may be used to refer to an adverse event.

[0102] As used herein, the abbreviation “ADL” means activities of daily living.

[0103] As used herein, the abbreviation “ALT” means alanine aminotransferase.

[0104] As used herein, the abbreviation “AUC” means area under the curve.

[0105] As used herein, the abbreviation “BID” means bis in de and refers to twice a day dosage.

[0106] As used herein, the abbreviation “BL” means baseline.

[0107] As used herein, the abbreviation “CF” means cystic fibrosis.Attorney Docket No. 433899-001802

[0108] As used herein, the abbreviation “Cmax” means peak drug concentration.

[0109] As used herein, the abbreviation “IPF” means Idiopathic Pulmonary Fibrosis.

[0110] As used herein, the abbreviation “CYP3A2” means Cytochrome P450 family 1 subfamily A member 2.[OHl] As used herein, the abbreviation “CYP3A4” means Cytochrome P450 family 3 subfamily A member 4.

[0112] As used herein, the abbreviation “CXCL8” means C-X-C motif chemokine ligand 8.

[0113] As used herein, the abbreviation “CXCL10” means C-X-C motif chemokine ligand 10.

[0114] As used herein, “ECso” refers to half maximal effective concentration.

[0115] As used herein, “EC90” refers to 90% effective concentration.

[0116] As used herein, “paECso” refers to the protein adjusted half maximal effective concentration.

[0117] As used herein, “paECgo” refers to the protein adjusted 90% effective concentration.

[0118] As used herein, “FEVi” refers to Forced Expiratory Volume in 1 second.

[0119] As used herein, “FVC” means Forced Vital Capacity.

[0120] Unless otherwise indicated, the abbreviation “h” refers to hours as a unit of time.

[0121] As used herein, the abbreviation “Scr” means screening.

[0122] As used herein, the abbreviation “IC” means informed consent.

[0123] As used herein, the abbreviation “MH” means medical history.

[0124] As used herein, the abbreviation “IE” means inclusion / exclusion criteria.

[0125] As used herein, the abbreviation “IC50” refers to half maximal inhibitory concentration.

[0126] As used herein, the abbreviation “PT” means pregnancy test.

[0127] As used herein, the abbreviation “T” means training of diaries, unless otherwise indicated.Attorney Docket No. 433899-001802

[0128] As used herein, the abbreviation “D” means diaries.

[0129] As used herein, the abbreviation “PE” means physical examination.

[0130] As used herein, the abbreviation “PEF” means peak expiratory flow.

[0131] As used herein, the abbreviation “PK” means pharmacokinetics.

[0132] As used herein, the abbreviation “LF” means lung function.

[0133] As used herein, the abbreviation “NL” means nasal lavage and nasosorption.

[0134] As used herein, the abbreviation “Bl” means blood chemistry and full blood count.

[0135] As used herein, the abbreviation “Bl-Ser” means RV-A16 serology, mediators.

[0136] As used herein, the abbreviation “Bl-PK” means pharmacodynamic testing of blood.

[0137] As used herein, the abbreviation “SAE” means serious adverse event.

[0138] As used herein, the abbreviation “Sp” means sputum.

[0139] As used herein, the abbreviation “SM” means safety assessment.

[0140] As used herein, the abbreviation “CM” means concomitant medications.

[0141] COPD is the third leading cause of death worldwide and fourth leading cause in the United States (US). Among adults with COPD in the US, there are approximately 1.5 million emergency department (ED) visits, 700,000 hospitalizations, and over 10 million office visits annually. According to the Center for Disease Control and Prevention (CDC), costs associated with COPD in the US were approximately $49 billion in 2020, increasing 52.6% from 2010.

[0142] Acute exacerbations resulting from rhinovirus (RV) and other enterovirus (EV) infections, are the primary contributors to the morbidity and mortality associated with COPD. Approximately 40 to 50% of COPD exacerbations (range 10 to 70%) are linked to RV infections, and are associated with increased airway inflammation; increased mucus production, delayed or deficient antiviral host defenses, and increases in pathogenic respiratory bacteria.

[0143] In a RV challenge model in patients with COPD, Mallia et al. demonstrated that RV infection induces the symptomatic, physiologic, and inflammatory features reported in naturally occurring COPD exacerbations, and that infection is associated with impaired IFNAttorney Docket No. 433899-001802 production and exaggerated neutrophilic inflammation, which may be important mechanisms for viral-induced exacerbations. This study also showed upper respiratory symptoms began shortly after viral challenge, with peak lower respiratory symptoms, neutrophil inflammation, and secondary bacterial infection following at time points > 1 week from onset of initial symptoms. This progressive time course suggests a potential treatment window for interruption of acute COPD exacerbations associated with RVs by using potent specific antiviral treatments.

[0144] Vapendavir (3-Ethoxy-6-{2-[l-(6-methylpyridazin-3-yl)piperidin-4-yl]ethoxy}- benzo[d]isoxazol) is a potent and broad spectrum antiviral agent active against >97% of RV- A and RV-B serotypes of RV (no available assay for RV-C, but clinical data indicate sensitivity similar to A and B) and 89% of other EVs evaluated in cell based assay systems. Vapendavir acts by binding to the viral capsid, thereby inhibiting viral attachment to the target cell and, independently, preventing release of viral RNA into the cell. Vapendavir has been in development for the treatment of infections with RV and other respiratory EVs for approximately a decade, with over 640 healthy adults and participants with asthma receiving treatment across 7 clinical studies. Vapendavir reduced RV viral load compared with placebo in three Phase 2 clinical trials and reduced respiratory symptoms in a Phase 2 clinical trial, both in adult participants with asthma. An acceptable safety and tolerability profile has been demonstrated to date, with no appreciable safety concerns noted following single doses up to 1,056 milligram (mg) and multiple doses up to 528 mg bis in de / twice a day (BID) for up to 7 days, and 400 mg BID, up to 10 days in a RV challenge model. Vapendavir has also been tested against the RV-A16 human challenge strain and demonstrated complete protection against viral replication and de novo infection at >0.312 micromolar (pM) using in vitro HeLa cell assays. Vapendavir may also be referred to as VPV. The chemical structure (Formula (I)) of vapendavir is shown below.Attorney Docket No. 433899-001802Formula (I)

[0145] Vapendavir Chloride

[0146] In some embodiments, there is provided a chloride salt of a compound of FormulaI:Formula I

[0147] The chloride salt of vapendavir (also referred to herein as vapendavir chloride) may have a molecular weight of about 418 g / mol.

[0148] In some embodiments, the chloride salt is in a crystalline form. The present disclosure encompasses the chloride salt of vapendavir and hydrates and solvates of vapendavir chloride. Polymorphs of each of vapendavir chloride, hydrated vapendavir chloride, and solvated vapendavir chloride are also contemplated and within the scope of this disclosure. It is contemplated that polymorphs of vapendavir chloride may convert to other polymorphs under certain physical conditions, without wishing to be bound by theory. The present disclosure includes such embodiments wherein a polymorph of vapendavir chloride or hydrates or solvates thereof may convert to one or more different polymorphs of vapendavir chloride or hydrates or solvates thereof.Attorney Docket No. 433899-001802

[0149] In some embodiments, the chloride salt is an amorphous form. In some embodiments, the chloride salt is a partially crystalline form, such that the chloride salt includes a mix of crystalline and amorphous vapendavir chloride.

[0150] In some embodiments, the chloride salt is anhydrous. In some embodiments, the chloride salt is non-solvated, such that the chloride salt is not a solvate. In some embodiments, the chloride salt is a solvate, wherein the solvent included in the solvate is not particularly limited. Solvents included in a solvate form of vapendavir chloride may include, but are not limited to dichloromethane, 2,2,2-trifluoroethanol, and the like. The chloride salt can, in some embodiments, be simultaneously solvated and anhydrous, wherein the solvent is not water.

[0151] In some embodiments, the vapendavir chloride is hygroscopic. In some embodiments, the vapendavir chloride is not hygroscopic, such that it does not tend to take up water from the surrounding atmosphere. Different crystalline forms of the vapendavir chloride as disclosed herein may be hygroscopic or non-hygroscopic. In some embodiments, the vapendavir chloride is in a stable form, such that it does not appreciably chemically decompose in ambient conditions. In some embodiments, the stoichiometry of vapendavir to chloride counterion is 1 : 1.

[0152] In some embodiments, the chloride salt of vapendavir has a melting point of about 50 °C to about 170 °C. For example, in some embodiments, the vapendavir chloride has a melting point of about 50 °C, about 60 °C, about 70 °C, about 80 °C, about 90 °C, about 100 °C, about 110 °C, about 120 °C, about 130 °C, about 135 °C, about 140 °C, about 145 °C, about 150 °C, about 155 °C, about 160 °C, about 165 °C, about 170 °C, or any value contained within a range formed by any two of the preceding values. Those of ordinary skill in the art will be familiar with methods and instruments for determining melting point, and any such method may be used, including but not limited to differential scanning calorimetry (DSC). When determining melting point by DSC, it will be understood that melting point refers to the peak observed via DSC, and that the onset of melting may be at a lower temperature, without wishing to be bound by theory.

[0153] In some embodiments, the vapendavir chloride is in a crystalline form referred to herein as Crystalline Form A. In some embodiments, Crystalline Form A is a hydrate. In some embodiments, Crystalline Form A has an X-ray powder diffraction (XRPD) pattern which includes peaks at diffraction angles of about 7°, about 10°, about 12°, about 16°, about 20°,Attorney Docket No. 433899-001802 about 22°, and about 26° (29 ± 0.2°). For example, in some embodiments, Crystalline Form A of vapendavir chloride has an X-ray powder diffraction (XRPD) pattern which exhibits peaks at diffraction angles of 7.0°, 9.8°, 16.0°, 19.1°, 19.6°, 20.5°, 22.6°, 25.5°, and 29.6° (29 ± 0.2°). FIG. 1 is an XRPD diffractogram of Crystalline Form A of vapendavir chloride. TABLE 1 is a peak table of the XRPD diffractogram shown in FIG. 1 with normalized intensities. In some embodiments, Crystalline Form A exhibits an endothermic thermal transition, as measured by DSC, at a temperature of about 169 °C. In some embodiments, the thermal behavior of Crystalline Form A by DSC may represent a melting point, a dehydration, or another thermal event. Without wishing to be bound by theory, the thermal transitions may represent a conversion to another crystalline form. For example, it contemplated that Crystalline Form A may convert to Crystalline Form B upon dehydration, without wishing to be bound by theory.

[0154] TABLE 1Attorney Docket No. 433899-001802

[0155] In some embodiments, the vapendavir chloride is in a crystalline form referred to herein as Crystalline Form B. In some embodiments, Crystalline Form B has an X-ray powder diffraction (XRPD) pattern which includes peaks at diffraction angles of about 14°, about 15°, about 23°, about 25°, and about 27° (29 ± 0.2°). For example, in some embodiments, Crystalline Form B of vapendavir chloride has an X-ray powder diffraction (XRPD) pattern which exhibits peaks at diffraction angles of 11.2°, 14.3°, 14.9°, 18.0°, 23.5°, 24.9°, 25.3°, 26.6°, and 28.7° (29 ± 9.2°). FIG. 2 is an XRPD diffractogram of Crystalline Form B of vapendavir chloride. TABLE 2 is a peak table of the XRPD diffractogram shown in FIG. 2 with normalized intensities. In some embodiments, Crystalline Form B exhibits an endothermic thermal transition, as measured by DSC, at a temperature of about 158 °C. In some embodiments, the thermal transition is a melting point.

[0156] TABLE 2Attorney Docket No. 433899-991892

[0157] In some embodiments, the vapendavir chloride is in a crystalline form referred to herein as Crystalline Form C. In some embodiments, Crystalline Form C has an X-ray powder diffraction (XRPD) pattern which includes peaks at diffraction angles of about 4°, about 8°, about 10°, about 12°, about 16°, about 18°, about 20°, and about 24° (29 ± 0.2°). For example, in some embodiments, Crystalline Form C of vapendavir chloride has an X-ray powder diffraction (XRPD) pattern which exhibits peaks at diffraction angles of 4.1°, 8.2°, 9.6°, 12.3°, 16.4°, 17.9°, 19.3°, 20.5°, 21.1°, 24.7°, and 27.6° (29 ± 9.2°). FIG. 3 is an XRPD diffractogramAttorney Docket No. 433899-001802 of Crystalline Form C of vapendavir chloride. TABLE 3 is a peak table of the XRPD diffractogram shown in FIG. 3 with normalized intensities.

[0158] TABLE 3Attorney Docket No. 433899-001802

[0159] In some embodiments, the vapendavir chloride is in a crystalline form referred to herein as Crystalline Form D. In some embodiments, Crystalline Form D has an X-ray powder diffraction (XRPD) pattern which exhibits peaks at diffraction angles of about 8°, about 12°, about 20°, about 24°, and about 26° (29 ± 0.2°). For example, in some embodiments, Crystalline Form D of vapendavir chloride has an X-ray powder diffraction (XRPD) pattern which includes peaks at diffraction angles of 8.2°, 12.3°, 15.8°, 17.5°, 19.8°, 23.5°, 25.4°, 26.3°, and 26.8° (29 ± 9.2°). FIG. 4 is an XRPD diffractogram of Crystalline Form D of vapendavir chloride. TABLE 4 is a peak table of the XRPD diffractogram shown in FIG. 4 with normalized intensities. In some embodiments, Crystalline Form D exhibits an endothermic thermal transition, as measured by DSC, at a temperature of about 169 °C. In some embodiments, the thermal transition may represent a melting point or another thermal event Without wishing to be bound by theory, the thermal transitions may represent a conversion to another crystalline form. For example, it contemplated that Crystalline Form D may convert to Crystalline Form B under certain conditions, without wishing to be bound by theory.

[0160] TABLE 4Attorney Docket No. 433899-001802

[0161] In some embodiments, the vapendavir chloride is a crystalline form referred to herein as Crystalline Form E, which may be present as a mixture with other forms described herein.

[0162] In some embodiments, the vapendavir chloride is a crystalline form referred to herein as Crystalline Form F, which may be present as a mixture with other forms described herein.

[0163] In some embodiments, the vapendavir chloride is in a crystalline form referred to herein as Crystalline Form G. In some embodiments, Crystalline Form G is a solvate of vapendavir chloride with dichloromethane (DCM). In some embodiments, Crystalline Form G has an X-ray powder diffraction (XRPD) pattern which includes peaks at diffraction angles ofAttorney Docket No. 433899-001802 about 12°, about 16°, about 18°, about 22°, and about 24° (29 ± 0.2°). For example, in some embodiments, Crystalline Form G of vapendavir chloride has an X-ray powder diffraction (XRPD) pattern which exhibits peaks at diffraction angles of 11.9°, 15.7°, 17.7°, 21.7°, 24.2°, 24.3°, and 25.3° (29 ± 9.2°). FIG. 5 is an XRPD diffractogram of Crystalline Form G of vapendavir chloride. TABLE 5 is a peak table of the XRPD diffractogram shown in FIG. 5 with normalized intensities. In some embodiments, Crystalline Form G exhibits an endothermic thermal transition, as measured by DSC, at a temperature of about 161 °C. In some embodiments, the thermal transition may represent a melting point or another thermal event. Without wishing to be bound by theory, the thermal transition may represent a conversion to another crystalline form. For example, it contemplated that Crystalline Form G may convert to another crystalline form, such as Crystalline Form B, under certain conditions, without wishing to be bound by theory.

[0164] TABLE 5Attorney Docket No. 433899-991892

[0165] In some embodiments, the vapendavir chloride is in a crystalline form referred to herein as Crystalline Form H. In some embodiments, Crystalline Form H is a solvate of vapendavir chloride with 2,2,2-trifluoroethanol (TFE). In some embodiments, Crystalline Form H has an X-ray powder diffraction (XRPD) pattern which includes peaks at diffraction angles of about 5°, about 8°, about 15°, about 20°, and about 26° (29 ± 0.2°). For example, in some embodiments, Crystalline Form H of vapendavir chloride has an X-ray powder diffraction (XRPD) pattern which exhibits peaks at diffraction angles of5.6°, 8.1°, 15.3°, 19.9°, 23.1°, and 25.5° (29 ± 9.2°). FIG. 6 is an XRPD diffractogram of Crystalline Form H of vapendavir chloride. TABLE 6 is a peak table of the XRPD diffractogram shown in FIG. 6 with normalized intensities. In some embodiments, Crystalline Form H exhibits an endothermic thermal transition, as measured by DSC, at a temperature of about 161 °C. In some embodiments, the thermal transition may represent a melting point or another thermal event Without wishing to be bound by theory, the thermal transition may represent a conversion to another crystalline form. For example, it contemplated that Crystalline Form H may convert to another crystalline form, such as Crystalline Form B, under certain conditions, without wishing to be bound by theory. FIG. 7B shows further detail on the thermal events of Crystalline Form H of vapendavir chloride, according to embodiments the present disclosure.Attorney Docket No. 433899-001802

[0166] TABLE 6

[0167] In some embodiments, the vapendavir chloride is in the form of a mixture of crystalline forms. The vapendavir chloride may be in the form of a mixture of any of the crystalline forms described herein in any combination or ratio. In some embodiments, the vapendavir chloride is in the form of a mixture of a crystalline form or forms as described herein along with a crystalline form which is not observed separately.Attorney Docket No. 433899-001802

[0168] FIG. 7A is an overlay of the DSC results for Crystalline Form A, Crystalline Form B, Crystalline Form D, Crystalline Form G, and Crystalline Form H of vapendavir chloride, according to embodiments the present disclosure.

[0169] The solubility of a compound in simulated gastric and intestinal fluid solutions may, in some embodiments, be useful in determining how the compound will dissolve when administered to a patient, without wishing to be bound by theory. It is contemplated that different crystalline forms of vapendavir chloride may exhibit different solubilities in various solvents and simulated fluids. In some embodiments, a change in crystalline form was observed in the vapendavir chloride after evaluation of solubility in simulated gastric and intestinal fluid solutions. For example, after evaluation of solubility in simulated gastric and intestinal fluid solutions, the solution may be removed and residual solids evaluated, and in some embodiments, the vapendavir chloride is in a different crystalline form than the crystalline form initially used in the solubility studies.

[0170] In some embodiments, the chloride salt of vapendavir has a solubility of about 3.5 mg / mL to about 5.0 mg / mL in a Fed State Simulated Intestinal Fluid (FeSSIF) solution, which has a pH of about 4.95. For example, in a FeSSIF solution or a solution having an equivalent pH, the vapendavir chloride may have a solubility of about 3.5 mg / mL, about 3.6 mg / mL, about3.7 mg / mL, about 3.8 mg / mL, about 3.9 mg / mL, about 4.0 mg / mL, about 4.1 mg / mL, about 4.2 mg / mL, about 4.3 mg / mL, about 4.4 mg / mL, about 4.5 mg / mL, about 4.6 mg / mL, about4.7 mg / mL, about 4.8 mg / mL, about 4.9 mg / mL, about 5.0 mg / mL, or any value contained within a range formed by any two of the preceding values. In some embodiments, vapendavir chloride exhibits higher solubility in a FeSSIF solution than vapendavir in a free base form.

[0171] In some embodiments, the chloride salt of vapendavir has a solubility of about 1.0 mg / mL to about 2.0 mg / mL in a Fasted State Simulated Intestinal Fluid (FaSSIF) solution, which has a pH of about 6.50. For example, in a FaSSIF solution or a solution having an equivalent pH, the vapendavir chloride may have a solubility of about 1.0 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about 1.5 mg / mL, about 1.6 mg / mL, about 1.7 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, about 2.0 mg / mL, or any value contained within a range formed by any two of the preceding values. In some embodiments, vapendavir chloride exhibits higher solubility in a FaSSIF solution than vapendavir in a free base form.Attorney Docket No. 433899-001802

[0172] In some embodiments, the chloride salt of vapendavir has a solubility of about1.5 mg / mL to about 2.5 mg / mL in a Fasted State Simulated Gastric Fluid (FaSSGF) solution, which has a pH of about 1.61. For example, in a FaSSGF solution or a solution having an equivalent pH, the vapendavir chloride may have a solubility of about 1.5 mg / mL, about1.6 mg / mL, about 1.7 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, about 2.0 mg / mL, about 2.1 mg / mL, about 2.2 mg / mL, about 2.3 mg / mL, about 2.4 mg / mL, about 2.5 mg / mL, or any value contained within a range formed by any two of the preceding values. In some embodiments, vapendavir chloride exhibits higher solubility in a FaSSGF solution than vapendavir in a free base form.

[0173] In some embodiments, the chloride salt of vapendavir has a solubility of about1.5 mg / mL to about 3.0 mg / mL in a phosphate buffer having a pH of about 7.4. For example, in a solution having a pH of about 7.5, the vapendavir chloride may have a solubility of about1.5 mg / mL, about 1.6 mg / mL, about 1.7 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, about2.0 mg / mL, about 2.1 mg / mL, about 2.2 mg / mL, about 2.3 mg / mL, about 2.4 mg / mL, about2.5 mg / mL, about 2.6 mg / mL, about 2.7 mg / mL, about 2.8 mg / mL, about 2.9 mg / mL, about3.0 mg / mL, or any value contained within a range formed by any two of the preceding values. In some embodiments, vapendavir chloride exhibits higher solubility in a phosphate buffer solution than vapendavir in a free base form.

[0174] It is contemplated that the vapendavir chloride may exhibit some solubility in various solvents and solvent combinations, including but not limited to methanol, ethyl acetate, isopropyl alcohol, tetrahydrofuran, acetonitrile, water, or combinations thereof. For example, the vapendavir may exhibit a solubility of greater than about 200 mg / mL in methanol at 25 °C, a solubility of greater than about 10 mg / mL in isopropyl alcohol at 25 °C, and a solubility of greater than about 15 mg / mL in acetonitrile at 25 °C. In some embodiments, vapendavir chloride exhibits higher solubility in one or more solvents than vapendavir in a free base form.

[0175] In some embodiments, a method of preparing vapendavir chloride can include dissolving vapendavir, in a free base form, in a solvent such as tetrahydrofuran and adding a chloride-containing compound, such as hydrochloric acid. Other methods of preparing vapendavir chloride may also be acceptable.

[0176] In some embodiments, the chemical purity of the vapendavir chloride may be determined by an analytical method, including but not limited to high performance liquidAttorney Docket No. 433899-001802 chromatography (HPLC). In some embodiments, the vapendavir chloride has a chemical purity of greater than or equal to about 95% by mass, such as about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, or any value contained within a range formed by any two of the preceding values. In some embodiments, the vapendavir chloride contains less than or equal to about 5% by mass of chemical impurities. The identity of the chemical impurities which may be included is not limited. Chemical impurities may be identified and quantified by any method or technique available to those skilled in the art.

[0177] Vapendavir Oxalate

[0178] In some embodiments, there is provided an oxalate salt of a compound of Formula I:Formula I

[0179] The oxalate salt of vapendavir (also referred to herein as vapendavir oxalate) may have a molecular weight of about 470 g / mol. In some embodiments, the vapendavir oxalate has a stoichiometry of 1 : 1 between the vapendavir and the oxalate counterion.

[0180] In some embodiments, the oxalate salt is in a crystalline form. The present disclosure encompasses the oxalate salt of vapendavir and hydrates and solvates of vapendavir oxalate. Polymorphs of each of vapendavir oxalate, hydrated vapendavir oxalate, and solvated vapendavir oxalate are also contemplated and within the scope of this disclosure. It is contemplated that polymorphs of vapendavir oxalate may convert to other polymorphs under certain physical conditions, without wishing to be bound by theory. The present disclosure includes such embodiments wherein a polymorph of vapendavir oxalate or hydrates or solvates thereof may convert to one or more different polymorphs of vapendavir oxalate or hydrates or solvates thereof.Attorney Docket No. 433899-001802

[0181] In some embodiments, the oxalate salt is an amorphous form. In some embodiments, the oxalate salt is a partially crystalline form, such that the oxalate salt includes a mix of crystalline and amorphous vapendavir oxalate.

[0182] In some embodiments, the oxalate salt is anhydrous. In some embodiments, the oxalate salt is non-solvated, such that the oxalate salt is not a solvate. In some embodiments, the oxalate salt is a solvate, wherein the solvent included in the solvate is not particularly limited. The oxalate salt can, in some embodiments, be simultaneously solvated and anhydrous, wherein the solvent is not water.

[0183] In some embodiments, the vapendavir oxalate is in a stable form, such that it does not appreciably chemically decompose in ambient conditions.

[0184] In some embodiments, the vapendavir oxalate is in a crystalline form which has an X-ray powder diffraction (XRPD) pattern which includes peaks at diffraction angles of about 4°, about 5°, about 11°, about 14°, about 19°, about 20°, about 21°, and about 22° (29 ± 0.2°). For example, in some embodiments, the vapendavir oxalate is in a crystalline form which has an X-ray powder diffraction (XRPD) pattern which exhibits peaks at diffraction angles of 3.8°, 5.2°, 9.5°, 10.9°, 13.9°, 19.0°, 19.8°, 20.9°, and 22.5° (29 ± 0.2°). FIG. 13 is an XRPD diffractogram of a crystalline form of vapendavir oxalate. TABLE 7 is a peak table of the XRPD diffractogram shown in FIG. 13 with normalized intensities.

[0185] TABLE 7Attorney Docket No. 433899-001802

[0186] In some embodiments, the vapendavir oxalate is in the form of a mixture of crystalline forms. The vapendavir oxalate may be in the form of a mixture of any of the crystalline forms described herein in any combination or ratio. In some embodiments, the vapendavir oxalate is in the form of a mixture of a crystalline form or forms as described herein along with a crystalline form which is not observed separately.

[0187] FIG. 14 is an image of crystals of vapendavir oxalate, according to an embodiment the present disclosure.

[0188] The solubility of a compound in simulated gastric and intestinal fluid solutions may, in some embodiments, be useful in determining how the compound will dissolve when administered to a patient, without wishing to be bound by theory. In some embodiments,Attorney Docket No. 433899-001802 vapendavir maleate exhibits higher solubility in various solvents, including but not limited to Fed State Simulated Intestinal Fluid (FeSSIF), Fasted State Simulated Intestinal Fluid (FaSSIF), Fasted State Simulated Gastric Fluid (FaSSGF), or combinations thereof, than vapendavir in a free base form.

[0189] It is contemplated that the vapendavir oxalate may exhibit some solubility in various solvents and solvent combinations, including but not limited to methanol, isopropyl alcohol, tetrahydrofuran, water, or combinations thereof.

[0190] In some embodiments, a method of preparing vapendavir oxalate can include dissolving vapendavir, in a free base form, in a solvent such as tetrahydrofuran, water, or combinations thereof, and adding an oxalate-containing compound such as oxalic acid. Other methods of preparing vapendavir oxalate may also be acceptable.

[0191] In some embodiments, the chemical purity of the vapendavir oxalate may be determined by an analytical method, including but not limited to high performance liquid chromatography (HPLC). In some embodiments, the vapendavir oxalate has a chemical purity of greater than or equal to about 95% by mass, such as about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, or any value contained within a range formed by any two of the preceding values. In some embodiments, the vapendavir oxalate contains less than or equal to about 5% by mass of chemical impurities. The identity of the chemical impurities which may be included is not limited. Chemical impurities may be identified and quantified by any method or technique available to those skilled in the art.

[0192] Vapendavir Maleate

[0193] In some embodiments, there is provided a maleate salt of a compound of Formula I:Attorney Docket No. 433899-001802Formula I

[0194] The maleate salt of vapendavir (also referred to herein as vapendavir maleate) may have a molecular weight of about 496 g / mol. In some embodiments, the vapendavir maleate has a stoichiometry of 1 : 1 between the vapendavir and the maleate counterion.

[0195] In some embodiments, the maleate salt is in a crystalline form. The present disclosure encompasses the maleate salt of vapendavir and hydrates and solvates of vapendavir maleate. Polymorphs of each of vapendavir maleate, hydrated vapendavir maleate, and solvated vapendavir maleate are also contemplated and within the scope of this disclosure. It is contemplated that polymorphs of vapendavir maleate may convert to other polymorphs under certain physical conditions, without wishing to be bound by theory. The present disclosure includes such embodiments wherein a polymorph of vapendavir maleate or hydrates or solvates thereof may convert to one or more different polymorphs of vapendavir maleate or hydrates or solvates thereof.

[0196] In some embodiments, the maleate salt is an amorphous form. In some embodiments, the maleate salt is a partially crystalline form, such that the maleate salt includes a mix of crystalline and amorphous vapendavir maleate.

[0197] In some embodiments, the maleate salt is anhydrous. In some embodiments, the maleate salt is non-solvated, such that the maleate salt is not a solvate. In some embodiments, the maleate salt is a solvate, wherein the solvent included in the solvate is not particularly limited. The maleate salt can, in some embodiments, be simultaneously solvated and anhydrous, wherein the solvent is not water.

[0198] In some embodiments, the vapendavir maleate is in a stable form, such that it does not appreciably chemically decompose in ambient conditions.

[0199] In some embodiments, the vapendavir maleate is in a crystalline form which has an X-ray powder diffraction (XRPD) pattern which includes peaks at diffraction angles ofAttorney Docket No. 433899-001802 about 3.5°, about 7°, about 14°, about 16°, about 21°, about 24°, about 25°, and about 28° (29 ± 0.2°). For example, in some embodiments, the vapendavir maleate is in a crystalline form which has an X-ray powder diffraction (XRPD) pattern which exhibits peaks at diffraction angles of 3.5°, 7.0°, 14.0°, 16.4°, 20.7°, 24.0°, 24.8°, and 28.1° (29 ± 9.2°). FIG. 15 is an XRPD diffractogram of a crystalline form of vapendavir maleate. TABLE 8 is a peak table of the XRPD diffractogram shown in FIG. 15 with normalized intensities.

[0200] TABLE 8

[0201] In some embodiments, the vapendavir maleate is in the form of a mixture of crystalline forms. The vapendavir maleate may be in the form of a mixture of any of theAttorney Docket No. 433899-001802 crystalline forms described herein in any combination or ratio. In some embodiments, the vapendavir maleate is in the form of a mixture of a crystalline form or forms as described herein along with a crystalline form which is not observed separately.

[0202] In some embodiments, vapendavir maleate exhibits a thermal transition at a temperature of less than about 100 °C, such as about 90 °C, by differential scanning calorimetry (DSC). In some embodiments, the thermal transition may be a melting point, or in some embodiments the thermal transition may represent another thermal event. The melting point of vapendavir maleate may be determined by any method known to those skilled in the art, including DSC, as shown in FIG. 16. FIG. 16 shows the DSC for vapendavir maleate.

[0203] The solubility of a compound in simulated gastric and intestinal fluid solutions may, in some embodiments, be useful in determining how the compound will dissolve when administered to a patient, without wishing to be bound by theory. In some embodiments, vapendavir maleate exhibits higher solubility in various solvents, including but not limited to Fed State Simulated Intestinal Fluid (FeSSIF), Fasted State Simulated Intestinal Fluid (FaSSIF), Fasted State Simulated Gastric Fluid (FaSSGF), or combinations thereof, than vapendavir in a free base form.

[0204] It is contemplated that the vapendavir maleate may exhibit some solubility in various solvents and solvent combinations, including but not limited to methanol, isopropyl alcohol, tetrahydrofuran, water, or combinations thereof.

[0205] In some embodiments, a method of preparing vapendavir maleate can include dissolving vapendavir, in a free base form, in a solvent such as tetrahydrofuran, water, or combinations thereof, and adding a maleate-containing compound such as maleic acid. Other methods of preparing vapendavir maleate may also be acceptable.

[0206] In some embodiments, the chemical purity of the vapendavir maleate may be determined by an analytical method, including but not limited to high performance liquid chromatography (HPLC). In some embodiments, the vapendavir maleate has a chemical purity of greater than or equal to about 95% by mass, such as about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, or any value contained within a range formed by any two of the preceding values. In some embodiments, the vapendavir maleate contains less than or equal to about 5% by mass of chemical impurities. The identity of the chemical impuritiesAttorney Docket No. 433899-001802 which may be included is not limited. Chemical impurities may be identified and quantified by any method or technique available to those skilled in the art.

[0207] Vapendavir Tartrate

[0208] In some embodiments, there is provided a tartrate salt of a compound of FormulaFormula I

[0209] The tartrate salt of vapendavir (also referred to herein as vapendavir tartrate) may have a molecular weight of about 530 g / mol. In some embodiments, the vapendavir tartrate has a stoichiometry of 1 : 1 between the vapendavir and the tartrate counterion.

[0210] In some embodiments, the tartrate salt is in a crystalline form. The present disclosure encompasses the tartrate salt of vapendavir and hydrates and solvates of vapendavir tartrate. Polymorphs of each of vapendavir tartrate, hydrated vapendavir tartrate, and solvated vapendavir tartrate are also contemplated and within the scope of this disclosure. It is contemplated that polymorphs of vapendavir tartrate may convert to other polymorphs under certain physical conditions, without wishing to be bound by theory. The present disclosure includes such embodiments wherein a polymorph of vapendavir tartrate or hydrates or solvates thereof may convert to one or more different polymorphs of vapendavir tartrate or hydrates or solvates thereof.

[0211] In some embodiments, the tartrate salt is an amorphous form. In some embodiments, the tartrate salt is a partially crystalline form, such that the tartrate salt includes a mix of crystalline and amorphous vapendavir tartrate.

[0212] In some embodiments, the tartrate salt is anhydrous. In some embodiments, the tartrate salt is non-solvated, such that the tartrate salt is not a solvate. In some embodiments, the tartrate salt is a solvate, wherein the solvent included in the solvate is not particularlyAttorney Docket No. 433899-001802 limited. The tartrate salt can, in some embodiments, be simultaneously solvated and anhydrous, wherein the solvent is not water.

[0213] In some embodiments, the vapendavir tartrate is non-hygroscopic. In some embodiments, the vapendavir tartrate is in a stable form, such that it does not appreciably chemically decompose in ambient conditions.

[0214] In some embodiments, the vapendavir tartrate is in a crystalline form which has an X-ray powder diffraction (XRPD) pattern which includes peaks at diffraction angles of about 4.5°, about 9°, about 13°, about 13.5°, about 17°, about 21.5°, about 22.5°, and about 28° (29 ± 0.2°). For example, in some embodiments, the vapendavir tartrate is in a crystalline form which has an X-ray powder diffraction (XRPD) pattern which exhibits peaks at diffraction angles of 4.4°, 8.7°, 13.0°, 13.3°, 17.3°, 21.7°, 22.5°, and 28.1° (29 ± 0.2°). FIG. 17 is an XRPD diffractogram of a crystalline form of vapendavir tartrate, according to an embodiment of the present disclosure. TABLE 9 is a peak table of the XRPD diffractogram shown in FIG. 17 with normalized intensities.

[0215] TABLE 9Attorney Docket No. 433899-001802

[0216] In some embodiments, the vapendavir tartrate is in the form of a mixture of crystalline forms. The vapendavir tartrate may be in the form of a mixture of any of the crystalline forms described herein in any combination or ratio. In some embodiments, the vapendavir tartrate is in the form of a mixture of a crystalline form or forms as described herein along with a crystalline form which is not observed separately.

[0217] In some embodiments, the tartrate salt of vapendavir has a melting point of about 130 °C to about 170 °C. For example, in some embodiments, the vapendavir tartrate has a melting point of about 130 °C, about 135 °C, about 140 °C, about 145 °C, about 150 °C, about 155 °C, about 160 °C, about 165 °C, about 170 °C, or any value contained within a range formed by any two of the preceding values. In some embodiments, the vapendavir tartrate has a melting point of about 153 °C. Those of ordinary skill in the art will be familiar with methods and instruments for determining melting point, and any such method may be used, including but not limited to differential scanning calorimetry (DSC). When determining melting point by DSC, it will be understood that melting point refers to the peak observed via DSC, and that the onset of melting may be at a lower temperature, without wishing to be bound by theory. FIG. 28 shows the DSC of vapendavir tartrate, according to an embodiment the present disclosure.

[0218] The solubility of a compound in simulated gastric and intestinal fluid solutions may, in some embodiments, be useful in determining how the compound will dissolve when administered to a patient, without wishing to be bound by theory. In some embodiments, the tartrate salt of vapendavir has a solubility of about 0.02 mg / mL to about 0.1 mg / mL in a Fed State Simulated Intestinal Fluid (FeSSIF) solution, which has a pH of about 4.95. For example, in a FeSSIF solution or a solution having an equivalent pH, the vapendavir tartrate may have a solubility of about 0.02 mg / mL, about 0.03 mg / mL, about 0.04 mg / mL, about 0.05 mg / mL, about 0.06 mg / mL, about 0.07 mg / mL, about 0.08 mg / mL, about 0.09 mg / mL, about 0.1Attorney Docket No. 433899-001802 mg / mL, or any value contained within a range formed by any two of the preceding values. In some embodiments, vapendavir tartrate exhibits higher solubility in a FeSSIF solution than vapendavir in a free base form.

[0219] In some embodiments, the tartrate salt of vapendavir has a solubility of about 0.1 mg / mL to about 1.5 mg / mL in a Fasted State Simulated Intestinal Fluid (FaSSIF) solution, which has a pH of about 6.50. For example, in a FaSSIF solution or a solution having an equivalent pH, the vapendavir tartrate may have a solubility of about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1.0 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about 1.5 mg / mL, or any value contained within a range formed by any two of the preceding values. In some embodiments, vapendavir tartrate exhibits higher solubility in a FaSSIF solution than vapendavir in a free base form.

[0220] In some embodiments, the tartrate salt of vapendavir has a solubility of about 1.0 mg / mL to about 2.0 mg / mL in a Fasted State Simulated Gastric Fluid (FaSSGF) solution, which has a pH of about 1.61. For example, in a FaSSGF solution or a solution having an equivalent pH, the vapendavir tartrate may have a solubility of about 1.0 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, 1.5 mg / mL, about 1.6 mg / mL, about 1.7 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, about 2.0 mg / mL, or any value contained within a range formed by any two of the preceding values. In some embodiments, vapendavir tartrate exhibits higher solubility in a FaSSGF solution than vapendavir in a free base form.

[0221] In some embodiments, the tartrate salt of vapendavir has a solubility of about 0.5 mg / mL to about 1.5 mg / mL in a phosphate buffer having a pH of about 7.4. For example, in a solution having a pH of about 7.5, the vapendavir tartrate may have a solubility of about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1.0 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about 1.5 mg / mL, or any value contained within a range formed by any two of the preceding values. In some embodiments, vapendavir tartrate exhibits higher solubility in a phosphate buffer solution than vapendavir in a free base form.

[0222] It is contemplated that the vapendavir tartrate may exhibit some solubility in various solvents and solvent combinations, including but not limited to methanol, isopropylAttorney Docket No. 433899-001802 alcohol, acetone, tetrahydrofuran, water, or combinations thereof. For example, the vapendavir tartrate may exhibit a solubility of greater than about 9 mg / mL in methanol at 25 °C, a solubility of greater than about 9 mg / mL in tetrahydrofuran at 25 °C, a solubility of greater than about 10 mg / mL in a mixture of isopropyl alcohol and water at 25 °C, and a solubility of greater than about 25 mg / mL in a mixture of tetrahydrofuran and water at 25 °C.

[0223] In some embodiments, a method of preparing vapendavir tartrate can include dissolving vapendavir, in a free base form, in a solvent such as tetrahydrofuran and adding a tartrate-containing compound, such as tartaric acid. Other methods of preparing vapendavir tartrate may also be acceptable.

[0224] In some embodiments, the chemical purity of the vapendavir tartrate may be determined by an analytical method, including but not limited to high performance liquid chromatography (HPLC). In some embodiments, the vapendavir tartrate has a chemical purity of greater than or equal to about 95% by mass, such as about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, or any value contained within a range formed by any two of the preceding values. In some embodiments, the vapendavir tartrate contains less than or equal to about 5% by mass of chemical impurities. The identity of the chemical impurities which may be included is not limited. Chemical impurities may be identified and quantified by any method or technique available to those skilled in the art.

[0225] Vapendavir Mesylate

[0226] In some embodiments, there is provided a mesylate salt of a compound of Formula I:Formula I.

[0227] The mesylate salt of vapendavir (also referred to herein as vapendavir methanesulfonate or vapendavir mesylate) may have a molecular weight of about 477 g / mol.Attorney Docket No. 433899-001802

[0228] In some embodiments, the stoichiometry of the vapendavir mesylate may be about one equivalent of methanesulfonic acid per equivalent of vapendavir. In some embodiments, the stoichiometry of the vapendavir mesylate may be about 0.5 equivalents of methanesulfonic acid per equivalent of vapendavir. In some embodiments, the stoichiometry of the vapendavir mesylate may be about two equivalents of methanesulfonic acid per equivalent of vapendavir.

[0229] In some embodiments, the vapendavir mesylate is in a crystalline form. The present disclosure encompasses the mesylate salt of vapendavir and hydrates and solvates of vapendavir mesylate. Polymorphs of each of vapendavir mesylate, hydrated vapendavir mesylate, and solvated vapendavir mesylate are also contemplated and within the scope of this disclosure. It is contemplated that polymorphs of vapendavir mesylate may convert to other polymorphs under certain physical conditions, without wishing to be bound by theory. The present disclosure includes such embodiments wherein a polymorph of vapendavir mesylate or hydrates or solvates thereof may convert to one or more different polymorphs of vapendavir mesylate or hydrates or solvates thereof.

[0230] In some embodiments, the mesylate salt is an amorphous form. In some embodiments, the mesylate salt is a partially crystalline form, such that the mesylate salt includes a mix of crystalline and amorphous vapendavir mesylate.

[0231] In some embodiments, the mesylate salt is anhydrous. In some embodiments, the mesylate salt is non-solvated, such that the mesylate salt is not a solvate.

[0232] In some embodiments, the mesylate salt is a solvate, wherein the solvent included in the solvate is not particularly limited. Solvents included in a solvate form of vapendavir mesylate may include, but are not limited to, organic solvents such as methanol, ethanol, butanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran, and the like. The mesylate salt can, in some embodiments, be simultaneously solvated and anhydrous, wherein the solvent is not water.

[0233] In some embodiments, the vapendavir mesylate is hygroscopic. In some embodiments, the vapendavir mesylate is non-hygroscopic. In some embodiments, the vapendavir mesylate is in a stable form, such that it does not appreciably chemically decompose in ambient conditions.Attorney Docket No. 433899-001802

[0234] In some embodiments, the vapendavir mesylate is in a crystalline form. In some embodiments, the vapendavir mesylate is in a crystalline form referred to herein as Crystalline Form 1. FIG. 19 is an XRPD diffractogram of Crystalline Form 1 of vapendavir mesylate obtained from a slurry in methanol, according to embodiments of the present disclosure. Crystalline Form 1 may, in some embodiments, have an X-ray powder diffraction (XRPD) pattern which exhibits peaks at diffraction angles of about 6.5°, about 10°, about 13°, about 16°, about 21°, and about 24° (29 ± 0.2°). In some embodiments, Crystalline Form 1 exhibits peaks shown in TABLE 10. Other solvents and crystallization conditions may result in Crystalline Form 1 as shown in FIG. 19 and as described in TABLE 10.

[0235] TABLE 10Attorney Docket No. 433899-001802

[0236] FIG. 20 is an XRPD diffractogram of Crystalline Form 1 of vapendavir mesylate obtained from a slurry in acetonitrile, according to embodiments of the present disclosure. In some embodiments, Crystalline Form 1 exhibits peaks shown in TABLE 11. Other solvents and crystallization conditions may result in Crystalline Form 1 as shown in FIG. 20 and as described in TABLE 11.

[0237] TABLE 11Attorney Docket No. 433899-001802Attorney Docket No. 433899-001802

[0238] In some embodiments, the vapendavir mesylate is in a crystalline form referred to herein as Crystalline Form 2. FIG. 21 is an XRPD diffractogram of Crystalline Form 2 of vapendavir mesylate obtained from a slurry in acetone, according to embodiments of the present disclosure. High performance liquid chromatography (HPLC) with a charged aerosol detector (CAD) displayed the presence of methanesulfonic acid in a sample of Crystalline Form 2 from acetone. It is contemplated that other crystalline forms, or samples from other solvents or conditions, may exhibit different stoichiometry and content of methanesulfonic acid.

[0239] Crystalline Form 2 may, in some embodiments, have an X-ray powder diffraction (XRPD) pattern which exhibits peaks at diffraction angles of about 6.5°, about 13°, about 14°, about 17.5°, about 18°, about 21°, about 22°, and about 23° (29 ± 0.2°). In some embodiments, Crystalline Form 2 exhibits peaks shown in TABLE 12.

[0240] TABLE 12Attorney Docket No. 433899-001802

[0241] FIG. 22 is an XRPD diffractogram of Crystalline Form 2 of vapendavir mesylate obtained from a slurry in tetrahydrofuran, according to embodiments of the present disclosure. Crystalline Form 2 may, in some embodiments, have an X-ray powder diffraction (XRPD) pattern which exhibits peaks at diffraction angles of about 6.5°, about 13°, about 14°, about 17.5°, about 18°, about 21°, about 22°, and about 23° (29 ± 0.2°). In some embodiments, Crystalline Form 2 exhibits peaks shown in TABLE 13.

[0242] TABLE 13Attorney Docket No. 433899-001802

[0243] In some embodiments, the vapendavir mesylate is in the form of a mixture of crystalline forms. The vapendavir mesylate may be in the form of a mixture of any of theAttorney Docket No. 433899-001802 crystalline forms described herein in any combination or ratio. In some embodiments, the vapendavir mesylate is in the form of a mixture of a crystalline form or forms as described herein along with a crystalline form which is not observed separately.

[0244] In some embodiments, the mesylate salt of vapendavir has a melting point of about 50 °C to about 220 °C. For example, in some embodiments, the vapendavir mesylate has a melting point of about 50 °C, about 60 °C, about 70 °C, about 80 °C, about 90 °C, about 100 °C, about 110 °C, about 120 °C, about 130 °C, about 135 °C, about 140 °C, about 145 °C, about 150 °C, about 155 °C, about 160 °C, about 165 °C, about 170 °C, about 175 °C, about 180 °C, about 185 °C, about 190 °C, about 195 °C, about 200 °C, about 205 °C, about 210 °C, about 215 °C, about 220 °C, or any value contained within a range formed by any two of the preceding values. Those of ordinary skill in the art will be familiar with methods and instruments for determining melting point, and any such method may be used, including but not limited to differential scanning calorimetry (DSC). Those skilled in the art will also be familiar with the use of analytical methods including thermogravimetric analysis (TGA) to further evaluate the thermal properties of a compound. When determining melting point by DSC, it will be understood that melting point refers to the peak observed via DSC, and that the onset of melting may be at a lower temperature, without wishing to be bound by theory.

[0245] FIG. 23 is a DSC / TGA trace of Crystalline Form 2 of vapendavir mesylate, according to embodiments of the present disclosure. As shown in FIG. 23, Crystalline Form 2 exhibits two endothermic transitions at about 60 °C and about 130 °C by differential scanning calorimetry (DSC). As further shown in FIG. 23, Crystalline Form 2 exhibits a mass loss of about 4.5% by thermogravimetric analysis (TGA). It will be understood that different crystalline forms, or mixtures of crystalline forms, of vapendavir mesylate may exhibit different thermal properties.

[0246] In some embodiments, the vapendavir mesylate may be a hydrate. In some embodiments, the vapendavir mesylate may be a dihydrate. Dynamic vapor sorption (DVS) may be used to evaluate vapendavir mesylate in relation to changes in humidity. FIG. 24 is a DVS isotherm plot of Crystalline Form 2 of vapendavir mesylate, according to embodiments of the present disclosure. As shown in FIG. 24, a reversible mass change of approximately 5.7% is observed between 0% relative humidity (RH) and 30% RH, and a 6.6% mass change is observed at 80%. It was noted that deliquescence was observed beyond 80% RH. The data in FIG. 24 supports that Crystalline Form 2 of vapendavir mesylate may exist as a hydrate.Attorney Docket No. 433899-001802

[0247] In some embodiments, the vapendavir mesylate has a water content of about 0.1% to about 6.5%, such as about 0.1%, about 0.5%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, about 5.0%, about 5.5%, about 6.0%, about 6.5%, or any value contained within a range formed by any two of the preceding values.

[0248] The solubility of vapendavir mesylate may be evaluated in various organic solvents. In some embodiments, the vapendavir mesylate has a solubility of less than about 3.0 mg / mL in toluene. In some embodiments, the vapendavir mesylate has a solubility between about 20.0 mg / mL and about 50 mg / mL in methyl ethyl ketone. In some embodiments, the vapendavir mesylate has a solubility of less than about 3.0 mg / mL in ethyl acetate. In some embodiments, the vapendavir mesylate has a solubility of greater than about 50.0 mg / mL in dichloromethane. In some embodiments, the vapendavir mesylate has a solubility of greater than about 45.0 mg / mL in chloroform. In some embodiments, the vapendavir mesylate has a solubility of greater than about 50.0 mg / mL in methanol. In some embodiments, the vapendavir mesylate has a solubility between about 25 mg / mL and about 50 mg / mL in acetone. In some embodiments, the vapendavir mesylate has a solubility of greater than about 45.0 mg / mL in acetonitrile. In some embodiments, the vapendavir mesylate has a solubility of greater than about 45.0 mg / mL in dimethylsulfoxide. In some embodiments, the vapendavir mesylate has a solubility of less than about 3.0 mg / mL in water.

[0249] The solubility of a compound in simulated gastric and intestinal fluid solutions may, in some embodiments, be useful in determining how the compound will dissolve when administered to a patient, without wishing to be bound by theory. It is contemplated that different crystalline forms of vapendavir mesylate may exhibit different solubilities in various solvents and simulated fluids. In some embodiments, a change in crystalline form was observed in the vapendavir mesylate after evaluation of solubility in simulated gastric and intestinal fluid solutions. For example, after evaluation of solubility in simulated gastric and intestinal fluid solutions, the solution may be removed and residual solids evaluated, and in some embodiments, the vapendavir mesylate is in a different crystalline form than the crystalline form initially used in the solubility studies.

[0250] In some embodiments, the mesylate salt of vapendavir has a solubility of about 0.5 mg / mL to about 6.0 mg / mL in a Fed State Simulated Intestinal Fluid (FeSSIF) solution, which has a pH of about 4.95. For example, in a FeSSIF solution or a solution having an equivalent pH, the vapendavir mesylate may have a solubility of about 0.5 mg / mL, about 0.6 mg / mL,Attorney Docket No. 433899-001802 about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1.0 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about 1.5 mg / mL, about 1.6 mg / mL, about 1.7 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, about 2.0 mg / mL, about 2.1 mg / mL, about 2.2 mg / mL, about 2.3 mg / mL, about 2.4 mg / mL, about 2.5 mg / mL, about 2.6 mg / mL, about 2.7 mg / mL, about 2.8 mg / mL, about 2.9 mg / mL, about 3.0 mg / mL, about 3.1 mg / mL, about 3.2 mg / mL, about 3.3 mg / mL, about 3.4 mg / mL, about 3.5 mg / mL, about 3.6 mg / mL, about 3.7 mg / mL, about 3.8 mg / mL, about 3.9 mg / mL, about 4.0 mg / mL, about 4.1 mg / mL, about 4.2 mg / mL, about 4.3 mg / mL, about 4.4 mg / mL, about 4.5 mg / mL, about 4.6 mg / mL, about 4.7 mg / mL, about 4.8 mg / mL, about 4.9 mg / mL, about 5.0 mg / mL, about 5.5 mg / mL, about 6.0 mg / mL, or any value contained within a range formed by any two of the preceding values. In some embodiments, vapendavir mesylate exhibits higher solubility in a FeSSIF solution than vapendavir in a free base form.

[0251] In some embodiments, the mesylate salt of vapendavir has a solubility of about 0.5 mg / mL to about 5.0 mg / mL in a Fasted State Simulated Intestinal Fluid (FaSSIF) solution, which has a pH of about 6.50. For example, in a FaSSIF solution or a solution having an equivalent pH, the vapendavir mesylate may have a solubility of about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1.0 mg / mL, about1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about 1.5 mg / mL, about1.6 mg / mL, about 1.7 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, about 2.0 mg / mL, about2.1 mg / mL, about 2.2 mg / mL, about 2.3 mg / mL, about 2.4 mg / mL, about 2.5 mg / mL, about2.6 mg / mL, about 2.7 mg / mL, about 2.8 mg / mL, about 2.9 mg / mL, about 3.0 mg / mL, about3.1 mg / mL, about 3.2 mg / mL, about 3.3 mg / mL, about 3.4 mg / mL, about 3.5 mg / mL, about3.6 mg / mL, about 3.7 mg / mL, about 3.8 mg / mL, about 3.9 mg / mL, about 4.0 mg / mL, about4.1 mg / mL, about 4.2 mg / mL, about 4.3 mg / mL, about 4.4 mg / mL, about 4.5 mg / mL, about4.6 mg / mL, about 4.7 mg / mL, about 4.8 mg / mL, about 4.9 mg / mL, about 5.0 mg / mL, or any value contained within a range formed by any two of the preceding values. In some embodiments, vapendavir mesylate exhibits higher solubility in a FaSSIF solution than vapendavir in a free base form.

[0252] In some embodiments, the mesylate salt of vapendavir has a solubility of about 0.5 mg / mL to about 5.0 mg / mL in a Fasted State Simulated Gastric Fluid (FaSSGF) solution, which has a pH of about 1.61. For example, in a FaSSGF solution or a solution having an equivalent pH, the vapendavir mesylate may have a solubility of about 0.5 mg / mL, about 0.6Attorney Docket No. 433899-001802 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1.0 mg / mL, about1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about 1.5 mg / mL, about1.6 mg / mL, about 1.7 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, about 2.0 mg / mL, about2.1 mg / mL, about 2.2 mg / mL, about 2.3 mg / mL, about 2.4 mg / mL, about 2.5 mg / mL, about2.6 mg / mL, about 2.7 mg / mL, about 2.8 mg / mL, about 2.9 mg / mL, about 3.0 mg / mL, about3.1 mg / mL, about 3.2 mg / mL, about 3.3 mg / mL, about 3.4 mg / mL, about 3.5 mg / mL, about3.6 mg / mL, about 3.7 mg / mL, about 3.8 mg / mL, about 3.9 mg / mL, about 4.0 mg / mL, about4.1 mg / mL, about 4.2 mg / mL, about 4.3 mg / mL, about 4.4 mg / mL, about 4.5 mg / mL, about4.6 mg / mL, about 4.7 mg / mL, about 4.8 mg / mL, about 4.9 mg / mL, about 5.0 mg / mL, or any value contained within a range formed by any two of the preceding values. In some embodiments, vapendavir mesylate exhibits higher solubility in a FaSSGF solution than vapendavir in a free base form.

[0253] In some embodiments, the mesylate salt of vapendavir has a solubility of about 0.5 mg / mL to about 5.0 mg / mL in a phosphate buffer having a pH of about 7.4. For example, in a solution having a pH of about 7.5, the vapendavir mesylate may have a solubility of about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about1.0 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about1.5 mg / mL, about 1.6 mg / mL, about 1.7 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, about2.0 mg / mL, about 2.1 mg / mL, about 2.2 mg / mL, about 2.3 mg / mL, about 2.4 mg / mL, about2.5 mg / mL, about 2.6 mg / mL, about 2.7 mg / mL, about 2.8 mg / mL, about 2.9 mg / mL, about3.0 mg / mL, about 3.1 mg / mL, about 3.2 mg / mL, about 3.3 mg / mL, about 3.4 mg / mL, about3.5 mg / mL, about 3.6 mg / mL, about 3.7 mg / mL, about 3.8 mg / mL, about 3.9 mg / mL, about4.0 mg / mL, about 4.1 mg / mL, about 4.2 mg / mL, about 4.3 mg / mL, about 4.4 mg / mL, about4.5 mg / mL, about 4.6 mg / mL, about 4.7 mg / mL, about 4.8 mg / mL, about 4.9 mg / mL, about5.0 mg / mL, or any value contained within a range formed by any two of the preceding values. In some embodiments, vapendavir mesylate exhibits higher solubility in a phosphate buffer solution than vapendavir in a free base form.

[0254] It is contemplated that the vapendavir mesylate may exhibit some solubility in various solvents and solvent combinations, including but not limited to methanol, ethanol, isopropyl alcohol, tetrahydrofuran, acetone, water, or combinations thereof.

[0255] In some embodiments, a method of preparing vapendavir mesylate can include dissolving vapendavir, in a free base form, in a solvent such as tetrahydrofuran and adding aAttorney Docket No. 433899-001802 mesylate-containing compound, such as methane sulfonic acid. Other methods of preparing vapendavir mesylate may also be acceptable.

[0256] In some embodiments, the chemical purity of the vapendavir mesylate may be determined by an analytical method, including but not limited to high performance liquid chromatography (HPLC). In some embodiments, the vapendavir mesylate has a chemical purity of greater than or equal to about 95% by mass, such as about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, or any value contained within a range formed by any two of the preceding values. In some embodiments, the vapendavir mesylate contains less than or equal to about 5% by mass of chemical impurities. The identity or identities of the chemical impurities which may be included is not limited. Chemical impurities may be identified and quantified by any method or technique available to those skilled in the art. Chemical impurities may be identified, reduced, or removed by methods available and familiar to those skilled in the art.

[0257] There is provided, in some embodiments, a pharmaceutical composition which includes a therapeutically effective amount of vapendavir mesylate as described herein. The vapendavir mesylate which is included in the pharmaceutical composition may be in a crystalline form, an amorphous form, or combinations thereof. The vapendavir mesylate which is included in the pharmaceutical composition may be in any of the crystalline forms or combinations thereof as disclosed herein. In some embodiments, the pharmaceutical composition includes vapendavir mesylate in Crystalline Form 1, wherein the vapendavir mesylate has an X-ray powder diffraction (XRPD) pattern which exhibits peaks at diffraction angles of about 6°, about 10°, about 13°, about 16°, and about 21° (29 ± 0.2°).

[0258] In some embodiments, the pharmaceutical composition includes vapendavir mesylate in Crystalline Form 2, wherein the vapendavir mesylate has an X-ray powder diffraction (XRPD) pattern which exhibits peaks at diffraction angles of about 6°, about 11.5°, about 14°, about 17.5°, about 22°, and about 23° (29 ± 0.2°).

[0259] Amorphous Vapendavir

[0260] In some embodiments, there is provided an amorphous form of a compound of Formula I:Attorney Docket No. 433899-001802Formula I

[0261] The amorphous form of vapendavir (also referred to herein as amorphous vapendavir) may have a molecular weight of about 382.5 g / mol.

[0262] The present disclosure encompasses the amorphous form of vapendavir free base, as well as salts, hydrates, and solvates of vapendavir which are in an amorphous form. The present disclosure includes such embodiments wherein a crystalline form of vapendavir or hydrates or solvates thereof may convert to amorphous vapendavir or hydrates or solvates thereof.

[0263] In some embodiments, the amorphous vapendavir does not include any crystalline vapendavir. In some embodiments, the amorphous form is a partially crystalline form, such that the vapendavir includes a mix of crystalline and amorphous vapendavir. For example, in some embodiments, the amorphous vapendavir may include at most about 20% by mass crystalline vapendavir, at most about 10% by mass crystalline vapendavir, at most about 5% by mass crystalline vapendavir, at most about 1% by mass crystalline vapendavir, or any value contained within a range formed by any two of the preceding values. The degree of crystallinity or amorphous content in vapendavir may be measured by analytical methods familiar to those skilled in the art, including but not limited to X-ray powder diffraction (XRPD) and scanning electron microscopy (SEM).

[0264] In some embodiments, the amorphous form is anhydrous. In some embodiments, the amorphous form is non-solvated, such that the amorphous form is not a solvate. In some embodiments, the amorphous form is a solvate, wherein the solvent included in the solvate is not particularly limited. Solvents included in a solvate form of amorphous vapendavir may include, but are not limited to, organic solvents such as ethanol, methanol, 1 -butanol, acetone, ethyl acetate, and the like. The amorphous form can, in some embodiments, be simultaneously solvated and anhydrous, wherein the solvent is not water.Attorney Docket No. 433899-001802

[0265] In some embodiments, the amorphous vapendavir is hygroscopic. In some embodiments, the amorphous vapendavir is non-hygroscopic. In some embodiments, the amorphous vapendavir is in a stable form, such that it does not appreciably chemically decompose in ambient conditions.

[0266] In some embodiments, a spray-dried dispersion including amorphous vapendavir exhibits a glass transition (Tg) temperature of about 50 °C to about 110 °C, such as about 50 °C, about 55 °C, about 60 °C, about 65 °C, about 70 °C, about 75 °C, about 80 °C, about 85 °C, about 90 °C, about 95 °C, about 100 °C, about 105 °C, about 110 °C, or any value contained within a range formed by any two of the preceding values. The glass transition temperature may be influenced by the other components of the spray-dried dispersion. Those of ordinary skill in the art will be familiar with methods and instruments for determining thermal properties such as melting point and glass transition temperature, and any such method may be used, including but not limited to differential scanning calorimetry (DSC). Those skilled in the art will also be familiar with the use of analytical methods including thermogravimetric analysis (TGA) to further evaluate the thermal properties of a compound. When determining thermal properties by DSC, it will be understood that melting point refers to the peak observed via DSC, and that the onset of melting may be at a lower temperature, without wishing to be bound by theory.

[0267] In some embodiments, the amorphous vapendavir exhibits typical SDD morphology with little or no evidence of crystalline material, including surface crystals. In some embodiments, typical SDD morphology may include collapsed spheres.

[0268] The solubility of a compound in simulated gastric and intestinal fluid solutions may, in some embodiments, be useful in determining how the compound will dissolve when administered to a patient, without wishing to be bound by theory. For example, after evaluation of solubility in simulated gastric and intestinal fluid solutions, the solution may be removed and residual solids evaluated, and in some embodiments, the amorphous vapendavir may remain amorphous, or may crystallize into a crystalline form.

[0269] In some embodiments, the amorphous form of vapendavir has a solubility of about 25 pg / mL to about 100 pg / mL in a Fed State Simulated Intestinal Fluid (FeSSIF) solution, which has a pH of about 5.0. For example, in a FeSSIF solution or a solution having an equivalent pH, the amorphous vapendavir may have a solubility of about 25 pg / mL, about 30Attorney Docket No. 433899-001802 gg / mL, about 35 gg / mL, about 40 gg / mL, about 45 gg / mL, about 50 gg / mL, about 55 gg / mL, about 60 gg / mL, about 65 gg / mL, about 70 gg / mL, about 75 gg / mL, about 80 gg / mL, about 85 gg / mL, about 90 gg / mL, about 95 gg / mL, about 100 gg / mL, or any value contained within a range formed by any two of the preceding values.

[0270] In some embodiments, the amorphous form of vapendavir has a solubility of about 1 gg / mL to about 100 gg / mL in a Fasted State Simulated Intestinal Fluid (FaSSIF) solution, which has a pH of about 6.50. For example, in a FaSSIF solution or a solution having an equivalent pH, the amorphous vapendavir may have a solubility of about 1 gg / mL, about 10 gg / mL, about 20 gg / mL, about 30 gg / mL, about 40 gg / mL, about 50 gg / mL, about 60 gg / mL, about 70 gg / mL, about 80 gg / mL, about 90 gg / mL, about 100 gg / mL, or any value contained within a range formed by any two of the preceding values.

[0271] In some embodiments, the amorphous form of vapendavir has a solubility of about 100 gg / mL to about 2000 gg / mL in a Fasted State Simulated Gastric Fluid (FaSSGF) solution, which has a pH of about 1.61. For example, in a FaSSGF solution or a solution having an equivalent pH, the amorphous vapendavir may have a solubility of about 100 gg / mL, about 200 gg / mL, about 300 gg / mL, about 400 gg / mL, about 500 gg / mL, about 600 gg / mL, about 700 gg / mL, about 800 gg / mL, about 900 gg / mL, about 1000 gg / mL, about 1100 gg / mL, about 1200 gg / mL, about 1300 gg / mL, about 1400 gg / mL, about 1500 gg / mL, about 1600 gg / mL, about 1700 gg / mL, about 1800 gg / mL, about 1900 gg / mL, about 2000 gg / mL, or any value contained within a range formed by any two of the preceding values.

[0272] In some embodiments, the amorphous form of vapendavir has a solubility of about 1 gg / mL to about 1000 gg / mL in a gastric fluid solution which has a pH of about 4.5. For example, the amorphous vapendavir may have a solubility of about 1 gg / mL, about 100 gg / mL, about 200 gg / mL, about 300 gg / mL, about 400 gg / mL, about 500 gg / mL, about 600 gg / mL, about 700 gg / mL, about 800 gg / mL, about 900 gg / mL, about 1000 gg / mL, or any value contained within a range formed by any two of the preceding values.

[0273] In some embodiments, a method of preparing amorphous vapendavir can include preparing a spray-dried dispersion (SDD) with one or more additives and a solvent. For example, a spray dried dispersion may include about 15 wt. % to about 60 wt. % vapendavir, such as about 15 wt. %, about 20 wt. %, about 25 wt. %, about 30 wt. %, about 35 wt. %, about 40 wt. %, about 45 wt. %, 50 wt. %, 55 wt. %, 60 wt. %, or any value contained within a rangeAttorney Docket No. 433899-001802 formed by any two of the preceding values. Other methods of preparing amorphous vapendavir may also be acceptable.

[0274] In some embodiments, the SDD may further include one or more additives. The one or more additives may include a polymer, such as poly(methacrylic acid-co-ethyl acrylate) 1 : 1 (Eudragit LIOO), Soluplus, hydroxypropyl methylcellulose (HPMC), hypromellose acetate succinate (HPMCAS-M), HP-P-CD, or combinations thereof. In some embodiments, the polymer has a high glass transition temperature, which may aid in suppressing crystallization of the vapendavir.

[0275] In some embodiments, the one or more additives includes an acid, such as methane sulfonic acid (MSA), ethane sulfonic acid (ESA), camphor sulfonic acid (CSA), or combinations thereof. It is contemplated that including in the SDD an acid which is soluble in a suitable organic solvent and forms a poorly crystallizing or low melting point salt may aid in suppressing crystallization of the vapendavir. In some embodiments, the SDD includes vapendavir and a polymer, an acid, or a combination of a polymer and an acid.

[0276] In some embodiments, the chemical purity of the amorphous vapendavir may be determined by an analytical method, including but not limited to high performance liquid chromatography (HPLC). In some embodiments, the amorphous vapendavir has a chemical purity of greater than or equal to about 95% by mass, such as about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, or any value contained within a range formed by any two of the preceding values. In some embodiments, the amorphous vapendavir contains less than or equal to about 5% by mass of chemical impurities. The identity or identities of the chemical impurities which may be included is not limited. Chemical impurities may be identified and quantified by any method or technique available to those skilled in the art. Chemical impurities may be identified, reduced, or removed by methods available and familiar to those skilled in the art.

[0277] There is provided, in some embodiments, a pharmaceutical composition which includes a therapeutically effective amount of amorphous vapendavir as described herein. The amorphous vapendavir which is included in the pharmaceutical composition may be in a fully amorphous form or may be in a mixture of amorphous and crystalline forms. In some embodiments, the pharmaceutical composition is in a spray-dried dispersion form as described herein.Attorney Docket No. 433899-001802

[0278] Methods of Treating

[0279] In some embodiments, there is provided a method of treating a respiratory enterovirus infection in a human subject with COPD, with includes orally administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof, thereby treating the respiratory enterovirus infection in the subject. In some embodiments, the vapendavir is in the form of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof.

[0280] In some embodiments, there is provided a method of treating a respiratory condition, wherein the respiratory condition is a respiratory enterovirus infection, an upper respiratory infection, a common cold, or combinations thereof, in a human subject with COPD, with includes orally administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof, thereby treating the respiratory enterovirus infection in the subject; wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is between about 250 mg and about 2,000 mg per day

[0281] In some embodiments, the subject has a respiratory enterovirus infection. In some embodiments, the respiratory enterovirus infection is acute, and in other embodiments, the respiratory enterovirus infection is not acute. In some embodiments, the respiratory enterovirus is selected from a rhinovirus, echovirus, EV-68, EV-71, coxsackie virus, a non-polio enterovirus and combinations thereof. In some embodiments, the subject has an upper respiratory infection. In some embodiments, the subject has a common cold.

[0282] In some embodiments, there is provided a method of treating a patient in need thereof including administering to the patient a pharmaceutical composition, such as a solid oral composition, including: a therapeutically effective amount, such as about 250 mg to about 2000 mg, of vapendavir sulfate; and one or more pharmaceutically acceptable excipients, such as a diluent, a disintegrant, a surfactant, a lubricant, a color coating, or any combination thereof. In some embodiments, the patient has a respiratory condition as described herein.

[0283] In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is between about 250 mg and about 2,000 mg per day, such as about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500Attorney Docket No. 433899-001802 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1,000 mg, about 1,050 mg, about 1,100 mg, about 1,150 mg, about 1,200 mg, about 1,250 mg, about 1,300 mg, about 1,350 mg, about 1,400 mg, about 1,450 mg, about 1,500 mg, about 1,550 mg, about 1,600 mg, about 1,650 mg, about 1,700 mg, about 1,750 mg, about 1,800 mg, about 1,850 mg, about 1,900 mg, about 1,950 mg, about 2,000 mg, or any range or value contained within these values.

[0284] In some embodiments, therapeutically effective amount of vapendavir sulfate is a loading dose followed by one or more maintenance doses. In some embodiments, the loading dose of vapendavir sulfate can be about 600 mg to about 1500 mg, such as about 600 mg, about 675 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1125 mg, about 1150 mg, about 1175 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, or any value contained within a range formed by two of the preceding values. In some embodiments, the maintenance dose of vapendavir sulfate is about 250 mg to about 750 mg, such as about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, or any value contained within a range formed by two of the preceding values.

[0285] In some embodiments, the therapeutically effective amount of vapendavir sulfate is a loading dose of about 600 mg followed by one or more maintenance doses of about 250 mg. In some embodiments, the therapeutically effective amount of vapendavir sulfate is a loading dose of about 700 mg followed by one or more maintenance doses of about 350 mg. In some embodiments, the therapeutically effective amount of vapendavir sulfate is a loading dose of about 700 mg followed by one or more maintenance doses of about 500 mg. In some embodiments, the therapeutically effective amount of vapendavir sulfate is a loading dose of about 750 mg followed by one or more maintenance doses of about 500 mg. In some embodiments, the therapeutically effective amount of vapendavir sulfate is a loading dose of about 800 mg followed by one or more maintenance doses of about 300 mg. In someAttorney Docket No. 433899-001802 embodiments, the therapeutically effective amount of vapendavir sulfate is a loading dose of about 800 mg followed by one or more maintenance doses of about 400 mg. In some embodiments, the therapeutically effective amount of vapendavir sulfate is a loading dose of about 800 mg followed by one or more maintenance doses of about 500 mg. In some embodiments, the therapeutically effective amount of vapendavir sulfate is a loading dose of about 900 mg followed by one or more maintenance doses of about 500 mg. In some embodiments, the therapeutically effective amount of vapendavir sulfate is a loading dose of about 1000 mg followed by one or more maintenance doses of about 300 mg. In some embodiments, the therapeutically effective amount of vapendavir sulfate is a loading dose of about 1000 mg followed by one or more maintenance doses of about 500 mg.

[0286] In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is between about 1 mg / kg and about 75 mg / kg, relative to the body weight of the subject. For example, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is, in some embodiments, about 1 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, or any range or value contained therein. In some embodiment, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is about 14 mg / kg. In some embodiment, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is about 7 mg / kg. In some embodiment, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is about 3.5 mg / kg.

[0287] In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / mL. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 6000 ng / mL. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 4000 ng / mL. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 3000 to about 6000 ng / mL. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achievesAttomey Docket No. 433899-001802 a Cmax of about 6000 to about 8000 ng / mL. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 8000 to about 10000 ng / mL. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 10000 to about 12000 ng / mL.

[0288] In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 500 mg to about 1,000 mg, such as about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, or any value contained within a range formed by any two of the preceding values, followed by one or more maintenance doses, wherein the maintenance dose is smaller than the loading dose.

[0289] In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg about every 12 hours. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg about every 12 hours for about 4 to about 10 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg about every 12 hours for about 5 to about 8 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 6 to about 8 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 7 days.

[0290] In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 4 to about 10 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose ofAttorney Docket No. 433899-001802 about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 5 to about 8 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 6 to about 8 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 7 days.

[0291] In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 4 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 5 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 6 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 7 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 8 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1000 mg every 12 hours for one day followed by a maintenance dose of about 500 mg every 12 hours for about 9 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1000 mg followed by a maintenance dose of about 500 mg every 12 hours for 10 days.

[0292] In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1000 mg followed by a maintenance dose of about 500 mg about every 12 hours for about 4 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1000 mg followed by a maintenance dose of about 500 mg about every 12 hours for about 5 days. In some embodiments, theAttorney Docket No. 433899-001802 therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 6 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1000 mg followed by a maintenance dose of about 500 mg about every 12 hours for about 7 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1000 mg followed by a maintenance dose of about 500 mg about every 12 hours for about 8 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1000 mg per day followed by a maintenance dose of about 500 mg about every 12 hours for about 9 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1000 mg followed by a maintenance dose of about 500 mg about every 12 hours for 10 days.

[0293] In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg about every 12 hours for a total of about 13 maintenance doses. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg about every 12 hours for a total of 13 maintenance doses. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of 13 maintenance doses.

[0294] In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1000 mg followed by about 10 to about 15 maintenance doses as described herein, such as about 10, about 11, about 12, about 13, about 14, about 15 maintenance doses as described herein.

[0295] In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 14 mg / kg for one dayAttorney Docket No. 433899-001802 followed by a maintenance dose of about 7 mg / kg every 12 hours for about 4 to about 10 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 14 mg / kg for one day followed by a maintenance dose of about 7 mg / kg every 12 hours for about 4 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 14 mg / kg for one day followed by a maintenance dose of about 7 mg / kg every 12 hours for about 5 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 14 mg / kg for one day followed by a maintenance dose of about 7 mg / kg every 12 hours for about 6 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 14 mg / kg for one day followed by a maintenance dose of about 7 mg / kg every 12 hours for about 7 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 14 mg / kg for one day followed by a maintenance dose of about 7 mg / kg every 12 hours for about 8 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 14 mg / kg for one day followed by a maintenance dose of about 7 mg / kg every 12 hours for about 9 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 14 mg / kg for one day followed by a maintenance dose of about 7 mg / kg every 12 hours for about 10 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 14 mg / kg for one day followed by a maintenance dose of about 7 mg / kg every 12 hours for a total of about 13 maintenance doses.

[0296] In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 14 mg / kg for about one day followed by a maintenance dose of about 7 mg / kg about every 12 hours for about 4 to about 10 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 14 mg / kg for about one day followed by a maintenance dose of about 7 mg / kg about every 12 hours for about 4 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 14 mg / kg for about one day followed by a maintenance dose of about 7 mg / kg about every 12 hours for about 5Attorney Docket No. 433899-001802 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 14 mg / kg for about one day followed by a maintenance dose of about 7 mg / kg about every 12 hours for about 6 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 14 mg / kg for about one day followed by a maintenance dose of about 7 mg / kg every 12 hours for about 7 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 14 mg / kg for about one day followed by a maintenance dose of about 7 mg / kg about every 12 hours for about 8 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 14 mg / kg for about one day followed by a maintenance dose of about 7 mg / kg about every 12 hours for about 9 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 14 mg / kg for about one day followed by a maintenance dose of about 7 mg / kg about every 12 hours for about 9 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 14 mg / kg for about one day followed by a maintenance dose of about 7 mg / kg about every 12 hours for a total of about 13 maintenance doses.

[0297] In some embodiments, the dosage regimen of vapendavir or a pharmaceutically acceptable salt thereof could be varied. For instance, the single loading dose could be adjusted within a range of about 500 mg to about 1500 mg, followed by a maintenance dose of about 250 mg to about 750 mg every 12 hours for about 3 to about 14 days. The specific dosage could be adjusted based on the patient's weight, age, severity of the COPD, and the specific strain of the respiratory enterovirus infection.

[0298] In some embodiments, the single loading dose is administered within about 24 hours of the subject displaying symptoms of a respiratory enterovirus infection. In some embodiments, the single loading dose is administered within about 48 hours of the subject displaying symptoms of a respiratory enterovirus infection. In some embodiments, the single loading dose is administered within about 72 hours of the subject displaying symptoms of a respiratory enterovirus infection. In some embodiments, the single loading dose is administered within about 96 hours of the subject displaying symptoms of a respiratoryAttorney Docket No. 433899-001802 enterovirus infection. In some embodiments, the single loading dose is administered within about 72 hours to about 96 hours of the subject displaying symptoms of a respiratory enterovirus infection. In some embodiments, the single loading dose is administered within about 1 to about 5 days of the subject displaying symptoms of a respiratory enterovirus infection. In some embodiments, the single loading dose is administered within about 1 to about 7 days of the subject displaying symptoms of a respiratory enterovirus infection. In some embodiments, the single loading dose is administered greater than 48 hours after the subject first displays symptoms of a respiratory enterovirus infection. In some embodiments, the single loading dose is administered prior to the subject achieving a peak viral load. In some embodiments, administration of single loading dose of about 1000 mg results in a Cmax of about 2150 ng / mL.

[0299] In some embodiments, the maintenance dose is first administered about 6 to about 12 hours following administering the single loading dose. In some embodiments, the maintenance dose may be administered about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, or any range or value contained therein, after administration of the single loading dose. In some embodiments, at least one maintenance dose is administered for about 6 days to about 10 days, such as about 6 days, about 7 days, about 8 days, about 9 days, or about 10 days.

[0300] In some embodiments, the single loading dose and the maintenance dose are administered within about 30 minutes of the subject consuming a meal with solid food (e.g. the subject is in a fed state). In some embodiments, the single loading dose and the maintenance dose are administered within about 30 minutes of the subject consuming a high fat meal with solid food (e.g. the subject is in a fed state). In some embodiments, administering the single loading dose and maintenance dose to a subject within about 30 minutes of the subject consuming a meal with solid food results in a higher plasma concentration of vapendavir or a pharmaceutically acceptable salt thereof than administering the single loading dose and maintenance dose to a subject in a fasted state. For example, administration of 500 mg vapendavir in normal healthy volunteers that were in a fed state prior to administration results in a Cmax of 2060 ng / mL (CV% 5 ng / mL) compared to 687 ng / mL (CV% 93ng / mL) in normal healthy volunteers that were in fasted state prior to administration.

[0301] In some embodiments, the subject is in a fasted state when the loading dose and the maintenance doses are administered. In some embodiments, the subject is in a fasted stateAttorney Docket No. 433899-001802 when the loading dose is administered, and may be in a fed state or a fasted state when the maintenance doses are administered. In some embodiments, the subject may be in a fed state or a fasted state when the loading dose or maintenance doses are administered.

[0302] In some embodiments, the single loading dose is administered after the subject has been diagnosed with a respiratory enterovirus infection, wherein the diagnosis is achieved by a clinical diagnosis, PCR testing, loop-mediated isothermal amplification, other forms of nucleic acid amplification, rapid antigen testing, direct fluorescent antibody testing, arterial blood gas testing, chest x-rays, peak flow meter testing, pleural fluid cultures, lung CT scanning, lung function tests, pulse oximetry testing, spirometry testing, sputum testing, nasal swab testing, throat swab testing, changes in physiologic parameters including but not limited to heart rate, temperature, respiratory rate, or any combination thereof.

[0303] In some embodiments, the maintenance dose of vapendavir or a pharmaceutically acceptable salt thereof is a dose of about 500 mg administered about every 12 hours for about6 to about 10 days and is administered to the subject in a fed state. In some embodiments, the maintenance dose of vapendavir or a pharmaceutically acceptable salt thereof is a dose of about 500 mg administered about every 12 hours for about 4 days and is administered to the subject in a fed state. In some embodiments, the maintenance dose of vapendavir or a pharmaceutically acceptable salt thereof is a dose of about 500 mg administered about every 12 hours for about 5 days and is administered to the subject in a fed state. In some embodiments, the maintenance dose of vapendavir or a pharmaceutically acceptable salt thereof is a dose of about 500 mg administered about every 12 hours for about 6 days and is administered to the subject in a fed state. In some embodiments, the maintenance dose of vapendavir or a pharmaceutically acceptable salt thereof is a dose of about 500 mg administered about every 12 hours for about7 days and is administered to the subject in a fed state. In some embodiments, the maintenance dose of vapendavir or a pharmaceutically acceptable salt thereof is a dose of about 500 mg administered about every 12 hours for about 8 days and is administered to the subject in a fed state. In some embodiments, the maintenance dose of vapendavir or a pharmaceutically acceptable salt thereof is a dose of about 500 mg administered about every 12 hours for about 9 days and is administered to the subject in a fed state. In some embodiments, the maintenance dose of vapendavir or a pharmaceutically acceptable salt thereof is a dose of about 500 mg administered about every 12 hours for about 10 days and is administered to the subject in a fed state.Attorney Docket No. 433899-001802

[0304] In some embodiments, a first dose of about 1000 mg per day is administered to the subject within about 24 hours, about 48 hours, about 72 hours, or about 1 day to about 5 days of the subject displaying symptoms of a respiratory enterovirus infection. In some embodiments, the first dose is administered after the subject has been diagnosed with a respiratory enterovirus infection, wherein the diagnosis is achieved by a clinical diagnosis, multiplex PCR testing, rapid antigen testing, direct fluorescent antibody testing, arterial blood gas testing, chest x-rays, peak flow meter testing, pleural fluid cultures, lung CT scanning, lung function tests, pulse oximetry testing, spirometry testing, sputum testing, nasal swab testing, throat swab testing, or any combination thereof.

[0305] In some embodiments, the symptoms of a respiratory enterovirus infection are selected from a cough, increased mucus production, sneezing, nasal congestion, runny nose, sore throat, headaches, muscle aches, breathlessness, tight chest, wheezing, fever, red eyes, swelling of the lymph nodes, fatigue, hoarse voice, rhinorrhea, malaise, nasal obstruction, sputum production, inability to function at normal level of activity, and any combinations thereof. In some embodiments, the subject is asymptomatic but has been diagnosed with a respiratory enterovirus infection.

[0306] In some embodiments, the subject is a human. In some embodiments, the subject is in a fed state. In some embodiments, the subject is a human between about 40 and about 85 years of age. In some embodiments, the subject been diagnosed with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 COPD, GOLD stage 2 COPD, GOLD stage 3 COPD, or GOLD stage 4 COPD.

[0307] In some embodiments, the subject is a female receiving an oral contraceptive, such as birth control. In such embodiments, administering a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof further includes administering additional birth control during treatment. In some embodiments, the subject is a female that is not receiving an oral contraceptive, such as birth control.

[0308] In some embodiments, the subject is receiving stable maintenance therapy for COPD. In some embodiments, stable maintenance therapy for COPD may include short-acting bronchodilators such as, but not limited to Albuterol, Levalbuterol, Ipratropium, or any combination thereof; long-acting bronchodilators such as, but not limited to Aclidinium, Arformoterol, Formoterol, Glycopyrrolate, Indacaterol, Olodaterol, Revefenacin, Salmeterol,Attorney Docket No. 433899-001802Tiotropium, Umeclidinium, or any combination thereof; corticosteroids such as, but not limited to Fluticasone, Budesonide, Prednisolone, Beclometasone or any combination thereof; LABA and LAMA combination bronchodilator therapies such as, but not limited to Aclidinium / formoterol, Glycopyrrolate / formoterol, Tiotropium / olodaterol,Umeclidinium / vilanterol, Glycopyrronium / indacaterol or any combination thereof; Combinations of an ICS and a long-acting bronchodilator such as, but not limited to Budesonide / formoterol, Fluticasone / salmeterol, Fluticasone / vilanterol,Beclometasone / formoterol or any combination thereof; Triple Combination Therapies (ICS / LAMA / LABA) such as but not limited to Fluticasone / umeclidinium / vilanterol, Budesonide / glycopironium / formoterol, Beclometasone / formoterol / glycopyrronium or any combination thereof; Methylxanthines such as, but not limited to Theophylline; Phosphodiesterase-4 inhibitors such as, but not limited to Roflumilast; Mucoactive drugs such as but not limited to Carbocysteine, Erdosteine, N-acetylcysteine or any combination thereof; Biologics / anti-eosinophilia drugs such as, but not limited to Mepolizumab, Benralizumab, Reslizumab, Dupilumab or any combination thereof; or any other drug prescribed for the treatment of COPD. In some embodiments, the subject may receive the same stable maintenance therapy for COPD than when the subject does not have a respiratory enterovirus infection. In some embodiments, the subject may receive a larger dose, a more frequent dosage, or any combination thereof, of the stable maintenance therapy for COPD than when the subject does not have a respiratory enterovirus infection. In some embodiments, the subject may receive a smaller dose, a less frequent dosage, or any combination thereof, of the stable maintenance therapy for COPD than when the subject does not have a respiratory enterovirus infection. In some embodiments, the method further includes administering a therapeutically effective amount of pleconaril, or another capsid inhibitor, to the subject in combination with vapendavir or a pharmaceutically acceptable salt thereof.

[0309] The subject may, in some embodiments, have had at least one respiratory enterovirus infection in the 12 months immediately prior to administering the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has not had a sore throat, sneezing, rhinorrhea, malaise, nasal obstruction, cough, or any combination thereof, in the 30 days prior to administering the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not have an active diagnosed infection or consistentAttorney Docket No. 433899-001802 symptoms thereof, with a viral or bacterial pathogen in addition to respiratory enterovirus infection.

[0310] In some embodiments, the subject has not been diagnosed with asthma; cystic fibrosis (CF); bronchiolitis obliterans; fibrosis such as tuberculosis (TB), idiopathic pulmonary fibrosis (IPF), other major respiratory diagnosis (e.g., pneumonia, aspergillosis), non-CF bronchiectasis, COPD due to alpha-1 antitrypsin deficiency, active allergic rhinitis, nasal disease, (e.g. nasal polyposis, significant septal deviation, chronic rhinosinusitis, etc.), any cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, hematological, psychiatric impairment that is not medically stable, or other major physical impairment that is not considered medically stable or controlled, or any combination thereof.

[0311] In some embodiments, the subject is not taking any medications that are known to be impacted by or significantly metabolized by CYP3A4. Such medications include but are not limited to Apalutamide, Amiodarone, Carbamazepine, Amprenavir, Dexamethasone, Atazanavir, Enzalutamide, Boceprevir, Fosphenytoin, Clarithromycin, Lumacaftor, Cobicistat, Midostaurin, Conivaptan, Mitotane, Curcumin, Pentobarbital, Danazol, Phenobarbital, Danoprevir, Phenytoin, Darunavir, Primidone, Delavirdine, Rifampicin, Diltiazem, Rifamycin, Ditiocarb, Rifapentine, Econazole, Rifaximin, Efavirenz, Rimexolone, Elvitegravir, St. John's Wort, Ergotamine, Idelalisib, Levoketoconazole, Naloxone, Indinavir, Itraconazole, Ketoconazole, Lonafamib, Loperamide, Lopinavir, Methimazole, Midostaurin, Nefazodone, Nelfinavir, Nilotinib, Posaconazole, Ribociclib, Ritonavir, Saquinavir, Stiripentol, Telaprevir, Telithromycin, Terfenadine, Tipranavir, Troleandomycin, Voriconazole, or combinations thereof. Such medications may also include H2 blockers such as Famotidine, Cimetidine, Nizatidine and Ranitidine. Such medications may also include proton pump inhibitors such as but not limited to Omeprazole, Esomeprazole, Lansoprazole, Rabeprazole, Pantoprazole, Dexlansoprazole and Zegerid. Such medications may also antacids such a Melox (Aluminum hydroxide, Magnesium hydroxide and Simethicone), Alginate, Aluminum hydroxide, Calcium carbonate, Magnesium carbonate, Magnesium hydroxide, Magnesium trisilicate, and Sodium bicarbonate. In some embodiments, the subject is not taking an acid reducer.

[0312] In some embodiments, the subject has no clinically relevant rhinovirus load in nasal lavage or sputum at a baseline visit (such as about 5 to about 10 days prior to beginning treatment, for example about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, orAttorney Docket No. 433899-001802 about 10 days), has no clinically relevant rhinovirus load in nasal lavage or sputum at day 0 of treatment, or a combination thereof. In some embodiments, a clinically relevant rhinovirus load may be less than about 20 copies per microliter of cDNA, such as about 20 copies, about 15 copies, about 10 copies, about 5 copies, and so forth, or any value contained within a range formed by any two of the preceding values.

[0313] In some embodiments, treating the respiratory condition in the subject includes decreasing and / or preventing an increase in one or more parameters or measurements known to those skilled in the art to be indicative of a subject’s health.

[0314] In some embodiments, treating the respiratory condition in the subject includes decreasing a viral load in the sputum, nasal passages, or a combination thereof in the subject compared with a viral load in the sputum, nasal passages, or a combination thereof of the subject prior to treatment.

[0315] Treating the respiratory condition in the subject may include, in some embodiments, decreasing the subject’s Evaluating Respiratory Symptoms in COPD Score (E- RS), including the subject’s Evaluating Respiratory Symptoms in COPD Score (E-RS), compared to the subject’s Evaluating Respiratory Symptoms in COPD Score (E-RS) prior to treatment. In some embodiments, treating the respiratory condition in the subject includes preventing an increase in the subject’s Evaluating Respiratory Symptoms in COPD Score (E- RS) compared to the subject’s Evaluating Respiratory Symptoms in COPD Score (E-RS) score prior to treatment.

[0316] In some embodiments, treating the respiratory condition in the subject includes decreasing the subject’s peak lower respiratory symptom score (LRSS), such as peak lower respiratory symptom score (LRSS), compared to the subject’s peak lower respiratory symptom score (LRSS) prior to treatment. Similarly, treating the respiratory condition in the subject may include preventing an increase in the subject’s LRSS compared to the subject’s LRSS prior to treatment. In some embodiments, treating the respiratory condition in the subject includes decreasing and / or preventing an increase in the subject’s peak upper respiratory symptom score (URSS), such as URSS, compared to the subject’s peak upper respiratory symptom score (URSS) prior to treatment.

[0317] In some embodiments, treating the respiratory condition in the subject includes decreasing the subject’s EXAcerbati on of Chronic Pulmonary Disease Tool - Patient ReportedAttorney Docket No. 433899-001802Outcome (EXACT-PRO), such as the subject’s EXAcerbation of Chronic Pulmonary Disease Tool - Patient Reported Outcome (EXACT-PRO) score, compared to the subject’s EXAcerbation of Chronic Pulmonary Disease Tool - Patient Reported Outcome (EXACT- PRO) prior to treatment. Similarly, treating the respiratory condition in the subj ect may include preventing an increase in the subj ect’ s EXACT -PRO, such as the subj ect’ s EXACT -PRO score. In some embodiments, treating the respiratory condition in the subject includes preventin an increase in the subject’s EXAcerbation of Chronic Pulmonary Disease Tool - Patient Reported Outcome (EXACT-PRO), such as the subject’s EXAcerbation of Chronic Pulmonary Disease Tool - Patient Reported Outcome (EXACT-PRO) score, compared to the subject’s EXAcerbation of Chronic Pulmonary Disease Tool - Patient Reported Outcome (EXACT- PRO) prior to treatment. Similarly, treating the respiratory condition in the subj ect may include preventing an increase in the subj ect’ s EXACT -PRO, such as the subj ect’ s EXACT -PRO score.

[0318] In some embodiments, treating the respiratory condition in the subject includes decreasing the subject’s EXAcerbation of Chronic Pulmonary Disease Tool - Patient Respiratory Symptoms (EXACT-RS), such as EXAcerbation of Chronic Pulmonary Disease Tool - Patient Respiratory Symptoms (EXACT-RS) score, compared to the subject’s EXAcerbation of Chronic Pulmonary Disease Tool - Patient Respiratory Symptoms (EXACT- RS) prior to treatment. In some embodiments, treating the respiratory condition in the subject includes preventing an increase in the subject’s EXACT-RS score. In some embodiments, treating the respiratory condition in the subject includes preventing an increase in the subject’s EXAcerbation of Chronic Pulmonary Disease Tool - Patient Respiratory Symptoms (EXACT- RS), such as EXAcerbation of Chronic Pulmonary Disease Tool - Patient Respiratory Symptoms (EXACT-RS) score, compared to the subject’s EXAcerbation of Chronic Pulmonary Disease Tool - Patient Respiratory Symptoms (EXACT-RS) prior to treatment. In some embodiments, treating the respiratory condition in the subject includes preventing an increase in the subject’s EXACT-RS score.

[0319] In some embodiments, treating the respiratory enterovirus in the subject may include an improvement in the subject’s E-RS score, EXACT-RS score, or a combination thereof from the start of treatment to day 21 of treatment.

[0320] In some embodiments, treating the respiratory condition in the subject includes decreasing and / or preventing an increase in the subject’s COPD assessment tool (CAT) score compared to the subject’s COPD assessment tool (CAT) score prior to treatment.Attorney Docket No. 433899-001802

[0321] In some embodiments, treating the respiratory condition in the subject includes decreasing the subject’s St. George's Respiratory Questionnaire (SGRQ) score compared to the subject’s St. George's Respiratory Questionnaire (SGRQ) score prior to treatment. In some embodiments, treating the respiratory condition in the subject includes preventing an increase in the subject’s St. George's Respiratory Questionnaire (SGRQ) score compared to the subject’s St. George's Respiratory Questionnaire (SGRQ) score prior to treatment.

[0322] In some embodiments, treating the respiratory condition in the subject includes decreasing, or preventing an increase in the subject’s upper airway symptoms as measured by Wisconsin or Jackson scores.

[0323] In some embodiments, treating the respiratory condition in the subject includes decreasing and / or preventing an increase in the subject’s upper airway symptoms as measured by Wisconsin Upper Respiratory Symptom Survey (WURSS) or Jackson Upper Respiratory Symptom Survey (JURSS) compared to the subject’s Wisconsin Upper Respiratory Symptom Survey (WURSS) or Jackson Upper Respiratory Symptom Survey (JURSS) prior to treatment. It is contemplated that in embodiments wherein the respiratory condition is an upper respiratory infection or a common cold, upper respiratory symptom measurement may be of particular interest, while lower respiratory symptom measurement may be less indicative of efficacy.

[0324] In some embodiments, treating the respiratory condition in the subject includes improving the subject’s lung function compared to the subject’s lung function prior to treatment. The subject’s lung function may, in some embodiments, be measured by methods familiar to those skilled in the art, including Forced Expiratory Volume -1 (FEV-i; in liters and % predicted), Forced Vital Capacity (FVC; in liters and % predicted) FEVi / FVC ratio and peak expiratory flow (PEF), or any combination thereof. In some embodiments, treating the respiratory condition in the subject includes preventing a decrease in the subject’s lung function compared to the subject’s lung function prior to treatment, wherein the subject’s lung function is measured by Forced Expiratory Volume -1 (FEV-i; in liters and % predicted), Forced Vital Capacity (FVC; in liters and % predicted) FEVi / FVC ratio and peak expiratory flow (PEF), or any combination thereof.

[0325] In some embodiments, treating the respiratory condition in the subject includes reducing the subject’s peak nasal lavage viral load compared to the subject’s peak nasal lavage viral load prior to treatment. In some embodiments, treating the respiratory condition in theAttorney Docket No. 433899-001802 subject includes preventing an increase in the subject’s peak nasal lavage viral load compared to the subject’s peak nasal lavage viral load prior to treatment. In some embodiments, treating the respiratory condition in the subject includes reducing and / or preventing an increase in the subject’s peak sputum lavage viral load compared to the subject’s peak sputum lavage viral load prior to treatment. In some embodiments, treating the respiratory condition in the subject includes reducing and / or preventing bacterial bronchitis, pneumonia, or combinations thereof.

[0326] In some embodiments, treating the respiratory condition in the subject includes reducing the subject’s AUC nasal viral load compared to the subject’s AUC nasal viral load prior to treatment, and in some embodiments, treating the respiratory condition in the subject includes preventing an increase in the subject’s AUC nasal viral load compared to the subject’s AUC nasal viral load prior to treatment. Treating the respiratory condition in the subject may, in some embodiments, include reducing and / or preventing an increase in the subject’s AUC sputum viral load compared to the subject’s AUC sputum viral load prior to treatment.

[0327] In some embodiments, treating the respiratory condition in the subject includes reducing the duration of viral shedding, reducing the number of days wherein the subject is positive for bacteria in the sputum, or combinations thereof.

[0328] In some embodiments, treating the respiratory condition in the subject by administering a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof as described herein results in a quicker time to resolution of the respiratory condition than administering a placebo. In some embodiments, treating the respiratory condition in the subject as described herein results in a time to resolution of the respiratory condition in the subject of less than about 8 days, such as about 7.5 days, about 6 days, about 5.5 days, about 5 days, about 4.5 days, about 4 days, about 3.5 days, about 3 days, about 2.5 days, about 2 days, about 1.5 days, about 1 day, about 0.5, or any value contained within a range formed by any two of the preceding values.

[0329] In some embodiments, treating the respiratory enterovirus in the subject results in fewer days with clinically significant deterioration, such as less than about 2 days.

[0330] In some embodiments, treating the respiratory condition in the subject includes reducing and / or preventing an increase in the subject’s peak sputum bacterial load compared to the subject’s peak sputum lavage bacterial load prior to treatment. In some embodiments, treating the respiratory condition in the subject includes reducing and / or preventing bacterialAttorney Docket No. 433899-001802 bronchitis, pneumonia, or combinations thereof. In some embodiments, treating the respiratory condition in the subject includes reducing and / or preventing an increase in the subject’s AUC sputum bacterial load compared to the subject’s AUC sputum bacterial load prior to treatment.

[0331] In some embodiments, treating the respiratory condition in the subject includes preventing, or reducing, acute exacerbations of COPD in the subject caused by the respiratory condition. Treating the respiratory condition in the subject may in some embodiments include a reduction in the frequency of acute COPD exacerbations in the subject, a reduction in the severity of acute COPD exacerbations in the subject, a reduction in the duration of acute COPD exacerbations in the subject or combinations thereof, caused by the respiratory condition. In some embodiments, treating the respiratory condition in the subject includes preventing an increase in the frequency of acute COPD exacerbations in the subject, an increase in the severity of acute COPD exacerbations in the subject, an increase in the duration of acute COPD exacerbations in the subject or combinations thereof, caused by the respiratory condition. In some embodiments, treating the respiratory condition in the subject as described herein may eliminate the need for a chronic immune therapy to be administered to the subject. In some embodiments, elimination of the need for chronic immune therapy is due to the compositions and methods of the present disclosure minimizing a Type 2 immune response phenotype in the subject. In some embodiments, elimination of the need for chronic immune therapy is due to direct anti-viral treatment of the exacerbation trigger, wherein the exacerbation trigger may be a respiratory enterovirus.

[0332] In some embodiments, administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof exceeds the paECso for human rhinoviruses. In some embodiments, the paECso for human rhinoviruses is about 75.4 ng / mL. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 4 to about 10 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / mL.Attorney Docket No. 433899-001802In some embodiments, the paECso for human rhinoviruses is exceeded for about 4 to about 10 days or until treatment is stopped.

[0333] In some embodiments, administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof exceeds the paECgo for human rhinoviruses. In some embodiments, the paECgo for human rhinoviruses is about 678.6 ng / mL. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 4 to about 10 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / mL. In some embodiments, the paECgo for human rhinoviruses is exceeded for about 4 to about 10 days or until treatment is stopped.

[0334] In some embodiments, administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof results in a Cmax that exceeds the paECso for human rhinoviruses. In some embodiments, the paECso for human rhinoviruses is about 75.4 ng / mL. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 4 to about 10 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / mL. In some embodiments, the paECso for human rhinoviruses is exceeded for about 4 to about 10 days or until treatment is stopped.

[0335] In some embodiments, administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof results in a Cmax that exceeds the paECgo for human rhinoviruses. In some embodiments, the paECgo for human rhinoviruses is about 678.6 ng / mL. In some embodiments, the therapeutically effective amountAttorney Docket No. 433899-001802 of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 4 to about 10 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / mL. In some embodiments, the paECgo for human rhinoviruses is exceeded for about 4 to about 10 days or until treatment is stopped.

[0336] In some embodiments, administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof exceeds the paECso for human rhinoviruses following a single dose. In some embodiments, the paECso for human rhinoviruses is about 75.4 ng / mL. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 4 to about 10 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / mL. In some embodiments, the paECso for human rhinoviruses is exceeded for about 4 to about 10 days or until treatment is stopped.

[0337] In some embodiments, administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof exceeds the paECgo for human rhinoviruses following a single dose. In some embodiments, the paECgo for human rhinoviruses is about 678.6 ng / mL. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 4 to about 10 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses. In some embodiments, the therapeutically effective amount of vapendavir or aAttorney Docket No. 433899-001802 pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / mL. In some embodiments, the paECgo for human rhinoviruses is exceeded for about 4 to about 10 days or until treatment is stopped.

[0338] In some embodiments, administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof results in the subject having a plasma concentration above paECgo and paECso after 1 day of treatment, after 2 days of treatment, after 5 days of treatment, or a combination thereof.

[0339] In some embodiments, there is provided a method of treating a respiratory enterovirus in a subject with asthma, which includes orally administering to the subject a therapeutically effective amount of vapendavir , thereby treating the respiratory enterovirus in the subject, wherein the vapendavir is in the form of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof, wherein the therapeutically effective amount of vapendavir is administered to the subject in a fed state, and wherein the subject is not taking an acid reducer.

[0340] In some embodiments, there is provided a method of treating a respiratory enterovirus in a subject with asthma, with includes orally administering to the subject a therapeutically effective amount of vapendavir , thereby treating the respiratory enterovirus in the subject; wherein the therapeutically effective amount is between about 250 mg and about 2,000 mg per day, wherein the vapendavir is in the form of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof, wherein the therapeutically effective amount of vapendavir is administered to the subject in in a fed state, and wherein the subject is not taking an acid reducer.

[0341] In some embodiments, the therapeutically effective amount of vapendavir is in a tablet form. In some embodiments, the vapendavir or pharmaceutically acceptable salt thereof is in a crystalline form. In some embodiments, the vapendavir or pharmaceutically acceptable salt thereof is in an amorphous form.

[0342] In some embodiments, the vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof has a chemical purity of greater than or equal to about 95% by mass, such as about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, or any value containedAttorney Docket No. 433899-001802 within a range formed by any two of the preceding values. In some embodiments, the vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof contains less than or equal to about 5% by mass of chemical impurities. The identity or identities of the chemical impurities which may be included is not limited. Chemical impurities may be identified and quantified by any method or technique available to those skilled in the art. Chemical impurities may be identified, reduced, or removed by methods available and familiar to those skilled in the art. In some embodiments, the chemical purity of the vapendavir may be determined by an analytical method, including but not limited to high performance liquid chromatography (HPLC).

[0343] In some embodiments, the vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof has a polymorphic purity of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or any value contained within a range formed by any two of the preceding values. For example, in some embodiments, the vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof may have a polymorphic purity of at least about 90%, meaning that at least about 90% by mass of the crystalline vapendavir is a particular crystalline form. In some embodiments, the polymorphic purity of the vapendavir can be evaluated by an analytical method such as quantitative XRPD. In some embodiments, the polymorphic purity of the vapendavir may be determined by evaluating the XRPD pattern and observing the absence of characteristic, non-overlapping peaks of other known crystal forms, and if no such peaks are present, the vapendavir is considered to be polymorphically pure within the limit of detection of the instrument used to perform XRPD.

[0344] In some embodiments, the method of treating a respiratory enterovirus in a subject with asthma includes orally administering to the subject a therapeutically effective amount of vapendavir free base.

[0345] In some embodiments, the method of treating a respiratory enterovirus in a subject with asthma includes orally administering to the subject a therapeutically effective amount of vapendavir phosphate.Attorney Docket No. 433899-001802

[0346] In some embodiments, the respiratory enterovirus is acute, and in other embodiments, the respiratory enterovirus is not acute. In some embodiments, the respiratory enterovirus is selected from a rhinovirus, echovirus, EV-68, EV-71, coxsackie virus, a nonpolio enterovirus and combinations thereof.

[0347] In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is between about 250 mg and about 2,000 mg per day, such as about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1,000 mg, about 1,050 mg, about 1,100 mg, about 1,150 mg, about 1,200 mg, about 1,250 mg, about 1,300 mg, about 1,350 mg, about 1,400 mg, about 1,450 mg, about 1,500 mg, about 1,550 mg, about 1,600 mg, about 1,650 mg, about 1,700 mg, about 1,750 mg, about 1,800 mg, about 1,850 mg, about 1,900 mg, about 1,950 mg, about 2,000 mg, or any value contained within a range formed by any two of the preceding values.

[0348] In some embodiments, the therapeutically effective amount of vapendavir free base is between about 250 mg and about 2,000 mg per day, such as about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1,000 mg, about 1,050 mg, about 1,100 mg, about 1,150 mg, about 1,200 mg, about 1,250 mg, about 1,300 mg, about 1,350 mg, about 1,400 mg, about 1,450 mg, about 1,500 mg, about 1,550 mg, about 1,600 mg, about 1,650 mg, about 1,700 mg, about 1,750 mg, about 1,800 mg, about 1,850 mg, about 1,900 mg, about 1,950 mg, about 2,000 mg, or any value contained within a range formed by any two of the preceding values.

[0349] In some embodiments, the therapeutically effective amount of vapendavir phosphate is between about 250 mg and about 2,000 mg per day, such as about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1,000 mg, about 1,050 mg, about 1,100 mg, about 1,150 mg, about 1,200 mg, about 1,250 mg, about 1,300 mg, about 1,350 mg, about 1,400 mg, about 1,450 mg, about 1,500 mg, about 1,550 mg, about 1,600 mg, about 1,650 mg, about 1,700 mg, about 1,750 mg,Attorney Docket No. 433899-001802 about 1,800 mg, about 1,850 mg, about 1,900 mg, about 1,950 mg, about 2,000 mg, or any value contained within a range formed by any two of the preceding values.

[0350] In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is between about 1 mg / kg and about 75 mg / kg, or any value contained within a range formed by any two of the preceding values, relative to the body weight of the subject. For example, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is, in some embodiments, about 1 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, or any range or value contained therein. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is about 14 mg / kg. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is about 7 mg / kg. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is about 3.5 mg / kg.

[0351] In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / ml. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is an amount that achieves a Cmax of about 2000 to about 6000 ng / ml. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is an amount that achieves a Cmax of about 2000 to about 4000 ng / ml. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is an amount thatAttorney Docket No. 433899-001802 achieves a Cmax of about 3000 to about 6000 ng / ml. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is an amount that achieves a Cmax of about 6000 to about 8000 ng / ml. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is an amount that achieves a Cmax of about 8000 to about 10000 ng / ml. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is an amount that achieves a Cmax of about 10000 to about 12000 ng / ml.

[0352] In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg about every 12 hours. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg about every 12 hours for about 4 to about 10 days. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg about every 12 hours for about 5 to about 8 days. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 6 to about 8 days. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 7 days.

[0353] In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphousAttorney Docket No. 433899-001802 vapendavir, or any combination thereof is a single loading dose of about 1000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 4 days. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 1000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 5 days. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 1000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 6 days. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 1000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 7 days. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 1000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 8 days. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 1000 mg every 12 hours for one day followed by a maintenance dose of about 500 mg every 12 hours for about 9 days. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 1000 mg followed by a maintenance dose of about 500 mg every 12 hours for 10 days.

[0354] In some embodiments, the therapeutically effective amount of vapendavir free base is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg about every 12 hours. In some embodiments, the therapeutically effective amount of vapendavir free base is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg about every 12 hours for about 4 to about 10 days.

[0355] In some embodiments, the therapeutically effective amount of vapendavir phosphate is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg aboutAttorney Docket No. 433899-001802 every 12 hours. In some embodiments, the therapeutically effective amount of vapendavir phosphate is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg about every 12 hours for about 4 to about 10 days.

[0356] In some embodiments, therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a loading dose followed by one or more maintenance doses. In some embodiments, the loading dose of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof can be about 600 mg to about 1500 mg, such as about 600 mg, about 675 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1125 mg, about 1150 mg, about 1175 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, or any value contained within a range formed by two of the preceding values. In some embodiments, the maintenance dose of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is about 250 mg to about 750 mg, such as about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, or any value contained within a range formed by two of the preceding values.

[0357] In some embodiments, the therapeutically effective amount of vapendavir free base is a loading dose of about 600 mg followed by one or more maintenance doses of about 250 mg. In some embodiments, the therapeutically effective amount of vapendavir free base is a loading dose of about 700 mg followed by one or more maintenance doses of about 350 mg. In some embodiments, the therapeutically effective amount of vapendavir free base is a loading dose of about 700 mg followed by one or more maintenance doses of about 500 mg. In some embodiments, the therapeutically effective amount of vapendavir free base is a loading dose of about 750 mg followed by one or more maintenance doses of about 500 mg. In some embodiments, the therapeutically effective amount of vapendavir free base is a loading dose ofAttorney Docket No. 433899-001802 about 800 mg followed by one or more maintenance doses of about 300 mg. In some embodiments, the therapeutically effective amount of vapendavir free base is a loading dose of about 800 mg followed by one or more maintenance doses of about 400 mg. In some embodiments, the therapeutically effective amount of vapendavir free base is a loading dose of about 800 mg followed by one or more maintenance doses of about 500 mg. In some embodiments, the therapeutically effective amount of vapendavir free base is a loading dose of about 900 mg followed by one or more maintenance doses of about 500 mg. In some embodiments, the therapeutically effective amount of vapendavir free base is a loading dose of about 1000 mg followed by one or more maintenance doses of about 300 mg. In some embodiments, the therapeutically effective amount of vapendavir free base is a loading dose of about 1000 mg followed by one or more maintenance doses of about 500 mg.

[0358] In some embodiments, the therapeutically effective amount of vapendavir phosphate is a loading dose of about 600 mg followed by one or more maintenance doses of about 250 mg. In some embodiments, the therapeutically effective amount of vapendavir phosphate is a loading dose of about 700 mg followed by one or more maintenance doses of about 350 mg. In some embodiments, the therapeutically effective amount of vapendavir phosphate is a loading dose of about 700 mg followed by one or more maintenance doses of about 500 mg. In some embodiments, the therapeutically effective amount of vapendavir phosphate is a loading dose of about 750 mg followed by one or more maintenance doses of about 500 mg. In some embodiments, the therapeutically effective amount of vapendavir phosphate is a loading dose of about 800 mg followed by one or more maintenance doses of about 300 mg. In some embodiments, the therapeutically effective amount of vapendavir phosphate is a loading dose of about 800 mg followed by one or more maintenance doses of about 400 mg. In some embodiments, the therapeutically effective amount of vapendavir phosphate is a loading dose of about 800 mg followed by one or more maintenance doses of about 500 mg. In some embodiments, the therapeutically effective amount of vapendavir phosphate is a loading dose of about 900 mg followed by one or more maintenance doses of about 500 mg. In some embodiments, the therapeutically effective amount of vapendavir phosphate is a loading dose of about 1000 mg followed by one or more maintenance doses of about 300 mg. In some embodiments, the therapeutically effective amount of vapendavir phosphate is a loading dose of about 1000 mg followed by one or more maintenance doses of about 500 mg.Attorney Docket No. 433899-001802

[0359] In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 12 maintenance doses. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg about every 12 hours for a total of about 13 maintenance doses. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg about every 12 hours for a total of 14 maintenance doses. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of 15 maintenance doses.

[0360] In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 14 mg / kg for one day followed by a maintenance dose of about 7 mg / kg every 12 hours for about 4 to about 10 days. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 14 mg / kg for one day followed by a maintenance dose of about 7 mg / kg every 12 hours for about 4 days. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 14 mg / kg for one day followed by a maintenance dose of about 7 mg / kg every 12 hours for about 5 days. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 14 mg / kg for one day followed by a maintenance dose of about 7 mg / kg every 12 hours for about 6 days. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate,Attorney Docket No. 433899-001802 vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 14 mg / kg for one day followed by a maintenance dose of about 7 mg / kg every 12 hours for about 7 days. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 14 mg / kg for one day followed by a maintenance dose of about 7 mg / kg every 12 hours for about 8 days. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 14 mg / kg for one day followed by a maintenance dose of about 7 mg / kg every 12 hours for about 9 days. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 14 mg / kg for one day followed by a maintenance dose of about 7 mg / kg every 12 hours for about 10 days. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 14 mg / kg for one day followed by a maintenance dose of about 7 mg / kg every 12 hours for a total of about 13 maintenance doses.

[0361] In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 14 mg / kg for about one day followed by a maintenance dose of about 7 mg / kg about every 12 hours for about 4 to about 10 days. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 14 mg / kg for about one day followed by a maintenance dose of about 7 mg / kg about every 12 hours for about 4 days. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 14 mg / kg for about one day followed by a maintenance dose of about 7 mg / kg about every 12 hours for about 5 days. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 14 mg / kgAttorney Docket No. 433899-001802 for about one day followed by a maintenance dose of about 7 mg / kg about every 12 hours for about 6 days. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 14 mg / kg for about one day followed by a maintenance dose of about 7 mg / kg every 12 hours for about 7 days. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 14 mg / kg for about one day followed by a maintenance dose of about 7 mg / kg about every 12 hours for about 8 days. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 14 mg / kg for about one day followed by a maintenance dose of about 7 mg / kg about every 12 hours for about 9 days. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 14 mg / kg for about one day followed by a maintenance dose of about 7 mg / kg about every 12 hours for about 9 days. In some embodiments, the therapeutically effective amount of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a single loading dose of about 14 mg / kg for about one day followed by a maintenance dose of about 7 mg / kg about every 12 hours for a total of about 13 maintenance doses.

[0362] In some embodiments, the single loading dose is administered within about 24 hours of the subject displaying symptoms of a respiratory enterovirus. In some embodiments, the single loading dose is administered within about 48 hours of the subject displaying symptoms of a respiratory enterovirus. In some embodiments, the single loading dose is administered within about 72 hours of the subject displaying symptoms of a respiratory enterovirus. In some embodiments, the single loading dose is administered within about 96 hours of the subject displaying symptoms of a respiratory enterovirus. In some embodiments, the single loading dose is administered within about 72 hours to about 96 hours of the subject displaying symptoms of a respiratory enterovirus. In some embodiments, the single loading dose is administered within about 1 to about 5 days of the subject displaying symptoms of a respiratory enterovirus. In some embodiments, the single loading dose is administered withinAttorney Docket No. 433899-001802 about 1 to about 7 days of the subject displaying symptoms of a respiratory enterovirus. In some embodiments, the single loading dose is administered greater than 48 hours after the subject first displays symptoms of a respiratory enterovirus. In some embodiments, the single loading dose is administered prior to the subject achieving a peak viral load. In some embodiments, administration of single loading dose of about 1000 mg results in a Cmax of about 2150 ng / ml.

[0363] In some embodiments, the maintenance dose is first administered about 6 to about 12 hours following administering the single loading dose. In some embodiments, the maintenance dose may be administered about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, or any range or value contained therein, after administration of the single loading dose. In some embodiments, the at least one maintenance dose is administered for about 6 days to about 10 days, such as about 6 days, about 7 days, about 8 days, about 9 days, or about 10 days.

[0364] In some embodiments, the maintenance dose of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a dose of about 500 mg administered about every 12 hours for about 6 to about 10 days and is administered to the subject in a fed state. In some embodiments, the maintenance dose of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a dose of about 500 mg administered about every 12 hours for about 4 days and is administered to the subject in a fed state. In some embodiments, the maintenance dose of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a dose of about 500 mg administered about every 12 hours for about 5 days and is administered to the subject in a fed state. In some embodiments, the maintenance dose of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a dose of about 500 mg administered about every 12 hours for about 6 days and is administered to the subject in a fed state. In some embodiments, the maintenance dose of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a dose of about 500 mg administered about every 12 hours for about 7 days and is administered to the subject in a fed state. In some embodiments, the maintenance dose of vapendavir chloride, vapendavirAttorney Docket No. 433899-001802 oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a dose of about 500 mg administered about every 12 hours for about 8 days and is administered to the subject in a fed state. In some embodiments, the maintenance dose of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a dose of about 500 mg administered about every 12 hours for about 9 days and is administered to the subject in a fed state. In some embodiments, the maintenance dose of vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof is a dose of about 500 mg administered about every 12 hours for about 10 days and is administered to the subject in a fed state.

[0365] In some embodiments, the single loading dose and the maintenance dose are administered within about 30 minutes of the subject consuming a meal with solid food (e.g. the subject is in a fed state). In some embodiments, the single loading dose and the maintenance dose are administered within about 30 minutes of the subject consuming a high fat meal with solid food (e.g. the subject is in a fed state). In some embodiments, administering the single loading dose and maintenance dose to a subject within about 30 minutes of the subject consuming a meal with solid food results in a higher plasma concentration of vapendavir or a pharmaceutically acceptable salt thereof than administering the single loading dose and maintenance dose to a subject in a fasted state. For example, administration of 500 mg vapendavir free base or vapendavir phosphate in normal healthy volunteers that were in a fed state prior to administration results in a Cmax of 2060 ng / ml (CV% 5 ng / ml) compared to 687 ng / ml (CV% 93ng / ml) in normal healthy volunteers that were in fasted state prior to administration.

[0366] In some embodiments, the vapendavir free base is administered to the subject in a fed state. In some embodiments, the vapendavir phosphate is administered to the subject in a fed state.

[0367] In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is in tablet form. The vapendavir is, in some embodiments, a free base, maleate salt, oxalate salt, phosphate salt, tartrate salt, mesylate salt, or chloride salt. In some embodiments, the vapendavir is an amorphous form of vapendavir or a pharmaceutically acceptable salt thereof. In some embodiments, the vapendavir is a crystalline form of vapendavir or a pharmaceutically acceptable salt thereof.Attorney Docket No. 433899-001802

[0368] There is provided, in some aspects of the present disclosure, a pharmaceutical composition which includes a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof. The vapendavir may be a free base, maleate salt, oxalate salt, phosphate salt, sulfate salt, or chloride salt. In some embodiments of the pharmaceutical composition, the vapendavir is an amorphous form of vapendavir or a pharmaceutically acceptable salt thereof. In some embodiments, the vapendavir is a crystalline form of vapendavir or a pharmaceutically acceptable salt thereof.

[0369] The routes for administration (delivery) include, but are not limited to, one or more of: oral (e.g., as a tablet, capsule, or as an ingestible solution), topical, mucosal (e.g., as a nasal spray or aerosol for inhalation), parenteral (e.g., by an injectable form), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intracerebroventricular, or other depot administration. Therefore, the compositions of the disclosure include those in a form especially formulated for the mode of administration. In certain embodiments, the pharmaceutical compositions of the disclosure are formulated in a form that is suitable for oral delivery.

[0370] The compounds of the disclosure may be formulated for administration in any convenient way for use in human or veterinary medicine and the disclosure therefore includes within its scope pharmaceutical compositions comprising a compound of the disclosure adapted for use in human or veterinary medicine. Such compositions may be presented for use in a conventional manner with the aid of one or more suitable carriers. Acceptable carriers for therapeutic use are well-known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). The choice of pharmaceutical carrier can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may include, in addition to the carrier, any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and / or solubilizing agent(s).

[0371] There may be different composition / formulation requirements depending on the different delivery systems. It is to be understood that not all of the compounds need to be administered by the same route. Likewise, if the composition includes more than one active component, then those components may be administered by different routes. By way of example, the pharmaceutical composition of the disclosure may be formulated to be delivered using a mini pump or by a mucosal route, for example, as a nasal spray or aerosol for inhalation or ingestible solution, or parenterally in which the composition is formulated by an injectableAttorney Docket No. 433899-001802 form, for delivery by, for example, an intravenous, intramuscular, or subcutaneous route. Alternatively, the formulation may be designed to be delivered by multiple routes.

[0372] Where appropriate, the pharmaceutical compositions can be administered by inhalation, by use of a skin patch, orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions, or suspensions containing flavoring or coloring agents, or they can be injected parenterally, for example intravenously, intramuscularly, or subcutaneously. For buccal or sublingual administration, the compositions may be administered in the form of tablets or lozenges, which can be formulated in a conventional manner.

[0373] The pharmaceutical compositions of the present disclosure can be administered in the form of tablets, capsules, troches, ovules, elixirs, solutions, or suspensions, for immediate- , delayed-, modified-, sustained-, pulsed-, or controlled-release applications. The pharmaceutical compositions of the present disclosure may also be presented in the form of solutions, gels, syrups, or suspensions, or a dry powder for reconstitution with water or other suitable vehicle before use. Solid compositions such as tablets, capsules, lozenges, troches, pastilles, pills, boluses, powder, pastes, granules, bullets, or premix preparations may also be used. Solid and liquid compositions for oral use may be prepared according to methods well- known in the art. Such compositions may also contain one or more pharmaceutically acceptable carriers and excipients which may be in solid or liquid form.

[0374] The pharmaceutical composition may, in some embodiments, include about 250 mg of vapendavir or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the pharmaceutical composition includes about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850Attorney Docket No. 433899-001802 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1,000 mg of vapendavir or a pharmaceutically acceptable salt thereof, or any range or value contained therein. In some embodiments, the pharmaceutical composition is a tablet. The pharmaceutical composition may further include a diluent, a disintegrant, a surfactant, a lubricant, a color coating, or any combination thereof.

[0375] Oral preparations may optionally include various standard pharmaceutical carriers and excipients, such as binders, fillers, buffers, lubricants, glidants, dyes, disintegrants, odorants, sweeteners, surfactants, mold release agents, antiadhesive agents, and coatings. Some excipients may have multiple roles in the compositions, e.g., act as both binders and disintegrants.

[0376] In some embodiments, the diluent is selected from Cellulose Microcrystalline Silicified (PROSOL VHD90) (USP / NF), anhydrous calcium phosphate, anhydrous lactose, calcium carbonate, calcium lactate, calcium sulfate dihydrate, corn starch, fructose, kaolin, lactose monohydrate, magnesium hydroxide, maltitol, maltose monohydrate, mannitol, sorbitol, sucrose, tribasic calcium phosphate, sodium citrate, glycine, croscarmellose sodium, ethanol, propylene glycol, glycerin, polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin, acacia, or any combination thereof.

[0377] In some embodiments, the disintegrant is selected from Starch Glycolate Sodium (USP / NF / EP), corn starch, potato starch, tapioca starch, croscarmellose sodium, pregelatinized starch, sodium carboxymethylcellulose, alginates, resins, aqueous aluminum silicates, cross-linked polyvinylpyrrolidone, or any combination thereof.

[0378] In some embodiments, the surfactant is selected from Pol oxamer Microprilled 188 (USP / NF / EP / JPE), sodium lauryl sulfate, polysorbates, or any combination thereof.

[0379] In some embodiments, the lubricant is selected from Magnesium Stearate 5712 (USP / NF / EP), stearic acid, glyceryl behenate, talc, carnauba wax, polymers of ethylene oxide, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, colloidal silicon dioxide, hydroxypropylmethylcellulose, hydroxypropylcellulose, acrylatemethacrylate copolymers, or any combination thereof.Attorney Docket No. 433899-001802

[0380] In some embodiments, the color coating is selected from Opadry II White 85F 18422 (Mfg. Std.), riboflavin, anthocyanin, paprika oleoresin, beet root, curcumin, indigo carmine, tartrazine, allura red, quinoline yellow, titanium dioxide, iron oxide, mica, betacarotene, or any combination thereof.

[0381] In some embodiments, the pharmaceutical composition includes vapendavir or a pharmaceutically acceptable salt thereof as described herein and further includes Cellulose Microcrystalline Silicified (PROSOL VHD90) (USP / NF), Starch Glycolate Sodium (USP / NF / EP), Poloxamer Microprilled 188 (USP / NF / EP / JPE), Magnesium Stearate 5712 (USP / NF / EP), and Opadry II White 85F 18422 (Mfg. Std.).

[0382] The pharmaceutical composition or unit dosage form of the disclosure may be administered according to a dosage and administration regimen defined by routine testing in the light of the guidelines given above in order to obtain optimal activity while minimizing toxicity or side effects for a particular subject. However, such fine tuning of the therapeutic regimen is routine in the light of the guidelines given herein.

[0383] The dosage of the compounds of the disclosure may vary according to a variety of factors such as underlying disease conditions, the individual's condition, weight, sex and age, and the mode of administration. An effective amount for treating a disorder can easily be determined by empirical methods known to those of ordinary skill in the art, for example by establishing a matrix of dosages and frequencies of administration and comparing a group of experimental units or subjects at each point in the matrix. The exact amount to be administered to a subject will vary depending on the state and severity of the disorder and the physical condition of the subject. A measurable amelioration of any symptom or parameter can be determined by a person skilled in the art or reported by the subject to the physician. It will be understood that any clinically or statistically significant attenuation or amelioration of any symptom or parameter of urinary tract disorders is within the scope of the disclosure. Clinically significant attenuation or amelioration means perceptible to the subject and / or to the physician. It will be understood that the pharmaceutical formulations of the disclosure need not necessarily contain the entire amount of the compound that is effective in treating the disorder, as such effective amounts can be reached by administration of a plurality of divided doses of such pharmaceutical formulations.Attorney Docket No. 433899-001802

[0384] In some embodiments, the pharmaceutical composition includes a diluent, such as Cellulose Microcrystalline Silicified (PROSOL VHD90) (USP / NF). In some embodiments, the pharmaceutical composition includes about 250 mg of a diluent, such as Cellulose Microcrystalline Silicified (PROSOLVHD90) (USP / NF). For example, the pharmaceutical composition may include about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg of the diluent, or any range or value contained therein. In some embodiments, the pharmaceutical composition includes about 500 mg of a diluent, such as Cellulose Microcrystalline Silicified (PROSOLVHD90) (USP / NF). For example, the pharmaceutical composition may include about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg of the diluent, or any range or value contained therein, of the diluent, or any range or value contained therein.

[0385] In some embodiments, the pharmaceutical composition includes a disintegrant, such as Starch Glycolate Sodium (USP / NF / EP). In some embodiments, the pharmaceutical composition includes about 50 mg of a disintegrant, such as Starch Glycolate Sodium (USP / NF / EP). For example, the pharmaceutical composition may include about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 of the disintegrant, or any range or value contained therein. In some embodiments, the pharmaceutical composition includes about 100 mg of a disintegrant, such as Starch Glycolate Sodium (USP / NF / EP). For example, the pharmaceutical composition may include about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 of the disintegrant, or any range or value contained therein.

[0386] In some embodiments, the pharmaceutical composition includes a surfactant, such as Poloxamer Microprilled 188 (USP / NF / EP / JPE). In some embodiments, the pharmaceutical composition includes about 10 mg of a surfactant, such as Poloxamer Microprilled 188 (USP / NF / EP / JPE). For example, the pharmaceutical composition may include about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg of the surfactant, or any range or value contained therein. In some embodiments, the pharmaceutical composition includes about 20 mg of a surfactant, such as Poloxamer Microprilled 188 (USP / NF / EP / JPE). For example, the pharmaceutical composition may include about 16 mg, about 18 mg, about 20 mg, about 22 mg, about 24 mg of the surfactant, or any range or value contained therein.Attorney Docket No. 433899-001802

[0387] In some embodiments, the pharmaceutical composition includes a lubricant, such as Magnesium Stearate 5712 (USP / NF / EP). In some embodiments, the pharmaceutical composition includes about 10 mg of a lubricant, such as Magnesium Stearate 5712 (USP / NF / EP). For example, the pharmaceutical composition may include about 8 mg, about9 mg, about 10 mg, about 11 mg, about 12 mg of the lubricant, or any range or value contained therein. In some embodiments, the pharmaceutical composition includes about 20 mg of a lubricant, such as Magnesium Stearate 5712 (USP / NF / EP). For example, the pharmaceutical composition may include about 16 mg, about 18 mg, about 20 mg, about 22 mg, about 24 mg of the lubricant, or any range or value contained therein.

[0388] In some embodiments, the pharmaceutical composition includes a color coating, such as Opadry II White 85F 18422 (Mfg. Std.). In some embodiments, the pharmaceutical composition includes about 15 mg of a color coating, such as Opadry II White 85F 18422 (Mfg. Std.). For example, the pharmaceutical composition may include about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg of the color coating, or any range or value contained therein. In some embodiments, the pharmaceutical composition includes about 15 mg of a color coating, such as Opadry II White 85F 18422 (Mfg. Std.). For example, the pharmaceutical composition may include about 24 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 34 mg, about 36 mg of the color coating, or any range or value contained therein.

[0389] In some embodiments, the pharmaceutical composition includes about 250 mg of vapendavir or a pharmaceutically acceptable salt thereof, about 250 mg of Cellulose Microcrystalline Silicified (PROSOL VHD90) (USP / NF), about 50 mg of Starch Glycolate Sodium (USP / NF / EP), about 10 mg of Poloxamer Microprilled 188 (USP / NF / EP / JPE), about10 mg of Magnesium Stearate 5712 (USP / NF / EP), and about 15 mg of Opadry II White 85F 18422 (Mfg. Std.).

[0390] In some embodiments, the pharmaceutical composition includes about 500 mg of vapendavir or a pharmaceutically acceptable salt thereof, about 500 mg of Cellulose Microcrystalline Silicified (PROSOL VHD90) (USP / NF), about 100 mg of Starch Glycolate Sodium (USP / NF / EP), about 20 mg of Poloxamer Microprilled 188 (USP / NF / EP / JPE), about 20 mg of Magnesium Stearate 5712 (USP / NF / EP), and about 30 mg of Opadry II White 85F 18422 (Mfg. Std.).Attorney Docket No. 433899-001802

[0391] Some embodiments are directed to methods of treating a respiratory enterovirus infection in a human subject with COPD comprising orally administering to the subject that is in a fed state, a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof, thereby treating the respiratory enterovirus infection in the subject; wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is between about 250 mg and about 2,000 mg per day; wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 4 to about 10 days, about 5 to about 8 days, about 6 to about 8 days or about 7 days; wherein treating the respiratory enterovirus infection in the subject comprises an improvement in the subject’s peak total lower respiratory symptom score (LRSS), an improvement in the signs and symptoms of the respiratory enterovirus infection, a decrease in respiratory enterovirus virus load and secondary bacterial infection frequency and severity, an improvement in pulmonary function tests (PFTs), or any combination thereof; and wherein the subject is not taking any medications that are known to be impacted by or significantly metabolized by CYP3A4. Preferably, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses.

[0392] There is provided a method of treating a respiratory condition, wherein the respiratory condition is a respiratory enterovirus infection, an upper respiratory infection, a common cold, or a combination thereof, in a subject with COPD comprising orally administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof, thereby treating the respiratory condition in the subject.

[0393] In some embodiments, the respiratory enterovirus is selected from a rhinovirus, echovirus, EV-68, EV-71, coxsackie virus, a non-polio enterovirus and combinations thereof.

[0394] In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is between about 250 mg and about 2,000 mg per day.

[0395] In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 4 to about 10 days.Attorney Docket No. 433899-001802

[0396] In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses.

[0397] In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / mL.

[0398] In some embodiments, the single loading dose is administered within about 48 hours of the subject displaying symptoms of a respiratory enterovirus infection.

[0399] In some embodiments, the subject is asymptomatic but has been diagnosed with a respiratory enterovirus infection.

[0400] In some embodiments, the maintenance dose is first administered about 6 to about 12 hours following administering the single loading dose.

[0401] In some embodiments, the single loading dose is administered after the subject has been diagnosed with a respiratory enterovirus infection, wherein the diagnosis is achieved by a clinical diagnosis, PCR testing, loop-mediated isothermal amplification, rapid antigen testing, direct fluorescent antibody testing, arterial blood gas testing, chest x-rays, peak flow meter testing, pleural fluid cultures, lung CT scanning, lung function tests, pulse oximetry testing, spirometry testing, sputum testing, nasal swab testing, throat swab testing, changes in physiologic parameters, or any combination thereof.

[0402] In some embodiments, the subject is in a fed state.

[0403] In some embodiments, the subject is in a fasted state.

[0404] In some embodiments, the single loading dose and maintenance dose are administered within about 30 minutes of the subject consuming a meal with solid food. In some embodiments, the single loading dose and maintenance dose are administered within about 30 minutes of the subject consuming a high fat meal with solid food. In some embodiments, administering the single loading dose and maintenance dose to a subject within about 30 minutes of the subject consuming a meal with solid food results in a higher plasma concentration of vapendavir or a pharmaceutically acceptable salt thereof than administering the single loading dose and maintenance dose to a subject in a fasted state.Attorney Docket No. 433899-001802

[0405] In some embodiments, the subject been diagnosed with GOLD stage 1 COPD, GOLD stage 2 COPD, GOLD stage 3 COPD, or GOLD stage 4 COPD.

[0406] In some embodiments, the subject is receiving stable maintenance therapy for COPD.

[0407] In some embodiments, treating the respiratory enterovirus infection in the subject includes decreasing a viral load in the sputum, nasal passages, or a combination thereof in the subject compared with a viral load in the sputum, nasal passages, or a combination thereof of the subject prior to treatment.

[0408] In some embodiments, treating the respiratory enterovirus infection in the subject includes decreasing, or preventing an increase in the subject’s Evaluating Respiratory Symptoms in COPD Score (E-RS) compared to the subject’s Evaluating Respiratory Symptoms in COPD Score (E-RS) prior to treatment.

[0409] In some embodiments, treating the respiratory enterovirus infection in the subject includes decreasing, preventing an increase in the subject’s peak lower respiratory symptom score (LRSS) compared to the subject’s peak lower respiratory symptom score (LRSS) prior to treatment.

[0410] In some embodiments, treating the respiratory enterovirus infection in the subject includes decreasing, or preventing an increase in the subject’s peak upper respiratory symptom score (URSS) compared to the subject’s peak upper respiratory symptom score (URSS) prior to treatment.

[0411] In some embodiments, treating the respiratory enterovirus infection in the subject includes decreasing, or preventing an increase in the subject’s EXAcerbation of Chronic Pulmonary Disease Tool - Patient Reported Outcome (EXACT-PRO) compared to the subject’s EXAcerbation of Chronic Pulmonary Disease Tool - Patient Reported Outcome (EXACT-PRO) prior to treatment.

[0412] In some embodiments, treating the respiratory enterovirus infection in the subject includes decreasing, preventing an increase in the subject’s EXAcerbation of Chronic Pulmonary Disease Tool - Patient Respiratory Symptoms (EXACT-RS) compared to theAttorney Docket No. 433899-001802 subject’s EXAcerbation of Chronic Pulmonary Disease Tool - Patient Respiratory Symptoms (EXACT-RS) prior to treatment.

[0413] In some embodiments, treating the respiratory enterovirus infection in the subject includes decreasing, or preventing an increase in the subject’s COPD assessment tool (CAT) compared to the subject’s COPD assessment tool (CAT) prior to treatment.

[0414] In some embodiments, treating the respiratory enterovirus infection in the subject includes decreasing, or preventing an increase in the subject’s St. George's Respiratory Questionnaire (SGRQ) compared to the subject’s St. George's Respiratory Questionnaire (SGRQ) prior to treatment.

[0415] In some embodiments, treating the respiratory enterovirus infection in the subject includes decreasing or preventing an increase in the subject’s upper airway symptoms as measured by Wisconsin Upper Respiratory Symptom Survey (WURSS) or Jackson Upper Respiratory Symptom Survey (JURSS) compared to the subject’s Wisconsin Upper Respiratory Symptom Survey (WURSS) or Jackson Upper Respiratory Symptom Survey (JURSS) prior to treatment.

[0416] In some embodiments, treating the respiratory enterovirus infection in the subject includes improving, or preventing a decrease in the subject's lung function compared to the subject’s lung function prior to treatment.

[0417] In some embodiments, the subject’s lung function is measured by Forced Expiratory Volume -1 (FEV-i; in liters and % predicted), Forced Vital Capacity (FVC; in liters and % predicted) FEVi / FVC ratio and peak expiratory flow (PEF), or any combination thereof.

[0418] In some embodiments, treating the respiratory enterovirus infection in the subject includes reducing, or preventing an increase in the subject’s peak nasal lavage viral load compared to the subject’s peak nasal lavage viral load prior to treatment.

[0419] In some embodiments, treating the respiratory enterovirus infection in the subject includes reducing, or preventing an increase in the subject’s peak sputum lavage viral load compared to the subject’s peak sputum lavage viral load prior to treatment.Attorney Docket No. 433899-001802

[0420] In some embodiments, treating the respiratory enterovirus infection in the subject includes reducing, or preventing an increase in the subject’s AUC nasal viral load compared to the subject’s AUC nasal viral load prior to treatment.

[0421] In some embodiments, treating the respiratory enterovirus infection in the subject includes reducing, or preventing an increase in the subject’s AUC sputum viral load compared to the subject’s AUC sputum viral load prior to treatment.

[0422] In some embodiments, treating the respiratory enterovirus infection in the subject includes reducing the duration of viral shedding.

[0423] In some embodiments, treating the respiratory enterovirus infection in the subject includes reducing, or preventing an increase in the subject’s peak sputum bacterial load compared to the subject’s peak sputum lavage bacterial load prior to treatment.

[0424] In some embodiments, treating the respiratory enterovirus infection in the subject includes reducing, or preventing an increase in the subject’s AUC sputum bacterial load compared to the subject’s AUC sputum bacterial load prior to treatment.

[0425] The ranges for Cmax and other pharmacokinetic parameters disclosed herein are intended to reflect the ranges for bioequivalence set by the Food and Drug Administration (FDA). It is generally understood that to establish bioequivalence of a particular drug, such as a generic, the calculated confidence interval should typically fall within 80-125% of the referenced drug. Further details on acceptable ranges for bioequivalence can be found in “Guidance for Industry: Statistical Approaches to Establishing Bioequivalence”, January 2001, from U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), which is incorporated by reference herein in its entirety. The December 2022 “Statistical Approaches to Establishing Bioequivalence” Draft Guidance, which is also incorporated by reference herein in its entirety, may also be consulted.

[0426] In some embodiments, administering to a subject in a fasted state a single loading dose of about 1000 mg of vapendavir or a pharmaceutically acceptable salt thereof as disclosed herein results in a Cmax value of about 1760 ng / mL to about 2750 ng / mL, such as about 1760 ng / mL, about 1800 ng / mL, about 1900 ng / mL, about 2000 ng / mL, about 2100 ng / mL, about 2200 ng / mL, about 2300 ng / mL, about 2400 ng / mL, about 2500 ng / mL, about 2600 ng / mL,Attorney Docket No. 433899-001802 about 2700 ng / mL, about 2750 ng / mL, or any value contained within a range formed any two of the preceding values.

[0427] In some embodiments, administering to a subject in a fed state a single loading dose of about 1000 mg of vapendavir or a pharmaceutically acceptable salt thereof as disclosed herein results in a Cmax value of about 3200 ng / mL to about 5000 ng / mL, such as about 3200 ng / mL, about 3400 ng / mL, about 3600 ng / mL, about 3800 ng / mL, about 4000 ng / mL, about 4200 ng / mL, about 4400 ng / mL, about 4600 ng / mL, about 4800 ng / mL, about 5000 ng / mL, or any value contained within a range formed any two of the preceding values.

[0428] In some embodiments, administering to a subject with COPD a single loading dose of about 1000 mg of vapendavir or a pharmaceutically acceptable salt thereof followed by administering one maintenance dose of about 500 mg results in an AUC value of about 8000 ng*h / mL to about 17500 ng*h / mL, such as about 8000 ng*h / mL, about 10000 ng*h / mL, about 12000 ng*h / mL, about 14000 ng*h / mL, about 16000 ng*h / mL, about 17000 ng*h / mL, about 17500 ng*h / mL, or any value contained within a range formed any two of the preceding values.

[0429] In some embodiments, treating the respiratory enterovirus infection in the subject includes reducing the number of days wherein the subject is positive for bacteria in the sputum.

[0430] In some embodiments, treating the respiratory enterovirus infection in the subject includes preventing, or reducing, acute exacerbations of COPD in the subject caused by the respiratory enterovirus infection.

[0431] In some embodiments, treating the respiratory enterovirus infection in the subject includes a reduction in the frequency of acute COPD exacerbations in the subject, a reduction in the severity of acute COPD exacerbations in the subject, a reduction in the duration of acute COPD exacerbations in the subject or combinations thereof, caused by the respiratory enterovirus infection.

[0432] In some embodiments, treating the respiratory enterovirus infection in the subject includes preventing an increase in the frequency of acute COPD exacerbations in the subject, an increase in the severity of acute COPD exacerbations in the subject, an increase in the duration of acute COPD exacerbations in the subject or combinations thereof, caused by the respiratory enterovirus infection.Attorney Docket No. 433899-001802

[0433] In some embodiments, administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof exceeds the paECso for human rhinoviruses. In some embodiments, the paECso for human rhinoviruses is about 75.4 ng / mL.

[0434] In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 4 to about 10 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / mL. In some embodiments, the paECso for human rhinoviruses is exceeded for about 4 to about 10 days or until treatment is stopped.

[0435] In some embodiments, administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof exceeds the paECLo for human rhinoviruses. In some embodiments, the paECgo for human rhinoviruses is about 678.6 ng / mL. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 4 to about 10 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / mL. In some embodiments, the paECgo for human rhinoviruses is exceeded for about 4 to about 10 days or until treatment is stopped.

[0436] In some embodiments, administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof results in a Cmax that exceeds the paECso for human rhinoviruses. In some embodiments, the paECso for human rhinoviruses is about 75.4 ng / mL. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of aboutAttorney Docket No. 433899-0018021,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 4 to about 10 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / mL. In some embodiments, the paECso for human rhinoviruses is exceeded for about 4 to about 10 days or until treatment is stopped.

[0437] In some embodiments, administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof results in a Cmax that exceeds the paECgo for human rhinoviruses. In some embodiments, the paECgo for human rhinoviruses is about 678.6 ng / mL. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 4 to about 10 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / mL. In some embodiments, the paECgo for human rhinoviruses is exceeded for about 4 to about 10 days or until treatment is stopped.

[0438] In some embodiments, administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof exceeds the paECso for human rhinoviruses following a single dose. In some embodiments, the paECso for human rhinoviruses is about 75.4 ng / mL. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 4 to about 10 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 toAttorney Docket No. 433899-001802 about 12000 ng / mL. In some embodiments, the paECso for human rhinoviruses is exceeded for about 4 to about 10 days or until treatment is stopped.

[0439] In some embodiments, administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof exceeds the paECgo for human rhinoviruses. In some embodiments, the paECgo for human rhinoviruses is about 678.6 ng / mL. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 4 to about 10 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / mL. In some embodiments, the paECgo for human rhinoviruses is exceeded for about 4 to about 10 days or until treatment is stopped.

[0440] In some embodiments, the subject has been diagnosed with asthma. In some embodiments, the subject is receiving stable maintenance therapy for asthma. In some embodiments, stable maintenance therapy for asthma may include short-acting bronchodilators such as, but not limited to Montelukast, Albuterol, Levalbuterol, Ipratropium, chronic oral steroids, or any combination thereof; long-acting bronchodilators such as, but not limited to Aclidinium, Arformoterol, Formoterol, Glycopyrrolate, Indacaterol, Olodaterol, Revefenacin, Salmeterol, Tiotropium, Umeclidinium, or any combination thereof; corticosteroids such as, but not limited to Fluticasone, Budesonide, Prednisolone, Beclometasone or any combination thereof; LABA and LAMA combination bronchodilator therapies such as, but not limited to Aclidinium / formoterol, Glycopyrrolate / formoterol, Tiotropium / olodaterol,Umeclidinium / vilanterol, Glycopyrronium / indacaterol or any combination thereof; Combinations of an ICS and a long-acting bronchodilator such as, but not limited to Budesonide / formoterol, Fluticasone / salmeterol, Fluticasone / vilanterol,Beclometasone / formoterol or any combination thereof; Triple Combination Therapies (ICS / LAMA / LABA) such as but not limited to Fluticasone / umeclidinium / vilanterol, Budesonide / glycopironium / formoterol, Beclometasone / formoterol / glycopyrronium or any combination thereof; Methylxanthines such as, but not limited to Theophylline;Attorney Docket No. 433899-001802Phosphodiesterase-4 inhibitors such as, but not limited to Roflumilast; Mucoactive drugs such as but not limited to Carbocysteine, Erdosteine, N-acetylcysteine or any combination thereof; Biologics / anti-eosinophilia drugs such as, but not limited to Mepolizumab, Benralizumab, Reslizumab, Dupilumab or any combination thereof; or any other drug prescribed for the treatment of asthma.

[0441] In some embodiments, the subject may receive the same stable maintenance therapy for asthma than when the subject does not have a respiratory enterovirus. In some embodiments, the subject may receive a larger dose, a more frequent dosage, or any combination thereof, of the stable maintenance therapy for asthma than when the subject does not have a respiratory enterovirus. In some embodiments, the subject may receive a smaller dose, a less frequent dosage, or any combination thereof, of the stable maintenance therapy for asthma than when the subject does not have a respiratory enterovirus.

[0442] The subject may, in some embodiments, have had at least one respiratory enterovirus in the 12 months immediately prior to administering the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has not had a sore throat, sneezing, rhinorrhea, malaise, nasal obstruction, cough, or any combination thereof, in the 30 days prior to administering the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not have an active diagnosed infection or consistent symptoms thereof, with a viral or bacterial pathogen in addition to respiratory enterovirus.

[0443] In some embodiments, the subject has an underlying condition in addition to asthma, such as cystic fibrosis (CF); bronchiolitis obliterans; fibrosis such as tuberculosis (TB), idiopathic pulmonary fibrosis (IPF), other major respiratory diagnosis (e.g., pneumonia, aspergillosis), non-CF bronchiectasis, COPD due to alpha- 1 antitrypsin deficiency, chronic allergies, active allergic rhinitis, nasal disease, (e.g. nasal polyposis, significant septal deviation, chronic rhinosinusitis, etc.), or combinations thereof. Such underlying conditions may or may not be formally diagnosed in the subject.

[0444] In some embodiments, treating the respiratory enterovirus in the subject includes decreasing and / or preventing an increase in one or more parameters or measurements known to those skilled in the art to be indicative of a subject’s health.Attorney Docket No. 433899-001802

[0445] In some embodiments, treating the respiratory enterovirus in the subject includes decreasing a viral load in the sputum, nasal passages, or a combination thereof in the subject compared with a viral load in the sputum, nasal passages, or a combination thereof of the subject prior to treatment.

[0446] In some embodiments, treating the respiratory enterovirus in the subject includes decreasing the subject’s St. George's Respiratory Questionnaire (SGRQ) score compared to the subject’s St. George's Respiratory Questionnaire (SGRQ) score prior to treatment. In some embodiments, treating the respiratory enterovirus in the subject includes preventing an increase in the subject’s St. George's Respiratory Questionnaire (SGRQ) score compared to the subject’s St. George's Respiratory Questionnaire (SGRQ) score prior to treatment.

[0447] In some embodiments, treating the respiratory enterovirus in the subject includes decreasing the subject’s Asthma Control Questionnaire (ACQ) score compared to the subject’s ACQ score prior to treatment. In some embodiments, treating the respiratory enterovirus in the subject includes preventing an increase in the subject’s Asthma Control Questionnaire (ACQ) score compared to the subject’s ACQ score prior to treatment. Different versions of the ACQ, including but not limited to versions 5, 6, or 7, may be used.

[0448] In some embodiments, treating the respiratory enterovirus in the subject includes decreasing the subject’s Asthma Control Test (ACT) score compared to the subject’s ACT score prior to treatment. In some embodiments, treating the respiratory enterovirus in the subject includes preventing an increase in the subject’s Asthma Control Test (ACT) score compared to the subject’s ACT score prior to treatment.

[0449] In some embodiments, treating the respiratory enterovirus in the subject includes decreasing the subject’s Pediatric Asthma Symptom Scale (PASS) score compared to the subject’s PASS score prior to treatment. In some embodiments, treating the respiratory enterovirus in the subject includes preventing an increase in the subject’s Pediatric Asthma Symptom Scale (PASS) score compared to the subject’s PASS score prior to treatment.

[0450] In some embodiments, treating the respiratory enterovirus in the subject includes decreasing the subject’s Asthma Severity Scoring System (ASSESS) score compared to the subject’s ASSESS score prior to treatment. In some embodiments, treating the respiratory enterovirus in the subject includes preventing an increase in the subject’s Pediatric AsthmaAttorney Docket No. 433899-001802Severity Scoring System (ASSESS) score compared to the subject’s ASSESS score prior to treatment.

[0451] In some embodiments, treating the respiratory enterovirus in the subject includes decreasing the subject’s Pediatric Asthma Score (PAS) score compared to the subject’s PAS score prior to treatment. In some embodiments, treating the respiratory enterovirus in the subject includes preventing an increase in the subject’s Pediatric Asthma Score (PAS) score compared to the subject’s PAS score prior to treatment.

[0452] In some embodiments, treating the respiratory enterovirus in the subject includes decreasing the subject’s Pediatric Respiratory Assessment Measure (PRAM) score compared to the subject’s PRAM score prior to treatment. In some embodiments, treating the respiratory enterovirus in the subject includes preventing an increase in the subject’s Pediatric Respiratory Assessment Measure (PRAM) compared to the subject’s PRAM score prior to treatment.

[0453] In some embodiments, treating the respiratory enterovirus in the subject includes decreasing the subject’s Pediatric Asthma Risk Score (PARS) score compared to the subject’s PARS score prior to treatment. In some embodiments, treating the respiratory enterovirus in the subject includes preventing an increase in the subject’s Pediatric Asthma Risk Score (PARS) compared to the subject’s PARS score prior to treatment.

[0454] In some embodiments, treating the respiratory enterovirus in the subject includes improving the subject’s lung function compared to the subjects’ lung function prior to treatment. The subjects’ lung function may, in some embodiments, be measured by methods familiar to those skilled in the art, including Forced Expiratory Volume -1 (FEV-i; in liters and % predicted), Forced Vital Capacity (FVC; in liters and % predicted) FEVi / FVC ratio and peak expiratory flow (PEF), or any combination thereof. In some embodiments, treating the respiratory enterovirus in the subject includes preventing a decrease in the subjects’ lung function compared to the subjects’ lung function prior to treatment, wherein the subjects’ lung function is measured by Forced Expiratory Volume -1 (FEV-i; in liters and % predicted), Forced Vital Capacity (FVC; in liters and % predicted) FEVi / FVC ratio and peak expiratory flow (PEF), or any combination thereof.

[0455] In some embodiments, treating the respiratory enterovirus in the subject includes reducing the subjects’ peak nasal lavage viral load compared to the subjects’ peak nasal lavage viral load prior to treatment. In some embodiments, treating the respiratory enterovirus in theAttorney Docket No. 433899-001802 subject includes preventing an increase in the subjects’ peak nasal lavage viral load compared to the subjects’ peak nasal lavage viral load prior to treatment. In some embodiments, treating the respiratory enterovirus in the subject includes reducing and / or preventing an increase in the subjects’ peak sputum lavage viral load compared to the subjects’ peak sputum lavage viral load prior to treatment. In some embodiments, treating the respiratory enterovirus in the subject includes reducing and / or preventing bacterial bronchitis, pneumonia, or combinations thereof.

[0456] In some embodiments, treating the respiratory enterovirus in the subject includes reducing the subjects’ AUC nasal viral load compared to the subjects’ AUC nasal viral load prior to treatment, and in some embodiments, treating the respiratory enterovirus in the subject includes preventing an increase in the subjects’ AUC nasal viral load compared to the subjects’ AUC nasal viral load prior to treatment. Treating the respiratory enterovirus in the subject may, in some embodiments, include reducing and / or preventing an increase in the subjects’ AUC sputum viral load compared to the subjects’ AUC sputum viral load prior to treatment.

[0457] In some embodiments, treating the respiratory enterovirus in the subject includes reducing the duration of viral shedding, reducing the number of days wherein the subject is positive for bacteria in the sputum, or combinations thereof.

[0458] In some embodiments, treating the respiratory enterovirus in the subject includes reducing and / or preventing an increase in the subjects’ peak sputum bacterial load compared to the subjects’ peak sputum lavage bacterial load prior to treatment. In some embodiments, treating the respiratory enterovirus in the subject includes reducing and / or preventing bacterial bronchitis, pneumonia, or combinations thereof. In some embodiments, treating the respiratory enterovirus in the subject includes reducing and / or preventing an increase in the subjects’ AUC sputum bacterial load compared to the subjects’ AUC sputum bacterial load prior to treatment.

[0459] In some embodiments, treating the respiratory enterovirus in the subject includes preventing, or reducing, acute exacerbations of asthma in the subject caused by the respiratory enterovirus. Treating the respiratory enterovirus in the subject may in some embodiments include a reduction in the frequency of acute asthma exacerbations in the subject, a reduction in the severity of acute asthma exacerbations in the subject, a reduction in the duration of acute asthma exacerbations in the subject or combinations thereof, caused by the respiratory enterovirus. In some embodiments, treating the respiratory enterovirus in the subject includesAttorney Docket No. 433899-001802 preventing an increase in the frequency of acute asthma exacerbations in the subject, an increase in the severity of acute asthma exacerbations in the subject, an increase in the duration of acute asthma exacerbations in the subject or combinations thereof, caused by the respiratory enterovirus. Treating the respiratory enterovirus in the subject may further reduce the need for acute care visits and hospitalizations. In some embodiments, treating the respiratory enterovirus in the subject may reduce the need for systemic treatments including but not limited to steroids.

[0460] In some embodiments, administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof exceeds the paECso for human rhinoviruses. In some embodiments, the paECso for human rhinoviruses is about 75.4 ng / ml. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 4 to about 10 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / ml. In some embodiments, the paECso for human rhinoviruses is exceeded for about 4 to about 10 days or until treatment is stopped.

[0461] In some embodiments, administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof exceeds the paECgo for human rhinoviruses. In some embodiments, the paECgo for human rhinoviruses is about 678.6 ng / ml. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 4 to about 10 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / ml. In some embodiments, the paECgo for human rhinoviruses is exceeded for about 4 to about 10 days or until treatment is stopped.Attorney Docket No. 433899-001802

[0462] In some embodiments, administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof results in a Cmax that exceeds the paECso for human rhinoviruses. In some embodiments, the paECso for human rhinoviruses is about 75.4 ng / ml. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 4 to about 10 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / ml. In some embodiments, the paECso for human rhinoviruses is exceeded for about 4 to about 10 days or until treatment is stopped.

[0463] In some embodiments, administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof results in a Cmax that exceeds the paECgo for human rhinoviruses. In some embodiments, the paECgo for human rhinoviruses is about 678.6 ng / ml. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 4 to about 10 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / ml. In some embodiments, the paECgo for human rhinoviruses is exceeded for about 4 to about 10 days or until treatment is stopped.

[0464] In some embodiments, administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof exceeds the paECso for human rhinoviruses following a single dose. In some embodiments, the paECso for human rhinoviruses is about 75.4 ng / ml. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 4 to aboutAttorney Docket No. 433899-00180210 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / ml. In some embodiments, the paECso for human rhinoviruses is exceeded for about 4 to about 10 days or until treatment is stopped.

[0465] In some embodiments, administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof exceeds the paECw for human rhinoviruses following a single dose. In some embodiments, the paECw for human rhinoviruses is about 678.6 ng / ml. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 4 to about 10 days. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses. In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / ml. In some embodiments, the paECgo for human rhinoviruses is exceeded for about 4 to about 10 days or until treatment is stopped.

[0466] In some embodiments, the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is in tablet form. In some embodiments, the vapendavir is a free base, maleate salt, oxalate salt, phosphate salt, sulfate salt, tartrate salt, mesylate salt, or chloride salt. In some embodiments, the vapendavir or a pharmaceutically acceptable salt thereof is an amorphous form of vapendavir.

[0467] Some embodiments are directed to pharmaceutical compositions including a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof. In some embodiments, the vapendavir is a free base, or a pharmaceutically acceptable salt thereof, such as a maleate salt, oxalate salt, phosphate salt, tartrate salt, mesylate salt, or chloride salt. In some embodiments, the vapendavir is an amorphous form of vapendavir or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceuticalAttorney Docket No. 433899-001802 composition includes about 250 mg of vapendavir or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is a tablet.

[0468] In some embodiments, the vapendavir or pharmaceutically acceptable salts thereof of the present disclosure may be used as prophylactics, particularly in at-risk populations such as the elderly or those with compromised immune systems. For example, there is provided a method of preventing a rhinovirus infection in a subject which includes administering a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof to the subject after exposure to rhinovirus.

[0469] Rhinovirus infections may be particularly concerning in children, as RV is often a cause of viral sepsis and meningitis in neonates. Respiratory syncytial virus (RSV) may be a cause for hospitalized bronchiolitis in children and related enteroviruses may lead to polio-like paralysis. It is contemplated that vapendavir or pharmaceutically acceptable salts thereof as described herein may be used in pediatrics to treat rhinoviruses and reduce or entirely avoid these serious complications.

[0470] In chronic disease patients, rhinoviruses are associated with the development of a Type 2 inflammatory phenotype. Accordingly, treating RV in these patients with vapendavir or pharmaceutically acceptable salts thereof as described here can reduce the need for chronic and costly immunotherapies.

[0471] The methods and compositions of the present disclosure may be employed in the following embodiments, which may be combined as appropriate to form new embodiments.1. A method of treating a respiratory enterovirus infection in a human subject with COPD comprising orally administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof, thereby treating the respiratory enterovirus infection in the subject.2. The method of embodiment 1, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is between about 250 mg and about 2,000 mg per day.3. The method of any of embodiments 1-2, wherein the respiratory enterovirus is selected from a rhinovirus, echovirus, EV-68, EV-71, coxsackie virus, a non-polio enterovirus and combinations thereof.Attorney Docket No. 433899-0018024. The method of any of embodiments 1-3, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 4 to about 10 days.5. The method of any of embodiments 1-4, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses.6. The method of any of embodiments 1-5, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / mL.7. The method of any of embodiments 1-6, wherein the single loading dose is administered within about 48 hours of the subject displaying symptoms of a respiratory enterovirus infection.8. The method of any of embodiments 1-7, wherein the single loading dose is administered within about 72 to about 96 hours of the subject displaying symptoms of a respiratory enterovirus infection.9. The method of any of embodiments 1-8, wherein the symptoms of a respiratory enterovirus infection are selected from a cough, increased mucus production, sneezing, nasal congestion, runny nose, sore throat, headaches, muscle aches, breathlessness, tight chest, wheezing, fever, red eyes, swelling of the lymph nodes, fatigue, hoarse voice, rhinorrhea, malaise, nasal obstruction, sputum production, inability to function at normal level of activity, and any combinations thereof.10. The method of any of embodiments 1-9, wherein the single loading dose is administered prior to the subject achieving a peak viral load.11. The method of any of embodiments 1-10, wherein the subject is asymptomatic but has been diagnosed with a respiratory enterovirus infection.12. The method of any of embodiments 1-11, wherein the maintenance dose is first administered about 6 to about 12 hours following administering the single loading dose.13. The method of any of embodiments 1-12, wherein the single loading dose is administered after the subject has been diagnosed with a respiratory enterovirus infection, wherein the diagnosis is achieved by a clinical diagnosis, multiplex PCR testing, rapid antigenAttorney Docket No. 433899-001802 testing, direct fluorescent antibody testing, arterial blood gas testing, chest x-rays, peak flow meter testing, pleural fluid cultures, lung CT scanning, lung function tests, pulse oximetry testing, spirometry testing, sputum testing, nasal swab testing, throat swab testing, or any combination thereof.14. The method of any of embodiments 1-13, wherein the single loading dose and maintenance dose are administered within about 30 minutes of the subject consuming a meal with solid food (e.g. the subject is in a fed state).15. The method of any of embodiments 1-14, wherein administering the single loading dose and maintenance dose to a subject within about 30 minutes of the subject consuming a meal with solid food results in a higher plasma concentration of vapendavir or a pharmaceutically acceptable salt thereof than administering the single loading dose and maintenance dose to a subject in a fasted state.16. The method of any of embodiments 1-15, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a dose of about 500 mg every 12 hours for about 4 to about 10 days.17. The method of any of embodiments 1-16, wherein a first dose is administered within about 48 hours of the subject displaying symptoms of a respiratory enterovirus infection.18. The method of any of embodiments 1-17, wherein a first dose is administered within about 72 to about 96 hours of the subject displaying symptoms of a respiratory enterovirus infection.19. The method of any of embodiments 1-18, wherein the symptoms of a respiratory enterovirus infection are selected from a cough, increased mucus production, sneezing, nasal congestion, runny nose, sore throat, headaches, muscle aches, breathlessness, tight chest, wheezing, fever, red eyes, swelling of the lymph nodes, fatigue, hoarse voice, rhinorrhea, malaise, nasal obstruction, sputum production, inability to function at normal level of activity, and any combinations thereof.20. The method of any of embodiments 1-19, wherein a first dose is administered prior to the subject achieving a peak viral load.21. The method of any of embodiments 1-20, wherein the subject is asymptomatic but has been diagnosed with a respiratory enterovirus infection.Attorney Docket No. 433899-00180222. The method of any of embodiments 1-21, wherein a first dose is administered after the subject has been diagnosed with a respiratory enterovirus infection, wherein the diagnosis is achieved by a clinical diagnosis, multiplex PCR testing, rapid antigen testing, direct fluorescent antibody testing, arterial blood gas testing, chest x-rays, peak flow meter testing, pleural fluid cultures, lung CT scanning, lung function tests, pulse oximetry testing, spirometry testing, sputum testing, nasal swab testing, throat swab testing, or any combination thereof.23. The method of any of embodiments 1 -22, wherein the dose is administered within about 30 minutes of the subject consuming a meal with solid food (e.g. the subject is in a fed state).24. The method of any of embodiments 1-23, wherein administering the dose to a subject within about 30 minutes of the subject consuming a meal with solid food results in a higher plasma concentration of vapendavir or a pharmaceutically acceptable salt thereof than administering the single loading dose and maintenance dose to a subject in a fasted state.25. The method of any of embodiments 1-24, wherein the subject is in a fed state.26. The method of any of embodiments 1 -25, wherein the subj ect is a human between about 40 and about 85 years of age.27. The method of any of embodiments 1-26, wherein the subject been diagnosed with GOLD stage 2 COPD, GOLD stage 3 COPD, or GOLD stage 4 COPD.28. The method of any of embodiments 1-27, wherein the subject is receiving stable maintenance therapy for COPD.29. The method of any of embodiments 1-28, wherein treating the respiratory enterovirus infection in the subject comprises decreasing a viral load in the sputum, nasal passages, or a combination thereof in the subject compared with a viral load in the sputum, nasal passages, or a combination thereof of the subject prior to treatment.30. The method of any of embodiments 1-29, wherein treating the respiratory enterovirus infection in the subject comprises decreasing, and / or preventing an increase in the subject’s Evaluating Respiratory Symptoms in COPD Score (E-RS) compared to the subject’s Evaluating Respiratory Symptoms in COPD Score (E-RS) prior to treatment.31. The method of any of embodiments 1-30, wherein treating the respiratory enterovirus infection in the subject comprises decreasing, and / or preventing an increase in the subject’sAttorney Docket No. 433899-001802 peak lower respiratory symptom score (LRSS) compared to the subject’s peak lower respiratory symptom score (LRSS) prior to treatment.32. The method of any of embodiments 1-31, wherein treating the respiratory enterovirus infection in the subject comprises decreasing, and / or preventing an increase in the subject’s peak upper respiratory symptom score (URSS) compared to the subject’s peak upper respiratory symptom score (URSS) prior to treatment.33. The method of any of embodiments 1-32, wherein treating the respiratory enterovirus infection in the subject comprises decreasing, and / or preventing an increase in the subject’s EXAcerbation of Chronic Pulmonary Disease Tool - Patient Reported Outcome (EXACT- PRO) compared to the subject’s EXAcerbation of Chronic Pulmonary Disease Tool - Patient Reported Outcome (EXACT-PRO) prior to treatment.34. The method of any of embodiments 1-33, wherein treating the respiratory enterovirus infection in the subject comprises decreasing, and / or preventing an increase in the subject’s EXAcerbation of Chronic Pulmonary Disease Tool - Patient Respiratory Symptoms (EXACT- RS) compared to the subject’s EXAcerbation of Chronic Pulmonary Disease Tool - Patient Respiratory Symptoms (EXACT-RS) prior to treatment.35. The method of any of embodiments 1-34, wherein treating the respiratory enterovirus infection in the subject comprises decreasing, and / or preventing an increase in the subject’s COPD assessment tool (CAT) compared to the subject’s COPD assessment tool (CAT) prior to treatment.36. The method of any of embodiments 1-35, wherein treating the respiratory enterovirus infection in the subject comprises decreasing, and / or preventing an increase in the subject’s St. George's Respiratory Questionnaire (SGRQ) compared to the subject’s St. George's Respiratory Questionnaire (SGRQ) prior to treatment.37. The method of any of embodiments 1-36, wherein treating the respiratory enterovirus infection in the subject comprises decreasing, and / or preventing an increase in the subject’s Wisconsin Upper Respiratory Symptom Survey (WURSS) compared to the subject’s Wisconsin Upper Respiratory Symptom Survey (WURSS) prior to treatment.Attorney Docket No. 433899-00180238. The method of any of embodiments 1-37, wherein treating the respiratory enterovirus infection in the subject comprises improving, and / or preventing a decrease in the subject’s lung function compared to the subject’s lung function prior to treatment.39. The method of any of embodiments 1-38, wherein the subject’s lung function is measured by Forced Expiratory Volume -1 (FEV-i; in liters and % predicted), Forced Vital Capacity (FVC; in liters and % predicted) FEVi / FVC ratio and peak expiratory flow (PEF), or any combination thereof.40. The method of any of embodiments 1-39, wherein treating the respiratory enterovirus infection in the subject comprises reducing, and / or preventing an increase in the subject’s peak nasal lavage viral load compared to the subject’s peak nasal lavage viral load prior to treatment.41. The method of any of embodiments 1-40, wherein treating the respiratory enterovirus infection in the subject comprises reducing, and / or preventing an increase in the subject’s peak sputum lavage viral load compared to the subject’s peak sputum lavage viral load prior to treatment.42. The method of any of embodiments 1-41, wherein treating the respiratory enterovirus infection in the subject comprises reducing, and / or preventing an increase in the subject’s AUC nasal viral load compared to the subject’s AUC nasal viral load prior to treatment.43. The method of any of embodiments 1-42, wherein treating the respiratory enterovirus infection in the subject comprises reducing, and / or preventing an increase in the subject’s AUC sputum viral load compared to the subject’s AUC sputum viral load prior to treatment.44. The method of any of embodiments 1-43, wherein treating the respiratory enterovirus infection in the subject comprises reducing the duration of viral shedding.45. The method of any of embodiments 1-44, wherein treating the respiratory enterovirus infection in the subject comprises reducing, and / or preventing an increase in the subject’s peak sputum bacterial load compared to the subject’s peak sputum lavage bacterial load prior to treatment.46. The method of any of embodiments 1-45, wherein treating the respiratory enterovirus infection in the subject comprises reducing, and / or preventing an increase in the subject’s AUC sputum bacterial load compared to the subject’s AUC sputum bacterial load prior to treatment.Attorney Docket No. 433899-00180247. The method of any of embodiments 1-46, wherein treating the respiratory enterovirus infection in the subject comprises reducing the number of days wherein the subject is positive for bacteria in the sputum.48. The method of any of embodiments 1-47, wherein treating the respiratory enterovirus infection in the subject comprises preventing, or reducing, acute exacerbations of COPD in the subject caused by the respiratory enterovirus infection.49. The method of any of embodiments 1-48, wherein treating the respiratory enterovirus infection in the subject comprises a reduction, and / or preventing an increase in in the frequency of acute COPD exacerbations in the subject, a reduction in the severity of acute COPD exacerbations in the subject, a reduction in the duration of acute COPD exacerbations in the subject or combinations thereof, caused by the respiratory enterovirus infection.50. The method of any of embodiments 1-49, wherein administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof exceeds the paECso for human rhinoviruses.51. The method of embodiment 1 -50, wherein the paECso for human rhinoviruses is about 75.4 ng / mL.52. The method of any of embodiments 1-51, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 4 to about 10 days.53. The method of any of embodiments 1-52, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses.54. The method of any of embodiments 1-53, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / mL.55. The method of any of embodiments 1-54, wherein the paECso for human rhinoviruses is exceeded for about 4 to about 10 days or until treatment is stopped.Attorney Docket No. 433899-00180256. The method of any of embodiments 1-55, wherein administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof exceeds the paECgo for human rhinoviruses.57. The method of any of embodiments 1-56, wherein the paECgo for human rhinoviruses is about 678.6 ng / mL.58. The method of any of embodiments 1-57, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 4 to about 10 days.59. The method of any of embodiments 1-58, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses.60. The method of any of embodiments 1-59, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / mL.61. The method of any of embodiments 1-60, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg per day for about 6 to about 10 days.62. The method of any of embodiments 1-63, wherein the paECgo for human rhinoviruses is exceeded for about 4 to about 10 days or until treatment is stopped.63. The method of any of embodiments 1-64, wherein administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof results in a Cmax that exceeds the paECso for human rhinoviruses.64. The method of any embodiments 1-65, wherein the paECso for human rhinoviruses is about 75.4 ng / mL.65. The method of any of embodiments 1-66, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of aboutAttorney Docket No. 433899-0018021,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses.66. The method of any of embodiments 1-67, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / mL.67. The method of any of embodiments 1-68, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg per day for about 6 to about 10 days.68. The method of any of embodiments 1-69, wherein the paECso for human rhinoviruses is exceeded for about 4 to about 10 days or until treatment is stopped.69. The method of any of embodiments 1-70, wherein administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof results in a Cmax that exceeds the paECgo for human rhinoviruses.70. The method of any of embodiments 1-71, wherein the paECgo for human rhinoviruses is about 678.6 ng / mL.71. The method of any of embodiments 1-72, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses.72. The method of any of embodiments 1-73, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / mL.73. The method of any of embodiments 1-74, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg per day for about 6 to about 10 days.74. The method of any of embodiments 1-75, wherein the paECgo for human rhinoviruses is exceeded for about 4 to about 10 days or until treatment is stopped.Attorney Docket No. 433899-00180275. The method of any of embodiments 1-76, wherein administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof exceeds the paECso for human rhinoviruses following a single dose.76. The method of any of embodiment 1-77, wherein the paECso for human rhinoviruses is about 75.4 ng / mL.77. The method of any of embodiments 1-78, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses.78. The method of any of embodiments 1-79, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / mL.79. The method of any of embodiments 1-80, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg per day for about 6 to about 10 days.80. The method of any of embodiments 1-81, wherein the paECso for human rhinoviruses is exceeded for about 4 to about 10 days or until treatment is stopped.81. The method of any of embodiments 1-82, wherein administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof exceeds the paECgo for human rhinoviruses.82. The method of any of embodiments 1-83, wherein the paECgo for human rhinoviruses is about 678.6 ng / mL.83. The method of any of embodiments 1-84, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses.Attorney Docket No. 433899-00180284. The method of any of embodiments 1-85, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / mL.85. The method of any of embodiments 1-86, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg per day for about 6 to about 10 days.86. The method of any of embodiments 1-87, wherein the paECgo for human rhinoviruses is exceeded for about 4 to about 10 days or until treatment is stopped.87. The method of any of embodiments 1-88, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is in tablet form.88. The method of any of embodiments 1-89, wherein the vapendavir is a free base, maleate salt, oxalate salt, phosphate salt, sulfate salt, tartrate salt, mesylate salt, or chloride salt.89. The method of any of embodiments 1 -90, wherein the vapendavir is an amorphous form of vapendavir or a pharmaceutically acceptable salt thereof.90. A pharmaceutical composition comprising a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof.91. The pharmaceutical composition of embodiment 90, wherein the vapendavir is a free base, maleate salt, oxalate salt, phosphate salt, sulfate salt, or chloride salt.92. The pharmaceutical composition of any of embodiments 90-91 , wherein the vapendavir is an amorphous form of vapendavir or a pharmaceutically acceptable salt thereof.93. The pharmaceutical composition of any of embodiments 90-92, comprising about 250 mg of vapendavir or a pharmaceutically acceptable salt thereof.94. The pharmaceutical composition of any of embodiments 90-93, comprising about 500 mg of vapendavir or a pharmaceutically acceptable salt thereof.95. The pharmaceutical composition of any of embodiments 90-94, wherein the pharmaceutical composition is a tablet.Attorney Docket No. 433899-00180296. The pharmaceutical composition of any of embodiments 90-95, further comprising a diluent, a disintegrant, a surfactant, a lubricant, a color coating, or any combination thereof.97. The pharmaceutical composition of any of embodiments 90-96, wherein the diluent is selected from Cellulose Microcrystalline Silicified (PROSOL VHD90) (USP / NF), anhydrous calcium phosphate, anhydrous lactose, calcium carbonate, calcium lactate, calcium sulfate dihydrate, corn starch, fructose, kaolin, lactose monohydrate, magnesium hydroxide, maltitol, maltose monohydrate, mannitol, sorbitol, sucrose, tribasic calcium phosphate, sodium citrate, glycine, croscarmellose sodium, ethanol, propylene glycol, glycerin, polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin, acacia, or any combination thereof.98. The pharmaceutical composition of any of embodiments 90-97, wherein the disintegrant is selected from Starch Glycolate Sodium (USP / NF / EP), corn starch, potato starch, tapioca starch, croscarmellose sodium, pre-gelatinized starch, sodium carboxymethylcellulose, alginates, resins, aqueous aluminum silicates, cross-linked polyvinylpyrrolidone, or any combination thereof.99. The pharmaceutical composition of any of embodiments 90-98, wherein the surfactant is selected from Pol oxamer Microprilled 188 (USP / NF / EP / JPE), sodium lauryl sulfate, polysorbates, or any combination thereof.100. The pharmaceutical composition of any of embodiments 90-99, wherein the lubricant is selected from Magnesium Stearate 5712 (USP / NF / EP), stearic acid, glyceryl behenate, talc, carnauba wax, polymers of ethylene oxide, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, colloidal silicon dioxide, hydroxypropylmethylcellulose, hydroxypropylcellulose, acrylate-methacrylate copolymers, or any combination thereof.101. The pharmaceutical composition of any of embodiments 90-100, wherein the color coating is selected from Opadry II White 85F 18422 (Mfg. Std.), riboflavin, anthocyanin, paprika oleoresin, beet root, curcumin, indigo carmine, tartrazine, allura red, quinoline yellow, titanium dioxide, iron oxide, mica, betacarotene, or any combination thereof.102. The pharmaceutical composition of any of embodiments 90-101, wherein the pharmaceutical composition further comprises Cellulose Microcrystalline Silicified (PROSOL VHD90) (USP / NF), Starch Glycolate Sodium (USP / NF / EP), PoloxamerAttorney Docket No. 433899-001802Microprilled 188 (USP / NF / EP / JPE), Magnesium Stearate 5712 (USP / NF / EP), and Opadry II White 85F 18422 (Mfg. Std.).103. The pharmaceutical composition of any of embodiments 90-102, wherein the pharmaceutical composition further comprises about 250 mg of Cellulose Microcrystalline Silicified (PROSOL VHD90) (USP / NF).104. The pharmaceutical composition of any of embodiments 90-103, wherein the pharmaceutical composition further comprises about 500 mg of Cellulose Microcrystalline Silicified (PROSOL VHD90) (USP / NF).105. The pharmaceutical composition of any of embodiments 90-104, wherein the pharmaceutical composition comprises about 50 mg of Starch Glycolate Sodium (USP / NF / EP).106. The pharmaceutical composition of any of embodiments 90-105, wherein the pharmaceutical composition comprises about 100 mg of Starch Glycolate Sodium (USP / NF / EP).107. The pharmaceutical composition of any of embodiments 90-106, wherein the pharmaceutical composition comprises about 10 mg of Pol oxamer Microprilled 188 (USP / NF / EP / JPE).108. The pharmaceutical composition of any of embodiments 90-107, wherein the pharmaceutical composition comprises about 20 mg of Pol oxamer Microprilled 188 (USP / NF / EP / JPE).109. The pharmaceutical composition of any of embodiments 90-108, wherein the pharmaceutical composition comprises about 10 mg of Magnesium Stearate 5712 (USP / NF / EP).110. The pharmaceutical composition of any of embodiments 90-109, wherein the pharmaceutical composition comprises about 20 mg of Magnesium Stearate 5712 (USP / NF / EP).111. The pharmaceutical composition of any of embodiments 90-110, wherein the pharmaceutical composition comprises about 15 mg of Opadry II White 85F 18422 (Mfg. Std.).Attorney Docket No. 433899-001802112. The pharmaceutical composition of any of embodiments 90-111, wherein the pharmaceutical composition comprises about 30 mg of Opadry II White 85F 18422 (Mfg. Std.).113. The pharmaceutical composition of any of embodiments 90-112, wherein the pharmaceutical composition comprises about 250 mg of vapendavir or a pharmaceutically acceptable salt thereof, about 250 mg of Cellulose Microcrystalline Silicified(PROSOLVHD90) (USP / NF), about 50 mg of Starch Glycolate Sodium (USP / NF / EP), about 10 mg of Pol oxamer Microprilled 188 (USP / NF / EP / JPE), about 10 mg of Magnesium Stearate 5712 (USP / NF / EP), and about 15 mg of Opadry II White 85F18422 (Mfg. Std.).114. The pharmaceutical composition of any of embodiments 90-113, wherein the pharmaceutical composition comprises about 500 mg of vapendavir or a pharmaceutically acceptable salt thereof, about 500 mg of Cellulose Microcrystalline Silicified (PROSOLVHD90) (USP / NF), about 100 mg of Starch Glycolate Sodium (USP / NF / EP), about 20 mg of Pol oxamer Microprilled 188 (USP / NF / EP / JPE), about 20 mg of Magnesium Stearate 5712 (USP / NF / EP), and about 30 mg of Opadry II White 85F18422 (Mfg. Std.).115. A method of treating a respiratory condition, wherein the respiratory condition is a respiratory enterovirus infection, an upper respiratory infection, a common cold, or a combination thereof, in a subject with COPD comprising orally administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof, thereby treating the respiratory condition in the subject.116. The method of embodiment 115, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is between about 250 mg and about 2,000 mg per day.117. The method of embodiment 115, wherein the respiratory condition is a respiratory enterovirus infection, and the respiratory enterovirus infection is selected from a rhinovirus, echovirus, EV-68, EV-71, coxsackie virus, a non-polio enterovirus and combinations thereof.118. The method of embodiment 115, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg to about 1000 mg daily for about 4 to about 10 days.Attorney Docket No. 433899-001802119. The method of embodiment 118, wherein the loading dose and maintenance dose are administered within about 30 minutes of the subject consuming a meal with solid food.120. The method of embodiment 118, wherein the subject is in a fed state when administering the loading dose and the maintenance doses.121. The method of embodiment 118, wherein the subject is in a fasted state when administering the loading dose and the maintenance doses.122. The method of embodiment 115, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / mL.123. The method of embodiment 115, wherein the vapendavir or a pharmaceutically acceptable salt thereof comprises vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof.124. The method of embodiment 115, wherein the subject been diagnosed with GOLD stage 1 COPD, GOLD stage 2 COPD, GOLD stage 3 COPD, or GOLD stage 4 COPD.125. The method of embodiment 115, wherein the subject is receiving stable maintenance therapy for COPD.126. The method of embodiment 115, wherein treating the respiratory condition in the subject comprises decreasing a viral load in the sputum, nasal passages, or a combination thereof in the subject compared with a viral load in the sputum, nasal passages, or a combination thereof of the subject prior to treatment.127. The method of embodiment 115, wherein treating the respiratory condition in the subject comprises decreasing a Evaluating Respiratory Symptoms in COPD Score (E-RS) in the subject compared to a Evaluating Respiratory Symptoms in COPD Score (E-RS) in the subject prior to treatment.128. The method of embodiment 115, wherein treating the respiratory condition in the subject comprises preventing an increase in a Evaluating Respiratory Symptoms in COPD Score (E-RS) in the subject compared to a Evaluating Respiratory Symptoms in COPD Score (E-RS) in the subject prior to treatment.Attorney Docket No. 433899-001802129. The method of embodiment 115, wherein treating the respiratory condition in the subject comprises decreasing a peak lower respiratory symptom score (LRSS) in the subject compared to a peak lower respiratory symptom score (LRSS) in the subject prior to treatment.130. The method of embodiment 115, wherein treating the respiratory condition in the subject comprises preventing an increase in a peak lower respiratory symptom score (LRSS) in the subject compared to a peak lower respiratory symptom score (LRSS) in the subject prior to treatment.131. The method of embodiment 115, wherein treating the respiratory condition in the subject comprises decreasing a peak upper respiratory symptom score (URSS) in the subject compared to a peak upper respiratory symptom score (URSS) in the subject prior to treatment.132. The method of embodiment 115, wherein treating the respiratory condition in the subject comprises preventing an increase in a peak upper respiratory symptom score (URSS) in the subject compared to a peak upper respiratory symptom score (URSS) in the subject prior to treatment.133. The method of embodiment 115, wherein treating the respiratory condition in the subject comprises decreasing or preventing an increase in an EXAcerbation of Chronic Pulmonary Disease Tool - Patient Reported Outcome (EXACT-PRO) in the subject compared to an EXAcerbation of Chronic Pulmonary Disease Tool - Patient Reported Outcome (EXACT-PRO) in the subject prior to treatment.134. The method of embodiment 115, wherein treating the respiratory condition in the subject comprises decreasing or preventing an increase in an EXAcerbation of Chronic Pulmonary Disease Tool - Patient Respiratory Symptoms (EXACT-RS) in the subject compared to an EXAcerbation of Chronic Pulmonary Disease Tool - Patient Respiratory Symptoms (EXACT-RS) in the subject prior to treatment.135. The method of embodiment 115, wherein treating the respiratory condition in the subject comprises preventing a decrease in lung function in the subject compared to lung function in the subject prior to treatment.136. The method of embodiment 135, wherein lung function in the subject is measured by Forced Expiratory Volume -1 (FEV-1; in liters and % predicted), Forced Vital Capacity (FVC;Attorney Docket No. 433899-001802 in liters and % predicted) FEV1 / FVC ratio and peak expiratory flow (PEF) or any combination thereof.137. The method of embodiment 115, wherein treating the respiratory condition in the subject comprises reducing or preventing an increase in a peak nasal lavage viral load in the subject compared to a peak nasal lavage viral load in the subject prior to treatment.138. The method of embodiment 115, wherein treating the respiratory condition in the subject comprises reducing or preventing an increase in a peak sputum lavage viral load in the subject compared to a peak sputum lavage viral load in the subject prior to treatment.139. The method of embodiment 115, wherein treating the respiratory condition in the subject comprises reducing or preventing an increase in an AUC nasal viral load in the subject compared to an AUC nasal viral load in the subject prior to treatment.140. The method of embodiment 115, wherein treating the respiratory condition in the subject comprises reducing or preventing an increase in an AUC sputum viral load in the subject compared to an AUC sputum viral load in the subject prior to treatment.141. The method of embodiment 115, wherein treating the respiratory condition in the subject comprises reducing the duration of viral shedding.142. The method of embodiment 115, wherein treating the respiratory condition in the subject comprises reducing or preventing an increase in a peak sputum bacterial load in the subject compared to a peak sputum lavage bacterial load in the subject prior to treatment.143. The method of embodiment 115, wherein treating the respiratory condition in the subject comprises reducing or preventing an increase in an AUC sputum bacterial load in the subject compared to an AUC sputum bacterial load in the subject prior to treatment.144. The method of embodiment 115, wherein treating the respiratory condition in the subject comprises reducing the number of days wherein the subject is positive for bacteria in the sputum.145. The method of embodiment 115, wherein treating the respiratory condition in the subject results in a time to resolution of less than about 3.5 days.146. The method of embodiment 115, wherein treating the respiratory condition in the subject results in less than about 2 days with clinically significant deterioration.Attorney Docket No. 433899-001802147. The method of embodiment 115, wherein treating the respiratory condition in the subject minimizes a Type 2 immune response phenotype in the subject.148. The method of embodiment 115, wherein treating the respiratory condition in the subject does not comprise administering a chronic immune therapy to the subject.149. The method of embodiment 115, further comprising administering to the subject a therapeutically effective amount of pleconaril to the subject.150. A method of treating a respiratory condition, wherein the respiratory condition is a respiratory enterovirus infection, an upper respiratory infection, a common cold, or a combination thereof, in a subject with asthma comprising orally administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof, thereby treating the respiratory condition in the subject.151. The method of embodiment 150, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is between about 250 mg and about 2,000 mg per day.152. The method of embodiment 150, wherein the respiratory condition is a respiratory enterovirus infection, and the respiratory enterovirus infection is selected from a rhinovirus, echovirus, EV-68, EV-71, coxsackie virus, a non-polio enterovirus and combinations thereof.153. The method of embodiment 150, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg to about 1000 mg daily for about 4 to about 10 days.154. The method of embodiment 153, wherein the loading dose and maintenance dose are administered within about 30 minutes of the subject consuming a meal with solid food.155. The method of embodiment 153, wherein the subject is in a fed state when administering the loading dose and the maintenance doses.156. The method of embodiment 153, wherein the subject is in a fasted state when administering the loading dose and the maintenance doses.Attorney Docket No. 433899-001802157. The method of embodiment 150, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / mL.158. The method of embodiment 150, wherein the vapendavir or a pharmaceutically acceptable salt thereof comprises vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof.159. The method of embodiment 150, wherein the subject has asthma, and wherein treating the respiratory enterovirus in the subject comprises decreasing the subject’s Asthma Control Questionnaire (ACQ) score compared to the subject’s ACQ score prior to treatment.160. The method of embodiment 150, wherein the subject has asthma, and wherein treating the respiratory enterovirus in the subject comprises preventing an increase in the subject’s Asthma Control Questionnaire (ACQ) score compared to the subject’s ACQ score prior to treatment.161. The method of embodiment 150, wherein the subject has asthma, and wherein treating the respiratory enterovirus in the subject comprises decreasing the subject’s Asthma Control Test (ACT) score compared to the subject’s ACT score prior to treatment.162. The method of embodiment 150, wherein the subject has asthma, and wherein treating the respiratory enterovirus in the subject comprises preventing an increase in the subject’s Asthma Control Test (ACT) score compared to the subject’s ACT score prior to treatment.163. The method of embodiment 150, wherein the subject has asthma, and wherein treating the respiratory enterovirus in the subject comprises decreasing the subject’s Pediatric Asthma Symptom Scale (PASS) score compared to the subject’s PASS score prior to treatment.164. The method of embodiment 150, wherein the subject has asthma, and wherein treating the respiratory enterovirus in the subject comprises preventing an increase in the subject’s Pediatric Asthma Symptom Scale (PASS) score compared to the subject’s PASS score prior to treatment.165. The method of embodiment 150, wherein the subject has asthma, and wherein treating the respiratory enterovirus in the subject comprises decreasing the subject’s Asthma Severity Scoring System (ASSESS) score compared to the subject’s ASSESS score prior to treatment.Attorney Docket No. 433899-001802166. The method of embodiment 150, wherein the subject has asthma, and wherein treating the respiratory enterovirus in the subject comprises preventing an increase in the subject’s Asthma Severity Scoring System (ASSESS) score compared to the subject’s ASSESS score prior to treatment.167. The method of embodiment 150, wherein the subject has asthma, and wherein treating the respiratory enterovirus in the subject comprises decreasing the subject’s Pediatric Asthma Score (PAS) score compared to the subject’s PAS score prior to treatment.168. The method of embodiment 150, wherein the subject has asthma, and wherein treating the respiratory enterovirus in the subject comprises preventing an increase in the subject’s Pediatric Asthma Score (PAS) score compared to the subject’s PAS score prior to treatment.169. The method of embodiment 150, wherein the subject has asthma, and wherein treating the respiratory enterovirus in the subject comprises decreasing the subject’s Pediatric Respiratory Assessment Measure (PRAM) score compared to the subject’s PRAM score prior to treatment.170. The method of embodiment 150, wherein the subject has asthma, and wherein treating the respiratory enterovirus in the subject comprises preventing an increase in the subject’s Pediatric Respiratory Assessment Measure (PRAM) score compared to the subject’s PRAM score prior to treatment.171. The method of embodiment 150, wherein the subject has asthma, and wherein treating the respiratory enterovirus in the subject comprises decreasing the subject’s Pediatric Asthma Risk Score (PARS) score compared to the subject’s PARS score prior to treatment.172. The method of embodiment 150, wherein the subject has asthma, and wherein treating the respiratory enterovirus in the subject comprises preventing an increase in the subject’s Pediatric Asthma Risk Score (PARS) score compared to the subject’s PARS score prior to treatment.173. The method of embodiment 150, wherein treating the respiratory enterovirus in the subject comprises preventing a decrease in the subject’s lung function compared to the subject’s lung function prior to treatment.174. The method of embodiment 173, wherein the subject’s lung function is measured by Forced Expiratory Volume -1 (FEV-1; in liters and % predicted), Forced Vital Capacity (FVC;Attorney Docket No. 433899-001802 in liters and % predicted) FEV1 / FVC ratio and peak expiratory flow (PEF) or any combination thereof.175. The method of embodiment 150, wherein treating the respiratory enterovirus in the subject comprises reducing or preventing an increase in the subject’s peak nasal lavage viral load compared to the subject’s peak nasal lavage viral load prior to treatment.176. The method of embodiment 150, wherein treating the respiratory enterovirus in the subject comprises reducing or preventing an increase in the subject’s peak sputum lavage viral load compared to the subject’s peak sputum lavage viral load prior to treatment.177. The method of embodiment 150, wherein treating the respiratory enterovirus in the subject comprises reducing or preventing an increase in the subject’s AUC nasal viral load compared to the subject’s AUC nasal viral load prior to treatment.178. The method of embodiment 150, wherein treating the respiratory enterovirus in the subject comprises reducing or preventing an increase in the subject’s AUC sputum viral load compared to the subject’s AUC sputum viral load prior to treatment.179. The method of embodiment 150, wherein treating the respiratory enterovirus in the subject comprises reducing the duration of viral shedding.180. The method of embodiment 150, wherein treating the respiratory enterovirus in the subject comprises reducing or prevent...

Claims

Attorney Docket No. 433899-001802CLAIMSWhat is claimed is:

1. A method of treating a respiratory condition, wherein the respiratory condition is a respiratory enterovirus infection, an upper respiratory infection, a common cold, or a combination thereof, in a subject with COPD comprising orally administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof, thereby treating the respiratory condition in the subject.

2. The method of claim 1, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is between about 250 mg and about 2,000 mg per day.

3. The method of claim 1, wherein the respiratory condition is a respiratory enterovirus infection, and the respiratory enterovirus infection is selected from a rhinovirus, echovirus, EV-68, EV-71, coxsackie virus, a non-polio enterovirus and combinations thereof.

4. The method of claim 1, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg to about 1000 mg daily for about 4 to about 10 days.

5. The method of claim 4, wherein the loading dose and maintenance dose are administered within about 30 minutes of the subject consuming a meal with solid food.

6. The method of claim 4, wherein the subject is in a fed state when administering the loading dose and the maintenance doses.

7. The method of claim 4, wherein the subject is in a fasted state when administering the loading dose and the maintenance doses.

8. The method of claim 1, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / mL.

9. The method of claim 1, wherein the vapendavir or a pharmaceutically acceptable salt thereof comprises vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof.Attorney Docket No. 433899-00180210. The method of claim 1, wherein the subject been diagnosed with GOLD stage 1 COPD, GOLD stage 2 COPD, GOLD stage 3 COPD, or GOLD stage 4 COPD.

11. The method of claim 1, wherein the subject is receiving stable maintenance therapy for COPD.

12. The method of claim 1, wherein treating the respiratory enterovirus in the subject comprises preventing a decrease in the subject’s lung function compared to the subject’s lung function prior to treatment.

13. The method of claim 12, wherein the subject’s lung function is measured by Forced Expiratory Volume -1 (FEV-i; in liters and % predicted), Forced Vital Capacity (FVC; in liters and % predicted) FEVi / FVC ratio and peak expiratory flow (PEF) or any combination thereof.

14. The method of claim 1, wherein treating the respiratory condition in the subject comprises decreasing a viral load in the sputum, nasal passages, or a combination thereof in the subject compared with a viral load in the sputum, nasal passages, or a combination thereof of the subject prior to treatment.

15. The method of claim 1, wherein treating the respiratory condition in the subject results in a time to resolution of less than about 3.5 days.

16. The method of claim 1, wherein treating the respiratory condition in the subject results in less than about 2 days with clinically significant deterioration.

17. The method of claim 1, wherein treating the respiratory condition in the subject minimizes a Type 2 immune response phenotype in the subject.

18. The method of claim 1, wherein treating the respiratory condition in the subject does not comprise administering a chronic immune therapy to the subject.

19. The method of claim 1 , further comprising administering to the subj ect a therapeutically effective amount of pleconaril to the subject.

20. A method of treating a respiratory condition, wherein the respiratory condition is a respiratory enterovirus infection, an upper respiratory infection, a common cold, or a combination thereof, in a subject with asthma comprising orally administering to the subject a therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof, thereby treating the respiratory condition in the subject.Attorney Docket No. 433899-00180221. The method of claim 20, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is between about 250 mg and about 2,000 mg per day.

22. The method of claim 20, wherein the respiratory condition is a respiratory enterovirus infection, and the respiratory enterovirus infection is selected from a rhinovirus, echovirus, EV-68, EV-71, coxsackie virus, a non-polio enterovirus and combinations thereof.

23. The method of claim 20, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is a loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg to about 1000 mg daily for about 4 to about 10 days.

24. The method of claim 23, wherein the loading dose and maintenance dose are administered within about 30 minutes of the subject consuming a meal with solid food.

25. The method of claim 23, wherein the subject is in a fed state when administering the loading dose and the maintenance doses.

26. The method of claim 23, wherein the subject is in a fasted state when administering the loading dose and the maintenance doses.

27. The method of claim 20, wherein the therapeutically effective amount of vapendavir or a pharmaceutically acceptable salt thereof is an amount that achieves a Cmax of about 2000 to about 12000 ng / mL.

28. The method of claim 20, wherein the vapendavir or a pharmaceutically acceptable salt thereof comprises vapendavir chloride, vapendavir oxalate, vapendavir maleate, vapendavir tartrate, vapendavir mesylate, amorphous vapendavir, or any combination thereof.

29. The method of claim 20, wherein treating the respiratory enterovirus in the subject comprises preventing a decrease in the subject’s lung function compared to the subject’s lung function prior to treatment.

30. The method of claim 29, wherein the subject’s lung function is measured by Forced Expiratory Volume -1 (FEV-i; in liters and % predicted), Forced Vital Capacity (FVC; in liters and % predicted) FEVi / FVC ratio and peak expiratory flow (PEF) or any combination thereof.

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