Treatment methods for enteroviruses in patients with chronic obstructive pulmonary disease

Abstract

[Solution] This disclosure describes a method for treating a respiratory enterovirus infection in a human subject having COPD, comprising the steps of: administering to the subject a therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof; and thereby treating the respiratory enterovirus infection in the subject. Pharmaceutical formulations of bapendavir are also disclosed.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims, pursuant to 35 U.S.C. § 119(e), the benefit of priority from U.S. Provisional Application No. 63 / 489,929 filed March 13, 2023, U.S. Provisional Application No. 63 / 578,073 filed August 28, 2023, U.S. Provisional Application No. 63 / 489,936 filed March 13, 2023, and U.S. Provisional Application No. 63 / 578,078 filed August 28, 2023. The disclosures of the aforementioned prior applications are deemed to constitute an entirety of the disclosures of this Specified and are incorporated herein by reference. [Background technology]

[0002] Rhinoviruses (RVs) are small RNA viruses that exhibit remarkable diversity within the Enterovirus (EV) genus, with over 180 different strains. RVs are the most common cause of upper respiratory tract infections (UTRIs) and frequent causes of community-acquired pneumonia in adults. While RVs are usually associated with mild, spontaneously resolving cold-like symptoms, they can cause significant morbidity and mortality through exacerbations of chronic respiratory diseases such as asthma, cystic fibrosis, primary ciliary dysplasia, or COPD.

[0003] Acute exacerbations are a major cause of morbidity and mortality associated with COPD. These exacerbations are associated with a decline in quality of life and an accelerated deterioration of lung function. Approximately 40–50% of COPD exacerbations are associated with RV infection. However, current treatments for managing COPD and treating acute exacerbations aim to alleviate symptoms and often have serious side effects. Current treatments such as long-acting muscarinic receptor antagonists (LAMAs), long-acting β2 receptor agonists (LABAs), inhaled corticosteroids (ICS), and antibiotics are only partially effective and fail to address the underlying mechanisms of the disease or the triggers for exacerbations.

[0004] Bapendavir (VPV) is a potent, broad-spectrum antiviral agent that is active against numerous RV serotypes and other enteroviruses, as evaluated in cell-based assays and human clinical trials. No significant safety concerns have been observed with single or multiple doses of babendavir in humans. There remains a need for effective treatments for RV infections, particularly in patients with chronic respiratory diseases such as COPD. [Overview of the Initiative]

[0005] Embodiments herein relate to a method for treating a respiratory enterovirus infection in a human subject having COPD, the method comprising the step of orally administering to the subject a therapeutically effective dose of babendavir or a pharmaceutically acceptable salt thereof, thereby treating the respiratory enterovirus infection in the subject.

[0006] In some embodiments, the respiratory enterovirus is selected from rhinovirus, echovirus, EV-68, EV-71, coxsackievirus, non-polioenterovirus, and combinations thereof.

[0007] In some embodiments, the therapeutically effective dose of babendavir or a pharmaceutically acceptable salt thereof is approximately 250 mg to approximately 2,000 mg per day.

[0008] In some embodiments, the therapeutically effective dose of babendavir 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 10 days.

[0009] In some embodiments, the therapeutically effective dose of babendavir or a pharmaceutically acceptable salt thereof is administered as a single loading dose of about 1,000 mg, followed by a total of about 13 maintenance doses of about 500 mg every 12 hours.

[0010] In some embodiments, the therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof is approximately 2,000 to approximately 12,000 ng / ml of C max It is the quantity that achieves that.

[0011] In some embodiments, the single loading dose is administered within approximately 48 hours of the subject exhibiting symptoms of respiratory enterovirus infection.

[0012] In some embodiments, the subject is asymptomatic but diagnosed with respiratory enterovirus infection.

[0013] In some embodiments, the maintenance dose is first administered about 6 to 12 hours after the single loading dose.

[0014] In some embodiments, the single loading dose is administered after the subject has been diagnosed with a respiratory enterovirus infection, and the diagnosis is achieved by clinical diagnosis, multiplex PCR testing, rapid antigen testing, direct immunofluorescence testing, arterial blood gas analysis, chest X-ray, peak flow metering, pleural fluid culture, lung CT, pulmonary function tests, pulse oximetry, spirometry, sputum testing, nasal swab testing, pharyngeal swab testing, or any combination thereof.

[0015] In some embodiments, the subject is in a feeding state at the time of administration.

[0016] In some embodiments, the single loading dose and maintenance dose are administered within approximately 30 minutes after the subject has ingested a meal containing solid food. In some embodiments, the single loading dose and maintenance dose are administered within approximately 30 minutes after the subject has ingested a meal containing high-fat solid food. In some embodiments, administering the single loading dose and maintenance dose to the subject within approximately 30 minutes after the subject has ingested a meal containing solid food results in higher plasma concentrations of bapendavir or its pharmaceutically acceptable salt compared to administering the single loading dose and maintenance dose to a fasted subject.

[0017] In some embodiments, the subject is diagnosed with GOLD Stage 1 COPD, GOLD Stage 2 COPD, GOLD Stage 3 COPD, or GOLD Stage 4 COPD.

[0018] In some embodiments, the subjects are receiving stable maintenance therapy for COPD.

[0019] In some embodiments, treatment of respiratory enterovirus infection in the subject includes reducing the viral load in sputum, nasal cavity, or a combination thereof compared to the viral load in the subject prior to treatment.

[0020] In some embodiments, treatment of respiratory enterovirus infection in the subject includes reducing the respiratory symptom rating score (E-RS) in the subject's COPD compared to the subject's COPD

[0021] In some embodiments, treatment of a respiratory enterovirus infection in the subject includes reducing the subject's subpeak subairway symptom score (LRSS) compared to the subject's pre-treatment LRSS, or preventing an increase thereof.

[0022] In some embodiments, treatment of a respiratory enterovirus infection in the subject includes reducing the subject's peak upper airway symptom score (URSS) compared to the subject's peak upper airway symptom score (URSS) before treatment, or preventing an increase thereof.

[0023] In some embodiments, treatment of respiratory enterovirus infection in the subject includes reducing or preventing an increase in the chronic lung disease exacerbation tool-patient reported outcome (EXACT-PRO) of the subject compared to the subject's chronic lung disease exacerbation tool-patient reported outcome (EXACT-PRO) before treatment.

[0024] In some embodiments, treatment of respiratory enterovirus infection in the subject includes reducing or preventing an increase in the subject's chronic lung disease exacerbation tool-patient respiratory symptoms (EXACT-RS) compared to the subject's chronic lung disease exacerbation tool-patient respiratory symptoms (EXACT-RS) before treatment.

[0025] In some embodiments, treatment of respiratory enterovirus infection in the subject includes reducing the COPD Assessment Tool (CAT) of the subject compared to the COPD Assessment Tool (CAT) of the subject before treatment, or preventing an increase thereof.

[0026] In some embodiments, treatment of a respiratory enterovirus infection in the subject includes reducing the St. George's Respiratory Questionnaire (SGRQ) score of the subject compared to the subject's SGRQ score before treatment, or preventing an increase thereof.

[0027] In some embodiments, treatment of a respiratory enterovirus infection in the subject includes reducing the Wisconsin Upper Respiratory Symptom Survey (WURSS) of the subject compared to the subject's WURSS before treatment, or preventing an increase thereof.

[0028] In some embodiments, treatment of a respiratory enterovirus infection in the subject includes improving or preventing a decline in the subject's lung function compared to the subject's lung function before treatment.

[0029] In some embodiments, the target lung function is defined as the forced expiratory volume in one second (FEV1). -1 It is measured by liters and predicted %), forced vital capacity (FVC; liters and predicted %), FEV1 / FVC ratio, and peak expiratory flow rate (PEF), or a combination thereof.

[0030] In some embodiments, treatment of respiratory enterovirus infection in the subject includes reducing the peak nasal lavage viral load in the subject compared to the peak nasal lavage viral load in the subject before treatment, or preventing an increase thereof.

[0031] In some embodiments, treatment of respiratory enterovirus infection in the subject includes reducing the peak sputum lavage viral load of the subject compared to the peak sputum lavage viral load of the subject before treatment, or preventing an increase thereof.

[0032] In some embodiments, treatment of a respiratory enterovirus infection in the subject includes reducing the AUC of the nasal viral load in the subject compared to the AUC of the nasal viral load in the subject before treatment, or preventing an increase thereof.

[0033] In some embodiments, treatment of respiratory enterovirus infection in the subject includes reducing the AUC of the sputum viral load in the subject compared to the AUC of the sputum viral load in the subject before treatment, or preventing an increase thereof.

[0034] In some embodiments, treatment of respiratory enterovirus infection in the subject includes shortening the period of viral shedding.

[0035] In some embodiments, treatment of respiratory enterovirus infection in the subject includes reducing the peak sputum lavage bacterial load of the subject compared to the peak sputum lavage bacterial load of the subject before treatment, or preventing an increase thereof.

[0036] In some embodiments, treatment of respiratory enterovirus infection in the subject includes reducing the AUC of the subject's sputum bacterial load compared to the AUC of the subject's sputum bacterial load before treatment, or preventing an increase thereof.

[0037] In some embodiments, treatment of respiratory enterovirus infection in the subject includes reducing the number of days the subject is bacterial-positive in sputum.

[0038] In some embodiments, treatment of respiratory enterovirus infection in the subject includes preventing or reducing acute exacerbations of COPD in the subject caused by respiratory enterovirus infection.

[0039] In some embodiments, treatment of respiratory enterovirus infection in the subject includes reducing the frequency of acute exacerbations of COPD in the subject caused by respiratory enterovirus infection, reducing the severity of acute exacerbations of COPD in the subject, reducing the duration of acute exacerbations of COPD in the subject, or a combination thereof.

[0040] In some embodiments, treatment of respiratory enterovirus infection in the subject includes preventing an increase in the frequency of acute exacerbations of COPD in the subject caused by respiratory enterovirus infection, preventing an increase in the severity of acute exacerbations of COPD in the subject, preventing an increase in the duration of acute exacerbations of COPD in the subject, or a combination thereof.

[0041] In some embodiments, administering a therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof to the subject allows for the treatment of paEC against human rhinovirus. 50exceeds. In some embodiments, the paEC against the human rhinovirus 50 is about 75.4 ng / ml.

[0042] In some embodiments, the therapeutically effective amount of the vaborbinal or a pharmaceutically acceptable salt thereof is to administer a maintenance dose of about 500 mg every 12 hours for about 4 to about 10 days following a single loading dose of about 1,000 mg. In some embodiments, the therapeutically effective amount of the vaborbinal or a pharmaceutically acceptable salt thereof is to administer a maintenance dose of about 500 mg every 12 hours as a total of about 13 maintenance dose administrations following a single loading dose of about 1,000 mg. In some embodiments, the therapeutically effective amount of the vaborbinal or a pharmaceutically acceptable salt thereof is an amount that achieves a C max In some embodiments, the paEC against the human rhinovirus 50 is exceeded for about 4 to about 10 days or until treatment is discontinued.

[0043] In some embodiments, by administering a therapeutically effective amount of the vaborbinal or a pharmaceutically acceptable salt thereof to the subject, the paEC against the human rhinovirus 90 is exceeded. In some embodiments, the paEC against the human rhinovirus 90 is about 678.6 ng / ml. In some embodiments, the therapeutically effective amount of the vaborbinal or a pharmaceutically acceptable salt thereof is to administer a maintenance dose of about 500 mg every 12 hours for about 4 to about 10 days following a single loading dose of about 1,000 mg. In some embodiments, the therapeutically effective amount of the vaborbinal or a pharmaceutically acceptable salt thereof is to administer a maintenance dose of about 500 mg every 12 hours as a total of about 13 maintenance dose administrations following a single loading dose of about 1,000 mg. In some embodiments, the therapeutically effective amount of the vaborbinal or a pharmaceutically acceptable salt thereof is an amount that achieves a C maxThis is the amount that achieves the goal of paEC against human rhinovirus. In some embodiments, paEC against human rhinovirus 90 This can last for approximately 4 to 10 days, or until treatment is discontinued.

[0044] In some embodiments, a therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof is administered to a subject to treat paEC against human rhinovirus. 50 Exceeding C max In some embodiments, paEC against human rhinovirus is obtained. 50 The C is approximately 75.4 ng / ml. In some embodiments, the therapeutic effective dose of babendavir or its pharmaceutically acceptable salt is a single loading dose of approximately 1,000 mg followed by a maintenance dose of approximately 500 mg every 12 hours for approximately 4 to 10 days. In some embodiments, the therapeutic effective dose of babendavir or its pharmaceutically acceptable salt is a single loading dose of approximately 1,000 mg followed by a maintenance dose of approximately 500 mg every 12 hours for a total of approximately 13 maintenance doses. In some embodiments, the therapeutic effective dose of babendavir or its pharmaceutically acceptable salt is approximately 2,000 to approximately 12,000 ng / ml C max This is the amount that achieves the goal of paEC against human rhinovirus. In some embodiments, paEC against human rhinovirus 50 This can last for approximately 4 to 10 days, or until treatment is discontinued.

[0045] In some embodiments, a therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof is administered to a subject to treat paEC against human rhinovirus. 90 Exceeding C max In some embodiments, paEC against human rhinovirus is obtained. 90The C is approximately 678.6 ng / ml. In some embodiments, the therapeutic effective dose of babendavir or its pharmaceutically acceptable salt is a single loading dose of approximately 1,000 mg followed by a maintenance dose of approximately 500 mg every 12 hours for approximately 4 to 10 days. In some embodiments, the therapeutic effective dose of babendavir or its pharmaceutically acceptable salt is a single loading dose of approximately 1,000 mg followed by a total of approximately 13 maintenance doses of approximately 500 mg every 12 hours. In some embodiments, the therapeutic effective dose of babendavir or its pharmaceutically acceptable salt is approximately 2,000 to approximately 12,000 ng / ml C max This is the amount that achieves the goal of paEC against human rhinovirus. In some embodiments, paEC against human rhinovirus 90 This can last for approximately 4 to 10 days, or until treatment is discontinued.

[0046] In some embodiments, administering a therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof to a subject results in a single dose of paEC against human rhinovirus. 50 It exceeds. In some embodiments, paEC against human rhinovirus. 50 The C is approximately 75.4 ng / ml. In some embodiments, the therapeutic effective dose of babendavir or its pharmaceutically acceptable salt is a single loading dose of approximately 1,000 mg followed by a maintenance dose of approximately 500 mg every 12 hours for approximately 4 to 10 days. In some embodiments, the therapeutic effective dose of babendavir or its pharmaceutically acceptable salt is a single loading dose of approximately 1,000 mg followed by a maintenance dose of approximately 500 mg every 12 hours for a total of approximately 13 maintenance doses. In some embodiments, the therapeutic effective dose of babendavir or its pharmaceutically acceptable salt is approximately 2,000 to approximately 12,000 ng / ml C max This is the amount that achieves the goal of paEC against human rhinovirus. In some embodiments, paEC against human rhinovirus 50 This can last for approximately 4 to 10 days, or until treatment is discontinued.

[0047] In some embodiments, a therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof is administered to a subject to treat paEC against human rhinovirus. 90 It exceeds. In some embodiments, paEC against human rhinovirus. 90 The C is approximately 678.6 ng / ml. In some embodiments, the therapeutic effective dose of babendavir or its pharmaceutically acceptable salt is a single loading dose of approximately 1,000 mg followed by a maintenance dose of approximately 500 mg every 12 hours for approximately 4 to 10 days. In some embodiments, the therapeutic effective dose of babendavir or its pharmaceutically acceptable salt is a single loading dose of approximately 1,000 mg followed by a total of approximately 13 maintenance doses of approximately 500 mg every 12 hours. In some embodiments, the therapeutic effective dose of babendavir or its pharmaceutically acceptable salt is approximately 2,000 to approximately 12,000 ng / ml C max This is the amount that achieves the goal of paEC against human rhinovirus. In some embodiments, paEC against human rhinovirus 90 This can last for approximately 4 to 10 days, or until treatment is discontinued.

[0048] In some embodiments, the therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof is in tablet form. In some embodiments, bapendavir is a free base, maleate, oxalate, phosphate, sulfate, tartrate, or chloride salt. In some embodiments, bapendavir or a pharmaceutically acceptable salt thereof is in amorphous form.

[0049] Some embodiments relate to pharmaceutical compositions comprising a therapeutically effective amount of bapendavir or a pharmaceutically acceptable salt thereof. In some embodiments, bapendavir is a free base or a pharmaceutically acceptable salt, such as a maleate, oxalate, phosphate, sulfate, tartrate, or chloride salt. In some embodiments, bapendavir is an amorphous form of bapendavir or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 250 mg of bapendavir or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is a tablet. [Brief explanation of the drawing]

[0050] The aspects, features, advantages and superiority of the embodiments described herein will become apparent with respect to the following description, the appended claims and the appended drawings.

[0051] [Figure 1] This is a diagram of the trial design for a clinical trial of bapendavir for the treatment of respiratory enterovirus infection in subjects with COPD. [Figure 2] The mean bapendavir plasma concentration versus time profiles (left = linear scale, right = logarithmic scale) in healthy volunteers (Group A) (Phase 1 and Phase 2 (fasting / feeding)) are shown. [Figure 3] The mean bapendavir plasma concentration-time profiles (left = linear scale, right = logarithmic scale) in healthy volunteers (Group A) (Treatment C) (Days 1-7) are shown. Day 1 = VPV 1,000 mg morning and 500 mg evening; Day 4 = VPV 500 mg BID; Day 7 = VPV 500 mg BID. [Figure 4] The mean bapendavir plasma concentration-time profiles (left = linear scale, right = logarithmic scale) in participants diagnosed with COPD (Group B - Treatment C) (Days 1-7) are shown. SD = standard deviation. Day 1 = VPV 1,000 mg morning and 500 mg evening, Day 4 = VPV 500 mg BID, Day 7 = VPV 500 mg BID. [Figure 5]The mean plasma concentrations after VPV administration for Group B-Treatment C (Days 1-7 (Day 1 = VPV 1,000 mg morning and 500 mg evening, Day 4 = VPV 500 mg BID, Day 7 = VPV 500 mg BID)) are shown, and the mean protein-corrected EC50 for human rhinovirus is also shown. [Figure 6] The mean plasma concentrations in COPD participants who received a 1,000 mg loading dose followed by a full 7-day course of 500 mg BID are shown. [Figure 7] The mean Cmax for the fasting group and the feeding group in COPD participants is shown. In the fasting group (Group B - Treatment C (Days 1-7 (Day 1 = VPV 1,000 mg morning dose and 500 mg evening dose, Day 4 = VPV 500 mg BID, Day 7 = VPV 500 mg BID))), the Cmax was shown on Day 1, Day 4, and Day 7. In the feeding group (1,000 mg loading dose followed by 500 mg BID for a full 7 days), the Cmax was shown on Day 1, Day 2, and Day 7. [Figure 8] The mean Cmax for the fasting group and the feeding group in COPD participants and healthy volunteers is shown. In the fasting group (Group A (healthy volunteers) and Group B (COPD) - Treatment C (Days 1-7 (Day 1 = VPV 1,000 mg morning dose and 500 mg evening dose, Day 4 = VPV 500 mg BID, Day 7 = VPV 500 mg BID))), the Cmax was shown on Day 1, Day 4, and Day 7. In the feeding group (1,000 mg loading dose followed by 500 mg BID for a full 7 days), the Cmax was shown on Day 1, Day 2, and Day 7. [Figure 9] This shows the average Cmin (12 hours) for the fasting group and the feeding group in COPD participants. For the fasting group (Group B - Treatment C (Days 1-7 (Day 1 = VPV 1,000 mg morning dose and 500 mg evening dose, Day 4 = VPV 500 mg BID, Day 7 = VPV 500 mg BID))), the average Cmin was calculated on Day 1, Day 4, and Day 7. For the feeding group (1,000 mg loading dose followed by 500 mg BID for a full 7 days), the average Cmin was calculated on Day 1, Day 2, and Day 7. [Figure 10]The mean Cmin (12 hours) for the fasting group and the feeding group in COPD participants and healthy volunteers is shown. In the fasting group (Group A (healthy volunteers) and Group B (COPD) - Treatment C (Days 1-7 (Day 1 = VPV 1,000 mg morning dose and 500 mg evening dose, Day 4 = VPV 500 mg BID, Day 7 = VPV 500 mg BID))), the mean Cmin was shown on Day 1, Day 4, and Day 7. In the feeding group (1,000 mg loading dose followed by 500 mg BID for a full 7 days), the mean Cmin was shown on Day 1, Day 2, and Day 7. [Figure 11] The Cmax for each treatment day for each COPD patient who was eating during the study is shown. [Figure 12] The Cmax for each treatment day for each COPD subject (Group B) who was in a fasting state during the study is shown. [Figure 13] The coefficient of variation of Cmax in the fasting group and the feeding group in COPD participants is shown. In the fasting group (Group B - Treatment C (Days 1-7 (Day 1 = VPV 1,000 mg morning administration and 500 mg evening administration, Day 4 = VPV 500 mg BID, Day 7 = VPV 500 mg BID))), the coefficients of variation were on Day 1, Day 4, and Day 7. In the feeding group (1,000 mg loading dose followed by 500 mg BID for a full 7 days), the coefficients of variation were on Day 1, Day 2, and Day 7. [Figure 14] The coefficient of variation of Cmin in the fasting group and the feeding group in COPD participants is shown. In the fasting group (Group B - Treatment C (Days 1-7 (Day 1 = VPV 1,000 mg morning administration and 500 mg evening administration, Day 4 = VPV 500 mg BID, Day 7 = VPV 500 mg BID))), the coefficients of variation were shown on Day 1, Day 4, and Day 7. In the feeding group (1,000 mg loading dose followed by 500 mg BID for a full 7 days), the coefficients of variation were shown on Day 1, Day 2, and Day 7. [Figure 15] The Kel (elimination rate constant) for each of the six participants in the feeding group (who received a loading dose of 1,000 mg followed by a full 7-day course of 500 mg BID) on day 7 is shown. [Modes for carrying out the invention]

[0052] Before describing the compounds, compositions, and methods in detail, it should be understood that this disclosure is not limited to the specific processes, compositions, or methodologies described, and that these may change. Furthermore, the terms used in the description are for the purpose of describing specific versions or embodiments and are not intended to limit the scope of this disclosure, but are limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art. Any methods and materials similar to or equivalent to those described may be used in carrying out or testing the embodiments described herein, but preferred methods, apparatus, and materials are described below.

[0053] Furthermore, while certain features of this disclosure are described in the context of separate embodiments for clarity, it should be understood that they can also be provided in combination in a single embodiment. Conversely, various features of this disclosure described in the context of a single embodiment for brevity can also be provided separately or in any appropriate partial combination.

[0054] As used herein, the singular forms "a," "an," and "the" are to include the plural form unless the context clearly requires otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art. The embodiments described herein shall not be construed as a concession that no prior invention has any rights prior to such disclosure. As used herein, the term "comprising" means "including, but not limited to."

[0055] As used herein, the term "about" means within ±20% of the number used. For example, "about 50%" means a range of 40-60%, including exactly 50%. The term "about" may also refer to ±1%, 5%, 10%, 15%, or 20% of the number used.

[0056] When used in connection with the compounds of this disclosure, "administering" means administering the compound directly into or onto a target tissue, or administering the compound systemically or locally to a patient or other subject.

[0057] As used herein, the term "animal" includes, but is not limited to, humans and non-human vertebrates, such as wild animals, laboratory animals, livestock, farm animals and pets. As used herein, the terms "subject," "individual," and "patient" are interchangeable and refer to any animal, including mammals, mice, rats and other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, non-human primates, and humans.

[0058] The term “improves” means that this disclosure alters the characteristics and / or physical attributes of the tissue to which it is administered, applied, or provided. The term “improves” may also be used in conjunction with a disease condition, in which case “improved” of a disease condition means that the symptoms or physical characteristics associated with the disease condition are reduced, lessened, disappear, delayed, or avoided.

[0059] The term "inhibiting" includes blocking, avoiding, or restoring the opposite outcome or process. With respect to treatment by administration of the compounds of this disclosure, "inhibiting" includes (partial or complete) protection against the onset of symptoms, delaying the onset of symptoms, reducing symptoms, or protection against, reduction, or elimination of a disease, condition, or disorder.

[0060] As used herein, the term "free base" refers to the non-salt form of the compounds described herein.

[0061] The term "salts" may include acid addition salts or salts of free bases. Salts described herein may be pharmaceutically acceptable. Examples of acids used to form pharmaceutically acceptable acid addition salts include, but are not limited to, salts obtained from non-toxic inorganic acids such as nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, or phosphoric acid, and salts obtained from non-toxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanoates, alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, acetic acid, maleic acid, succinic acid, or citric acid. Examples of non-restrictive salts include napadisylates, besilates, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, hydrochlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacinates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, methanesulfonates, etc. Salts of amino acids are also considered, with examples including alginates, glucons, and galacturonic acids.

[0062] Those skilled in organic chemistry will understand that many organic compounds can form complexes with the solvents from which they react or from which they precipitate or crystallize. For example, complexes with water are known as "hydrates." Solvates of the compounds of this disclosure are included within the scope of this disclosure. Salts of any compound of any formula described herein can form solvates (e.g., hydrates), and this disclosure encompasses all such solvates. The meaning of the term "solvates" is well known to those skilled in the art as compounds formed by the interaction (i.e., solvation) of a solvent and a solute. Techniques for preparing solvates are well established in the art.

[0063] As used herein, unless otherwise specified, the term “active ingredient” refers to any compound of any formula described herein.

[0064] The term “pharmaceutically acceptable” refers to molecular entities and compositions that are generally considered safe and non-toxic. In particular, pharmaceutically acceptable carriers, diluents, or other excipients used in the pharmaceutical compositions of this disclosure are physiologically tolerable, compatible with other components, and do not typically cause allergic or similar undesirable reactions (e.g., stomach discomfort, dizziness, etc.) when administered to a subject. In some embodiments, the term “pharmaceutically acceptable” as used herein means that it is approved by a federal or state regulatory authority or is listed in the United States Pharmacopeia or other generally accepted pharmacopoeia for use in animals, particularly humans. The term “pharmaceutically acceptable salt(s)” includes salts of the compounds of this disclosure that are safe and effective for use in mammals and possess the desired biological activity. pharmaceutically acceptable salts of the compounds of this disclosure include salts of acidic or basic groups present in the compounds of this disclosure or compounds identified according to the methods of this disclosure. Pharmacovigilantly acceptable acid addition salts include, but are not limited to, hydrochlorides, hydrobroms, hydroiodides, nitrates, sulfates, bisulfates, phosphates, hydrogen phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, pantothenates, hydrogen tartrates, ascorbic acid, succinates, maleates, gentisinates, fumarates, glucons, glucurons, saccharates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, and pamoates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Certain compounds of this disclosure may 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. Pharmacologically acceptable base addition salts can also be formed with amines, such as organic amines.Suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.

[0065] As used herein, the term "therapeutic" means a drug used to treat, counteract, alleviate, protect against, or improve an undesirable condition or disease.

[0066] "Therapeutically effective amount" or "effective amount" means, for example, a predetermined amount of a compound such as bapendavir or a composition of the Disclosure that produces a therapeutic effect on a subject, based on a reasonable benefit / risk ratio applicable to any medical procedure. The therapeutic effect may be objective in the sense that it can be measured by a test or marker, or subjective in the sense that the subject shows or feels an effect, or a physician observes a change. The effects envisioned herein include, where appropriate, medical treatment. The specific dose of a compound administered in accordance with the Disclosure is, of course, determined by the specific circumstances surrounding the case, including the compound administered, the route of administration, concomitant use of other active ingredients, the condition being treated, the activity of the specific compound used, the specific composition used, the subject's age, weight, general condition, sex and diet, timing of administration, route of administration, excretion rate of the specific compound used and duration of treatment. The effective dose administered is determined by the physician in light of such relevant circumstances and the exercise of appropriate medical judgment. The therapeutically effective amount of the compounds disclosed herein, for example, bapendavir, is typically sufficient to effectively achieve systemic or local tissue concentrations when administered in a physiologically tolerable excipient composition.

[0067] As used herein, the terms “treat,” “treated,” or “treating” refer to therapeutic actions aimed at achieving beneficial or desired clinical outcomes, such as partial or complete protection against an undesirable physiological condition, disorder, or disease, or delaying its progression (e.g., reduction or postponement of onset), or partial or complete recovery of a parameter, value, function, or outcome that was or could have been abnormal, or inhibition of its decline. In this disclosure, beneficial or desired clinical outcomes include, but are not limited to, symptom relief, reduction of the extent, intensity, or rate of progression of a condition, disorder, or disease, stabilization of the condition, disorder, or disease (i.e., no worsening), delay of onset or inhibition of progression of a condition, disorder, or disease, improvement of a condition, disorder, or disease, or partial or complete remission. These do not necessarily have to result in immediate relief of actual clinical symptoms. They also include strengthening or improvement of a condition, disorder, or disease. Treatment is intended to elicit a clinically significant response without excessive side effects. Treatment may include extending survival time compared to the expected survival time without treatment.

[0068] As used herein, the term "adverse event" refers to any undesirable medical event occurring in a human being in connection with the use of a drug, whether or not it is related to the drug. The abbreviation "AE" is sometimes used to refer to an adverse event.

[0069] As used herein, the abbreviation "ADL" refers to activities of daily living.

[0070] As used herein, the abbreviation "ALT" stands for alanine aminotransferase.

[0071] As used herein, the abbreviation "AUC" stands for area under the curve.

[0072] As used herein, the abbreviation "BID" means bis in de, referring to administration twice daily.

[0073] In this specification, the abbreviation "BL" stands for baseline.

[0074] As used herein, the abbreviation "CF" stands for cystic fibrosis.

[0075] Abbreviations used in this specification include "C max " " stands for peak drug concentration.

[0076] As used herein, the abbreviation "IPF" refers to Idiopathic Pulmonary Fibrosis.

[0077] As used herein, the abbreviation "CYP3A2" means Cytochrome P450 family 1 subfamily A member 2.

[0078] As used herein, the abbreviation "CYP3A4" refers to Cytochrome P450 family 3 subfamily A member 4.

[0079] As used herein, the abbreviation "CXCL8" refers to CXC motif chemokine ligand 8.

[0080] As used herein, the abbreviation "CXCL10" refers to CXC motif chemokine ligand 10.

[0081] The term "EC" as used herein 50 " refers to half maximal effective concentration.

[0082] The term "EC" as used herein 90 "90% effective concentration" refers to a 90% effective concentration.

[0083] The term "paEC" as used herein 50 " refers to protein-adjusted half-maximal effective concentration.

[0084] The term "paEC" as used herein 90 " " refers to protein adjusting 90% effective concentration.

[0085] As used herein, the term "FEV1" refers to Forced Expiratory Volume in 1 second.

[0086] As used herein, the term "FVC" refers to Forced Vital Capacity.

[0087] Unless otherwise specified, the abbreviation "h" refers to a unit of time.

[0088] In this specification, the abbreviation "Scr" stands for screening.

[0089] In this specification, the abbreviation "IC" stands for informed consent.

[0090] In this specification, the abbreviation "MH" stands for medical history.

[0091] As used herein, the abbreviation "IE" stands for inclusion / exclusion criteria.

[0092] The abbreviation "IC" used in this specification 50 " refers to half maximal inhibitory concentration.

[0093] In this specification, the abbreviation "PT" stands for pregnancy test.

[0094] In this specification, the abbreviation "T" means "training of diaries" unless otherwise specified.

[0095] In this specification, the abbreviation "D" stands for diaries.

[0096] In this specification, the abbreviation "PE" stands for physical examination.

[0097] As used herein, the abbreviation "PEF" stands for peak expiratory flow.

[0098] In this specification, the abbreviation "PK" stands for pharmacokinetics.

[0099] In this specification, the abbreviation "LF" stands for lung function.

[0100] As used herein, the abbreviation "NL" stands for nasal lavage and nasosorption.

[0101] In this specification, the abbreviation "Bl" stands for blood chemistry and full blood count.

[0102] As used herein, the abbreviation "Bl-Ser" refers to RV-A16 serology, mediators.

[0103] As used herein, the abbreviation "Bl-PK" stands for pharmacodynamic testing of blood.

[0104] As used herein, the abbreviation "SAE" stands for serious adverse event.

[0105] In this specification, the abbreviation "Sp" means sputum.

[0106] In this specification, the abbreviation "SM" stands for safety assessment.

[0107] In this specification, the abbreviation "CM" means concomitant medications.

[0108] COPD is the third leading cause of death globally and the fourth leading cause of death in the United States. In the U.S., there are approximately 1.5 million emergency room visits, 700,000 hospitalizations, and over 10 million outpatient visits annually among adults with COPD. According to the Centers for Disease Control and Prevention (CDC), the cost of COPD-related illnesses in the United States was approximately $49 billion in 2020, a 52.6% increase from 2010.

[0109] Acute exacerbations caused by rhinovirus (RV) and other enterovirus (EV) infections are major contributors to morbidity and mortality associated with COPD. Approximately 40–50% (range 10–70%) of COPD exacerbations are associated with RV infection and are linked to increased airway inflammation, increased mucus production, delayed or absent antiviral host defense, and increased pathogenic respiratory bacteria.

[0110] In an RV challenge model in COPD patients, Mallia et al. demonstrated that RV infection triggers the symptomatic, physiological, and inflammatory features reported in spontaneously occurring COPD exacerbations, and that infection is associated with impaired IFN production and excessive neutrophilic inflammation, which may be a key mechanism of virus-induced exacerbations. This study also showed that upper respiratory tract symptoms begin shortly after viral challenge, with a peak in lower respiratory tract symptoms, neutrophilic inflammation, and secondary bacterial infection occurring more than one week after the onset of initial symptoms. This progressive temporal change suggests a potential therapeutic opportunity to interrupt RV-associated acute COPD exacerbations with the use of potent and specific antiviral therapy.

[0111] Bapendavir (3-Ethoxy-6-{2-[1-(6-methylpyridazin-3-yl)piperidin-4-yl]ethoxy}-benzo[d]isoxazol) is a potent and broad-spectrum antiviral agent that is active against over 97% of RV-A and RV-B serotypes (no available assays exist for RV-C, but clinical data show similar susceptibility to A and B), and 89% of other EVs evaluated by cell-based assay systems. Bapendavir acts by binding to the viral capsid, thereby inhibiting the attachment of the virus to target cells and independently preventing the release of viral RNA into cells. Bapendavir has been under development for approximately 10 years for the treatment of RV and other respiratory EV infections, and has been administered to over 640 healthy adults and asthma patients in 7 clinical trials to date. In 3 Phase II clinical trials, babendavir reduced RV viral load compared to placebo, and in 1 Phase II clinical trial, it reduced respiratory symptoms in adult asthma patients. To date, an acceptable safety and tolerable profile has been demonstrated, with no safety concerns observed with repeated doses up to 1,056 mg in a single dose, up to 528 mg twice daily (BID) for up to 7 days, and up to 400 mg BID for up to 10 days in the RV challenge model. Bapendavir has also been tested against the RV-A16 human challenge strain and showed complete protection against viral replication and de novo infection at ≥0.312 μM in in vitro HeLa cell assays. Bapendavir is also referred to as "VPV". The chemical structure of bapendavir (formula (I)) is shown below. TIFF2026510948000002.tif59141

[0112] In some embodiments, a method is provided for treating a respiratory enterovirus infection in a human subject having COPD, comprising the steps of orally administering a therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof to the subject, and thereby treating the respiratory enterovirus infection in the subject.

[0113] In some embodiments, a method is provided for treating a respiratory enterovirus infection in a human subject having COPD, comprising the steps of: orally administering a therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof to the subject; and thereby treating the respiratory enterovirus infection in the subject, wherein the therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof is approximately 250 mg to approximately 2,000 mg per day.

[0114] 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 rhinovirus, echovirus, EV-68, EV-71, coxsackievirus, non-polioenterovirus, and combinations thereof.

[0115] In some embodiments, the therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof is approximately 250 mg to approximately 2,000 mg per day, for example, approximately 250 mg, approximately 300 mg, approximately 350 mg, approximately 400 mg, approximately 450 mg, approximately 500 mg, approximately 550 mg, approximately 600 mg, approximately 650 mg, approximately 700 mg, approximately 750 mg, approximately 800 mg, approximately 850 mg, approximately 900 mg, approximately 950 mg, approximately 1,000 mg, approximately 1,050 mg, approximately 1,100 mg, approximately 1,150 mg, approximately 1,200 mg, approximately 1,250 mg, approximately 1,300 mg, approximately 1,350 mg, approximately 1,400 mg, approximately 1,450 mg, approximately 1,500 mg, approximately 1,550 mg, approximately 1,600 mg, approximately 1,650 mg, approximately 1,700 mg, approximately 1,750 mg, approximately 1,800 mg, approximately 1,850 mg, approximately 1,900 mg, approximately 1,950 mg, approximately 2,000 mg, or any range or value included within these values.

[0116] In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is about 1 mg / kg to about 75 mg / kg relative to the body weight of the subject. For example, in some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is 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 included therein. In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is about 14 mg / kg. In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is about 7 mg / kg. In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is approximately 3.5 mg / kg.

[0117] In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is C max The amount reaches approximately 2000 ng / ml to approximately 12000 ng / ml. In some embodiments, the therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof is C max The amount reaches approximately 2000 ng / ml to approximately 6000 ng / ml. In some embodiments, the therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof is C max This amount reaches approximately 2000 ng / ml to approximately 4000 ng / ml. In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is C max This amount reaches approximately 3000 ng / ml to approximately 6000 ng / ml. In some embodiments, the therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof is C max This amount reaches approximately 6000 ng / ml to approximately 8000 ng / ml. In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is C maxThis amount reaches approximately 8000 ng / ml to approximately 10000 ng / ml. In some embodiments, the therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof is C max This amount reaches approximately 10,000 ng / ml to 12,000 ng / ml.

[0118] In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is administered as 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 dose of bapendavir or its pharmaceutically acceptable salt is administered as 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 10 days. In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is administered as a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 5 to 8 days. In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is administered as 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 8 days. In some embodiments, the therapeutically effective dose of babendavir 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.

[0119] In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is administered as 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 dose of bapendavir or its pharmaceutically acceptable salt is administered as 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 10 days. In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is administered as a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg every 12 hours for about 5 to 8 days. In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is administered as 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 8 days. In some embodiments, the therapeutically effective dose of babendavir 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.

[0120] In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is administered as 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 dose of bapendavir or its pharmaceutically acceptable salt is administered as 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 dose of bapendavir or its pharmaceutically acceptable salt is administered as 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 dose of bapendavir or its pharmaceutically acceptable salt is administered as 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 dose of bapendavir or a pharmaceutically acceptable salt thereof is administered as 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 dose of bapendavir or a pharmaceutically acceptable salt thereof is administered as a single loading dose of about 1000 mg every 12 hours for about 1 day, followed by a maintenance dose of about 500 mg every 12 hours for about 9 days. In some embodiments, the therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof is administered as a single loading dose of about 1000 mg followed by a maintenance dose of about 500 mg every 12 hours for 10 days.

[0121] In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is administered as 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 dose of bapendavir or its pharmaceutically acceptable salt is administered as 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 dose of bapendavir or its pharmaceutically acceptable salt is administered as 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 dose of bapendavir or its pharmaceutically acceptable salt is administered as 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 dose of bapendavir or a pharmaceutically acceptable salt thereof is administered as 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 dose of bapendavir or a pharmaceutically acceptable salt thereof is administered as a single loading dose of about 1000 mg for about 1 day, followed by a maintenance dose of about 500 mg every 12 hours for about 9 days. In some embodiments, the therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof is administered as a single loading dose of about 1000 mg, followed by a maintenance dose of about 500 mg every 12 hours for 10 days.

[0122] In some embodiments, the therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof is administered as a single loading dose of about 1,000 mg, followed by maintenance doses of about 500 mg every 12 hours, for a total of about 13 maintenance doses. In some embodiments, the therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof is administered as a single loading dose of about 1,000 mg, followed by maintenance doses of about 500 mg every 12 hours, for a total of about 13 maintenance doses. In some embodiments, the therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof is administered as a single loading dose of about 1,000 mg, followed by maintenance doses of about 500 mg every 12 hours, for a total of 13 maintenance doses. In some embodiments, the therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof is a single loading dose of about 1,000 mg followed by maintenance doses of about 500 mg every 12 hours, for a total of 13 maintenance doses.

[0123] In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is administered as a single dose of approximately 14 mg / kg for 1 day, followed by a maintenance dose of approximately 7 mg / kg every 12 hours for approximately 4 to 10 days. In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is administered as a single dose of approximately 14 mg / kg for 1 day, followed by a maintenance dose of approximately 7 mg / kg every 12 hours for approximately 4 days. In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is administered as a single dose of approximately 14 mg / kg for 1 day, followed by a maintenance dose of approximately 7 mg / kg every 12 hours for approximately 5 days. In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is administered as a single dose of approximately 14 mg / kg for 1 day, followed by a maintenance dose of approximately 7 mg / kg every 12 hours for approximately 6 days. In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is administered as a single dose of approximately 14 mg / kg for 1 day, followed by a maintenance dose of approximately 7 mg / kg every 12 hours for approximately 7 days. In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is administered as a single dose of approximately 14 mg / kg for 1 day, followed by a maintenance dose of approximately 7 mg / kg every 12 hours for approximately 8 days. In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is administered as a single dose of approximately 14 mg / kg for 1 day, followed by a maintenance dose of approximately 7 mg / kg every 12 hours for approximately 9 days. In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is administered as a single dose of approximately 14 mg / kg for 1 day, followed by a maintenance dose of approximately 7 mg / kg every 12 hours for approximately 10 days. In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is a single loading dose of approximately 14 mg / kg administered over one day, followed by a maintenance dose of approximately 7 mg / kg every 12 hours for a total of approximately 13 maintenance doses.

[0124] In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is administered as a single dose of approximately 14 mg / kg for approximately 1 day, followed by a maintenance dose of approximately 7 mg / kg every approximately 12 hours for approximately 4 to 10 days. In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is administered as a single dose of approximately 14 mg / kg for approximately 1 day, followed by a maintenance dose of approximately 7 mg / kg every approximately 12 hours for approximately 4 days. In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is administered as a single dose of approximately 14 mg / kg for approximately 1 day, followed by a maintenance dose of approximately 7 mg / kg every approximately 12 hours for approximately 5 days. In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is administered as a single dose of approximately 14 mg / kg for approximately 1 day, followed by a maintenance dose of approximately 7 mg / kg every approximately 12 hours for approximately 6 days. In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is administered as a single dose of approximately 14 mg / kg for approximately 1 day, followed by a maintenance dose of approximately 7 mg / kg every 12 hours for approximately 7 days. In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is administered as a single dose of approximately 14 mg / kg for approximately 1 day, followed by a maintenance dose of approximately 7 mg / kg every 12 hours for approximately 8 days. In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is administered as a single dose of approximately 14 mg / kg for approximately 1 day, followed by a maintenance dose of approximately 7 mg / kg every 12 hours for approximately 9 days. In some embodiments, the therapeutically effective dose of bapendavir or its pharmaceutically acceptable salt is administered as a single dose of approximately 14 mg / kg for approximately 1 day, followed by a total of approximately 13 maintenance doses of approximately 7 mg / kg every 12 hours.

[0125] In some embodiments, the administration regimen of bapendavir or a pharmaceutically acceptable salt thereof may be modified. For example, a single loading dose may be adjusted within the 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 dose may be adjusted based on the patient's weight, age, severity of COPD, and the specific strain of respiratory enterovirus infection.

[0126] In some embodiments, the single dose is administered within approximately 24 hours of the subject exhibiting symptoms of respiratory enterovirus infection. In some embodiments, the single dose is administered within approximately 48 hours of the subject exhibiting symptoms of respiratory enterovirus infection. In some embodiments, the single dose is administered within approximately 72 hours of the subject exhibiting symptoms of respiratory enterovirus infection. In some embodiments, the single dose is administered within approximately 96 hours of the subject exhibiting symptoms of respiratory enterovirus infection. In some embodiments, the single dose is administered between approximately 72 and 96 hours of the subject exhibiting symptoms of respiratory enterovirus infection. In some embodiments, the single dose is administered between approximately 1 and 5 days of the subject exhibiting symptoms of respiratory enterovirus infection. In some embodiments, the single dose is administered between approximately 1 and 7 days of the subject exhibiting symptoms of respiratory enterovirus infection. In some embodiments, the single dose is administered more than 48 hours after the subject first exhibits symptoms of respiratory enterovirus infection. In some embodiments, the single dose is administered before the subject reaches the peak viral load. In some embodiments, administration of a single dose of approximately 1000 mg is C max This results in a concentration of approximately 2150 ng / ml.

[0127] In some embodiments, the maintenance dose is initially administered between approximately 6 and 12 hours after a single loading dose. In some embodiments, the maintenance dose may be administered at approximately 6, 7, 8, 9, 10, 11, 12 hours, or any range or value within these periods, after a single loading dose. In some embodiments, at least one maintenance dose is administered between approximately 6 and 10 days, for example, between approximately 6, 7, 8, 9, or 10 days.

[0128] In some embodiments, the single load and maintenance dose are administered within approximately 30 minutes after the subject has ingested a meal containing solid food (i.e., the subject is in a feeding state). In some embodiments, the single load and maintenance dose are administered within approximately 30 minutes after the subject has ingested a meal containing high-fat solid food (i.e., the subject is in a feeding state). In some embodiments, administering the single load and maintenance dose within approximately 30 minutes after the subject has ingested a meal containing solid food results in higher plasma concentrations of bapendavir or its pharmaceutically acceptable salt than administering the single load and maintenance dose when the subject is in a fasting state. For example, in a normal healthy subject, administering 500 mg of bapendavir when the subject is in a feeding state before administration results in C max The concentration was 2060 ng / ml (CV% 5 ng / ml), compared to 687 ng / ml (CV% 93 ng / ml) in normal, healthy subjects who were fasted before administration.

[0129] In some embodiments, the single dose is administered after the subject has been diagnosed with a respiratory enterovirus infection, and the diagnosis is achieved by clinical diagnosis, multiplex PCR testing, rapid antigen testing, direct immunofluorescence testing, arterial blood gas analysis, chest X-ray, peak flow metering, pleural fluid culture, lung CT, pulmonary function tests, pulse oximetry, spirometry, sputum testing, nasal swab testing, pharyngeal swab testing, or any combination thereof.

[0130] In some embodiments, the maintenance dose of bapendavir or a pharmaceutically acceptable salt thereof is administered at approximately 500 mg every approximately 12 hours for approximately 6 to 10 days, provided that the subject is feeding. In some embodiments, the maintenance dose is administered at approximately 500 mg every approximately 12 hours for approximately 4 days, provided that the subject is feeding. In some embodiments, the maintenance dose is administered at approximately 500 mg every approximately 12 hours for approximately 5 days, provided that the subject is feeding. In some embodiments, the maintenance dose is administered at approximately 500 mg every approximately 12 hours for approximately 6 days, provided that the subject is feeding. In some embodiments, the maintenance dose is administered at approximately 500 mg every approximately 12 hours for approximately 7 days, provided that the subject is feeding. In some embodiments, the maintenance dose is administered at approximately 500 mg every approximately 12 hours for approximately 8 days, provided that the subject is feeding. In some embodiments, the maintenance dose is administered at approximately 500 mg every 12 hours for approximately 9 days, provided that the subject is feeding. In some embodiments, the maintenance dose is administered at approximately 500 mg every 12 hours for approximately 10 days, provided that the subject is feeding.

[0131] In some embodiments, the subject is administered an initial dose of approximately 1000 mg / day at approximately 24 hours, 48 ​​hours, 72 hours, or between 1 and 5 days after the onset of symptoms of respiratory enterovirus infection. In some embodiments, the initial dose is administered after the subject has been diagnosed with respiratory enterovirus infection, and the diagnosis is achieved by clinical diagnosis, multiplex PCR testing, rapid antigen testing, direct immunofluorescence testing, arterial blood gas analysis, chest X-ray, peak flow metering, pleural fluid culture, lung CT, pulmonary function tests, pulse oximetry, spirometry, sputum testing, nasal swab testing, pharyngeal swab testing, or any combination thereof.

[0132] In some embodiments, the symptoms of the respiratory enterovirus infection are selected from cough, increased mucus production, sneezing, nasal congestion, runny nose, sore throat, headache, muscle pain, shortness of breath, chest tightness, wheezing, fever, conjunctival congestion, lymphadenopathy, malaise, hoarseness, runny nose, general discomfort, nasal obstruction, sputum production, dysfunction at normal activity levels, and any combination thereof. In some embodiments, the subject is asymptomatic but diagnosed with respiratory enterovirus infection.

[0133] In some embodiments, the subject is human. In some embodiments, the subject is feeding. In some embodiments, the subject is human, approximately 40 to approximately 85 years old. In some embodiments, the subject has been diagnosed with Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stage 1 COPD, Stage 2 COPD, Stage 3 COPD, or Stage 4 COPD.

[0134] In some embodiments, the subjects are women taking oral contraceptives (e.g., birth control). In such embodiments, the step of administering a therapeutically effective dose of babendavir or a pharmaceutically acceptable salt thereof further includes the step of administering additional birth control during treatment. In some embodiments, the subjects are women not taking oral contraceptives (e.g., birth control).

[0135] In some embodiments, the subject is receiving maintenance therapy for COPD. In some embodiments, maintenance therapy for COPD includes short-acting bronchodilators (e.g., albuterol, revalbuterol, ipratropium, or any combination thereof), long-acting bronchodilators (e.g., aclidinium, alformoterol, formoterol, glycopyrrolate, indacaterol, orodaterol, rebefenacin, salmeterol, tiotropium, umeclidinium, or any combination thereof), Luticosteroids (e.g., but not limited to fluticasone, budesonide, prednisolone, beclomethasone, or any combination thereof), combination bronchodilator therapy with LABA and LAMA (e.g., but not limited to aclidinium / formoterol, glycopyrrolate / formoterol, tiotropium / olodaterol, umeclidinium / vilanterol, glycopyrronium / indacaterol, or any combination thereof), combination therapy with ICS and long-acting bronchodilators (e.g., , but not limited to, budesonide / formoterol, fluticasone / salmeterol, fluticasone / vilanterol, beclomethasone / formoterol, or any combination thereof), triple therapy (ICS / LAMA / LABA) (for example, but not limited to, fluticasone / umeclidinium / vilanterol, budesonide / glycopyrronium / formoterol, beclomethasone / formoterol / glycopyrronium, or any combination thereof), methylxanthines (for example, but not limited to This includes, but is not limited to, theophylline, phosphodiesterase-4 inhibitors (e.g., roflumilast), expectorants (e.g., carbocysteine, erdosteine, N-acetylcysteine, or any combination thereof), biological agents / antieosinophils (e.g., e.g., mepolizumab, benralizumab, rezlizumab, dupilumab, or any combination thereof), or other medications prescribed for the treatment of COPD.In some embodiments, the subject can receive the same maintenance therapy for COPD as if they did not have a respiratory enterovirus infection. In some embodiments, the subject can receive the maintenance therapy for COPD at a higher dose, more frequent doses, or any combination thereof than if they did not have a respiratory enterovirus infection. In some embodiments, the subject can receive the maintenance therapy for COPD at a lower dose, fewer frequent doses, or any combination thereof than if they did not have a respiratory enterovirus infection.

[0136] In some embodiments, the subject may have suffered at least one respiratory enterovirus infection within 12 months immediately preceding the administration of a therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not have a sore throat, sneezing, runny nose, discomfort, nasal congestion, cough, or any combination thereof within 30 days immediately preceding the administration of a therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof. In some embodiments, in addition to a respiratory enterovirus infection, the subject does not have an active infection or persistent symptoms thereof due to a viral or bacterial pathogen.

[0137] In some embodiments, the subjects are not diagnosed with asthma; cystic fibrosis (CF); bronchiolitis obstructive; tuberculosis (TB); fibrosis such as idiopathic pulmonary fibrosis (IPF); other major respiratory diseases (e.g., pneumonia, aspergillosis); non-CF bronchiectasis; COPD due to α-1 antitrypsin deficiency; active allergic rhinitis; nasal diseases (e.g., nasal polyps, significant deviated septum, chronic sinusitis, etc.); medically unstable cardiovascular, gastrointestinal, hepatic, renal, nervous, musculoskeletal, infectious, endocrine, metabolic, hematological, mental disorders; or other major physical disorders that are medically unstable or uncontrolled, or any combination thereof.

[0138] In some embodiments, the subjects have not taken any drugs known to be affected or significantly metabolized by CYP3A4. These drugs include, but are not limited to, apalutamide, amiodarone, carbamazepine, amprenavir, dexamethasone, atazanavir, enzalutamide, boceprevir, fosphenytoin, clarithromycin, lumafutol, cobicistat, midostaurin, conivaptan, mitotane, curcumin, pentobarbital, danazol, phenobarbital, danoprevir, phenytoin, darunavir, primidone, delavirdin, rifampicin, dithiocarba, rifapentin, econazole, rifaximin, and This includes favirenz, rimexolone, elvitegravir, St. John's wort, ergotamine, idelalisib, levocetoconazole, naloxone, indinavir, itraconazole, ketoconazole, ronafarnib, loperamide, lopinavir, methimazole, midostaurin, nefazodone, nelfinavir, nilotinib, posaconazole, ribociclib, ritonavir, saquinavir, stiripentol, telaprevir, telithromycin, terfenadine, tipranavir, troreandmycin, voriconazole, or combinations thereof. These drugs may also include H2 blockers such as famotidine, cimetidine, nizatidine, and ranitidine. These drugs may also include, but are not limited to, proton pump inhibitors such as omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole, dexlansoprazole, and zegerid. These drugs may also include antacids such as melox (aluminum hydroxide, magnesium hydroxide, and simethicone), alginates, aluminum hydroxide, calcium carbonate, magnesium carbonate, magnesium hydroxide, magnesium trisilicate, and sodium bicarbonate.

[0139] In some embodiments, treatment of a respiratory enterovirus infection in the subject includes preventing a decrease and / or increase in one or more parameters or measurements that indicate the health status of the subject, as known to those skilled in the art.

[0140] In some embodiments, treatment of respiratory enterovirus infection in the subject includes reducing the viral load in the subject's sputum, nasal cavity, or combination thereof compared to the viral load in the subject's sputum, nasal cavity, or combination thereof prior to treatment.

[0141] In some embodiments, treatment of a respiratory enterovirus infection in the subject includes reducing the subject's COPD respiratory symptom rating score (E-RS) compared to the subject's COPD respiratory symptom rating score (E-RS) before treatment. In some embodiments, treatment of a respiratory enterovirus infection in the subject includes preventing an increase in the subject's COPD respiratory symptom rating score (E-RS) compared to the subject's COPD respiratory symptom rating score (E-RS) before treatment.

[0142] In some embodiments, treatment of a respiratory enterovirus infection in a subject includes reducing the subject's subpeak subairway symptom score (LRSS), e.g., subpeak subairway symptom score (LRSS), compared to the subject's pre-treatment LRSS. Similarly, treatment of a respiratory enterovirus infection in a subject includes preventing an increase in the subject's LRSS, compared to the subject's pre-treatment LRSS. In some embodiments, treatment of a respiratory enterovirus infection in a subject includes reducing and / or preventing an increase in the subject's upper peak airway symptom score (URSS), e.g., URSS, compared to the subject's pre-treatment upper peak airway symptom score (URSS).

[0143] In some embodiments, treatment of respiratory enterovirus infection in the subject includes reducing the subject's chronic lung disease exacerbation tool-patient reported outcome (EXACT-PRO), for example, the subject's chronic lung disease exacerbation tool-patient reported outcome (EXACT-PRO) score, compared to the subject's chronic lung disease exacerbation tool-patient reported outcome (EXACT-PRO) score before treatment. Similarly, treatment of respiratory enterovirus infection in the subject includes preventing an increase in the subject's EXACT-PRO, for example, the subject's EXACT-PRO score. In some embodiments, treatment of respiratory enterovirus infection in the subject includes preventing an increase in the subject's chronic lung disease exacerbation tool-patient reported outcome (EXACT-PRO), for example, the subject's chronic lung disease exacerbation tool-patient reported outcome (EXACT-PRO) score, compared to the subject's chronic lung disease exacerbation tool-patient reported outcome (EXACT-PRO) score before treatment. Similarly, treatment of respiratory enterovirus infection in the subject includes preventing an increase in the subject's EXACT-PRO, for example, the subject's EXACT-PRO score.

[0144] In some embodiments, treatment of respiratory enterovirus infection in the subject includes reducing the subject's chronic lung disease exacerbation tool-patient respiratory symptoms (EXACT-RS) score, for example, the EXACT-RS score, compared to the subject's chronic lung disease exacerbation tool-patient respiratory symptoms (EXACT-RS) score before treatment. In some embodiments, treatment of respiratory enterovirus infection in the subject includes preventing an increase in the subject's EXACT-RS score. In some embodiments, treatment of respiratory enterovirus infection in the subject includes preventing an increase in the subject's chronic lung disease exacerbation tool-patient respiratory symptoms (EXACT-RS) score, for example, the EXACT-RS score, compared to the subject's chronic lung disease exacerbation tool-patient respiratory symptoms (EXACT-RS) score before treatment. In some embodiments, treatment of respiratory enterovirus infection in the subject includes preventing an increase in the subject's EXACT-RS score.

[0145] In some embodiments, treatment of a respiratory enterovirus infection in the subject includes reducing and / or preventing an increase in the subject's COPD Assessment Tool (CAT) score compared to the subject's COPD Assessment Tool (CAT) score before treatment.

[0146] In some embodiments, treatment of a respiratory enterovirus infection in a subject includes reducing the subject's St. George's Respiratory Questionnaire (SGRQ) score compared to the subject's St. George's Respiratory Questionnaire (SGRQ) score before treatment. In some embodiments, treatment of a respiratory enterovirus infection in a 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 before treatment.

[0147] In some embodiments, treatment of a respiratory enterovirus infection in the subject includes reducing and / or preventing an increase in the subject's Wisconsin Upper Airway Symptom Survey (WURSS) score compared to the subject's WURSS score before treatment.

[0148] In some embodiments, treatment of respiratory enterovirus infection in the subject includes improving the subject's lung function compared to the subject's lung function before treatment. In some embodiments, the subject's lung function is improved by methods known to those skilled in the art, for example, forced expiratory volume in one second (FEV1). -1 The lung function of the subject is measured by forced expiratory volume in one second (FEV1 / FVC ratio) and predicted value in 1 second, forced vital capacity (FVC) in 1 second, and predicted value in 1 second, FEV1 / FVC ratio and peak expiratory flow rate (PEF), or a combination thereof. In some embodiments, treatment of respiratory enterovirus infection in the subject includes preventing a decline in the subject's lung function compared to the subject's lung function before treatment, where the subject's lung function is measured by forced expiratory volume in one second (FEV1 / FVC ratio). -1 It is measured by liters and predicted %), forced vital capacity (FVC; liters and predicted %), FEV1 / FVC ratio and peak expiratory flow rate (PEF), or a combination thereof.

[0149] In some embodiments, treatment of respiratory enterovirus infection in the subject includes reducing the peak viral load in the nasal lavage of the subject compared to the peak viral load in the nasal lavage of the subject before treatment. In some embodiments, treatment of respiratory enterovirus infection in the subject includes preventing an increase in the peak viral load in the nasal lavage of the subject compared to the peak viral load in the nasal lavage of the subject before treatment. In some embodiments, treatment of respiratory enterovirus infection in the subject includes reducing and / or preventing an increase in the peak viral load in the sputum lavage of the subject compared to the peak viral load in the sputum lavage of the subject before treatment. In some embodiments, treatment of respiratory enterovirus infection in the subject includes reducing and / or preventing bacterial bronchitis, pneumonia, or a combination thereof.

[0150] In some embodiments, treatment of respiratory enterovirus infection in the subject includes reducing the AUC nasal virus load of the subject compared to the AUC nasal virus load of the subject before treatment; in some embodiments, treatment of respiratory enterovirus infection in the subject includes preventing an increase in the AUC nasal virus load of the subject compared to the AUC nasal virus load of the subject before treatment; in some embodiments, treatment of respiratory enterovirus infection in the subject includes reducing and / or preventing an increase in the AUC sputum virus load of the subject compared to the AUC sputum virus load of the subject before treatment.

[0151] In some embodiments, treatment of respiratory enterovirus infection in the subject includes shortening the viral shedding period, reducing the number of days the subject is bacterial-positive in sputum, or a combination thereof.

[0152] In some embodiments, treatment of respiratory enterovirus infection in the subject includes reducing and / or preventing an increase in the peak bacterial load of the sputum of the subject compared to the peak bacterial load of the sputum lavage of the subject before treatment. In some embodiments, treatment of respiratory enterovirus infection in the subject includes reducing and / or preventing bacterial bronchitis, pneumonia, or a combination thereof. In some embodiments, treatment of respiratory enterovirus infection in the subject includes reducing and / or preventing an increase in the AUC sputum bacterial load of the subject compared to the AUC sputum bacterial load of the subject before treatment.

[0153] In some embodiments, treatment of respiratory enterovirus infection in the subject includes preventing or reducing acute exacerbations of COPD in the subject caused by the respiratory enterovirus infection. In some embodiments, treatment of respiratory enterovirus infection in the subject includes reducing the frequency, severity, duration, or a combination thereof of acute exacerbations of COPD in the subject caused by the respiratory enterovirus infection. In some embodiments, treatment of respiratory enterovirus infection in the subject includes preventing an increase in the frequency, severity, duration, or a combination thereof of acute exacerbations of COPD in the subject caused by the respiratory enterovirus infection.

[0154] In some embodiments, administration of a therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof to the subject is used to treat paEC against human rhinovirus. 50 It exceeds. In some embodiments, paEC against human rhinovirus. 50The C is approximately 75.4 ng / ml. In some embodiments, the therapeutically effective dose of babendavir or its pharmaceutically acceptable salt is a single loading dose of approximately 1000 mg followed by a maintenance dose of approximately 500 mg every 12 hours for approximately 4 to 10 days. In some embodiments, the therapeutically effective dose of babendavir or its pharmaceutically acceptable salt is a single loading dose of approximately 1000 mg followed by a maintenance dose of approximately 500 mg every 12 hours for a total of approximately 13 doses. In some embodiments, the therapeutically effective dose of babendavir or its pharmaceutically acceptable salt is approximately 2000 to approximately 12000 ng / ml of C max This is the amount that achieves the goal of paEC against human rhinovirus. In some embodiments, paEC against human rhinovirus 50 This can last for approximately 4 to 10 days, or until treatment is discontinued.

[0155] In some embodiments, administration of a therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof to the subject is used to treat paEC against human rhinovirus. 90 It exceeds. In some embodiments, paEC against human rhinovirus. 90 The C is approximately 678.6 ng / ml. In some embodiments, the therapeutically effective dose of babendavir or its pharmaceutically acceptable salt is a single loading dose of approximately 1000 mg followed by a maintenance dose of approximately 500 mg every 12 hours for approximately 4 to 10 days. In some embodiments, the therapeutically effective dose of babendavir or its pharmaceutically acceptable salt is a single loading dose of approximately 1000 mg followed by a maintenance dose of approximately 500 mg every 12 hours for a total of approximately 13 doses. In some embodiments, the therapeutically effective dose of babendavir or its pharmaceutically acceptable salt is approximately 2000 to approximately 12000 ng / ml of C max This is the amount that achieves the goal of paEC against human rhinovirus. In some embodiments, paEC against human rhinovirus 90 This can last for approximately 4 to 10 days, or until treatment is discontinued.

[0156] In some embodiments, administering a therapeutically effective dose of babendavir or a pharmaceutically acceptable salt thereof to the subject is equivalent to paEC against human rhinovirus. 50 Exceeding C max This results in paEC against human rhinovirus in some embodiments. 50 The C is approximately 75.4 ng / ml. In some embodiments, the therapeutically effective dose of babendavir or its pharmaceutically acceptable salt is a single loading dose of approximately 1000 mg followed by a maintenance dose of approximately 500 mg every 12 hours for approximately 4 to 10 days. In some embodiments, the therapeutically effective dose of babendavir or its pharmaceutically acceptable salt is a single loading dose of approximately 1000 mg followed by a maintenance dose of approximately 500 mg every 12 hours for a total of approximately 13 doses. In some embodiments, the therapeutically effective dose of babendavir or its pharmaceutically acceptable salt is approximately 2000 to approximately 12000 ng / ml of C max This is the amount that achieves the goal of paEC against human rhinovirus. In some embodiments, paEC against human rhinovirus 50 This can last for approximately 4 to 10 days, or until treatment is discontinued.

[0157] In some embodiments, administering a therapeutically effective dose of babendavir or a pharmaceutically acceptable salt thereof to the subject is equivalent to paEC against human rhinovirus. 90 Exceeding C max This results in paEC against human rhinovirus in some embodiments. 90 The C is approximately 678.6 ng / ml. In some embodiments, the therapeutically effective dose of babendavir or its pharmaceutically acceptable salt is a single loading dose of approximately 1000 mg followed by a maintenance dose of approximately 500 mg every 12 hours for approximately 4 to 10 days. In some embodiments, the therapeutically effective dose of babendavir or its pharmaceutically acceptable salt is a single loading dose of approximately 1000 mg followed by a maintenance dose of approximately 500 mg every 12 hours for a total of approximately 13 doses. In some embodiments, the therapeutically effective dose of babendavir or its pharmaceutically acceptable salt is approximately 2000 to approximately 12000 ng / ml of C maxThis is the amount that achieves the goal of paEC against human rhinovirus. In some embodiments, paEC against human rhinovirus 90 This can last for approximately 4 to 10 days, or until treatment is discontinued.

[0158] In some embodiments, after administering a single therapeutic dose of bapendavir or a pharmaceutically acceptable salt thereof to the subject, paEC against human rhinovirus is administered. 50 It exceeds. In some embodiments, paEC against human rhinovirus. 50 The C is approximately 75.4 ng / ml. In some embodiments, the therapeutically effective dose of babendavir or its pharmaceutically acceptable salt is a single loading dose of approximately 1000 mg followed by a maintenance dose of approximately 500 mg every 12 hours for approximately 4 to 10 days. In some embodiments, the therapeutically effective dose of babendavir or its pharmaceutically acceptable salt is a single loading dose of approximately 1000 mg followed by a maintenance dose of approximately 500 mg every 12 hours for a total of approximately 13 doses. In some embodiments, the therapeutically effective dose of babendavir or its pharmaceutically acceptable salt is approximately 2000 to approximately 12000 ng / ml of C max This is the amount that achieves the goal of paEC against human rhinovirus. In some embodiments, paEC against human rhinovirus 50 This can last for approximately 4 to 10 days, or until treatment is discontinued.

[0159] In some embodiments, after administering a single therapeutic dose of bapendavir or a pharmaceutically acceptable salt thereof to the subject, paEC against human rhinovirus is administered. 90 It exceeds. In some embodiments, paEC against human rhinovirus. 90The C is approximately 678.6 ng / ml. In some embodiments, the therapeutically effective dose of babendavir or its pharmaceutically acceptable salt is a single loading dose of approximately 1000 mg followed by a maintenance dose of approximately 500 mg every 12 hours for approximately 4 to 10 days. In some embodiments, the therapeutically effective dose of babendavir or its pharmaceutically acceptable salt is a single loading dose of approximately 1000 mg followed by a maintenance dose of approximately 500 mg every 12 hours for a total of approximately 13 doses. In some embodiments, the therapeutically effective dose of babendavir or its pharmaceutically acceptable salt is approximately 2000 to approximately 12000 ng / ml of C max This is the amount that achieves the goal of paEC against human rhinovirus. In some embodiments, paEC against human rhinovirus 90 This can last for approximately 4 to 10 days, or until treatment is discontinued.

[0160] In some embodiments, the therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof is in tablet form. In some embodiments, bapendavir is a free base, maleate, oxalate, phosphate, sulfate, tartrate, or chloride salt. In some embodiments, bapendavir is the amorphous form of bapendavir or a pharmaceutically acceptable salt thereof. In some embodiments, bapendavir is the crystalline form of bapendavir or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments of this disclosure, pharmaceutical compositions are provided comprising a therapeutically effective amount of bapendavir or a pharmaceutically acceptable salt thereof. The bapendavir is a free base, maleate, oxalate, phosphate, sulfate, or chloride salt. In some embodiments of the pharmaceutical composition, the bapendavir is an amorphous form of bapendavir or a pharmaceutically acceptable salt thereof. In some embodiments, the bapendavir is a crystalline form of bapendavir or a pharmaceutically acceptable salt thereof.

[0162] Routes of administration (delivery) include, but are not limited to, oral (e.g., tablets, capsules, or orally administered solutions), topical, mucosal (e.g., nasal sprays or inhaled aerosols), parenteral (e.g., injections), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intraventricular, or other depot administration. Accordingly, the compositions of this disclosure include forms particularly suited to the form of administration. In certain embodiments, the pharmaceutical compositions of this disclosure are formulated into forms suitable for oral administration.

[0163] The compounds of this disclosure can be formulated for administration by any convenient method for use in human or veterinary applications, and this disclosure therefore encompasses, to the extent of, pharmaceutical compositions containing the compounds of this disclosure adapted for human or veterinary applications. Such compositions are put into use by conventional methods with one or more suitable carriers. Carriers acceptable for therapeutic use are well known in the pharmaceutical field and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (ARGennaro, ed., 1985). The selection of a pharmaceutical carrier can be made based on the intended route of administration and standard pharmaceutical practice. The pharmaceutical composition, in addition to the carrier, comprises a suitable binder, lubricant, suspending agent, coating agent and / or solubilizer.

[0164] In some embodiments, the requirements of the composition / formulation may differ depending on the different delivery system. Not all compounds need to be administered via the same route. Similarly, if a composition contains multiple active ingredients, these ingredients may be administered via different routes. For example, the pharmaceutical compositions of this disclosure may be formulated for delivery using a minipump, or as a mucosal route, e.g., a nasal spray, an inhaled aerosol, or an orally administered solution, or prepared as an injectable formulation and delivered, e.g., intravenous, intramuscular, or subcutaneous route. Alternatively, the formulation may be designed to be delivered via multiple routes.

[0165] Where appropriate, the pharmaceutical compositions of this disclosure may be administered by inhalation, by using a skin patch, or orally in the form of tablets containing excipients such as starch or lactose; or they may be administered alone or as capsules or oval capsules mixed with excipients; or they may be administered in the form of elixirs, solutions or suspensions containing fragrances or colorants. The pharmaceutical compositions of this disclosure may also be administered extraenterally, for example, by injection intravenously, intramuscularly or subcutaneously. For administration via the buccal mucosa or sublingually, the compositions may be administered in the form of conventionally formulated tablets or oral tablets.

[0166] The pharmaceutical compositions of this disclosure may be administered in the form of tablets, capsules, lozenges, oval capsules, elixirs, solutions, or suspensions for immediate-release, delayed-release, modified-release, sustained-release, pulsed-release, or controlled-release applications. The pharmaceutical compositions of this disclosure may also be provided in the form of solutions, gels, syrups, or suspensions, or as dry powders that are reconstituted with water or other suitable media before use. Solid formulations such as tablets, capsules, oral tablets, lozenges, pastilles, pills, boluses, powders, pastes, granules, suppositories, or premix formulations may also be used. Solid and liquid compositions for oral use can be prepared according to methods well known to those skilled in the art. Such compositions may contain one or more pharmaceutically acceptable carriers and excipients in solid or liquid form.

[0167] The pharmaceutical compositions of the present invention may, in some embodiments, contain about 250 mg of bapendavir or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the pharmaceutical compositions may contain 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 390mg, approximately 400mg, approximately 410mg, approximately 420mg, approximately 430mg, approximately 440mg, approximately 450mg, approximately 460mg, approximately 470mg, approximately 480mg, approximately 490mg, approximately 500mg, approximately 510mg, approximately 520mg, approximately 530mg, approximately 540mg, approximately 550mg, approximately 560mg, approximately 570mg, approximately 580mg, approximately 590mg, approximately 600mg, approximately 610mg, approximately 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, about 700mg, about 710mg, about 720mg, about 730 mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about The pharmaceutical composition contains 850 mg, approximately 860 mg, approximately 870 mg, approximately 880 mg, approximately 890 mg, approximately 900 mg, approximately 910 mg, approximately 920 mg, approximately 930 mg, approximately 940 mg, approximately 950 mg, approximately 960 mg, approximately 970 mg, approximately 980 mg, approximately 990 mg, or approximately 1000 mg of bapendavir or a pharmaceutically acceptable salt thereof, or any range or value contained within these values. In some embodiments, the pharmaceutical composition is a tablet. The pharmaceutical composition further contains a diluent, a disintegrant, a surfactant, a lubricant, a color coating, or any combination thereof.

[0168] Oral formulations may optionally contain various standard pharmaceutical carriers and excipients, such as binders, fillers, buffers, lubricants, colorants, disintegrants, fragrances, sweeteners, surfactants, release agents, anti-adhesion agents, and coating agents. Some excipients may have multiple roles in the composition, for example, acting as both a binder and a disintegrant.

[0169] In some embodiments, the diluent is selected from Cellulose Microcrystalline Silicified (PROSOLVHD90) (USP / NF), anhydrous calcium phosphate, anhydrous lactose, calcium carbonate, calcium lactate, calcium sulfate dihydrate, corn starch, fructose, kaolin, lactose monohydrate, magnesium hydroxide, maltitol, monohydrate maltose, mannitol, sorbitol, sucrose, tricalcium phosphate, sodium citrate, glycine, croscarmellose sodium, ethanol, propylene glycol, glycerin, polyvinylpyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin, acacia, or any combination thereof.

[0170] In some embodiments, the disintegrant is selected from Starch Glycolate Sodium (USP / NF / EP), corn starch, potato starch, tapioca starch, croscarmellose sodium, pregelatinized starch, carboxymethylcellulose sodium, alginate, resin, hydrated aluminum silicate, cross-linked polyvinylpyrrolidone, or any combination thereof.

[0171] In some embodiments, the surfactant is selected from Poloxamer Microprilled 188 (USP / NF / EP / JPE), sodium lauryl sulfate, polysorbates, or any combination thereof.

[0172] 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, hydroxypropyl methylcellulose, hydroxypropylcellulose, acrylate-methacrylate copolymers, or any combination thereof.

[0173] In some embodiments, the colored coating is selected from Opadry II White 85F18422 (Mfg. Std.), riboflavin, anthocyanin, paprika oleoresin, beetroot, curcumin, indigo carmine, tartrazine, allura red, quinoline yellow, titanium dioxide, iron oxide, mica, beta-carotene, or any combination thereof.

[0174] In some embodiments, the pharmaceutical composition comprises bapendavir or a pharmaceutically acceptable salt thereof as described herein, and further comprises Cellulose Microcrystalline Silicified (PROSOLVHD90) (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 85F18422 (Mfg.Std.).

[0175] The pharmaceutical compositions or unit dose forms of the present invention can be administered according to doses and administration regimens defined by routine testing based on the above guidelines, in order to obtain optimal activity while minimizing toxicity or side effects for a particular target. However, fine-tuning of such treatment regimens is routinely performed in accordance with the guidelines provided herein.

[0176] The dosage of the compounds disclosed herein may vary depending on various factors such as the underlying disease state, the subject's condition, weight, sex and age, and the route of administration. The effective dose for treating the disease can be easily determined by empirical methods well known to those skilled in the art, for example, by setting up a dosage-frequency matrix and comparing the group of test units or subjects at each point on the matrix. The exact amount administered to a subject will vary depending on the disease state and severity, as well as the subject's physical condition. Measurable improvement in any symptom or parameter may be determined by those skilled in the art or reported by the subject to a physician. It is understood that clinically or statistically significant relief or improvement of any symptom or parameter of urinary tract disease is included within the scope of this disclosure. Clinically significant relief or improvement means that it is perceptible to the subject and / or the physician. The pharmaceutical formulations disclosed herein do not necessarily have to contain the entire amount of the compound effective for treating the disease, and it is understood that such an effective dose may be achieved by administering such pharmaceutical formulations in multiple doses.

[0177] In some embodiments, the pharmaceutical composition contains a diluent such as Cellulose Microcrystalline Silicified (PROSOLVHD90) (USP / NF). In some embodiments, the pharmaceutical composition contains about 250 mg of a diluent such as Cellulose Microcrystalline Silicified (PROSOLVHD90) (USP / NF). For example, the pharmaceutical composition contains 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 contains about 500 mg of a diluent such as Cellulose Microcrystalline Silicified (PROSOLVHD90) (USP / NF). For example, the pharmaceutical composition contains approximately 400 mg, approximately 410 mg, approximately 420 mg, approximately 430 mg, approximately 440 mg, approximately 450 mg, approximately 460 mg, approximately 470 mg, approximately 480 mg, approximately 490 mg, approximately 500 mg, approximately 510 mg, approximately 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg, approximately 560 mg, approximately 570 mg, approximately 580 mg, approximately 590 mg, or approximately 600 mg of the diluent, or any range or value contained therein.

[0178] In some embodiments, the pharmaceutical composition contains a disintegrant such as Starch Glycolate Sodium (USP / NF / EP). In some embodiments, the pharmaceutical composition contains about 50 mg of a disintegrant such as Starch Glycolate Sodium (USP / NF / EP). For example, the pharmaceutical composition contains about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg of the disintegrant, or any range or value contained therein. In some embodiments, the pharmaceutical composition contains about 100 mg of a disintegrant such as Starch Glycolate Sodium (USP / NF / EP). For example, the pharmaceutical composition contains about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg of the disintegrant, or any range or value contained therein.

[0179] In some embodiments, the pharmaceutical composition contains a surfactant such as Poloxamer Microprilled 188 (USP / NF / EP / JPE). In some embodiments, the pharmaceutical composition contains about 10 mg of a surfactant such as Poloxamer Microprilled 188 (USP / NF / EP / JPE). For example, the pharmaceutical composition contains about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg of the surfactant, or any range or value included therein. In some embodiments, the pharmaceutical composition contains about 20 mg of a surfactant such as Poloxamer Microprilled 188 (USP / NF / EP / JPE). For example, the pharmaceutical composition contains about 16 mg, about 18 mg, about 20 mg, about 22 mg, about 24 mg of the surfactant, or any range or value included therein.

[0180] In some embodiments, the pharmaceutical composition contains a lubricant such as Magnesium Stearate 5712 (USP / NF / EP). In some embodiments, the pharmaceutical composition contains about 10 mg of a lubricant such as Magnesium Stearate 5712 (USP / NF / EP). For example, the pharmaceutical composition contains about 8 mg, about 9 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 contains about 20 mg of a lubricant such as Magnesium Stearate 5712 (USP / NF / EP). For example, the pharmaceutical composition contains 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.

[0181] In some embodiments, the pharmaceutical composition includes a colored coating such as Opadry II White 85F18422 (Mfg. Std.). In some embodiments, the pharmaceutical composition contains about 15 mg of a colored coating such as Opadry II White 85F18422 (Mfg. Std.). For example, the pharmaceutical composition contains about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg of the colored coating, or any range or value included therein. In some embodiments, the pharmaceutical composition contains about 15 mg of a colored coating such as Opadry II White 85F18422 (Mfg. Std.). For example, the pharmaceutical composition contains about 24 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 34 mg, about 36 mg of the colored coating, or any range or value included therein.

[0182] In some embodiments, the pharmaceutical composition comprises about 250 mg of babendavir or a pharmaceutically acceptable salt thereof, about 250 mg of Cellulose Microcrystalline Silicified (PROSOLVHD90) (USP / NF) (PROSOLVHD90) (USP / NF), about 50 mg of Starch Glycolate Sodium (USP / NF / EP), about 10 mg of Poloxamer 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.).

[0183] In some embodiments, the pharmaceutical composition comprises about 500 mg of babendavir 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 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 85F18422 (Mfg.Std.).

[0184] Some embodiments are directed toward a method comprising the steps of orally administering a therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof to a human subject having COPD while the subject is feeding, thereby treating a respiratory enterovirus infection in the subject. The therapeutically effective dose of babendavir or a pharmaceutically acceptable salt thereof is in the range of approximately 250 mg to approximately 2000 mg per day; the therapeutically effective dose of babendavir or a pharmaceutically acceptable salt thereof is administered as a single loading dose of approximately 1000 mg followed by a maintenance dose of approximately 500 mg every 12 hours for approximately 4 to 10 days, approximately 5 to 8 days, approximately 6 to 8 days, or approximately 7 days; the treatment of respiratory enterovirus infection in the subject includes improvement of the subject's subpeak airway symptom score (LRSS), improvement of signs and symptoms of respiratory enterovirus infection, reduction of respiratory enterovirus viral load and frequency and severity of secondary bacterial infections, improvement of pulmonary function tests (PFTs), or a combination thereof; furthermore, the subject is not taking any drugs known to be affected or significantly metabolized by CYP3A4. Preferably, the therapeutically effective dose of babendavir or a pharmaceutically acceptable salt thereof is administered as a single loading dose of about 1000 mg, followed by a maintenance dose of about 500 mg every 12 hours for a total of about 13 doses.

[0185] The methods and compositions disclosed herein can be used in the following embodiments and may be combined as needed to form new embodiments.

[0186] 1. A method for treating a respiratory enterovirus infection in a human subject having COPD, comprising the steps of: orally administering a therapeutically effective amount of bapendavir or a pharmaceutically acceptable salt thereof to the subject; and thereby treating the respiratory enterovirus infection in the subject.

[0187] 2. The method according to Embodiment 1, wherein the therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof is approximately 250 mg to approximately 2000 mg per day.

[0188] 3. A method according to any one of Embodiments 1 to 2, wherein the respiratory enterovirus is selected from rhinovirus, echovirus, EV-68, EV-71, coxsackievirus, nonpolioenterovirus, and combinations thereof.

[0189] 4. A method according to any of Embodiments 1 to 3, wherein the therapeutically effective amount of bapendavir or a pharmaceutically acceptable salt thereof is administered as a single loading dose of about 1000 mg, followed by a maintenance dose of about 500 mg every 12 hours for about 4 to 10 days.

[0190] 5. A method according to any of Embodiments 1 to 4, wherein the therapeutically effective amount of bapendavir or a pharmaceutically acceptable salt thereof is administered approximately 13 times in total, with a maintenance dose of approximately 500 mg every 12 hours, following a single loading dose of approximately 1000 mg.

[0191] 6. The method according to any of Embodiments 1 to 5, wherein the therapeutically effective amount of bapendavir or a pharmaceutically acceptable salt thereof is approximately 2000 to approximately 12000 ng / ml of C max The quantity or method that achieves this.

[0192] 7. A method according to any one of Embodiments 1 to 6, wherein the single loading dose is administered within approximately 48 hours after the subject exhibits symptoms of respiratory enterovirus infection.

[0193] 8. A method according to any one of Embodiments 1 to 7, wherein the single loading dose is administered within approximately 72 to approximately 96 hours after the subject exhibits symptoms of respiratory enterovirus infection.

[0194] 9. A method according to any one of Embodiments 1 to 8, wherein the symptoms of the respiratory enterovirus infection are selected from cough, increased mucus production, sneezing, nasal congestion, runny nose, sore throat, headache, muscle pain, shortness of breath, chest tightness, wheezing, fever, conjunctival congestion, lymphadenopathy, malaise, hoarseness, runny nose, general discomfort, nasal obstruction, sputum production, dysfunction at normal activity levels, and any combination thereof.

[0195] 10. A method according to any one of Embodiments 1 to 9, wherein the single loading dose is administered before the subject reaches a peak viral load.

[0196] 11. A method according to any of Embodiments 1 to 10, wherein the subject is asymptomatic but has been diagnosed with a respiratory enterovirus infection.

[0197] 12. A method according to any of Embodiments 1 to 11, wherein the maintenance dose is first administered about 6 to about 12 hours after the administration of the single loading dose.

[0198] 13. A method according to any one of Embodiments 1 to 12, wherein the single loading dose is administered after the subject has been diagnosed with a respiratory enterovirus infection, and the diagnosis is achieved by clinical diagnosis, multiplex PCR testing, rapid antigen testing, direct immunofluorescence testing, arterial blood gas analysis, chest X-ray, peak flow metering, pleural fluid culture, lung CT scanning, pulmonary function tests, pulse oximetry, spirometry, sputum testing, nasal swab testing, pharyngeal swab testing, or any combination thereof.

[0199] 14. A method according to any of Embodiments 1 to 13, wherein the single loading dose and the maintenance dose are administered within approximately 30 minutes after the subject has ingested a meal containing solid food (i.e., while the subject is eating).

[0200] 15. A method according to any of Embodiments 1 to 14, wherein the single loading dose and maintenance dose are administered to the subject within approximately 30 minutes after the subject has ingested a meal containing solid food, thereby increasing the plasma concentration of bapendavir or a pharmaceutically acceptable salt thereof compared to when the subject is administered the single loading dose and maintenance dose in a fasted state.

[0201] 16. A method according to any of Embodiments 1 to 15, wherein the therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof is administered in a dose of about 500 mg every 12 hours for about 4 to 10 days.

[0202] 17. A method according to any of Embodiments 1 to 16, wherein the initial dose is administered within approximately 48 hours of the subject exhibiting symptoms of respiratory enterovirus infection.

[0203] 18. A method according to any of Embodiments 1 to 17, wherein the initial dose is administered within approximately 72 to 96 hours after the subject exhibits symptoms of respiratory enterovirus infection.

[0204] 19. A method according to any of Embodiments 1 to 18, wherein the symptoms of the respiratory enterovirus infection are selected from cough, increased mucus production, sneezing, nasal congestion, runny nose, sore throat, headache, muscle pain, shortness of breath, chest tightness, wheezing, fever, conjunctival congestion, lymphadenopathy, malaise, hoarseness, runny nose, general discomfort, nasal obstruction, sputum production, dysfunction at normal activity levels, and any combination thereof.

[0205] 20. A method according to any of Embodiments 1 to 19, wherein the first dose is administered before the subject reaches a peak viral load.

[0206] 21. A method according to any of Embodiments 1 to 20, wherein the subject is asymptomatic but has been diagnosed with a respiratory enterovirus infection.

[0207] 22. A method according to any of Embodiments 1 to 21, wherein the initial dose is administered after the subject has been diagnosed with a respiratory enterovirus infection, the diagnosis being achieved by clinical diagnosis, multiplex PCR testing, rapid antigen testing, direct fluorescent antibody testing, arterial blood gas analysis, chest X-ray, peak flow metering, pleural fluid culture, lung CT, pulmonary function tests, pulse oximetry, spirometry, sputum testing, nasal swab testing, pharyngeal swab testing, or any combination thereof.

[0208] 23. A method according to any of Embodiments 1 to 22, wherein the dose is administered within approximately 30 minutes after the subject has ingested a meal containing solid food (i.e., while the subject is eating).

[0209] 24. A method according to any of Embodiments 1 to 23, wherein the dose is administered within approximately 30 minutes after the subject has ingested a meal containing solid food, thereby increasing the plasma concentration of bapendavir or a pharmaceutically acceptable salt thereof compared to when the subject is administered the single loading dose and maintenance dose in a fasted state.

[0210] 25. A method according to any of Embodiments 1 to 24, wherein the subject is in a feeding state.

[0211] 26. A method according to any of Embodiments 1 to 25, wherein the subject is a human being aged approximately 40 to approximately 85 years.

[0212] 27. A method according to any of Embodiments 1 to 26, wherein the subject is diagnosed with GOLD Stage 2 COPD, GOLD Stage 3 COPD, or GOLD Stage 4 COPD.

[0213] 28. A method according to any one of Embodiments 1 to 27, wherein the subject is receiving maintenance therapy for COPD.

[0214] 29. A method according to any of Embodiments 1 to 28, wherein the treatment of a respiratory enterovirus infection in the subject comprises reducing the viral load in the sputum, nasal cavity, or combination thereof of the subject compared to the viral load in the sputum, nasal cavity, or combination thereof of the subject before treatment.

[0215] 30. A method according to any one of Embodiments 1 to 29, wherein treatment of a respiratory enterovirus infection in the subject reduces and / or prevents an increase in the respiratory symptom rating score (E-RS) in the subject's COPD compared to the subject's COPD

[0216] 31. A method according to any one of Embodiments 1 to 30, wherein treatment of a respiratory enterovirus infection in the subject reduces and / or prevents an increase in the subject's subpeak subairway symptom score (LRSS) compared to the subject's subpeak subairway symptom score (LRSS) before treatment.

[0217] 32. A method according to any one of Embodiments 1 to 31, wherein treatment of a respiratory enterovirus infection in the subject reduces and / or prevents an increase in the subject's peak upper airway symptom score (URSS) compared to the subject's peak upper airway symptom score (URSS) before treatment.

[0218] 33. A method according to any one of Embodiments 1 to 32, comprising: treatment of a respiratory enterovirus infection in the subject reducing and / or preventing an increase in the chronic lung disease exacerbation tool-patient reported outcome (EXACT-PRO) of the subject compared to the subject's chronic lung disease exacerbation tool-patient reported outcome (EXACT-PRO) before treatment.

[0219] 34. A method according to any one of Embodiments 1 to 33, comprising treating a respiratory enterovirus infection in the subject to reduce and / or prevent an increase in the chronic lung disease exacerbation tool-patient respiratory symptoms (EXACT-RS) of the subject compared to the subject's chronic lung disease exacerbation tool-patient respiratory symptoms (EXACT-RS) before treatment.

[0220] 35. A method according to any one of Embodiments 1 to 34, comprising treatment of a respiratory enterovirus infection in the subject to reduce and / or prevent an increase in the subject's COPD Assessment Tool (CAT) compared to the subject's COPD Assessment Tool (CAT) before treatment.

[0221] 36. A method according to any one of Embodiments 1 to 35, wherein treatment of a respiratory enterovirus infection in the subject reduces and / or prevents an increase in the St. George's Respiratory Questionnaire (SGRQ) of the subject compared to the subject's SGRQ before treatment.

[0222] 37. A method according to any one of Embodiments 1 to 36, comprising treatment of a respiratory enterovirus infection in the subject to reduce and / or prevent an increase in the Wisconsin Upper Respiratory Symptom Survey (WURSS) of the subject compared to the subject's WURSS before treatment.

[0223] 38. A method according to any one of Embodiments 1 to 37, wherein the treatment of a respiratory enterovirus infection in the subject improves and / or prevents a decline in the lung function of the subject compared to the lung function of the subject before treatment.

[0224] 39. A method according to any one of embodiments 1 to 38, wherein the target lung function is the forced expiratory volume in one second (FEV1). -1A method that measures liters and predicted values, forced vital capacity (FVC; liters and predicted values), FEV1 / FVC ratio, and peak expiratory flow rate (PEF), or a combination thereof.

[0225] 40. A method according to any one of Embodiments 1 to 39, wherein the treatment of a respiratory enterovirus infection in the subject reduces the peak nasal lavage viral load of the subject compared to the peak nasal lavage viral load of the subject before treatment, and / or prevents an increase thereof.

[0226] 41. A method according to any one of Embodiments 1 to 40, wherein treatment of a respiratory enterovirus infection in the subject reduces the peak sputum lavage viral load of the subject compared to the peak sputum lavage viral load of the subject before treatment, and / or prevents an increase thereof.

[0227] 42. A method according to any one of Embodiments 1 to 41, wherein the treatment of a respiratory enterovirus infection in the subject reduces the AUC of the nasal viral load in the subject compared to the AUC of the nasal viral load in the subject before treatment, and / or prevents an increase thereof.

[0228] 43. A method according to any one of Embodiments 1 to 42, wherein the treatment of a respiratory enterovirus infection in the subject comprises reducing the AUC of the sputum viral load of the subject compared to the AUC of the sputum viral load of the subject before treatment, and / or preventing an increase thereof.

[0229] 44. A method according to any one of Embodiments 1 to 43, wherein the treatment of a respiratory enterovirus infection in the subject comprises shortening the period of viral shedding.

[0230] 45. A method according to any one of Embodiments 1 to 44, wherein treatment of a respiratory enterovirus infection in the subject reduces the peak sputum lavage bacterial load of the subject compared to the peak sputum lavage bacterial load of the subject before treatment, and / or prevents an increase thereof.

[0231] 46. ​​A method according to any one of Embodiments 1 to 45, wherein the treatment of a respiratory enterovirus infection in the subject comprises reducing the AUC of the sputum bacterial load in the subject compared to the AUC of the sputum bacterial load in the subject before treatment, and / or preventing an increase thereof.

[0232] 47. A method according to any one of Embodiments 1 to 46, wherein treatment of a respiratory enterovirus infection in the subject comprises reducing the number of days the subject is positive for bacteria in sputum.

[0233] 48. A method according to any one of Embodiments 1 to 47, wherein the treatment of a respiratory enterovirus infection in the subject includes preventing or reducing acute exacerbations of COPD in the subject caused by the respiratory enterovirus infection.

[0234] 49. A method according to any of Embodiments 1 to 48, wherein the treatment of a respiratory enterovirus infection in the subject comprises reducing the frequency and / or preventing an increase in acute exacerbations of COPD in the subject caused by the respiratory enterovirus infection, reducing the severity of acute exacerbations of COPD in the subject, reducing the duration of acute exacerbations of COPD in the subject, or a combination thereof.

[0235] 50. A method according to any of Embodiments 1 to 49, wherein a therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof is administered to the subject, thereby enabling paEC against human rhinovirus. 50 A method that surpasses this.

[0236] 51. A method according to any one of Embodiments 1 to 50, wherein paEC against the human rhinovirus 50 The concentration is approximately 75.4 ng / ml, according to the method.

[0237] 52. A method according to any one of Embodiments 1 to 51, wherein the therapeutically effective dose of babendavir or a pharmaceutically acceptable salt thereof is administered as 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.

[0238] 53. A method according to any one of Embodiments 1 to 52, wherein the therapeutically effective dose of babendavir or a pharmaceutically acceptable salt thereof is administered as a single loading dose of about 1,000 mg, followed by a total of about 13 maintenance doses of about 500 mg every 12 hours.

[0239] 54. The method according to any of Embodiments 1 to 53, wherein the therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof is about 2,000 to about 12,000 ng / ml of C max The quantity or method that achieves this.

[0240] 55. A method according to any one of Embodiments 1 to 54, wherein paEC against the human rhinovirus 50 This method can be used for approximately 4 to 10 days, or until treatment is discontinued.

[0241] 56. A method according to any of Embodiments 1 to 55, wherein a therapeutically effective dose of babendavir or a pharmaceutically acceptable salt thereof is administered to the subject, thereby enabling paEC against human rhinovirus. 90 A method that surpasses this.

[0242] 57. A method according to any one of Embodiments 1 to 56, wherein paEC against the human rhinovirus 90 The value is approximately 678.6 ng / ml, according to the method.

[0243] The method according to any one of Embodiments 1 to 57, wherein the therapeutically effective amount of the bupendavil or a pharmaceutically acceptable salt thereof is administered as a maintenance dose of about 500 mg every 12 hours for about 4 to about 10 days following a single loading dose of about 1,000 mg.

[0244] The method according to any one of Embodiments 1 to 58, wherein the therapeutically effective amount of the bupendavil or a pharmaceutically acceptable salt thereof is administered as a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance doses following a single loading dose of about 1,000 mg.

[0245] The method according to any one of Embodiments 1 to 59, wherein the therapeutically effective amount of the bupendavil or a pharmaceutically acceptable salt thereof is an amount that achieves a C of about 2,000 to about 12,000 ng / ml. max

[0246] The method according to any one of Embodiments 1 to 60, wherein the therapeutically effective amount of the bupendavil or a pharmaceutically acceptable salt thereof is administered as a maintenance dose of about 500 mg for about 6 to about 10 days following a single loading dose of about 1,000 mg.

[0247] The method according to any one of Embodiments 1 to 63, wherein the paEC against the human rhinovirus is exceeded for about 4 to about 10 days or until treatment is discontinued. 90

[0248] The method according to any one of Embodiments 1 to 64, wherein administering a therapeutically effective amount of the bupendavil or a pharmaceutically acceptable salt thereof to the subject results in a C that exceeds the paEC against the human rhinovirus.

[0279] max

[0249] The method according to any one of Embodiments 1 to 65, wherein the paEC against the human rhinovirus is about 75.4 ng / ml. 50 ​​​​​

[0250] 65. A method according to any of Embodiments 1 to 66, wherein the therapeutically effective dose of babendavir or a pharmaceutically acceptable salt thereof is administered as a single loading dose of about 1,000 mg, followed by a total of about 13 maintenance doses of about 500 mg every 12 hours.

[0251] 66. The method according to any of Embodiments 1 to 67, wherein the therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof is about 2,000 to about 12,000 ng / ml of C max The quantity or method that achieves this.

[0252] 67. A method according to any of Embodiments 1 to 68, wherein the therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof is administered as a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg for about 6 to about 10 days.

[0253] 68. A method according to any one of Embodiments 1 to 69, wherein paEC against the human rhinovirus 50 This method can be used for approximately 4 to 10 days, or until treatment is discontinued.

[0254] 69. A method according to any of Embodiments 1 to 70, wherein a therapeutically effective dose of babendavir or a pharmaceutically acceptable salt thereof is administered to the subject, thereby enabling paEC against human rhinovirus. 90 Exceeding C max A method to obtain it.

[0255] 70. A method according to any one of Embodiments 1 to 71, wherein paEC against the human rhinovirus 90 The value is approximately 678.6 ng / ml, according to the method.

[0256] 71. A method according to any one of Embodiments 1 to 72, wherein the therapeutically effective amount of the bupendavil or a pharmaceutically acceptable salt thereof is administered as a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance dose administrations following a single loading dose administration of about 1,000 mg.

[0257] 72. A method according to any one of Embodiments 1 to 73, wherein the therapeutically effective amount of the bupendavil or a pharmaceutically acceptable salt thereof is an amount that achieves a C of about 2,000 to about 12,000 ng / ml. max

[0258] 73. A method according to any one of Embodiments 1 to 74, wherein the therapeutically effective amount of the bupendavil or a pharmaceutically acceptable salt thereof is administered as a maintenance dose of about 500 mg for about 6 to about 10 days following a single loading dose administration of about 1,000 mg.

[0259] 74. A method according to any one of Embodiments 1 to 75, wherein the paEC against the human rhinovirus is exceeded for about 4 to about 10 days or until treatment is discontinued. 90

[0260] 75. A method according to any one of Embodiments 1 to 76, wherein by administering a therapeutically effective amount of the bupendavil or a pharmaceutically acceptable salt thereof to the subject, the paEC against the human rhinovirus is exceeded after a single administration. 50

[0261] 76. A method according to any one of Embodiments 1 to 77, wherein the paEC against the human rhinovirus is about 75.4 ng / ml. 50

[0262] <00​​

[0263] 78. A method according to any one of embodiments 1 to 79, wherein the therapeutically effective amount of the vaperdavir or a pharmaceutically acceptable salt thereof is a C of about 2,000 to about 12,000 ng / ml max achieved amount, method.

[0264] 79. A method according to any one of embodiments 1 to 80, wherein the therapeutically effective amount of the vaperdavir or a pharmaceutically acceptable salt thereof is administered as a maintenance dose of about 500 mg for about 6 to about 10 days following a single loading dose of about 1,000 mg.

[0265] 80. A method according to any one of embodiments 1 to 81, wherein the paEC against the human rhinovirus 50 is exceeded for about 4 to about 10 days or until treatment is discontinued.

[0266] 81. A method according to any one of embodiments 1 to 82, wherein by administering a therapeutically effective amount of the vaperdavir or a pharmaceutically acceptable salt thereof to the subject, the paEC against the human rhinovirus 90 is exceeded. [[ID=二十二]]

[0267] 82. A method according to any one of embodiments 1 to 83, wherein the paEC against the human rhinovirus 90 is about 678.6 ng / ml.

[0268] 83. A method according to any one of embodiments 1 to 84, wherein the therapeutically effective amount of the vaperdavir or a pharmaceutically acceptable salt thereof is administered as a maintenance dose of about 500 mg every 12 hours for a total of about 13 maintenance dose administrations following a single loading dose of about 1,000 mg.

[0269] 84. A method according to any one of embodiments 1 to 85, wherein the therapeutically effective amount of the vaperdavir or a pharmaceutically acceptable salt thereof is a C of about 2,000 to about 12,000 ng / ml max achieved amount, method.

[0270] 85. A method according to any of Embodiments 1 to 86, wherein the therapeutically effective dose of babendavir or a pharmaceutically acceptable salt thereof is administered as a single loading dose of about 1,000 mg followed by a maintenance dose of about 500 mg for about 6 to about 10 days.

[0271] 86. A method according to any one of Embodiments 1 to 87, wherein paEC against the human rhinovirus 90 This method can be used for approximately 4 to 10 days, or until treatment is discontinued.

[0272] 87. A method according to any of Embodiments 1 to 88, wherein the therapeutically effective dose of bapendavir or a pharmaceutically acceptable salt thereof is in tablet form.

[0273] 88. A method according to any one of Embodiments 1 to 89, wherein the bapendavir is a free base, maleate, oxalate, phosphate, sulfate, tartrate, or chloride salt.

[0274] 89. A method according to any of Embodiments 1 to 90, wherein the bapendavir or a pharmaceutically acceptable salt thereof is an amorphous form of bapendavir.

[0275] 90. A pharmaceutical composition comprising a therapeutically effective amount of bapendavir or a pharmaceutically acceptable salt thereof.

[0276] 91. A pharmaceutical composition according to Embodiment 90, wherein the bapendavir is a free base, maleate, oxalate, phosphate, sulfate, tartrate, or chloride salt.

[0277] 92. A pharmaceutical composition according to any one of embodiments 90 to 91, wherein the bapendavir is an amorphous form of bapendavir or a pharmaceutically acceptable salt thereof.

[0278] 93. A pharmaceutical composition according to any one of embodiments 90 to 92, comprising about 250 mg of bapendavir or a pharmaceutically acceptable salt thereof.

[0279] 94. A pharmaceutical composition according to any of embodiments 90 to 93, comprising about 500 mg of bapendavir or a pharmaceutically acceptable salt thereof.

[0280] 95. A pharmaceutical composition according to any one of embodiments 90 to 94, wherein the pharmaceutical composition is a tablet.

[0281] 96. A pharmaceutical composition according to any one of embodiments 90 to 95, further comprising a diluent, a disintegrant, a surfactant, a lubricant, a colored coating, or any combination thereof.

[0282] 97. A pharmaceutical composition according to any of Embodiments 90 to 96, wherein the diluent is selected from Cellulose Microcrystalline Silicified (PROSOLVHD90) (USP / NF), anhydrous calcium phosphate, anhydrous lactose, calcium carbonate, calcium lactate, calcium sulfate dihydrate, corn starch, fructose, kaolin, lactose monohydrate, magnesium hydroxide, maltitol, monohydrate maltose, mannitol, sorbitol, sucrose, tricalcium phosphate, sodium citrate, glycine, croscarmellose sodium, ethanol, propylene glycol, glycerin, polyvinylpyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin, acacia, or any combination thereof.

[0283] 98. A pharmaceutical composition according to any of embodiments 90 to 97, wherein the disintegrant is selected from Starch Glycolate Sodium (USP / NF / EP), corn starch, potato starch, tapioca starch, croscarmellose sodium, pregelatinized starch, carboxymethylcellulose sodium, alginate, resin, hydrated aluminum silicate, crosslinked polyvinylpyrrolidone, or any combination thereof.

[0284] 99. A pharmaceutical composition according to any of embodiments 90 to 98, wherein the surfactant is selected from Poloxamer Microprilled 188 (USP / NF / EP / JPE), sodium lauryl sulfate, polysorbates, or any combination thereof.

[0285] 100. A pharmaceutical composition according to any of Embodiments 90 to 99, wherein the lubricant is selected from Magnesium Stearate 5712 (USP / NF / EP), stearic acid, glyceryl behenate, talc, carnauba wax, polymer of ethylene oxide, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, colloidal silicon dioxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, acrylate-methacrylate copolymer, or any combination thereof.

[0286] 101. A pharmaceutical composition according to any one of Embodiments 90 to 100, wherein the colored coating is selected from Opadry II White 85F18422 (Mfg. Std.), riboflavin, anthocyanin, paprika oleoresin, beetroot, curcumin, indigo carmine, tartrazine, allura red, quinoline yellow, titanium dioxide, iron oxide, mica, beta-carotene, or any combination thereof.

[0287] 102. A pharmaceutical composition according to any one of embodiments 90 to 101, wherein the pharmaceutical composition further comprises Cellulose Microcrystalline Silicified (PROSOLVHD90) (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 85F18422 (Mfg.Std.).

[0288] 103. A pharmaceutical composition according to any one of embodiments 90 to 102, wherein the pharmaceutical composition further comprises about 250 mg of Cellulose Microcrystalline Silicified (PROSOLVHD90) (USP / NF).

[0289] 104. A pharmaceutical composition according to any one of embodiments 90 to 103, wherein the pharmaceutical composition further comprises about 500 mg of Cellulose Microcrystalline Silicified (PROSOLVHD90) (USP / NF).

[0290] 105. A pharmaceutical composition according to any of embodiments 90 to 104, wherein the pharmaceutical composition comprises about 50 mg of Starch Glycolate Sodium (USP / NF / EP).

[0291] 106. A pharmaceutical composition according to any of embodiments 90 to 105, wherein the pharmaceutical composition comprises about 100 mg of Starch Glycolate Sodium (USP / NF / EP).

[0292] 107. A pharmaceutical composition according to any of embodiments 90 to 106, wherein the pharmaceutical composition contains about 10 mg of Poloxamer Microprilled 188 (USP / NF / EP / JPE).

[0293] 108. A pharmaceutical composition according to any of embodiments 90 to 107, wherein the pharmaceutical composition contains about 20 mg of Poloxamer Microprilled 188 (USP / NF / EP / JPE).

[0294] 109. A pharmaceutical composition according to any of embodiments 90 to 108, wherein the pharmaceutical composition comprises about 10 mg of Magnesium Stearate 5712 (USP / NF / EP).

[0295] 110. A pharmaceutical composition according to any of embodiments 90 to 109, wherein the pharmaceutical composition comprises about 20 mg of Magnesium Stearate 5712 (USP / NF / EP).

[0296] 111. A pharmaceutical composition according to any one of Embodiments 90 to 110, wherein the pharmaceutical composition comprises about 15 mg of Opadry II White 85F18422 (Mfg. Std.).

[0297] 112. A pharmaceutical composition according to any one of Embodiments 90 to 111, wherein the pharmaceutical composition comprises about 30 mg of Opadry II White 85F18422 (Mfg. Std.).

[0298] 113. A pharmaceutical composition according to any of Embodiments 90 to 112, wherein the pharmaceutical composition comprises about 250 mg of bapendavir or a pharmaceutically acceptable salt thereof, about 250 mg of Cellulose Microcrystalline Silicified (PROSOLVHD90) (USP / NF) (PROSOLVHD90) (USP / NF), about 50 mg of Starch Glycolate Sodium (USP / NF / EP), about 10 mg of Poloxamer 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.).

[0299] 114. A pharmaceutical composition according to any of Embodiments 90 to 113, wherein the pharmaceutical composition comprises about 500 mg of bapendavir 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 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 85F18422 (Mfg.Std.).

[0300] The following embodiments have been or will be carried out in accordance with the embodiments of this disclosure. [Examples]

[0301] Example 1 - A double-blind, randomized, placebo-controlled trial to evaluate the effect of bapentavir on the development of lower respiratory tract symptoms after rhinovirus challenge in patients with chronic obstructive pulmonary disease (COPD).

[0302] Introduction: Rhinovirus and Chronic Obstructive Pulmonary Disease (COPD) Rhinoviruses (RVs) are small, ubiquitous RNA viruses, and it is believed that there are more than 180 different strains. Based on sequence homology, RVs are classified into the RV-A, RV-B, and RV-C families. In healthy individuals, RVs are usually associated with mild, spontaneously resolving illnesses, but they can cause significant morbidity and mortality by exacerbating pre-existing chronic respiratory diseases such as asthma, COPD, or cystic fibrosis, and can cause complications in immunocompromised individuals such as transplant patients, and can induce moderate to severe illness in the elderly. Currently, there are no approved treatments or vaccines for RV infections, and only a few RV-specific antiviral drugs are in late-stage clinical development.

[0303] Importantly, approximately 40–50% (range 10–70%) of COPD exacerbations are associated with RV infection. Current treatments used for the management of COPD and acute exacerbations (e.g., long-acting muscarinic receptor antagonists (LAMAs), long-acting β2 receptor agonists (LABAs), inhaled corticosteroids (ICS), and antibiotics) remain only partially effective, have significant side effects, and often fail to address the underlying mechanisms of the disease or triggers the exacerbations. Exacerbations are associated with increased airway inflammation, increased mucus production, delayed or impaired antiviral host defense, and an increase in pathogenic respiratory bacteria.

[0304] The complex biology of COPD exacerbations has recently been elucidated using the RV challenge model in COPD patients. Mallia et al. showed that RV infection induces the symptoms, physiological features, and inflammatory features reported in spontaneously occurring COPD exacerbations, and that this infection is associated with impaired antiviral host factors and excessive neutrophilic inflammation. This study also clarified the temporal relationship between symptoms, viral load, and disease mechanism, showing that upper respiratory tract symptoms begin immediately after viral challenge, while the most severe lower respiratory tract symptoms, neutrophilic inflammation, and secondary bacterial infections occur more than one week after the onset of initial symptoms. Therefore, the use of the RV challenge model in COPD subjects reveals a potential therapeutic opportunity to intervene in RV-associated acute COPD exacerbations with potent and specific antiviral therapy.

[0305] Dosage The dosage selected in this study is a loading dose of 1000 mg followed by a 500 mg BID for 7 days. If the loading dose is administered in the morning, the second dose is given on day 1 (12 hours later). The second dose on day 2 (12 hours later) is 500 mg, and from day 2 to day 7 (only the first dose on day 7) 500 mg BIDs (at 12-hour intervals) are administered.

[0306] Research basis Effective and easily administered treatments for RV infection have the potential to mitigate serious health damage in vulnerable populations such as COPD patients. Treatment of RV infection can reduce the severity and frequency of acute COPD exacerbations, preserve lung function, prevent secondary bacterial infections, and reduce the need for expensive medical interventions, including inhalants, steroids, antibiotics, emergency care, hospitalization, and mechanical ventilation. Therefore, early treatment of RV infection can improve both the quality of life and lifespan of COPD patients.

[0307] the purpose • To evaluate the effectiveness of bapentavir versus placebo. • To evaluate the safety and tolerability of bapentavir versus placebo. • Evaluate the PK / PD relationship between babendavir exposure, viral load, and other outcomes of interest.

[0308] Key evaluation criteria In this study, the primary endpoint in COPD patients was to compare patients treated with babendavir with those treated with placebo, evaluating the peak lower airway symptom score (LRSS) from the start of treatment to day 42 according to the method defined by Mallia et al.

[0309] Secondary evaluation items The secondary endpoints in COPD patients are as follows: • To evaluate the effects of bapendavir versus placebo on the signs and symptoms of RV infection. • To evaluate the effects of bapendavir versus placebo on RV viral load and the frequency and severity of secondary bacterial infections. • To evaluate the effect of bapentavir versus placebo on pulmonary function tests (PFT). • To evaluate the safety and tolerability of bapentavir versus placebo.

[0310] Exploratory evaluation items The exploratory endpoints in COPD patients are as follows: • Evaluate the PK / PD relationship between babendavir exposure, viral load, and other outcomes of interest. • Evaluate the impact of bapentavir versus placebo in the event of a change in medication (e.g., need for antibiotics, rescue medication for lung exacerbations). • To evaluate the impact of bapentavir versus placebo on the use of medical resources (e.g., emergency room visits, hospitalization). • To evaluate the effects of bapendavir versus placebo on inflammatory markers / other biomarkers. • To evaluate the effect of bapendavir versus placebo on the molecular quantification of respiratory viruses and bacteria.

[0311] Overall study design Randomization will be 1:1, with patients receiving either babendavir or placebo. Patients will receive treatment twice daily for 7 days. Treatment will begin after symptom onset or when the patient determines they have a clinical cold. After 20±4 patients have completed 7 days of treatment and undergone a further 7 days of follow-up, the DSMB and sponsor will review the data from an interim analysis consisting of available safety and efficacy endpoints for the first 20 patients (10±2 babendavir:10±2 placebo) and make one of the following recommendations regarding the trial: • Continue the examination • Make modifications and continue testing. • To complete the exam

[0312] The planned completion of this clinical trial will be defined as the final visit of the last patient.

[0313] Patient selection Inclusion criteria: • At the time of signing the informed consent document, the person must be a male or female between the ages of 40 and 75. • Diagnosed with Stage 2 COPD according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), defined as having a % predicted forced expiratory volume in one second (FEV1) of 50% or more and a FEV1 / forced vital capacity (FVC) ratio of less than 70%. A patient with a history of acute exacerbation of COPD is defined as someone who answered "yes" to the question, "Do your COPD symptoms clearly worsen when you catch a cold?" • If receiving maintenance therapy, you must be medically stable for at least two months prior to registration. • No exacerbations within the two months prior to registration, and clinically stable. • No other viral pathogens are present in baseline prenasal cavity specimens using Genmark (Roche) molecular assay or a similar respiratory panel.

[0314] Exclusion criteria: • Patients with other causes of chronic airflow limitation • This includes, but is not limited to, asthma (including mixed asthma with COPD), cystic fibrosis (CF), bronchiolitis obliterans, fibrosis such as tuberculosis (TB) or idiopathic pulmonary fibrosis (IPF), or other major respiratory diagnoses (e.g., pneumonia, aspergillosis, etc.). • NonCF bronchiectasis • Cardiovascular, digestive, hepatic, renal, nervous, musculoskeletal, infectious, endocrine, metabolic, hematological, mental, and other diseases that are medically unstable or deemed medically unstable / unmanageable by the principal investigator. • Drugs that are affected by CYP3A4 induction, which may cause serious complications in patients during treatment, and which cannot be safely discontinued with a sufficient drug-free period before starting babendavir. • A history of a clinically significant infection (respiratory or non-respiratory) requiring antibiotics or more than 10 mg of systemic steroids per day within 30 days prior to the planned RV challenge. • Women who are pregnant, planning to become pregnant, or breastfeeding during the treatment period or within 30 days of treatment. • You have had cold symptoms such as sore throat, sneezing, runny nose, discomfort, nasal congestion, or cough within the past six weeks. • At the time of screening, serum rhinovirus 16 neutralizing antibody titers must be present at a dilution of 1 / 4 or greater. • Active allergic rhinitis, nasal polyps, chronic sinusitis, and other active nasal diseases • At the discretion of the principal investigator, active alcohol and / or drug abuse • Within one month prior to registration, you have used any over-the-counter cold prevention products containing nasal sprays, vitamin C, zinc, echinacea, or estrogen-based hormone replacement therapy. • Patients who participated in a drug trial within 30 days prior to registration or within the half-life of five drugs (whichever is longer) • Hypersensitivity / allergy to either the active ingredient or the placebo / component. • Patients in an immunosuppressed state (e.g., those with human immunodeficiency virus (HIV), transplant patients receiving anti-rejection drugs, or those receiving chemotherapy or immunotherapy) • Other factors that the principal investigator deems to be risky

[0315] Test integrity This study is a double-blind, placebo-controlled trial.

[0316] Number of patients This trial will enroll up to 50 patients to complete the trial procedures (maximum 25 patients per group).

[0317] Lung function All pulmonary function (spirometry) assessments are performed according to the British Thoracic Society guidelines. During the clinic visit, trained personnel will perform pulmonary function tests using calibrated equipment, measuring FEV1 (liters and predicted %), FVC (liters and predicted %), FEV1 / FVC ratio, and PEF.

[0318] Intranasal RV-A16 Challenge Patients are challenged in a negative pressure chamber at the Imperial College Healthcare NHS Trust's ICRRU using rhinovirus RV-A16 at a 100-tissue culture infectious dose (TCID50) that causes 50% cytotoxicity in tissue cultures. This process is carried out according to SOPs or facility operating manuals. RV-A16 is diluted and introduced into both nostrils four times using an atomizer (De Vilbiss Co.). Patients are instructed to sit quietly for several minutes without swallowing to allow the challenge virus to enter the nasal cavity.

[0319] placebo The placebo will be distributed by the study team on day 0 of the clinical visit to the study site. Patients will be given enough placebo for a 7-day treatment period (e.g., days 2-8). Treatment will be administered twice daily, in the morning and afternoon, at 12-hour ± 2-hour intervals. Placebo tablets will be prepared to match the effective treatment and administered orally for 7 days as follows: On day 1 of the administration period, when symptoms appear or when the patient answers "yes" to the question "Do you think you have a cold?", four tablets will be administered as the initial dose (e.g., day 2), followed by two more tablets on the same day (e.g., day 2) or the following day. Thus, treatment will last a total of 7 days (consisting of 13 doses of two tablets following the initial dose of four tablets). Treatment may be administered at home on non-clinical day days. All tablets should be swallowed with plenty of water and taken within 30 minutes after eating a meal, including solid food.

[0320] Bapendaville Babendavir will be administered by the study team on day 0 of the clinical visit to the study site. Patients will be given sufficient babendavir for a 7-day treatment period (e.g., days 2-8). Treatment will be administered twice daily, in the morning and afternoon, at 12-hour ± 2-hour intervals. Babendavir micronized free base tablets (250 mg each) will be administered orally starting with a loading dose of 1000 mg (4 tablets) when symptoms appear or when the patient answers "yes" to the question "Do you think you have a cold?", followed by 500 mg (2 tablets) on the same day (e.g., day 2) or the following day. Thus, the treatment will last a total of 7 days and will consist of an initial 1000 mg dose (4 tablets) followed by 13 doses of 500 mg (2 tablets). Treatment may be administered at home on non-clinical day days. All tablets should be swallowed with plenty of water and taken within 30 minutes after eating a meal, including solid food.

[0321] Concomitant medications, treatments, and procedures The use of standard therapeutic agents for the management of chronic COPD is acceptable. Examples are shown in Table 1. Oral steroids >10 mg / day are not acceptable at screening / baseline. [Table 1] TIFF2026510948000004.tif183141TIFF2026510948000005.tif101141

[0322] statistical methods Key evaluation criteria The primary statistical endpoint of this study is the difference in the change from baseline to peak total LRSS from the start of treatment to day 42, as defined by Mallia et al. The total LRSS for each day is calculated as the average of the total LRSS scores for the morning and afternoon of that day. The total LRSS consists of the sum of the individual symptom scores in each scoring system. The peak is defined as the highest total symptom score on any given day. The change from baseline is calculated by subtracting the mean baseline total LRSS score from the scores for each other day (days 0 through 42).

[0323] Secondary evaluation items Some secondary objectives in this study have sufficient power with 50 patients per group, but not all secondary objectives do. The secondary objectives are as follows: 1. Evaluate the effect of babendavir versus placebo on the signs and symptoms of RV infection. All values ​​will be calculated as changes from baseline: • Difference in peak total URSS; from the start of treatment to day 42 • Difference in peak EXACT-RS; from the start of treatment to day 42 • Differences in peak EXACT-PRO levels; from the start of treatment to day 42 • Differences in AUC LRSS; from the start of treatment to day 42 • Differences in AUC URSS; from the start of treatment to day 42 • Difference between AUC EXACT-RS; from the start of treatment to day 42 • Differences in AUC EXACT-PRO; from the start of treatment to day 42 • Any number of URSS days; from the start of treatment until day 42 • Any number of LRSS days; from the start of treatment until day 42 • Difference between peak total EXACT-RS and EXACT-PRO scores; from the start of treatment to the 14th day. • Difference between peak total EXACT-RS and EXACT-PRO scores; from the start of treatment to day 28. • Difference in peak total EXACT-RS score; from the start of treatment to day 42 • Percentage of patients showing a change of ≥2 points in the total EXACT-RS score from before administration to day 7. • Percentage of patients showing a change of ≥2 points in their total EXACT-RS score from before administration to day 14. • Percentage of patients showing a change of ≥2 points in their total EXACT-RS score from before administration to day 28. • Mean change in AUC ER-S from the start of administration to the 7th day of treatment and the additional 7 days of follow-up. • Mean change from baseline to peak LRSS • Difference in peak total EXACT-PRO score from baseline before administration to day 7. • Difference in peak total EXACT-PRO score from baseline before administration to day 14. • Difference in peak total SGRQ from baseline before administration to day 28. 2. Evaluation of the effects of bapendavir versus placebo on RV viral load and secondary bacterial infection. • Peak nasal lavage viral load (from the start of treatment to day 42) • Peak sputum viral load (from the start of treatment to day 42) • AUC nasal viral load (from the start of treatment to day 42) • AUC sputum viral load (from the start of treatment to day 42) • Virus shedding period (number of days with positive virus test, from day 1 to day 42) • Percentage of patients with positive sputum bacteria (NHS Microbiology, from the start of treatment to day 42) • Peak sputum bacterial load (NHS microbiology, from the start of treatment to day 42) • AUC (Area of ​​Uncancerous Calcium) of sputum bacteria (NHS Microbiology, from the start of treatment to day 42) • Number of days positive for bacteria (NHS Microbiology, from the start of treatment to day 42) 3. Evaluation of the effects of bapentavir versus placebo on pulmonary function tests. • Maximum percentage change from baseline in each pulmonary function test (FEV1, FVC, FEV1 / FVC, predicted %FEV1, predicted %FVC); follow-up for 7 days after treatment and at least 7 days after completion of treatment. • Differences in AUC for each pulmonary function test; 7 days of treatment, and follow-up for at least 7 days after completion of treatment. 4. Safety evaluation of bapentavir versus placebo • Differences in hematological test results on any given day; from the start of treatment to day 42. • Differences in liver function test (LFTs) results on any given day; from the start of treatment to day 42. • Differences in blood biochemistry test results on any given day; from the start of treatment to day 42. • Differences in the number of AEs or SAEs; from the start of treatment to day 42 • Differences in the number of patients reporting AEs or SAEs; from the start of treatment to day 42 • Differences in the number of concomitant medications; from the start of treatment to day 42 • Differences in vital signs on any given day; from the start of treatment to day 42. • Differences in the number of patients discontinued due to safety or tolerability reasons

[0324] Exploratory evaluation items Not all exploratory endpoints are detected by the 50 patients in each group. These include: 1. Evaluation of the relationship between babendavir exposure, viral load, and other outcomes of interest. • Correlation between viral load in nasal lavage fluid and bapendavir PK-PD • Correlation between sputum viral load and bapendavir PK-PD 2. Evaluation of the effect of bapentavir versus placebo on medication changes in COPD patients. • Percentage of patients requiring increased frequency and / or dosage of chronic COPD medications (e.g., LAMA, LABA) (from day 1 to day 28) • Changes to β-agonists, antimuscarinic inhalants, or other respiratory medications (dosage / frequency of use) (from day 1 to day 28) • Percentage of patients requiring new systemic corticosteroid treatment (from day 1 to day 28) • Percentage of patients requiring new antibiotic treatment (from day 1 to day 28) • Percentage of patients requiring both new systemic corticosteroid and antibiotic treatment (from day 1 to day 28) 3. Evaluation of the impact of bapentavir versus placebo on the use of medical resources in COPD patients. • Percentage of patients diagnosed with pneumonia (from the start of treatment to day 28) • Percentage of patients requiring ED evaluation • Percentage of patients requiring hospitalization 4. Evaluation of the effects of bapentavir versus placebo on inflammatory markers / other biomarkers in COPD patients. • Serum CRP peak value (from the start of treatment to day 42) • Serum CRP AUC (from the start of treatment to day 42) • Peak levels of nasal cytokines (for each cytokine, from the start of treatment to day 42) • AUC of nasal cytokines (for each cytokine, from the start of treatment to day 42) • Peak values ​​of sputum cytokines (for each cytokine, from the start of treatment to day 42) • AUC of sputum cytokines (for each cytokine, from the start of treatment to day 42) • Peak value of total sputum cell count (from the start of treatment to day 42) • AUC of total sputum cells (from the start of treatment to day 42) • Peak values ​​of specific sputum cell subsets (from the start of treatment to day 42) • AUC of specific sputum cell subsets (from the start of treatment to day 42) 5. To evaluate the effect of bapentavir versus placebo on the quantitative measurement of microorganisms. • Peak value of sputum 16S rRNA (from the start of treatment to day 42) • AUC of sputum 16S rRNA (from the start of treatment to day 42) • Peak value of specific pathogenic bacterial load in sputum (qPCR, from the start of treatment to day 42) • AUC of specific pathogenic bacterial load in sputum (qPCR, from the start of treatment to day 42) • Number of pathogens in sputum or nasal lavage fluid (Genmark assay, from the start of treatment to day 42) • Number of patients who tested positive for any pathogen in sputum or nasal lavage (Genmark assay, from the start of treatment to day 42) Comparison of RV qPCR results and Genmark RV results for nasal lavage fluid and sputum. [Examples]

[0325] Example 2 - Intermediate pharmacokinetic results in patients diagnosed with COPD and healthy volunteers. Group A - Healthy volunteers - (Phase 1 / Phase 2 - Single dose, fasting / feeding state - 500 mg; Phase 3 - 7 days of MAD BID administration).

[0326] Patients diagnosed with Group B-COPD (7-day BID administration).

[0327] General considerations: Healthy volunteers (Group A) received 500 mg during Phase 1 and Phase 2 (fasting / feeding phases). Healthy volunteers (Group A) and patients diagnosed with COPD (Group B) received a 1000 mg loading dose in the morning of Day 1, followed by a 500 mg dose in the afternoon, and then 500 mg BID doses until Day 7. For pharmacokinetic (PK) parameter calculations, BLQ values ​​prior to the first measurable concentration were replaced with zero (0.00), and all other values ​​were treated as missing. If the RSQ-corrected value was less than 0.80, the PK parameter related to the elimination phase was unreliable, and the AUC was used. 0-inf , residual area, T 1 / 2el Cl / F and V / F were not shown.

[0328] Group A concentration data - Healthy volunteers (Group A - Phase 1 and Phase 2 (fasting state / feeding state)) Table 2 shows descriptive statistics of babendavir plasma concentration versus time (Group A - Phase 1 and Phase 2 (Fasting / Feeding)). Under feeding conditions, measurable concentrations were observed up to 72.0 hours post-administration in most patients, whereas under fasting conditions, measurable concentrations were observed up to 48 hours post-administration in 8 patients and up to 72 hours post-administration in 4 patients. Based on visual assessment, under feeding conditions, the mean concentration increased from pre-administration to 8 hours post-administration, and then decreased up to 72 hours. Under fasting conditions, the mean concentration increased from pre-administration to 1 hour post-administration, and then decreased up to 72 hours. Higher concentrations were observed after administration under feeding conditions compared to administration under fasting conditions. [Table 2]

[0329] Figure 2 shows the mean bapendavir plasma concentration versus time profile in Group A (Phase 1 and Phase 2 (fasting / feeding)) (left = linear scale, right = logarithmic scale).

[0330] Table 3 shows descriptive statistics and discussion of pharmacokinetic (PK) parameters (healthy volunteers (Group A - Phase 1 and Phase 2 (fasting / eating))). Consumption of a standard high-fat meal before a single 500 mg VPV dose resulted in higher plasma concentrations of VPV compared to a single 500 mg dose in a fasted state. The resulting geometric LS mean ratios were 325.36%, 329.51%, 316.11%, and 274.03%. Food intake significantly increases overall VPV exposure. Mean peak concentration (T max The elimination half-life of VPV was delayed under feeding conditions (3.06 hours) compared to fasting conditions (1.67 hours). The plasma elimination half-life of VPV was similar between the feeding and fasting groups. However, CL / F and V z / F was higher under fasting conditions. [Table 3]

[0331] Table 4 shows descriptive statistics of plasma concentration versus time (Group A - Treatment C (Days 1-7)). Measurable concentrations were observed up to 12.0 hours post-administration in all patients on Day 1. The first measurable concentration was observed at 0.500 hours in most patients. Measurable concentrations were observed from 0.00 hours to 12.0 hours post-administration on Day 4. On Day 7, measurable concentrations were observed up to 48.0 hours post-administration (end of the Day 7 sampling schedule) in all patients. Based on visual assessment, concentrations on Day 1 were lower compared to Days 4 and 7. Concentrations on Day 4 were lower compared to Day 7. [Table 4]

[0332] Figure 3 shows the mean bapendavir plasma concentration versus time profile for Group A (Treatment C) (Days 1-7) (left = linear scale, right = logarithmic scale). Day 1 = VPV 1000 mg in the morning and 500 mg in the afternoon, Day 4 = VPV 500 mg BID, Day 7 = VPV 500 mg BID.

[0333] Table 5 shows descriptive statistics and discussion of PK parameters (Group A - Treatment C (Days 1-7)). Tmax was similar on all days. The concentrations obtained, and the resulting observed exposures, were lower after the loading dose (1000 mg) on ​​Day 1 compared to the data obtained based on the morning doses (500 mg) on ​​Days 4 and 7. In the comparison between Day 7 and Day 4, RA AUCtau and RA Cmax Based on this, a small accumulation was observed, yielding geometric mean least squares ratios of 132.28% and 126.08%, respectively. [Table 5]

[0334] Table 6 shows descriptive statistics of plasma concentration versus time for Group B-Treatment C (Days 1-7). Measurable concentrations were observed up to 12.0 hours post-administration in all patients on Day 1. The first measurable concentration was observed at 0.500 hours in most patients. Measurable concentrations were observed from 0.00 hours to 12.0 hours post-administration on Day 4. On Day 7, measurable concentrations were observed up to 48.0 hours post-administration (end of the Day 7 sampling schedule) in all patients. Based on visual assessment, concentrations on Day 1 were lower compared to Days 4 and 7. Concentrations on Day 4 were lower compared to Day 7. [Table 6]

[0335] Figure 4 shows the mean bapendavir plasma concentration versus time profile for Group B - Treatment C (Days 1-7) (left = linear scale, right = logarithmic scale). SD = standard deviation. Day 1 = VPV 1000 mg in the morning and 500 mg in the afternoon, Day 4 = VPV 500 mg BID, Day 7 = VPV 500 mg BID.

[0336] Table 7 shows descriptive statistics of pharmacokinetic (PK) parameters for Group B-Treatment C (Days 1-7). Tmax was similar on all days. The concentrations obtained, and the resulting observed exposures, were lower after the loading dose (1000 mg) on ​​Day 1 compared to the data obtained based on the morning doses (500 mg) on ​​Days 4 and 7. In the comparison between Day 7 and Day 4, RA AUCtau and RA Cmax Based on this, no accumulation was observed, and geometric mean least squares ratios of 100.57% and 95.38% were obtained, respectively. [Table 7]

[0337] Table 8 shows a comparison between healthy volunteers and patients diagnosed with COPD (Part A vs. Part B). [Table 8]

[0338] Day 1: Higher exposure was observed in patients diagnosed with COPD compared to healthy volunteers. In fact, the geometric mean least squares ratios (healthy volunteers vs. patients diagnosed with COPD) were 51.48% and 46.82%, respectively.

[0339] Day 4: Higher exposure was observed in patients diagnosed with COPD compared to healthy volunteers. In fact, the geometric mean least squares ratios (HVS vs. COPD) obtained were 72.20% and 64.40%, respectively.

[0340] Day 7: Patients diagnosed with COPD showed similar levels of exposure compared to healthy volunteers. Indeed, the geometric mean least squares ratio and confidence interval ratio were 97.28% (65.53%–144.43%) and 86.62% (53.54%–140.14%), respectively. However, the wide range of confidence interval ratios indicates high data variability.

[0341] In patients diagnosed with COPD (Group B), when bapendavir was administered for 7 days (Day 1 = VPV 1000 mg in the morning and 500 mg in the afternoon, Day 4 = VPV 500 mg BID, Day 7 = VPV 500 mg BID), the mean plasma concentration was the EC after protein correction for human rhinovirus. 50 This exceeded (see Figure 5). This data indicates that the treatment regimens disclosed herein were effective against human rhinovirus after protein correction. 50 This indicates that it results in average plasma concentration levels exceeding [a certain level], suggesting a therapeutic effect.

[0342] In healthy volunteers, administration of 500 mg of bapendavir to a fed state before administration resulted in a lower C500 mg score compared to healthy volunteers who were fasted before administration. max The blood glucose level was 2060 ng / mL (CV% 5 ng / mL), and in the fasting state it was 687 ng / mL (CV% 93 ng / mL).

[0343] Surprisingly, administering a 1000 mg loading dose in COPD is C max The result was 2150 ng / mL (CV 73 ng / mL), and the C in healthy volunteers was 2150 ng / mL. max Compared to 1060 ng / mL (CV% 106 ng / mL), the 1000 mg loading dose in patients diagnosed with COPD resulted in higher plasma concentrations, suggesting a greater effect than in healthy volunteers. This is surprising, at least in part, given that COPD patients tend to be older (typically over 70 years old) and have known reduced drug absorption.

[0344] These data suggest that the use of loading doses may have significant benefits in treating COPD patients, and that treating patients in a fed state may allow for even higher bapendavir concentrations compared to treating patients in a fasted state. [Examples]

[0345] Example 3 - Supplemental pharmacokinetic results obtained from patients diagnosed with COPD This study was conducted to clarify the effect of diet on bapendavir (VPV) exposure in COPD patients. This included clarifying the overall VPV exposure (7-day maintenance dose following a loading dose) in COPD patients who were eating, and further clarifying the variability of VPV exposure in COPD patients who were eating.

[0346] Six new COPD patients (without crossover from the previous study described in Example 2) received a loading dose of 1000 mg, followed by 500 mg BID over the entire 7-day course. Administration was performed under normal eating conditions, with a moderate-fat diet, not a high-fat diet. This was to better approximate the patients' actual home diet in the challenge trial and phase 2 / 3 randomized controlled trial. PK sampling was performed on days 2 and 3, and excluded on day 4. PK sampling was also extended to 144 hours after the final dose on day 7 to better characterize the end-elimination half-life.

[0347] Four patients experienced a total of eight adverse events (AEs): itching, dizziness, rash, intermittent increased urination, abrasions, daytime sleepiness, bloating, and neck pain. All AEs were grade 1 (mild) and were assessed as unrelated, with the exception of daytime sleepiness. Daytime sleepiness was assessed as potentially related by the principal investigator.

[0348] In COPD patients who received a loading dose of 1000 mg followed by 500 mg BID for 7 days, the mean plasma concentration after protein correction for human rhinovirus was higher. 50 The result exceeded [value]. Figure 6 shows the VPV concentration over time. This data indicates that the treatment regimens disclosed herein were effective against human rhinovirus after protein correction. 50 and EC 90 This indicates that it results in average plasma concentration levels exceeding [a certain level], suggesting a therapeutic effect.

[0349] When VPV is administered to patients who are eating, C is lower compared to patients who are fasting. max The concentration increased. Figure 7 shows the mean C2 levels in the fasting group (Group B - Treatment C (Days 1-7 (Day 1 = VPV 1000 mg in the morning and 500 mg in the afternoon, Day 4 = VPV 500 mg BID, Day 7 = VPV 500 mg BID))) on days 1, 4, and 7, and in the feeding group (1000 mg loading dose followed by 500 mg BID administered over the entire 7-day course) on days 1, 2, and 7, compared to the fasting group. max Figure 8 shows the mean C2c in fasting versus eating states in COPD patients and healthy volunteers. max The results are shown below. In the fasting group (Group A (healthy volunteers) and Group B (COPD) - Treatment C (Days 1-7 (Day 1 = VPV 1000 mg in the morning and 500 mg in the afternoon, Day 4 = VPV 500 mg BID, Day 7 = VPV 500 mg BID))), evaluations were performed on Days 1, 4, and 7. In the feeding group (1000 mg loading dose followed by 500 mg BID administered over the entire 7-day course), evaluations were performed on Days 1, 2, and 7. Figure 9 shows the mean Cmin (12-hour value) in the fasting state versus the feeding state in COPD patients. In the fasting group (Group B - Treatment C (Days 1-7 (Day 1 = VPV 1000 mg in the morning and 500 mg in the afternoon, Day 4 = VPV 500 mg BID, Day 7 = VPV 500 mg BID))), evaluations were performed on Days 1, 4, and 7. In the feeding group (1000 mg loading dose followed by 500 mg BID administered over the entire 7-day course), evaluations were performed on Days 1, 2, and 7. Figure 10 shows the mean Cmin (12-hour value) in fasting versus feeding states in COPD patients and healthy volunteers. In the fasting group (Group A (healthy volunteers) and Group B (COPD) - Treatment C (Days 1-7 (Day 1 = VPV 1000 mg in the morning and 500 mg in the afternoon, Day 4 = VPV 500 mg BID, Day 7 = VPV 500 mg BID))), evaluations were performed on Days 1, 4, and 7. In the feeding group (1000 mg loading dose followed by 500 mg BID administered over the entire 7-day course), evaluations were performed on Days 1, 2, and 7.

[0350] Figure 11 shows the C levels for each COPD patient who was eating during this study, for each treatment day. max Figure 12 shows the C levels for each COPD patient (Group B) who was in a fasting state during this study, on each treatment day. max Figure 13 shows the difference in C in a fasting state versus a fed state in COPD patients. max The coefficient of variation is shown. In the fasting group (Group B - Treatment C (Days 1-7 (Day 1 = VPV 1000 mg in the morning and 500 mg in the afternoon, Day 4 = VPV 500 mg BID, Day 7 = VPV 500 mg BID))), evaluations were performed on Days 1, 4, and 7, while in the feeding group (1000 mg loading dose followed by 500 mg BID administered over the entire 7-day course), evaluations were performed on Days 1, 2, and 7. Figure 14 shows the coefficient of variation of Cmin in COPD patients in fasting versus feeding states. In the fasting group (Group B - Treatment C (Days 1-7 (Day 1 = VPV 1000 mg in the morning and 500 mg in the afternoon, Day 4 = VPV 500 mg BID, Day 7 = VPV 500 mg BID))), evaluations were performed on Days 1, 4, and 7. In the feeding group (1000 mg loading dose followed by 500 mg BID administered over the entire 7-day course), evaluations were performed on Days 1, 2, and 7. Figure 15 shows the K values ​​on Day 7 for each of the six patients in the feeding group (1000 mg loading dose followed by 500 mg BID administered over the entire 7-day course). el (Disappearance rate constant) is shown.

[0351] These data suggest that the use of loading doses may have significant benefits in treating COPD patients, and that treating patients in a fed state leads to even higher bapendavir concentrations compared to treating patients in a fasted state. [Examples]

[0352] Example 4 - Exemplary dosing regimen for a loading dose of 1000 mg and 13 doses of 500 mg every 12 hours. TIFF2026510948000013.tif251134

[0353] This disclosure is not limited to the specific systems, apparatus, and methods described, and these may change. The terms used herein are for the purpose of describing a particular version or embodiment and are not intended to limit their scope.

[0354] The accompanying drawings, which are referenced in the detailed description above, constitute part of this description. In the drawings, similar symbols generally identify similar components, unless otherwise specified in the context. The exemplary embodiments described in the detailed description, drawings and claims are not intended to be limiting. Other embodiments may be used, and other modifications may be made without departing from the spirit or scope of the subject matter disclosed herein. It will be readily apparent that each aspect of this disclosure, as generally described herein and illustrated in the drawings, can be arranged, substituted, combined, separated and designed in a variety of configurations, all of which are expressly considered herein.

[0355] This disclosure is not limited to the specific embodiments described herein, which are intended to illustrate various aspects. It will be apparent to those skilled in the art that many modifications and variations can be made without departing from the spirit and scope of this disclosure. Functionally equivalent methods and apparatus within the scope of this disclosure, in addition to those listed herein, will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to be within the scope of the appended claims. This disclosure should be limited only by the full scope of the language of the appended claims and the equivalents that such claims naturally encompass. It should be understood that this disclosure is not limited to specific methods, reagents, compounds, compositions, or biological systems, which are naturally subject to change. Furthermore, it should be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

[0356] With regard to the use of substantially any plural and / or singular terms herein, those skilled in the art can appropriately interpret plural to singular or singular to plural depending on the context and / or application. For clarification, various singular / plural combinations may be explicitly described herein.

[0357] Those skilled in the art will understand that, in this specification, the terms used in particular in the appended claims (e.g., the claim bodies) are generally intended to be “open” terms. For example, “including” is to be interpreted as “including but not limited to,” “having” as “having at least,” and “includes” as “including but not limited to.” Various compositions, methods and apparatuses are expressed as “including” various components or processes (to be interpreted as “including but not limited to”), but these compositions, methods and apparatuses can also “consist essentially of” or “consist of” various components and processes, and such terms should be interpreted as defining essentially closed sets of components. Furthermore, those skilled in the art will understand that where a particular number is intended in an introduced claim, that intention is explicitly stated in the claim, and unless such a statement is made, no such intention exists.

[0358] As an example to aid understanding, the claims attached below may introduce the claim description using introductory phrases such as “at least one” and “one or more.” However, the use of such phrases should not be interpreted as meaning that the claim is limited to embodiments containing only one such description, even if the claim description is introduced with the indefinite article “a” or “an.” This is also true when the same claim contains both an introductory phrase such as “one or more” or “at least one” and an indefinite article such as “a” or “an” (for example, “a” and / or “an” should be interpreted as meaning “at least one” or “one or more”). The same applies when the claim description is introduced with the definite article.

[0359] Furthermore, even if a specific number is explicitly stated in the introduced claim, a person skilled in the art will understand that such statement should be interpreted as meaning at least the number stated (for example, the unlimited statement “two statements” means at least two statements, i.e., two or more statements). Furthermore, when a similar expression is used, such configuration is generally intended in the sense understood by a person skilled in the art (for example, “a system having at least one of A, B, and C” includes, but is not limited to, A only, B only, C only, a combination of A and B, a combination of A and C, a combination of B and C, and a combination of A, B, and C). Similarly, when a similar expression is used, it is also intended in the sense understood by a person skilled in the art (for example, “a system having at least one of A, B, or C” includes, but is not limited to, A only, B only, C only, a combination of A and B, a combination of A and C, a combination of B and C, and a combination of A, B, and C). Furthermore, any disjunctive word or phrase presenting two or more options in this specification should be understood, whether in the description, claims, or drawings, to include either one, either the other, or both. For example, the phrase "A or B" should be understood to include "A" or "B" or "A and B".

[0360] Furthermore, if any feature or aspect of this disclosure is described from the perspective of the Markush group, a person skilled in the art will understand that this disclosure is also described from the perspective of an individual member or subgroup of the Markush group.

[0361] As will be understood by those skilled in the art, for any purpose, including description, all scopes disclosed herein encompass all possible subranges and their combinations. It will be readily apparent that any arbitrarily listed scopes adequately describe and implement the same scope which can be divided into at least two, three, four, five, ten, etc. As a non-limiting example, each scope discussed herein can be readily divided into a lower third, a middle third, an upper third, etc. It will also be understood by those skilled in the art that phrases such as "up to" and "at least" include the number stated and mean a scope that can be divided into subranges as described above. Furthermore, the scope includes individual members. Thus, for example, "group having 1 to 3 compounds" means a group having 1, 2, or 3 compounds, and similarly, "group having 1 to 5 cells" means a group having 1, 2, 3, 4, or 5 compounds.

[0362] The various features and functions disclosed above, or their substitutes, can be combined with many other different systems or applications. Various substitutes, modifications, variations, or improvements not currently foreseen or anticipated may subsequently be made by those skilled in the art, each of which is also intended to be incorporated into embodiments of this disclosure.

Claims

1. A method for treating a respiratory enterovirus infection in a human subject having COPD, comprising the steps of: orally administering a therapeutically effective amount of bapendavir or a pharmaceutically acceptable salt thereof to the subject; and thereby treating the respiratory enterovirus infection in the subject.

2. The method according to claim 1, wherein the therapeutically effective amount of bapendavir or a pharmaceutically acceptable salt thereof is about 250 mg to about 2000 mg per day.

3. A method according to claim 1, wherein the respiratory enterovirus is selected from rhinovirus, echovirus, EV-68, EV-71, coxsackievirus, nonpolioenterovirus, and combinations thereof.

4. A method according to claim 1, wherein a therapeutically effective amount of bapendavir or a pharmaceutically acceptable salt thereof is administered as a single loading dose of about 1000 mg, followed by a maintenance dose of about 500 mg every 12 hours for about 4 to 10 days.

5. A method according to claim 4, wherein the therapeutically effective amount of bapendavir or a pharmaceutically acceptable salt thereof is administered approximately 13 times in total, with a maintenance dose of approximately 500 mg every 12 hours, following a single loading dose of approximately 1000 mg.

6. The method according to claim 1, wherein the therapeutically effective amount of bapendavir or a pharmaceutically acceptable salt thereof is approximately 2,000 to approximately 12,000 ng / ml of C ｍａｘ The quantity or method that achieves this.

7. A method according to claim 1, wherein the object is in a feeding state.

8. A method according to claim 4, wherein the single loading dose and the maintenance dose are administered within approximately 30 minutes after the subject ingests a meal containing solid food.

9. A method according to claim 8, wherein the single loading dose and maintenance dose are administered to the subject within approximately 30 minutes after the subject has ingested a meal containing solid food, thereby increasing the plasma concentration of bapendavir or a pharmaceutically acceptable salt thereof compared to when the subject is administered the single loading dose and maintenance dose in a fasted state.

10. The method according to claim 1, wherein the subject is diagnosed with GOLD stage 1 COPD, GOLD stage 2 COPD, GOLD stage 3 COPD, or GOLD stage 4 COPD.

11. A method according to claim 1, wherein the subject is receiving maintenance therapy for COPD.

12. A method according to claim 1, wherein the treatment of a respiratory enterovirus infection in the subject comprises reducing the viral load in the sputum, nasal cavity, or combination thereof of the subject compared to the viral load in the sputum, nasal cavity, or combination thereof of the subject before treatment.

13. A method according to claim 1, comprising the treatment of a respiratory enterovirus infection in the subject reducing the respiratory symptom rating score (E-RS) in the subject's COPD compared to the subject's COPD

14. A method according to claim 1, wherein the treatment of a respiratory enterovirus infection in the subject prevents an increase in the respiratory symptom rating score (E-RS) in the subject's COPD compared to the subject's COPD

15. A method according to claim 1, comprising treating a respiratory enterovirus infection in the subject to reduce the lower peak airway symptom score (LRSS) of the subject compared to the subject's lower peak airway symptom score (LRSS) before treatment.

16. A method according to claim 1, wherein the treatment of a respiratory enterovirus infection in the subject includes preventing an increase in the subject's lower-peak airway symptom score (LRSS) compared to the subject's lower-peak airway symptom score (LRSS) before treatment.

17. A method according to claim 1, comprising treating a respiratory enterovirus infection in the subject to reduce the peak upper airway symptom score (URSS) of the subject compared to the subject's peak upper airway symptom score (URSS) before treatment.

18. A method according to claim 1, wherein the treatment of a respiratory enterovirus infection in the subject prevents an increase in the subject's peak upper airway symptom score (URSS) compared to the subject's peak upper airway symptom score (URSS) before treatment.

19. A method according to claim 1, comprising treating a respiratory enterovirus infection in the subject to reduce or prevent an increase in the chronic lung disease exacerbation tool-patient reported outcome (EXACT-PRO) of the subject compared to the chronic lung disease exacerbation tool-patient reported outcome (EXACT-PRO) of the subject before treatment.

20. A method according to claim 1, wherein treatment of a respiratory enterovirus infection in the subject reduces or prevents an increase in the chronic lung disease exacerbation tool-patient respiratory symptoms (EXACT-RS) of the subject compared to the chronic lung disease exacerbation tool-patient respiratory symptoms (EXACT-RS) of the subject before treatment.

21. A method according to claim 1, wherein the treatment of a respiratory enterovirus infection in the subject includes preventing a decline in the subject's lung function compared to the subject's lung function before treatment.

22. A method according to any of the claims 21, wherein the target lung function is the forced expiratory volume in one second (FEV) －１ ; liters and predicted value %), forced vital capacity (FVC; liters and predicted value %), FEV １ A method measured by the FVC ratio and / or peak expiratory flow rate (PEF), or a combination thereof.

23. A method according to claim 1, wherein treatment of a respiratory enterovirus infection in the subject reduces the peak nasal lavage viral load of the subject compared to the peak nasal lavage viral load of the subject before treatment, or prevents an increase thereof.

24. A method according to claim 1, wherein treatment of a respiratory enterovirus infection in the subject reduces the peak sputum lavage viral load of the subject compared to the peak sputum lavage viral load of the subject before treatment, or prevents an increase thereof.

25. A method according to claim 1, comprising treating a respiratory enterovirus infection in the subject to reduce the AUC of the nasal viral load in the subject compared to the AUC of the nasal viral load in the subject before treatment, or preventing an increase thereof.

26. A method according to claim 1, wherein treatment of a respiratory enterovirus infection in the subject comprises reducing the AUC of the sputum viral load in the subject, or preventing an increase thereof, compared to the AUC of the sputum viral load in the subject before treatment.

27. A method according to claim 1, wherein the treatment of a respiratory enterovirus infection in the subject comprises shortening the period of viral shedding.

28. A method according to claim 1, comprising treating a respiratory enterovirus infection in the subject to reduce the peak sputum lavage bacterial count of the subject compared to the peak sputum lavage bacterial count of the subject before treatment, or preventing an increase thereof.

29. A method according to claim 1, wherein treatment of a respiratory enterovirus infection in the subject includes reducing the AUC of the sputum bacteria of the subject compared to the AUC of the sputum bacteria of the subject before treatment, or preventing an increase thereof.

30. A method according to claim 1, wherein treatment of a respiratory enterovirus infection in the subject comprises reducing the number of days the subject is positive for bacteria in its sputum.

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