Phosphatidylinositol 4-kinase beta inhibitor compositions for treating human rhinovirus infection

Abstract

The disclosure provides phosphatidylinositol 4-kinase beta inhibitor compositions and their uses in treating diseases caused or exacerbated by human rhinovirus infection.

Description

PHOSPHATIDYLINOSITOL 4-KINASE BETA INHIBITOR COMPOSITIONS FOR TREATING HUMAN RHINO VIRUS INFECTIONFIELD

[0001] The present disclosure relates to phosphatidylinositol 4-kinase beta (PI4KB) inhibitor compositions and their uses / methods in treating diseases caused or exacerbated by human rhinovirus (HRV) infection.BRIEF SUMMARY

[0002] In one aspect, the disclosure provides a method of treating a human rhinovirus (HRV) infection, the method comprising administering to a human subject in need thereof a dose of about 0.1 mg, about 0.5 mg, or about 1.5 mg of a compound of Formula (I):pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is in a dry powder formulation and administered by inhalation, and wherein the human subject has a disease caused or exacerbated by the HRV infection. In one embodiment, the dose is about 0.5 mg, or about 1.5 mg.

[0003] In another aspect, the disclosure provides a method of treating a disease caused or exacerbated by a human rhinovirus (HRV) infection, the method comprising administering to a human subject in need thereof a daily dose of about 0.1 mg, about 0.5 mg, or about 1.5 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound ofFormula (I) is administered by inhalation and is in a dry powder formulation. In one embodiment, the dose is about 0.5 mg, or about 1.5 mg.

[0004] In another aspect, the disclosure provides a compound for use in treating a human rhinovirus (HRV) infection in a human subject, wherein the compound is used at a dose of about 0.1 mg, about 0.5 mg, or about 1.5 mg and is of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is in a dry powder formulation for inhalation, and wherein the human subject has a disease caused or exacerbated by the HRV infection. In one embodiment, the dose is about 0.5 mg, or about 1.5 mg.

[0005] In another aspect, the disclosure provides use of a compound for the manufacture of a medicament for the treatment of a human rhinovirus (HRV) infection in a human subject, wherein the compound is used at a dose of about 0.1 mg, about 0.5 mg, or about 1.5 mg and is of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is in a dry powder formulation for inhalation, and wherein the human subject has a disease caused or exacerbated by the HRV infection. In one embodiment, the dose is about 0.5 mg, or about 1.5 mg. In an embodiment, the dose is about 0.1 mg. In an embodiment, the dose is about 0.5 mg. In an embodiment, the dose is about 1.5 mg.

[0006] In an embodiment, the dose is administered once per day. In an embodiment, the dose is administered once per day for one or more treatment periods of 5 to 21 days, such as 7 to 14 days, or 10 to 14 days. In an embodiment, the dose is administered once per day for one or more treatment periods of 10 days. In a further embodiment, the dose is administered once per day for a treatment period of up to 10 days, wherein treatment may be discontinued earlier upon complete symptom resolution. In an embodiment, the human subject is elderly or immunocompromised.

[0007] In an embodiment, the human subject has a lung transplant or stem cell transplant or secondary bacterial infection.

[0008] In an embodiment, the disease is asthma, chronic obstructive pulmonary disease (COPD), interstitial lung disease, cystic fibrosis, bronchiectasis, congestive heart failure, acute respiratory distress syndrome, acute lung injury, bronchiolitis, otitis media, sinusitis, acute bronchitis, a secondary bacterial infection, or pneumonia.

[0009] In an embodiment, the disease is asthma or COPD. In one embodiment, the disease is asthma. In another embodiment, the disease is COPD.

[0010] In one embodiment, the disease is bronchiectasis, in a more particular embodiment it is non-cystic fibrosis bronchiectasis.

[0011] In an embodiment, the treatment is initiated no more than 4 days after onset of rhinovirus symptoms, such as no more than 3 days or no more than 2 days after onset of rhinovirus symptoms. In the context of this invention, the term “rhinovirus symptoms” refers to symptoms consistent with a rhinovirus infection, for example, upper or lower respiratory tract symptoms.

[0012] In one aspect, the disclosure provides a method of treating a human rhinovirus (HRV) infection, the method comprising administering to a human subject in need thereof a compound of Formula (I):pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is administered at a dose of from about 0.5 mg to about 1.5 mg once daily for up to ten days, wherein treatment is initiated no more than 4 days after onset of rhino virus symptoms, and wherein the human subject is either a) elderly or immunocompromised, or b) has a disease whose symptoms are at risk of being exacerbated by an HRV infection. In one embodiment, treatment is initiated no more than 3 days after onset of rhinovirus symptoms. In one embodiment, the compound of Formula (I) is administered at a dose of from about 0.5 mg to about 1.5 mg once daily for ten days. In one embodiment, the compoundof Formula (I) is administered by inhalation. In a further embodiment, the compound of Formula (I) is in a dry powder formulation. In one embodiment, the human subject is elderly or immunocompromised. In another embodiment, the human subject has a disease whose symptoms are at risk of being exacerbated by an HRV infection.

[0013] In one aspect, the disclosure provides a method of reducing exacerbations of an airways disease, the method comprising administering to a human subject in need thereof a compound of Formula (I):pharmaceutically acceptable salt thereof following onset of rhino virus symptoms, wherein the compound of Formula (I) is administered at a dose of from about 0.5 mg to about 1.5 mg once daily for up to ten days, wherein treatment is initiated no more than 4 days after onset of rhinovirus symptoms.

[0014] In another aspect, the disclosure provides a method of reducing exacerbations of a human rhinovirus infection (HRV) in a human subject that is elderly or immunocompromised, the method comprising administering to the subject a compound of Formula (I):pharmaceutically acceptable salt thereof following onset of rhino virus symptoms, wherein the compound of Formula (I) is administered at a dose of from about 0.5 mg to about 1.5 mg once daily for up to ten days, wherein treatment is initiated no more than 4 days after onset of rhinovirus symptoms.

[0015] In an embodiment, the dose is administered using a dry powder inhaler (DPI).

[0016] In an embodiment, the dry powder formulation is present in one or more capsules, cartridges, or blister pockets.

[0017] In an embodiment, the dry powder formulation is present in a blister pocket, for example in two blister pockets wherein each of the blister pockets contains a pre-metered dose of 0.75 mg of the compound of Formula (I) to administer simultaneously, or for example a single blister pocket that contains a pre-metered dose of 0.5 mg of the compound of Formula (I).

[0018] In an embodiment, the method herein reduces the human subject’s lower respiratory tract symptom (LRTS) score and / or upper respiratory tract symptom (URTS) score after the treatment starts. In an embodiment, the LRTS score and / or URTS score is reduced by at least 40%, such as at least 50%, at least 60%, at least 70%, or at least 80%.

[0019] In an embodiment, the compound of Formula (I) is used in combination with one or more doses of a mild or moderate CYP3A4 inhibitor. In one embodiment, the compound of Formula (I) is not used in combination with one or more doses of a strong CYP3A4 inhibitor such as itraconazole. In another embodiment, a low dose (e.g. a daily dose of 0.5 mg) of the compoundof Formula (I) may be used in combination with one or more doses of a strong CYP3A4 inhibitor, but a high dose (e.g. a daily dose of 1.5 mg) of the compound of Formula (I) may not used in combination with one or more doses of a strong CYP3A4 inhibitor such as itraconazole. In one embodiment, a daily dose of 0.5 mg of the compound of Formula (I) may not be used in combination with one or more doses of a strong CYP3A4 inhibitor such as itraconazole. In one embodiment, a daily dose of 0.5 mg to 1.5 mg of the compound of Formula (I) may not be used in combination with one or more doses of a strong CYP3A4 inhibitor such as itraconazole.

[0020] In an embodiment, the inhalation is oral inhalation.BRIEF DESCRIPTION OF THE DRAWINGS

[0021] FIG. 1 shows a mean (95% CI) plot of daily total LRTS (lower respiratory tract symptoms) scores for Cohort 2 (1.5 mg dose). The two vertical dashed lines represent time of infection and time of treatment start. Daily symptom scores are calculated as the average of assessments collected on the same planned day.

[0022] FIG. 2 shows median values of predicted target engagement (TE) profiles for a dose range from 50 to 3000 pg.

[0023] FIG. 3 shows the median of dose normalized plasma concentration of compound of Formula (I) against time in both a linear scale and a semi-logarithmic scale. The concentrations of compound of Formula (I) are for each dose and study day and have been dose normalized and multiplied by nominal dose 500 pg SD.

[0024] FIG. 4 shows the Exposure-Response relationship of the asthma participants challenged with human rhinovirus (dosed with either placebo, 1500 pg or 3000 pg of the compound of Formula (I)). The Y axis is the area under the curve of change from baseline of lower respiratory tract symptoms and the X axis is the steady state drug area under the curve per dosing interval. The solid curve is the median predicted from a non-linear regression model and the dashed curve is the 95% confidence interval predicted from a non-linear regression model. The boxplots in the lower panel represent the distribution of exposure at each dose investigated (from Example

[0025] FIG. 5 shows the pharmacokinetic concentration-time profile with the inhaled compound of Formula (I) administration using ELLIPTA and the MONODOSE inhaler (from Example 7)DETAILED DESCRIPTION

[0026] The present disclosure provides an improved method of treating a human rhinovirus infection (HRV), with select doses and dosage forms of an inhibitor to phosphatidylinositol 4- kinase beta (PI4KB). Such improvement is demonstrated by the clinical results described herein, for example by significant reduction in LRTS scores after oral inhalation with the method herein.

[0027] As a selective and potent inhibitor of PI4KB, a compound of Formula (I) has the structure described as Compound 22 in the patent publication WO2019141694A1:Formula (I).

[0028] The term “about” may mean a value within a range of plus or minus 10% of its referred number.

[0029] The terms “a” “an” and “the” may refer to a singular or plural form.

[0030] The term “dry powder” means a solid form of powder without liquid.

[0031] The terms “compound of Formula (I)” and “Formula (I)” may be used interchangeably.Methods of Use for Treating Human Rhinovirus Infection

[0032] Described herein are methods of treating a rhinovirus infection a human subject in need thereof, wherein the human subject has a disease caused or exacerbated by a rhinovirus infection.

[0033] In one aspect, the disclosure provides a method of treating a rhinovirus infection, the method comprising administering to a human subject in need thereof a daily dose of about 0.1 mg to about 1.5 mg of (5)-7V-(l-hydroxypropan-2-yl)-5-(5-(2-hydroxypropan-2-yl)-2-methyl-7-((3- (l-methyl-17 / -imidazol-2-yl)benzyl)amino)pyrazolo[l,5-a]pyrimidin-3-yl)- V,2- dimethylbenzamide (compound of Formula (I)), or a pharmaceutically acceptable salt thereof, wherein the dose is administered by inhalation as a dry powder formulation and wherein the human subject has a disease caused or exacerbated by a rhinovirus infection. In an embodiment, the method comprises administering a daily dose of about 0.5 mg to about 1.5 mg of a compound of Formula (I).

[0034] In an embodiment, the method comprises administering a dose of about 0.1 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1.0 mg, or about 1.5 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for example once a day. In an embodiment, the method comprises administering a daily dose of about 0.1 mg or about 0.5 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In an embodiment, the method comprises administering a daily dose of about 0.5 mg or about 1.5 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In an embodiment, the method comprises administering a daily dose of about 0.1 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In an embodiment, the method comprises administering a daily dose of about 0.5 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In an embodiment, the method comprises administering a daily dose of about 1.5 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0035] In an embodiment, compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered once per day or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. In an embodiment, the dose is administered once daily. In an embodiment, the dose is administered twice daily. In an embodiment, the dailydose is divided into two or more smaller portions and each portion is administered at separate times during the day. For example, one-half of the daily dose may be administered two times daily, one- third of the daily dose may be administered three times daily, or one-fourth of the daily dose may be administered four times daily.

[0036] In an embodiment, the dose is administered according to a regimen that delivers the dose every day. In an embodiment, the dose is administered once daily for 5 to 21 days, such as 7 to 14 days, or 10 to 14 days. In an embodiment, the dose is administered once daily for 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days. In an embodiment, the dose is administered until the desired therapeutic effect is achieved.

[0037] In an embodiment, the dose is administered once per day for one or more treatment periods of 10 days. In a further embodiment, the dose is administered once per day for a treatment period of up to 10 days, wherein treatment may be discontinued earlier upon complete symptom resolution. In an embodiment, the human subject has a disease caused or exacerbated by a rhinovirus infection. In an embodiment, the human subject has asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis (e.g. non-cystic fibrosis bronchiectasis), congestive heart failure, acute respiratory distress syndrome, or acute lung injury. In an embodiment, the human subject has asthma or COPD. In an embodiment, the human subject has bronchiolitis, otitis media, sinusitis, or acute bronchitis. In an embodiment, the human subject has a secondary bacterial infection. In an embodiment, the human subject has pneumonia, including pneumonia caused by a secondary bacterial infection.

[0038] The term “exacerbated” would be readily understood by one of ordinary skill in the art to refer to a worsening of symptoms, such that a disease exacerbated by a rhinovirus infection is a disease that is not caused by the rhinovirus infection directly, but a disease whose symptoms may be worsened by a rhinovirus infection. Therefore, a person skilled in the art would understand that a human subject with a disease exacerbated by a human rhinovirus infection is a human subject that has a disease wherein the symptoms of the disease are, or are at risk of, being worsened due to a human rhinovirus infection. In one embodiment, a human subject with a disease exacerbated by a human rhino virus infection is a human subject that has a disease wherein the symptoms ofthe disease are at risk of being worsened due to a human rhinovirus infection. In some instances, the episodes of worsening symptoms or exacerbations may be medically significant and require “rescue” therapy. It is expected that treating a rhinovirus infection in such patients may reduce the incidence of such exacerbations and reduce the need for rescue therapy.

[0039] In one embodiment, the human subject has COPD. In a more particular embodiment, the human subject with COPD exhibits a post-bronchodilator forced expiratory volume in 1 second (FEVl) / forced vital capacity (FVC) ratio <0.7, and / or a post-bronchodilator FEV1 <80% predicted.

[0040] In one embodiment, the human subject has asthma. In a more particular embodiment, the human subject with asthma has a daily inhaled corticosteroid (ICS) dose >250 mcg fluticasone propionate (or equivalent). Examples of equivalent doses of commonly prescribed ICS medication are provided in the GINA guidelines.

[0041] In one embodiment, the human subject has non-cystic fibrosis bronchiectasis.

[0042] In an embodiment, treatment is initiated no more than 4 days after onset of rhinovirus symptoms, such as no more than 3 days or no more than 2 days after onset of rhinovirus symptoms.

[0043] In one aspect, the disclosure provides compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a rhinovirus infection in a human subject having a disease caused or exacerbated by a rhino virus infection, wherein compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in a daily dose of about 0.1 mg to about 1.5 mg, such as about 0.1 mg, about 0.5 mg, or about 1.5 mg. In one embodiment, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in a daily dose of about 0.5 mg to about 1.5 mg, such as about 0.5 mg, or about 1.5 mg.

[0044] In one aspect, the disclosure provides the use of compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a rhinovirus infection in a human subject having a disease caused or exacerbated by a rhinovirus infection, wherein compound of Formula (I), or a pharmaceutically acceptable salt thereof, is formulated for administration in a daily dose of about 0.1 mg to about 1.5 mg, such as about 0.1mg, about 0.5 mg, or about 1.5 mg. In one embodiment, the daily dose is from about 0.5 mg to about 1.5 mg, such as about 0.5 mg, or about 1.5 mg

[0045] In an embodiment, the disclosure provides the use of about 1.5 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a rhinovirus infection in a human subject having a disease caused or exacerbated by a rhino virus infection, wherein the 1.5 mg compound of Formula (I) is administered as a daily dose.

[0046] In an embodiment, the disclosure provides the use of about 0.5 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a rhinovirus infection in a human subject having a disease caused or exacerbated by a rhino virus infection, wherein the 0.5 mg compound of Formula (I) is administered as a daily dose.

[0047] In one aspect, the disclosure provides a method of treating a human rhinovirus (HRV) infection, the method comprising administering to a human subject in need thereof a compound of Formula (I):pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is administered at a dose of from about 0.5 mg to about 1.5 mg once daily for up to ten days, wherein treatment is initiated no more than 4 days after onset of rhinovirus symptoms, and wherein the human subject is either a) elderly or immunocompromised, or b) has a disease whose symptoms are at risk of being exacerbated by an HRV infection. In one embodiment, treatment is initiated no more than 3 days after onset ofsymptoms. In one embodiment, the compound of Formula (I) is administered at a dose of from about 0.5 mg to about 1.5 mg once daily for ten days. In one embodiment, the dose of the compound of Formula (I) is 0.5 mg. In another embodiment, the dose of the compound of Formula (I) is 1.5 mg. In one embodiment, the compound of Formula (I) is administered by inhalation. In a further embodiment, the compound of Formula (I) is in a dry powder formulation. In one embodiment, the human subject is elderly or immunocompromised. In another embodiment, the human subject has a disease whose symptoms are at risk of being exacerbated by an HRV infection. In a more particular embodiment, the disease whose symptoms are at risk of being exacerbated by an HRV infection is an airways disease. In another embodiment, the disease whose symptoms are at risk of being exacerbated by an HRV infection is a non-airways disease.

[0048] As used herein, “an airways disease” may include both obstructive airways disorders (e.g. COPD and asthma) and restrictive airways diseases (e.g. fibrotic lung disease). Patients with an obstructive airways disorder may typically have any of a reduced FEV1 (<80% of the predicted normal), reduced FVC (but to a lesser extent than FEV1), FEV1 / FVC ratio reduced (<0.7), wherein the predicted normal is based off a person with the same sex, age, and height. Patients with a restrictive airways disease may typically have any of a reduced FEV1 (<80% of the predicted normal), reduced FVC (<80% of the predicted normal), FEV1 / FVC ratio reduced (<0.7), wherein the predicted normal is based off a person with the same sex, age, and height.

[0049] In one aspect, the disclosure provides a method of reducing exacerbations of an airways disease, the method comprising administering to a human subject in need thereof a compound of Formula (I):pharmaceutically acceptable salt thereof following onset of rhino virus symptoms, wherein the compound of Formula (I) is administered at a dose of from about 0.5 mg to about 1.5 mg once daily for up to ten days, wherein treatment is initiated no more than 4 days after onset of rhinovirus symptoms. In one embodiment, treatment is initiated no more than 3 days after onset of symptoms. In one embodiment, the compound of Formula (I) is administered at a dose of from about 0.5 mg to about 1.5 mg once daily for ten days. In one embodiment, the dose of the compound of Formula (I) is 0.5 mg. In another embodiment, the dose of the compound of Formula (I) is 1.5 mg. In one embodiment, the compound of Formula (I) is administered by inhalation. In a further embodiment, the compound of Formula (I) is in a dry powder formulation.

[0050] In another aspect, the disclosure provides a method of reducing exacerbations of a human rhinovirus infection (HRV) in a human subject that is elderly or immunocompromised, the method comprising administering to the subject a compound of Formula (I):pharmaceutically acceptable salt thereof following onset of rhino virus symptoms, wherein the compound of Formula (I) is administered at a dose of from about 0.5 mg to about 1.5 mg once daily for up to ten days, wherein treatment is initiated no more than 4 days after onset of rhinovirus symptoms. In one embodiment, treatment is initiated no more than 3 days after onset of symptoms. In one embodiment, the compound of Formula (I) is administered at a dose of from about 0.5 mg to about 1.5 mg once daily for ten days. In one embodiment, the dose of the compound of Formula (I) is 0.5 mg. In another embodiment, the dose of the compound of Formula (I) is 1.5 mg. In one embodiment, the compound of Formula (I) is administered by inhalation. In a further embodiment, the compound of Formula (I) is in a dry powder formulation. In one embodiment, the human subject is immunocompromised. In another embodiment, the human subject is elderly.

[0051] In one aspect, the disclosure provides a method of treating a human rhinovirus (HRV) infection, the method comprising administering to a human subject in need thereof a daily dose of about 0.5 mg or about 1.5 mg of a compound of Formula (I):pharmaceutically acceptable salt thereof. In an embodiment, the human subject has a disease caused or exacerbated by the HRV infection. In an embodiment, the human subject is either a) elderly or immunocompromised, or b) has a disease whose symptoms are at risk of being exacerbated by an HRV infection. In one embodiment, the dose is about 0.5 mg. In one embodiment, the dose is about 1.5 mg.

[0052] In one aspect, the disclosure provides a method of treating a human rhinovirus (HRV) infection, the method comprising administering to a human subject in need thereof a compound of Formula (I):pharmaceutically acceptable salt; wherein the compound of Formula (I) is administered at a dose of from about 0.5 mg to about 1.5 mg once daily for up to ten days, wherein treatment is initiated no more than 4 days after onset ofrhinovirus symptoms. In an embodiment, the human subject has a disease caused or exacerbated by the HRV infection. In an embodiment, the human subject is either a) elderly or immunocompromised, or b) has a disease whose symptoms are at risk of being exacerbated by an HRV infection. In one embodiment, the dose is about 0.5 mg. In one embodiment, the dose is about 1.5 mg.

[0053] In one aspect, the disclosure provides a method of reducing exacerbations of an airways disease, the method comprising administering to a human subject in need thereof a daily dose of about 0.5 mg or about 1.5 mg of the compound of Formula (I):pharmaceutically acceptable salt thereof. In one embodiment, the daily dose is about 0.5 mg. In one embodiment, the daily dose is about 1.5 mg.

[0054] In one aspect, the disclosure provides a method of reducing exacerbations of an airways disease, the method comprising administering to a human subject in need thereof a dose of from about 0.5 mg to about 1.5 mg of the compound of Formula (I):pharmaceutically acceptable salt thereof, once daily for up to ten days; wherein treatment is initiated no more than 4 days after onset of rhinovirus symptoms.Methods of Use for Diseases Caused or Exacerbated by Human Rhinovirus Infection

[0055] Described herein are methods of treating a disease caused or exacerbated by a rhinovirus infection in a human subject in need thereof.

[0056] In one aspect, the disclosure provides a method of treating a disease caused or exacerbated by a rhinovirus infection, the method comprising administering to a human subject in need thereof a daily dose of about 0.1 mg to about 1.5 mg of (S)- V-(l-hydroxypropan-2-yl)-5-(5- (2-hy dr oxypr opan-2-yl)-2-methyl-7-((3 -(1 -methyl- \H- imidazol-2- yl)benzyl)amino)pyrazolo[l,5-a]pyrimidin-3-yl)- V,2-dimethylbenzamide (compound of Formula (I)), or a pharmaceutically acceptable salt thereof, wherein the dose is administered by inhalation as a dry powder formulation. In one embodiment, the daily dose is from about 0.5 mg to about 1.5 mg.

[0057] In an embodiment, the method comprises administering a daily dose of about 0.1 mg, about 0.5 mg, or about 1.5 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In an embodiment, the method comprises administering a daily dose of about 0.1 mg or about 0.5 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In an embodiment, the method comprises administering a daily dose of about 0.5 mg or about 1.5 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In an embodiment,the method comprises administering a daily dose of about 0.1 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In an embodiment, the method comprises administering a daily dose of about 0.5 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In an embodiment, the method comprises administering a daily dose of about 1.5 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0058] In an embodiment, compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered once per day or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. In an embodiment, the dose is administered once daily. In an embodiment, the dose is administered twice daily. In an embodiment, the daily dose is divided into two or more smaller portions and each portion is administered at separate times during the day. For example, one-half of the daily dose may be administered two times daily, one- third of the daily dose may be administered three times daily, or one-fourth of the daily dose may be administered four times daily.

[0059] In an embodiment, the dose is administered according to a regimen that delivers the dose every day. In an embodiment, the dose is administered once daily for 5 to 21 days, such as 7 to 14 days, or 10 to 14 days. In an embodiment, the dose is administered once daily for 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days. In an embodiment, the dose is administered until the desired therapeutic effect is achieved.

[0060] In an embodiment, the disease caused or exacerbated by a rhinovirus infection is asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, congestive heart failure, acute respiratory distress syndrome, or acute lung injury. In an embodiment, the disease caused or exacerbated by a rhinovirus infection is asthma or COPD. In an embodiment, the disease caused or exacerbated by a rhinovirus infection is bronchiolitis, otitis media, sinusitis, or acute bronchitis. In an embodiment, the disease caused or exacerbated by a rhinovirus infection is a secondary bacterial infection. In an embodiment, the disease caused or exacerbated by a rhinovirus infection is pneumonia, including pneumonia caused by a secondary bacterial infection.

[0061] In an embodiment, the disease caused or exacerbated by a rhinovirus infection is a disease exacerbated by a rhinovirus infection. As discussed above, in one embodiment, a disease exacerbated by a rhinovirus infection is a disease whose symptoms may be worsened (or “exacerbated”) by the rhinovirus infection.

[0062] In one embodiment, the disease exacerbated by a rhinovirus infection is an airways disease, or a non-airways disease. In one embodiment, the airway disease is asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, or acute lung injury. In a more particular embodiment, the airways disease is asthma or COPD. In one embodiment, the airways disease is asthma as defined herein. In another embodiment, the airways disease is COPD as defined herein. In a different embodiment, the non-airway disease is interstitial lung disease, cardiovascular disease, or metabolic disease.

[0063] Examples of diseases wherein the symptoms of the disease are at risk of being worsened due to the HRV infection (i.e. diseases exacerbated by an HRV infection) include asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, acute lung injury, interstitial lung disease, cardiovascular disease, and metabolic disease.

[0064] In an embodiment, treatment is initiated no more than 4 days after onset of rhinovirus symptoms, such as no more than 3 days or no more than 2 days after onset of rhinovirus symptoms.

[0065] In one aspect, the disclosure provides compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a disease caused or exacerbated by a rhinovirus infection in a human subject, wherein compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in a daily dose of about 0.1 mg to about 1.5 mg, such as about 0.1 mg, about 0.5 mg, or about 1.5 mg.

[0066] In one aspect, the disclosure provides the use of compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease caused or exacerbated by a rhinovirus infection in a human subject, wherein compound of Formula (I), or a pharmaceutically acceptable salt thereof, is formulated for administration in a daily dose of about 0.1 mg to about 1.5 mg, such as about 0.1 mg, about 0.5 mg, or about 1.5 mg.Symptom Reduction

[0067] Reduction in symptoms of a rhinovirus infection can be assessed, for example, by lowering respiratory tract symptoms (LRTS) score and / or upper respiratory tract symptoms (URTS) score.

[0068] LRTS score may be assessed based on chest / respiratory symptoms such as cough, chest tightness, shortness of breath, wheezing, daily activity / nighttime awakenings. In an embodiment, the symptoms may include trouble breathing, chest congestion, chest tightness, dry or hacking cough, wet or loose cough, coughing, cough up mucus, phlegm, or any combination thereof. These symptoms may be measured using rating scales well known to those in the art. For example, the Flu-PRO rating scale measures each symptom on a 5 point scale. Alternatively, as described in the Examples, eeach of the symptoms may be assessed on a 4-point scale, with shortness of breath and wheezing measured on a 5 -point scale. URTS score may be assessed based on nose and throat symptoms such as runny nose, stuffy nose, sneezing and sore throat. In an embodiment, the symptoms may include runny or dripping nose, congestion or stuffy nose, sneezing, sinus pressure, scratchy or itchy throat, sore or painful throat, difficulty swallowing, or any combination thereof. These symptoms may be measured using rating scales well known to those in the art. For example, the Flu-PRO rating scale measures each symptom on a 5 point scale. Alternatively, as described in the Examples, each of the symptoms may be assessed on a 4-point scale.

[0069] In an embodiment, LRTS score and / or URTS score is reduced in subjects receiving compound of Formula (I) compared to a control population receiving a placebo. In an embodiment, LRTS and / or URTS score is reduced by at least 40%, such as at least 50%, at least 60%, at least 70%, or at least 80%. Reduction in LRTS and / or URTS score can be assessed as the area under the curve (AUC) change from baseline (CfB) in the total LRTS and / or URTS score. In an embodiment, AUC is measured from inoculation up to discharge. In an embodiment, AUC is measured from first dose up to discharge or recovery. In an embodiment, AUC is measured from inoculation for 2 to 14 days, such as for 2 to 6 days, for 7 to 14 days, for 2 to 5 days, for 5 to 7 days, for 7 to 10 days, or for 10 to 14 days. In an embodiment, AUC is measured from first dose for 2 to 14 days, such as for 2 to 6 days, for 7 to 14 days, for 2 to 5 days, for 5 to 7 days, for 7 to 10 days, or for 10 to 14 days.

[0070] Human subjects that are elderly or immunocompromised are more likely to suffer exacerbations following HRV infection. For example, elderly or immunocomprised individuals are more likely to develop a secondary bacterial infection, or pneumonia.

[0071] In one embodiment, treatment success can be measured by reduction in the incidence of pneumonia over a given period (the period of a single rhinovirus infection or over a more prolonged period in which there may be multiple infection / treatment cycles). In a clinical trial setting, the comparator would be a placebo group. The skilled person would appreciate that real world data is difficult to obtain in view of the fact data about rhinoviral infections that are resolved without the need for additional treatment is rarely captured.

[0072] In a further embodiment, where the disease whose symptoms are worsened or exacerbated by a rhino virus infection in a human subject is an airways disease, treatment success in a patient population may be measured by reductions in exacerbations of the airways disease. In one embodiment, this is determined by comparing the number of moderate and / or severe exacerbations exhibited by treated and untreated populations over a specified time period. This may be the period of a single rhinovirus infection or a more prolonged period in which there may be multiple infection / treatment cycles.

[0073] A moderate exacerbation refers to a worsening of symptoms of the underlying airways disease that requires treatment with systemic antibiotics and / or corticosteroids (including dose increases) in an out-patient setting. Accordingly, in an embodiment where the disease exacerbated by a rhinovirus infection is an airways disease (e.g. asthma, COPD or non-cystic fibrosis bronchiectasis), treatment success in a patient population may be measured by reduction in systemic antibiotic and / or rescue corticosteroid usage in the period (the period of a single rhinovirus infection or a prolonged period in which there may be multiple infection / treatment cycles). In a clinical trial setting, the comparator would be a placebo group. The skilled person would appreciate that real world data is difficult to obtain in view of the fact data about that rhinoviral infections that are resolved without the need for additional treatment is rarely captured.

[0074] A severe exacerbation is one that requires (unplanned) hospitalization or emergency department / urgent care visit. Accordingly, in an embodiment where the disease exacerbated by a rhinovirus infection is an airways disease (e.g. asthma, COPD or non-cystic fibrosisbronchiectasis), treatment success in a patient population may be measured by a reduction in unplanned hospitalization or in the number of emergency department / urgent care visits in the period (the period of a single rhinovirus infection or over a more prolonged period in which there may be multiple infection / treatment cycles). In a clinical trial setting, the comparator would be a placebo group. The skilled person would appreciate that real world data is difficult to obtain in view of the fact data about that rhinoviral infections that are resolved without the need for additional treatment is rarely captured.

[0075] In a further embodiment , where the disease whose symptoms are worsened or exacerbated by a rhino virus infection in a human subject is an airways disease, treatment success can be measured by reduction in the incidence of administration of supplementary oxygen or ventilatory support in the period (the period of a single rhinovirus infection or over a more prolonged period in which there may be multiple infection / treatment cycles). In a clinical trial setting, the comparator would be a placebo group. The skilled person would appreciate that real world data is difficult to obtain in view of the fact data about that rhinoviral infections that are resolved without the need for additional treatment is rarely captured.Formulations

[0076] In an embodiment, the dose is administered by inhalation as a dry powder formulation. In an embodiment, compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided in a dosage form adapted for administration to a subject by inhalation such as oral inhalation, for example, as a dry powder. Dry powder formulations for delivery to the lung by inhalation typically comprise compound of Formula (I), or a pharmaceutically acceptable salt thereof, as a finely divided powder together with one or more pharmaceutically acceptable excipients as finely divided powders. Pharmaceutically acceptable excipients particularly suited for use in dry powders include, but are not limited to, lactose, starch, mannitol, and monosaccharides, disaccharides, and polysaccharides. The finely divided powder may be prepared by, for example, micronization and milling. Generally, the size-reduced (e.g., micronized) compound can be defined by a D50 value of about 1 to about 10 microns (for example as measured using laser diffraction). 1

[0077] The dry powder may be administered to the human subject via a reservoir dry powder inhaler (RDPI) having a reservoir suitable for storing multiple (un-metered doses) of medicament in dry powder form. RDPIs typically include a means for metering each medicament dose from the reservoir to a delivery position. For example, the metering means may comprise a metering cup, which is movable from a first position where the cup may be filled with medicament from the reservoir to a second position where the metered medicament dose is made available to the human subject for inhalation.

[0078] The dry powder formulations for use in accordance with the present disclosure may be administered via inhalation devices. As an example, such devices can encompass capsules and cartridges of for example gelatin, or blisters of, for example, laminated aluminum foil. In various embodiments, each capsule, cartridge or blister may contain doses of formulation according to the teachings presented herein. Examples of inhalation devices may include those intended for unit dose or multi-dose delivery of formulation, including all of the devices set forth herein. As an example, in the case of multi-dose delivery, the formulation can be pre-metered. An example of a unit-dose device is ROTAHALER. In one embodiment, the DISKUS inhalation device comprises an elongate strip formed from a base sheet having a plurality of recesses spaced along its length and a lid sheet peelably sealed thereto to define a plurality of containers, each container having therein an inhalable formulation containing the compound optionally with other excipients and additive taught herein. The peelable seal is an engineered seal, and in one embodiment the engineered seal is a hermetic seal. In some embodiments, the strip is sufficiently flexible to be wound into a roll. The lid sheet and base sheet may have leading end portions which are not sealed to one another and at least one of the leading end portions is constructed to be attached to a winding means. In some embodiments, the engineered seal between the base and lid sheets extends over their whole width. The lid sheet may be peeled from the base sheet in a longitudinal direction from a first end of the base sheet.

[0079] A dry powder formulation may also be presented in an inhalation device which permits separate containment of two different components of the formulation, Thus, for example, these components are administrable simultaneously but are stored separately, e.g., in separate pharmaceutical formulations.

[0080] In one embodiment an inhalation device permitting separate containment of components is an inhaler device having two peelable blister strips, each strip containing premetered doses in blister pockets arranged along its length, e.g., multiple containers within each blister strip. Said device has an internal indexing mechanism which, each time the device is actuated, peels opens a pocket of each strip and positions the blisters so that each newly exposed dose of each strip is adjacent to the manifold which communicates with the mouthpiece of the device. When the human subject inhales at the mouthpiece, each dose is simultaneously drawn out of its associated pocket into the manifold and entrained via the mouthpiece into the human subject's respiratory tract. The ELLIPTA device is one such device that has blister strips with an internal indexing mechanism. ELLIPTA is an inhalation device marketed by GSK. A further device that permits separate containment of different components is DUOHALER of Innovata. In addition, various structures of inhalation devices provide for the sequential or separate delivery of the pharmaceutical formulation(s) from the device, in addition to simultaneous delivery.

[0081] Where the ELLIPTA device is used, this may be used with a strip configuration as provided in Table 1.Table 1. Inhaler configuration

[0082] For the 1.5 mg dose, a patient will inhale the contents of both strips together.

[0083] Alternatively, the dry powder may be presented in capsules (e.g., gelatin or plastic), cartridges, or blister packs for use in a multi-dose dry powder inhaler (MDPI). MDPIs are inhalers wherein the medicament is comprised within a multi-dose pack containing (or otherwise carrying) multiple defined doses (or parts thereof) of medicament. When the dry powder is presented as a blister pack, it comprises multiple blisters for containment of the medicament in dry powder form. The blisters are typically arranged in regular fashion for ease of release of the medicament therefrom. For example, the blisters may be arranged in a generally circular fashion on a disc-form blister pack, or the blisters may be elongate in form, for example comprising a strip or a tape. Each capsule, cartridge, or blister may, for example, contain between 0.1 mg to 1.5 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0084] Capsules and cartridges for use in an inhaler or insufflator, of for example gelatine, may be formulated containing a powder mix for inhalation of compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a suitable powder base such as lactose or starch. Each capsule or cartridge may generally contain from 0.1 mg to 1.5 mg of compound of Formula (I), or a pharmaceutically acceptable salt thereof. Alternatively, compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be presented without excipients such as lactose.

[0085] The compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a formulation depends on the precise type of formulation to be prepared but will generally be within the range of from 0.01 to 10% by weight. Generally, for most types of preparations, the proportion used will be within the range of from 0.05 to 1%, for example from 0.1 to 0.5%.

[0086] “Pharmaceutically acceptable” refers to those compounds, materials, formulations, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0087] Suitable pharmaceutically acceptable salts can include acid addition salts. Such acid addition salts can be formed by reaction of the compound of Formula (I) with the appropriate acid, optionally in a suitable solvent such as an organic solvent, to give the salt which can be isolated by a variety of methods, including crystallization and filtration.

[0088] Salts may be prepared in situ during the final isolation and purification of the compound of Formula (I). If the compound of Formula (I) is isolated as a salt, the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base.

[0089] Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2, 5 -dihydroxybenzoate, disuccinate, dodecylsulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane- 1 ,2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galactarate (mucate), gentisate (2,5- dihydroxybenzoate), glucoheptonate (gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphorate, glycolate, hexylresorcinate, hippurate, hydrabamine (N,N'- di(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methylsulfate, mucate, naphthalene-l,5-disulfonate (napadisylate), naphthalene-2-sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p- aminobenzenesulfonate, p-aminosalicyclate, pamoate (embonate), pantothenate, pectinate, persulfate, phenylacetate, phenylethylbarbiturate, phosphate, polygalacturonate, propionate, p- toluenesulfonate (tosylate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, teoclate (8-chlorotheophyllinate), thiocyanate, triethiodide, undecanoate, undecylenate, and valerate.Combination Therapy

[0090] In an embodiment, compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy. In an embodiment, compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with at least one additional treatment.

[0091] Compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered together with an anti-inflammatory agent such as a corticosteroid or a pharmaceuticalformulation thereof, for the treatment of a rhinovirus infection or a disease caused or exacerbated by a rhino virus infection. For example, compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be formulated together with an anti-inflammatory agent, such as a corticosteroid, in a single formulation, such as a dry powder formulation for inhalation. Alternatively, a pharmaceutical formulation comprising compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered in conjunction with a pharmaceutical formulation comprising an anti-inflammatory agent, such as a corticosteroid, either simultaneously or sequentially. For example, a pharmaceutical formulation comprising compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a further pharmaceutical formulation comprising an anti-inflammatory agent, such as a corticosteroid, may each be held in a device suitable for the simultaneous administration of both formulations via inhalation. In an embodiment, the antiinflammatory agent is an inhibitor of phosphatidylinositol-4,5-bisphosphate 3-kinase-delta (PI3K 8), such as nemiralisib.

[0092] Suitable corticosteroids for administration together with compound of Formula (I), or a pharmaceutically acceptable salt thereof, include fluticasone furoate, fluticasone propionate, beclomethasone diproprionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide and prednisilone. Suitable corticosteroids for administration together with compound of Formula (I), or a pharmaceutically acceptable salt thereof, via inhalation include fluticasone furoate, fluticasone propionate, beclomethasone diproprionate, budesonide, ciclesonide, mometasone furoate, and flunisolide.

[0093] A compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered together with one or more bronchodilators, or pharmaceutical formulations thereof, for the treatment of a rhinovirus infection or a disease caused or exacerbated by a rhinovirus infection. For example, compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be formulated together with one or more bronchodilators in a single formulation, such as a dry powder formulation for inhalation. Alternatively, a pharmaceutical formulation comprising compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered in conjunction with a pharmaceutical formulation comprising one or more bronchodilators, either simultaneously or sequentially. In a further alternative, a formulation comprising compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a bronchodilator may beadministered in conjunction with a pharmaceutical formulation comprising a further bronchodilator. For example, a pharmaceutical formulation comprising compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a further pharmaceutical formulation comprising one or more bronchodilators may each be held in a device suitable for the simultaneous administration of both formulations via inhalation.

[0094] Suitable bronchodilators for administration together with compound of Formula (I), or a pharmaceutically acceptable salt thereof, include 02 -adrenoreceptor agonists and anticholinergic agents. Examples of 02-adrenoreceptor agonists, include, for example, vilanterol, salmeterol, salbutamol, formoterol, salmefamol, fenoterol carmoterol, etanterol, naminterol, clenbuterol, pirbuterol, flerbuterol, reproterol, bambuterol, indacaterol, terbutaline and salts thereof, for example the xinafoate (1 -hydroxy -2 -naphthalenecarboxylate) salt of salmeterol, the sulphate salt of salbutamol or the fumarate salt of formoterol. Examples of anticholinergic agents include umeclidinium (for example as the bromide), ipratropium (for example, as the bromide), oxitropium (for example, as the bromide) and tiotropium (for example, as the bromide). In one embodiment, compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered together with a 02-adrenoreceptor agonist, such as vilanterol, and an anticholinergic agent, such as, umeclidinium.

[0095] It is understood that any and all embodiments of the present disclosure may be taken in combination with any other embodiment or embodiments to describe additional more embodiments. It is also to be understood that each individual element of the embodiments is its own independent embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.NUMBERED EMBODIMENTS

[0096] The invention may be described by means of the following numbered embodiments:1. A method of treating a human rhinovirus (HRV) infection, the method comprising administering to a human subject in need thereof a dose of about 0.1 mg, about 0.5 mg, or about 1.5 mg of a compound of Formula (I):pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is in a dry powder formulation and administered by inhalation, and wherein the human subject has a disease caused or exacerbated by the HRV infection.2. The method of embodiment 1, wherein the dose is about 0.5 mg.3. The method of embodiment 1, wherein the dose is about 1.5 mg.4. The method of any one of the preceding embodiments, wherein the dose is administered once per day.5. The method of embodiment 4, wherein the dose is administered once per day for one or more treatment periods of 5 to 21 days.6. The method of embodiment 5, wherein the treatment period is 7 to 14 days.7. The method of embodiment 6, wherein the treatment period is 10 to 14 days.8. The method of any one of the preceding embodiments, wherein the human subject is an adult with at least one characteristic or underlying medical condition associated with increased risk of the disease due to the HRV infection.9 The method of embodiment 8, wherein the medical condition is that human subject is elderly or immunocompromised.10. The method of embodiment 9, wherein the human subject has a lung transplant or stem cell transplant.11. The method of any one of the preceding embodiments, wherein the disease is asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, interstitial lung disease, cystic fibrosis, congestive heart failure, acute respiratory distress syndrome, acute lung injury, bronchiolitis, otitis media, sinusitis, acute bronchitis, a secondary bacterial infection, or pneumonia.12. The method of embodiment 11, wherein the disease is asthma.13. The method of embodiment 11, wherein the disease is COPD.15. The method of any one of the preceding embodiments, wherein treatment is initiated no more than 4, 3, or 2 days after onset of rhinovirus symptoms.16. The method of any one of the preceding embodiments, wherein the dose is administered using a dry powder inhaler (DPI).17. The method of any one of the preceding embodiments, wherein the dry powder formulation is present in one or more capsules, cartridges, or blister pockets.18. The method of embodiment 16, wherein the dry powder formulation is present in a blister pocket.19. The method of embodiment 17, wherein the dry powder formulation is present in two blister pockets, and wherein each of the two blister pockets contains a pre-metered dose of 0.75 mg of the compound of Formula (I) to administer simultaneously.20. The method of embodiment 17, wherein the dry powder formulation is present in a single blister pocket that contains a pre-metered dose of 0.5 mg of the compound of Formula (I).21. The method of any one of the preceding embodiments, wherein the method reduces the human subject’s respiratory tract symptom (LRTS) score and / or upper respiratory tract symptom (URTS) score after the treatment starts.22. The method of embodiment 20, wherein the LRTS score and / or URTS score is reduced by at least 40%.23. The method of embodiment 20, wherein the LRTS score and / or URTS score is reduced by at least 50%.24. The method of embodiment 20, wherein the LRTS score and / or URTS score is reduced by at least 60%.25. The method of any one of the preceding embodiments, wherein the compound of Formula (I) is administered in combination with one or more doses of itraconazole.26. The method of any one of the preceding embodiments, wherein the inhalation is oral inhalation.27. A compound for use in treating a human rhinovirus (HRV) infection in a human subject, wherein the compound is used at a dose of about 0.1 mg, about 0.5 mg, or about 1.5 mg and is of Formula (I):or a pharmaceutically acceptable salt thereof, wherein the compound is in a dry powder formulation for inhalation, and wherein the human subject has a disease caused or exacerbated by the HRV infection.28. Use of a compound for the manufacture of a medicament for the treatment of a human rhinovirus (HRV) infection in a human subject, wherein the compound is used at a dose of about 0.1 mg, about 0.5 mg, or about 1.5 mg and is of Formula (I):or a pharmaceutically acceptable salt thereof, wherein the compound is in a dry powder formulation for inhalation, and wherein the human subject has a disease caused or exacerbated by the HRV infection.EXAMPLES

[0097] The following examples are provided to illustrate, but not limit, the disclosure.Example 1. Phase lb Viral Challenge Study

[0098] A study was conducted to evaluate the safety, efficacy, tolerability, pharmacokinetics, and pharmacodynamics of inhaled compound of Formula (I) during experimental human rhinovirus infection in participants with asthma. The Human Viral Challenge (HVC) model, which involves the experimental exposure of study participants to a viral pathogen, has been shown to produce a high infection rate (up to -90%) and induce disease that is comparable to that of natural infections with infection establishing in the nose and subsequently migrating down to the lower respiratory tract.Study Design

[0099] The study was a single center, randomized, double-blind, placebo-controlled study to assess compound of Formula (I) administered as an inhalation powder blend (capsules for inhalation) via Monodose RS01 inhaler in participants with asthma during experimental human rhinovirus 16 (HRV-16) infection. Participants were admitted to the clinical trial unit on Day -1 and inoculated with HRV-16 on Day 1. Treatment of participants was initiated 2 days (48 hours) post-viral inoculation. Participants meeting the following criteria were randomized to receive study treatment: (1) an increase of at least 2 points in total upper respiratory tract symptoms (URTS) score compared to the average of 3 pre-inoculation measurements at a single time point within 48 hours of inoculation and before dosing; or (2) an increase of at least 1 point in total URTS score compared to the average of 3 pre-inoculation measurements at two or more consecutive time points within 48 hours of inoculation and before dosing. The 3 pre-inoculation measurements include Day -1 afternoon, Day -1 evening and Day 1 morning.

[0100] The dose of compound of Formula (I) was 3 mg once daily for Cohort 1 and 1.5 mg once daily for Cohort 2. The study population for Cohort 1 was mild intermittent asthmatics. The study population for Cohort 2 was expanded to include mild persistent and moderate asthmatics. Participants were dosed for 10 days and remained resident at the unit until discharge on Day 15, during which time efficacy, safety, tolerability, pharmacokinetic (PK), and pharmacodynamics (PD) assessments were completed.Endpoints

[0101] A primary endpoint of the study was area under the curve (AUC) change from baseline (CfB) in total lower respiratory tract symptoms (LRTS) score from time of inoculation up to discharge. The AUC CfB in total URTS score was also evaluated from time of first dose up to discharge.

[0102] Secondary endpoints included maximal CfB in total URTS score from day of inoculation up to discharge, AUC CfB in total upper respiratory tract symptoms (URTS) score from day of inoculation up to discharge, mean percent CfB in trough force expiratory volume (FEV1) from day of inoculation up to discharge, and mean percent CfB in morning and evening peak expiratory flow (PEF) from day of inoculation up to discharge. These secondary endpointsmay also be evaluated from time of first dose up to discharge. Other secondary endpoints included occurrence of adverse events (AEs) and serious adverse events (SAE) (challenge emergent events were excluded unless judged by the Investigator to be of a greater severity than expected), and clinically significant changes in vital signs, 12-lead electrocardiogram (ECG) and clinical laboratory parameters up to follow up visit.

[0103] Pharmacokinetic endpoints included area under the concentration-time curve from time 0 (pre-dose) to time tau [(AUC(O-T)) for Doses 1 and 10 (T=24 h for once-a-day dosing regimen) (if determined), and maximum observed concentration (Cmax) and time to reach maximum observed plasma concentration (Tmax) for Doses 1 and 10.Inclusion Criteria

[0104] Participants are eligible to be included in the study only if all of the following criteria are met:1. Between 18 and 65 years of age inclusive, at the time of signing the informed consent.2. A physician diagnosis of asthma, as defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory airflow limitation at least 6 months before Screening. The criteria for diagnosis of asthma should be documented in the participant’s source data, including relevant history.3. A screening pre-bronchodilator FEV1 >65% predicted normal value.Note: Predicted values based on European Respiratory Society (ERS) guidelines (Quanjer, P. H. et al. Eur Respir J. 2012;40(6): 1324-1343).4. Positive Methacholine challenge test, defined as >20% fall in FEV1 at a methacholine concentration <16 mg / mL, at Screening Visit.Note: previous documented positive methacholine challenge test is acceptable if within 6 months of admission. If methacholine challenge test is negative or participant is unable to perform this test, then bronchodilator reversibility is allowed as an alternative as follows: Positivebronchodilator reversibility test, defined as an increase in FEV1 >12% and >200 mL from baseline, 10 to 15 minutes after administration of 400 mcg salbutamol (or equivalent).Note: reversibility test should be performed after a washout period of at least 6 hours for SABA and 12 hours for long-acting beta agonists (LABAs) (including fixed combinations of inhaled corticosteroid (ICS) and LABA).5. Positive skin prick test to at least one allergen (e.g., house dust mite, cat dander, grass pollen) at Screening Visit.Note: previous documented positive skin prick test is acceptable if within 5 years of admission.6. Serology suitable for the challenge virus: The serology results obtained from the HRV-16 neutralization antibody assay suggests that the participant will be susceptible to HRV-16 infection (i.e., they are likely to be infected following inoculation with the challenge virus).7. Participants with controlled asthma, according to Investigator judgement, using:(i) Short-acting beta agonist (SABA) alone or with one of the following: Intermittent inhaled corticosteroid (ICS) or ICS / long-acting beta agonist (LABA) therapy used as rescue. Note: Participants using intermittent ICS or ICS / LABA therapy will be required to switch to SABA only treatment from at least 14 days before admission until discharge from the unit; or(ii) Regular ICS or ICS / LABA used as controller. Note: Participants on regular ICS or ICS / LABA therapy will be permitted to continue use during the study. Maximum allowed daily doses of ICS are outlined in Table 1.8. Body weight at least 50.0 kg (110 lbs) and body mass index (BMI) within the range 18.5 to 34.0 kg / m2(inclusive).9. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: (i) is a woman of non-childbearing potential (WONCBP); or (ii) is a woman of childbearing potential (WOCBP) and using an acceptable contraceptive method during the intervention period and for at least 28 days after inoculation. The investigatorshould evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated in relationship to the first dose of study intervention).A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 48 hours before the first dose of study intervention or Viral Challenge (whichever occurs first).Note: If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. The Investigator is responsible for review of medical history, menstrual history and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.10. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.Meals and Dietary Restrictions

[0105] Participants must refrain from consumption of grapefruit or grapefruit juice, and pomelos, from 7 days before inoculation or first dose (whichever occurs first) until discharge from the unit.

[0106] No water is allowed from 1 hour before dosing until 1 hour after dosing. Water is allowed ad libitum at all other times.

[0107] Participants must fast overnight (at least 6 hours) until 1 hour after each dose.Caffeine, Alcohol, and Tobacco

[0108] During each dosing session, participants will abstain from ingesting caffeine- or xanthine-containing products (e.g., coffee, cola drinks, and chocolate) for 12 hours before the start of dosing until after collection of the final pharmacokinetic (PK) and / or pharmacodynamic sample. Decaffeinated drinks are permitted.

[0109] During each dosing session, participants will abstain from alcohol for at least 72 hours before the start of dosing until after collection of the final PK and / or pharmacodynamic sample.

[0110] Use of tobacco or nicotine containing products is not permitted during this study.Activity

[0111] Participants will abstain from strenuous exercise for at least 72 hours before each blood collection for clinical laboratory tests. Participants may participate in light recreational activities during the study (e.g., watching television, reading).Prohibited Medications

[0112] The following medications are prohibited from the specified timeline before Viral Challenge or first dose of study intervention (whichever occurs first) until discharge from the clinical unit: inhaled corticosteroids (14 days; except where part of regular prescribed treatment as described below in Permitted Medications), systemic corticosteroids (8 weeks), treatments for hay fever (e.g., antihistamines) (5 days), decongestants (5 days), and other treatments for respiratory tract infection (e.g., cold remedies) (excluding permitted medications listed below) (5 days).

[0113] Participants must abstain from taking other over-the-counter (OTC), except simple analgesics, or prescription medication (including recreational drugs and dietary or herbal supplements (other than vitamins)) at least 5 days before the Viral Challenge or first dose of study intervention (whichever occurs first), unless in the opinion of the Investigator and Medical Monitor, the medication will not interfere with the study procedures or compromise participant safety.Permitted Medications

[0114] Paracetamol / Acetaminophen, at doses of < 4 grams / day, and / or use of simple analgesics is permitted for use any time prior to the study.

[0115] The following asthma “standard of care” will be used throughout the study as prescribed by a treating physician: (i) participants using intermittent ICS or ICS / LABA will be required to switch to SABA only use from at least 14 days before admission until discharge fromthe clinical unit; (ii) participant using regular ICS or ICS / LABA may continue on their regular treatment up to the maximum allowed daily dose (as defined in Table 1) during the study.Table 1. Maximum permitted daily low doses of inhaled corticosteroidHFA: hydrofluoroalkane propellant

[0116] Other concomitant medication may be considered on a case-by-case basis by the Investigator in consultation with the Medical Monitor.Rescue Medicine

[0117] For participants in this study SABA (e.g., salbutamol) will be permitted to be used as rescue medication as required. This will be provided by the Sponsor or if necessary, supplied by the study site.

[0118] The use of rescue medication is allowed at any time during the study. The date and time of rescue medication administration as well as the name, dosage, regimen and number of puffs, of the rescue medication must be recorded.Efficacy AssessmentsSymptom Measures

[0119] This study collected upper and lower respiratory tract symptom (URTS & LRTS) data using an electronic diary (eDiary) device. Symptoms were assessed 3 times daily (approximately 8 hours apart) in the morning (on waking), afternoon and evening (before bedtime).

[0120] Symptoms analyzed in this study include:URTS: Runny nose, stuffy nose, sneezing and sore throat. Each symptom was assessed on a 4- point scale.LRTS: Cough, chest tightness, shortness of breath, wheezing, daily activity (afternoon and evening assessments only) and nighttime awakenings (morning assessments only). Each symptom was assessed on a 4-point scale, shortness of breath and wheezing will be measured on a 5 -point scale.Lung Function Measurements

[0121] Spirometry was performed at the site using available equipment.

[0122] For each time point, at least 3 acceptable spirometry maneuvers (from a maximum of 8 attempts) should be achieved. The highest forced expiratory volume in one second (FEV1) will be entered into the electronic case report form (eCRF). Participants should withhold use of shortacting bronchodilators for at least 6 hours and LABA for at least 12 hours prior to each spirometry measurement.

[0123] Peak expiratory flow (PEF) was performed and recorded in the eCRF.RESULTS

[0124] Compared to placebo, the oral inhalation with the compound Formula (I) reduced the daily total LRTS scores rapidly and continuously, as shown in FIG. 1, indicating the effectiveness of the treatment methods described herein.

[0125] The LRTS results are also shown in Table 2. LRTS of cough, chest tightness, shortness of breath, wheezing, and nighttime awakenings / daily activity were assessed on a 4-point scale(0=absent, 3=most severe) at 3 time points a day (morning, afternoon, and evening). Area under the curve (AUC) of LRTS from first dose to discharge was assessed for Cohorts 1 and 2.For Cohort 1, a 70% reduction in AUC of LRTS was observed in the Formula (I) treatment group (N=9) compared with placebo (N=9). For Cohort 2, a 62% reduction in AUC of LRTS was observed in the Formula (I) treatment group (N=10) compared with placebo (N=18 pooled across Cohorts 1 and 2).Table 2. AUC of LRTS from first dose to dischargeCrI=Credible IntervalExample 2. A randomized, double-blind, placebo controlled, single and repeat dose study to assess the safety, tolerability, and pharmacokinetics of inhaled PI4KB inhibitor in participants with Chronic Obstructive Pulmonary Disease (COPD)

[0126] A single cohort study was conducted to evaluate the safety, tolerability, and plasma pharmacokinetics of inhaled compound of Formula (I) in participants with stable COPD, to support further studies in which COPD patients is treated at the onset of cold-like symptoms and possibly at the beginning of an infective exacerbation.Study Design

[0127] This study was a single cohort, randomized, double-blind, placebo controlled single and repeat dose study designed to assess the safety, tolerability and plasma pharmacokinetics (PK) of compound of Formula (I) administered as an inhalation powder blend in participants with stable COPD. This study contained two parts, a single ascending dose followed by 14-days repeat dosing.

[0128] The single ascending dose part assessed two dose levels of inhalation powder or placebo across two treatment periods in a single crossover cohort of participants. The repeat dose part assessed one dose level of inhalation powder or placebo in one treatment period in the same cohort of participants.

[0129] The study treatment was one day for the single dose assessments and 14 days for the repeat dose assessment. The study duration was from 64 to 71 days. A total of 12 participants with COPD were enrolled in this study. Sufficient patients were screened and those who met the study entry criteria were randomized to receive the drug inhalation powder or placebo in a 3: 1 ratio with the intention of a minimum of 8 and a maximum of 12 participants to complete the study.

[0130] Eligible participants were divided into four groups and received active treatment or placebo according to Table 3. Patients either received placebo or a single dose (SD) of Formula (I) 500 mcg in Treatment Period 1 followed by placebo or a single dose of (SD) of Formula (I) 1000 mcg in Treatment Period 2. Patients also received a repeat dose of placebo or Formula (I) 1500 mcg in Treatment Period 3. There was a washout period between each treatment period. Participants had a follow-up of 14 days after the last dose of Formula (I).Table 3. Study treatment sequence and randomizationA=active dose, P=placebo

[0131] The total duration of study participation is shown in Table 4.Table 4. Study duration by treatmentIntervention Groups and Duration:

[0132] This single cohort, randomized, double-blind, placebo-controlled study contained two single and one repeat dose treatments. The GSK manufactured medical devices (or devices manufactured for GSK by a third party) provided for use in this study were the Monodose RS01 (manufacturer Plastiape S.p.A).Single Dose

[0133] The starting dose was 500 mcg. Progression to the next single dose level of 1000 mcg occurred on an individual participant basis and only if, in the judgement of the Investigator, it was supported by the safety and tolerability profile in that patient taking 500 mcg. Participants were enrolled for approximately 42 days for the single dose assessments (up to 30 days screening, 2 assessment / washout periods up to 6 days each), see Table 4.Repeat Dose

[0134] The repeat dose treatment assessed 1500 mcg of Formula (I) in the same cohort of participants that has completed single dose assessments. Participants received either Formula (I) or placebo as an inhalation powder once daily for 14 days. Participants were enrolled for approximately 15 days for the repeat dose period and follow-up period from 7 to 14 days. In total,participants were enrolled for approximately 64 to 71 days in the study (42 days for two single dose periods including screen and washouts, and 15 days for one repeat dose period including a 7 to 14-day follow-up), see Table 4.Study population and patient eligibility

[0135] A total of 12 participants with stable COPD were enrolled in the study.

[0136] Inclusion criteria:1. Between 40 and 70 years of age inclusive, at the time of signing the informed consent. Participants must show evidence of complete COVID-19 vaccination before being eligible to participate. A complete COVID-19 vaccination is currently defined as having taken either two basic vaccinations plus one booster three months afterwards or two vaccinations plus a confirmed CO VID-19 infection before vaccinations.2. The participant has a confirmed diagnosis of COPD for > 6 months, as defined by the GOLD guidelines.3. The participant has a post-bronchodilator FEV1 / FVC ratio < 0.7 within 30 min after administration of 400 pg salbutamol or equivalent and post-bronchodilator FEV1 > 40% to < 80% of predicted value.4. Participant is a smoker or an ex-smoker with a smoking history of at least 10 pack years. The following equation should be used to calculate pack years: pack years=((cigarettes smoked per day) / 20)xnumber of years smoked5. Body weight at least 45 kg and BMI within the range 18.0 to 32 kg / m2 (inclusive).6. Males and female participants, as follows:Male Participants: No additional requirements.Female Participants: A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: a WONCBP or WOCBP and using an acceptable contraceptive method during the intervention period for at least 10 days afterthe last dose of study intervention. A WOCBP must have both: a confirmed menstrual period before the first dose of study intervention AND a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 30 days before the first dose of study intervention. If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant is excluded from participation if the serum pregnancy result is positive.7. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the Informed Consent Form and in this protocol.Endpoints

[0137] The primary objective of this study was to assess the safety and tolerability of compound of Formula (I) following single and repeat inhaled administration in participants with COPD. The endpoints for this objective was set as (i) the occurrence of adverse events (AEs) and serious adverse events (SAEs) (ii) clinically significant changes in laboratory values, vital signs, 12-lead electrocardiogram (ECG) and spirometry measurements up to Follow Up.

[0138] The secondary objective of this study was to evaluate the plasma pharmacokinetics of compound of Formula (I) following single and repeat inhaled administration in participants with COPD. The endpoints for this objective was (i) the area under the plasma-concentration time curve (AUC): area under the concentration time curve form time 0 (predose) to 24 hours post dose administration following the first dose (AUQO-24]) or area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC[0-t]) for single dose and area under the concentration-time curve from time 0 (predose) to 6 hours post dose administration following the first dose (AUC[0-6]) for repeat dose and (ii) the maximum observed plasma drug concentration (Cmax), time to maximum observed plasma drug concentration (Tmax).Safety Assessments

[0139] An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is any untoward medical occurrence that, at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization,results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or any other situation according to medical or scientific judgment. Adverse events which were not serious, were considered as non-serious adverse events.Statistical Analyses

[0140] The statistical analysis plan was finalized prior to FPFV and included a more technical and detailed description of the statistical analyses described in this section. This section is a summary of the planned statistical analyses of the primary and secondary endpoints.

[0141] General Considerations. Unless otherwise specified, baseline was the last value / assessment before the first dose of study treatment (Day 1 pre-dose). If there were multiple assessments collected at the same scheduled time, the average of these assessments was used as the baseline.Primary Endpoints Analysis

[0142] Adverse Events and Serious Adverse Events (AEs). The proportion of participants reporting AEs was tabulated by study intervention and by dose for participants. AEs were tabulated by severity and relationship to study product. AEs was tabulated using MedDRA preferred terms. The number and percentage of participants experiencing each specific AEs (All AEs, Grade 2 or higher, and SAEs) was tabulated by severity and by relationship to study product. For the calculations in these tables, each participant’s AEs were counted once under the maximum severity or the strongest relationship to study product. AEs leading to withdrawal were summarized.

[0143] Laboratory values, vital signs, 12-lead electrocardiogram and Spirometry. Whilst all data collected was summarized, only measurements which were clinically significant at any timepoint between randomization and follow up were reported as part of the primary endpoint. This data included laboratory results for hematology, clinical chemistry and urinalysis, vital Signs measurements for semi supine systolic and diastolic blood pressure, pulse rate, respiratory rate and temperature, 12-lead safety electrocardiogram (ECG) measurements for heart rate, PR, QRS, QT and QT interval corrected for heart rate according to Frederica’s formula (QTcF) intervals, and spirometry measurements for FEV1.Secondary Endpoint Analysis

[0144] All pharmacokinetic analyses was performed on the PK Population. Plasma concentration-time data was analyzed by non-compartmental methods with WinNonlin. Calculations were based on the actual sampling times recorded during the study. From the plasma concentration-time data, the following pharmacokinetic parameters were determined if data permitting, for each dose: Treatment period 1 & 2 (single ascending doses): AUC(O-t), AUC(0- 24), Cmax and Tmax; and Treatment period 3 (repeat dose): Cmax, Tmax and AUC(0-6) on Day 1 and Day 14.

[0145] Analysis of dose proportionality and dose accumulation following repeated dosing (period 3 only) were conducted. A population PK model (POP PK) may be developed with all available data from this and historical studies as appropriate and is reported separately.ResultsSafety Results

[0146] No serious adverse events were observed in this study, and there was only one adverse event of moderate severity in the placebo repeat dose arm. All other adverse events were mild. Incidence of adverse events were comparable across the active and placebo arms. This is shown in Table 5. Treatment emergent adverse events are undesirable events not present prior to medical treatment or an already present event that worsens either in intensity or frequency following the treatment.Table 5. Overview of treatment emergent adverse eventsTolerability Results

[0147] No participants were reported to have clinically significant changes in hematology and clinical chemistry laboratory parameters following single dose or the repeat dose of Formula (I). There were further no participants reported to have clinically significant changes in vital signs and 12-lead electrocardiogram findings following single dose or the repeat dose of Formula (I).PK Results

[0148] Blood samples were collected at specific time points for pharmacokinetic (PK) analysis of compound of Formula (I).

[0149] A mixed effect model was used to assess accumulation including day as a continuous fixed effect and subject as a random effect. An unstructured covariance matrix was used. Participants with incomplete data were excluded from statistical analysis. An adjusted geometricmean ratio of 1 indicates no accumulation. There was no accumulation observed in the repeat dose period of the study (1500 mcg of Formula (I)) between Day 1 and Day 14, as shown in Table 6.Table 6. Summary of PK results

[0150] Dose proportionality was observed between the three doses (500 mcg Formula (I), 1000 mcg Formula (I), and 1500 mcg Formula (I)). This is as shown in Figure 3, which provides the median of dose normalized plasma Formula (I) concentration-time plots (semi-log) by dose and study day (Day 1 500 mcg SD, Day 1 1000 mcg SD, Day 1 1500 mcg RD, Day 14 1500 mcg RD). The concentrations were dose normalized and multiplied by nominal dose (500 mcg SD).Conclusion

[0151] 12 participants with COPD were enrolled in the study and all 12 participants completed the study. Incidences of AEs were comparable across the active and placebo arms, where the active arms included 500 mcg SD of Formula (I), 1000 mcg SD of Formula (I), 1500 mcg RD of Formula (I). Formula (I) was well-tolerated in participants with COPD across the different dose levels. The reported side effects were found to be mild and no major safety issues were identified.

[0152] It was concluded that single and repeat doses of Formula (I) were quickly absorbed by the lungs after inhalation. The amount of Formula (I) absorbed by the lungs also increased similar to the changes in dose levels of Formula (I) and dose proportionality was observed. No accumulation was observed of Formula (I) in the blood in the repeat dose period of 1500 mcg through the repeat dose period of 14 days.Example 3. Study Of PI4KB Inhibitor Alone or In Combination with Itraconazole

[0153] This study aims to understand how a PI4KB inhibitor such as a compound of Formula (I) behaves in the body, when given alone and when given along with another medicine called itraconazole. Itraconazole slows down a process in the body that breaks down some other medicines so that itraconazole can make the medicines stay in the body longer. The main goals are to assess the safety, tolerability, and the amount of compound of Formula (I) in the blood at different points of time when given alone as a single dose and when given along with repeated doses of itraconazole. The study will also investigate how itraconazole and its by-products behave in the body when given with compound of Formula (I).

[0154] In this study, participants will take part in two treatment periods. In the first treatment period, participants will receive compound of Formula (I) alone and in the second treatment period, they will receive it alongside itraconazole. The entire study, from screening to follow-up, is expected to take up to 60 days per participant. Compound of Formula (I) will be administered as a single dose (0.5 mg in an inhalation powder form) using an inhaler device (an integral drug device combination inhaler which was the ELLIPTA device) in both treatment periods. Itraconazole (200 mg) will be given once daily as an oral capsule during treatment period 2.

[0155] This research is important to understand how compound of Formula (I) interacts with other medications commonly used by patients, e.g., those with COPD. By closely monitoring participants' health and analyzing the data collected, researchers will be able to figure out the best dose of compound of Formula (I) when it is used with other medications. This study will be conducted in agreement with the protocol and considering international ethical guidelines. All measures will be taken to minimize risks to participants, ensuring their safety and well-being throughout the study.

[0156] Participants are eligible to be included in the study only if all of the following criteria apply:Age Between 18 and 65 years of age inclusive, at the time of signing the informed consent. Note: Participants over 50 years of age must show evidence of COVID-19 vaccination, aligned with site local policy, before being eligible to participate. INC#1Type of participant. Participants who are overtly healthy as determined by medical evaluation based on screening medical history, physical examination, vital signs, ECG assessment, pulmonary function testing and laboratory tests. INC#2 Note: Fully resolved childhood asthma is acceptable.Body weight at least 50.0 kg (110 lbs) for males and females and BMI within the range 18.5 to 32.0 kg / m2 (inclusive). INC#3Sex: Males and female participants, as follows: INC#4. Male Participants: No additional requirements. Female Participants: A female participant is eligible to participate if the participant is a WONCBP.Informed consent. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and the protocol. INC#5

[0157] PK Endpoint (primary): Derived compound of Formula (I) pharmacokinetic parameters without itraconazole co-administration in Period 1 and with itraconazole co-administration in Period 2: AUC(O-t), AUC(O-oo), Cmax, and Tmax.

[0158] Timepoint(s) of evaluation of this end point: Timepoints after completion of Day 3 Treatment Period 1 (single 500mcg dose compound of Formula (I)) and Day 11 of Period 2 (single 500 mcg dose compound of Formula (I) and 200 mg Itraconazole). PK endpoints are evaluated pre-dose and post dose: pre-dose and at multiple time points post dose up to completion of Day 3 Treatment Period 1 and at pre-dose on Day 5 and at multiple times post-dose up to Day 11 of Period 2.

[0159] Safety Endpoint (Secondary): Occurrence of AEs and SAEs; Clinically significant changes in laboratory values, vital signs and 12-lead ECG measurements (on treatment till Follow Up). Itraconazole PK endpoint (Secondary): Derived pharmacokinetic itraconazole and hydroxyitraconazole parameters for Treatment Period 2, Days 1 and 5: AUC(O-t), AUC(O-oo), Cmax, and Tmax.

[0160] Timepoint(s) of evaluation of this end point: Safety Endpoint (Secondary): Timepoints after completion of Day 3 Treatment Period 1 (single 500mcg dose compound of Formula (I)) and Day 11 of Period 2 (single 500 mcg dose compound of Formula (I) and 200 mg Itraconazole).Itraconazole PK endpoint (Secondary): Timepoints after completion of Days 1 and 5 of Treatment Period 2 (single 500 mcg dose compound of Formula (I) and 200 mg Itraconazole).Statistical Analyses

[0161] AUC(O-oo) and Cmax of the compound of Formula (I) with Itraconazole (Period 2) and without Itraconazole (Period 1) were statistically analyzed.Results

[0162] The geometric mean ratios for AUC(0- oo) and Cmax of the compound of Formula (I) were 238% [ratio 2.38, 90%CI: 2.17, 2.61] and 220% [ratio 2.20, 90%CI: 1.92, 2.52], respectively, when co-administered with itraconazole.Conclusions

[0163] This study demonstrates that co-administration of repeat doses of itraconazole (ITZ; a strong CYP3A4 inhibitor) with a single inhaled 500 mcg dose of a compound of Formula (I) altered the extent of systemic exposure to the compound of Formula (I) with an approximate 2.4- fold and 2.2-fold increase in geometric mean AUC and Cmax respectively of the compound of Formula (I).PBPK DDI Predictions

[0164] A PBPK interaction model (based on in vitro (animal) data and human microsomal and enzyme metabolism assays and evaluated with FTIH study date for the compound of Formula (I)) was updated with the observed PK data from this drug-drug interaction study.

[0165] The updated PBPK interaction model predicts that co-administration of 500 mcg inhaled compound of Formula (I) with Itraconazole may result in an approximate 2.9-fold increase in AUC (0-oo) and a 2-fold increase in Cmax for the compound of Formula (I). These predictions classify the resulting drug-drug interaction risk with Itraconazole as moderate.

[0166] Systemic exposures were simulated for inhaled 1500 mcg of the compound of Formula (I) when co-administered with CYP3A4 inducers and inhibitors, from the weak,moderate and strong categories. For simulations of the compound of Formula (I) exposure after co-administration with CYP3A4 inhibitors, weak inhibitors were predicted as carrying no DDI risk, moderate inhibitors were predicted to result in weak DDI (1.25-to-2-fold increase in the compound of Formula (I) exposure) and strong CYP3A4 inhibitors were predicted to result in moderate DDI (approximately 2-to-5-fold increase in the compound of Formula (I) exposure).

[0167] The use of strong CYP3A4 inhibitors therefore may present a risk for drug interaction with a 1500 mcg dose of compound of Formula (I). For weak and moderate CYP3A4 inhibitors the simulations based on PBPK model outputs predict there may be weak or no risk for drug interaction with 1500 mcg dose of the compound of Formula (I).Example 4. Target Engagement

[0168] Due to a lack of in vivo preclinical models of HRV infection, the relationship between target engagement, inhibition of viral replication and efficacy is not well characterized. However, in a mouse model of coxsackievirus B4-induced pancreatitis, which also replicates through PI4KB, efficacy was observed at 8 and 24 hours when target engagement (TE) was >50% and < 25% respectively. As Coxsackie and HRV are both enteroviruses that are both dependent on PI4KB for replication, doses were selected based on probability of TE at trough (24 hour for once daily treatment) >50% and >25% for Formula (I). A pharmacokinetic / pharmacodynamic (PKPD) and physiologically -based pharmacokinetics (PBPK) model based on preclinical and clinical data were used to estimate the TE for Formula (I). Rationale for the selection of doses is provided in Table 7 and FIG. 2, plus additional safety considerations for selecting suitable dose(s). The PBPK model integrates the human physiology of tissues and organs with compound-specific data, to allow prediction of the time course of drug concentrations in plasma and tissues. The PKPD model utilises the predicted drug concentrations and the in vitro enzyme kinetics data, for example the synthesis and degradation of the enzyme, and the on and off rate of the compound at the target to allow the dynamic prediction of the target engagement.Table 7. Dose rationale

[0169] The PBPK model was calibrated using observed PK data (plasma and epithelial lining fluid from a first time in human study with the compound of Formula (I)) and predicted that target engagement was 62.4% and 79.0% for the model-simulated median steady state trough concentrations following repeat dosing of 500 mcg and 1500 mcg of the compound of Formula (I), respectively.Example 5. Exposure-Response analysis

[0170] An Exposure-Response (ER) analysis was conducted to explore the relationship between the compound of Formula (I) plasma SS exposure and area under the curve (AUC) of change from baseline (CfB) in LRTS score from first dose to discharge from the study described in Example 1 (with mild asthma participants challenged with human rhinovirus infection).Summary of the Data

[0171] LRTS score data from 37 participants from the study in Example 1 were available for ER modelling. Study randomization comprised placebo (N=18) and active treatment arms from Cohort 1 (3000 mcg; N=9) and Cohort 2 (1500 mcg; N=10) administering once daily (QD) dosing of inhaled compound of Formula (I).Calculation of PK Exposures

[0172] Steady state (SS) exposures for each participant were derived using the post hoc Empirical Bayes Estimates (EBEs) from a population pharmacokinetic (PopPK) model which is based on clinical data. For each study participant, intensive (0 to day 11, every 0.1 h) individual PK profiles were simulated using their actual dosing history. The simulated PK curves were then used to calculate the following SS exposures on day 10 after the initial dose: minimum concentration (Cmin,ss), maximum concentration (Cmax,ss), AUC per dosing interval (AUCtau,ss) andcumulative AUC (AUCcumui). AUCtau.ss was calculated by taking the difference in cumulative AUC from dose times on day 9 and day 10 (i.e., SS dosing interval).ER Analysis and Conclusions

[0173] A linear or nonlinear (e.g., inhibitory Emax) regression model was used to investigate the relationship between SS plasma exposure and the AUC of Change from Baseline LRTS. This included data from those participants that were administered placebo (i.e., when exposure = 0).

[0174] The ER Relationship in Asthma Participants challenged with HRV is shown in Figure 4. Based on the ER analysis, a 3000 mcg daily dose regimen is unlikely to provide additional benefit over the 1500 mcg daily dose and suggests a maximum dose of 1500 mcg of the compound of Formula (I) inhaled, since it represents the plateau of the ER relationship.Predictions from the PopPK and ER models suggested that assessment of a 3-fold lower dose (500 mcg) may provide exposures and response that delineates placebo from the 1500 mcg dose.Example 6. Number of days to symptom resolution

[0175] The results from Example 1 were analyzed to determine the number of days to symptom resolution from start of treatment.

[0176] The time to resolution of Lower Respiratory Tract Symptoms (LRTS) was defined as no LRTS symptoms for 2 days. The start of treatment was 72 hours after infection.

[0177] The median time to resolution of LRTS from first dose was 4.75 days in Placebo arm (pooled Cohorts 1 & 2), the median time to resolution of LRTS from first dose was 2 days in the 1500 mcg daily dose of compound of Formula (I) arm (Cohort 2), and the median time to resolution of LRTS from first dose was 3.1 days in the 3000 mcg daily dose of compound of Formula (I) arm (Cohort 1).

[0178] This indicates for the 1500 mcg daily dose of the compound of Formula (I) that there was a 2.75 days reduction in median time to resolution of LRTS compared to Placebo.

[0179] This indicates for the 3000 mcg daily dose of the compound of Formula (I) that there was a 1.65 days reduction in median time to resolution of LRTS compared to Placebo.

[0180] For both the 1500 mcg daily dose and the 3000 mcg daily dose arms, 9 out of 10 subjects exhibited resolution of the LTRS within 10 days from the first dose.Example 7. ELLIPTA equivalence to MONODOSE inhaler

[0181] The PK parameters and profile of the compound of Formula (I) were compared after administration of a single 1500 mcg dose of the compound of Formula (I) with the ELLIPTA inhaler (from a study with healthy participants of European ancestry) with a single 1500 mcg dose of MONODOSE inhaler (from the study as described in Example 1 in participants with mild / moderate asthma). PK is anticipated to be similar in healthy participants and in participants with asthma.

[0182] As both studies had similarities in study design, dosing, generation of PK exposure from a single dose or first day of dosing and assay methodologies (as shown in Table 9), the PK data from the studies can be compared.Table 9. Attributes of the studies to allow for PK comparison

[0183] PK exposure (Cmax and AUC(O-inf) after administration with ELLIPTA and MONODOSE inhaler were generally similar, though the administration of the compound of Formula (I) via ELLIPTA produced lower between-subject variability than MONODOSE inhaler. The inter-subject coefficients of variation (CVb%) for the study with the ELLIPTA were 11.1% and 18.3% for AUC(0-24) and Cmax, respectively. The inter-subject coefficients of variation (CVb%) for the study with the MONODOSE were 27.49% and 23.86% for AUC(0-24) and Cmax, respectively.

[0184] The median Tmax was similar after inhaled compound of Formula (I) administration with ELLIPTA and MONODOSE inhalers, demonstrating a similar and rapid absorption. The PK exposure after administration of 1500 mcg of the compound of Formula (I) with MONODOSE and ELLIPTA inhaler, as shown by PK concentration time profiles and geometric mean AUC(0-24) and Cmax were generally similar. A comparison of the PK parameters are shown in Table 10. The MONODOSE inhaler and ELLIPTA inhaler produced similar PK conc- time profiles after a single dose, as shown in Figure 5.

[0185] The MONODOSE inhaler used in this example is a Monodose RS01 inhaler that was developed by Plastiape.Table 10. PK parameters for both studiesData reported as geometric mean.

[0186] The pharmacokinetic data from both studies supports the administration of the compound of Formula (I) via ELLIPTA at a dose of 1500 mcg.

[0187] While the present disclosure has been described and illustrated herein by references to various specific materials, procedures and examples, it is understood that the disclosure is not restricted to the particular combinations of materials and procedures selected for that purpose. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the disclosure being indicated by the following claims. All references, patents, and patent applications referred to in this application are herein incorporated by reference in their entirety.

Claims

WHAT IS CLAIMED IS:

1. A method of treating a human rhinovirus (HRV) infection, the method comprising administering to a human subject in need thereof a dose of about 0.1 mg, about 0.5 mg, or about 1.5 mg of a compound of Formula (I):(I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is in a dry powder formulation and administered by inhalation, and wherein the human subject has a disease caused or exacerbated by the HRV infection.

2. The method of claim 1, wherein the dose is administered once per day.

3. The method of claim 1 or claim 2, wherein the treatment period is 7 to 14 days.

4. The method of claim 3, wherein the treatment period is 10 to 14 days.

5. The method of any one of the preceding claims, wherein treatment is initiated no more than 4, 3, or 2 days after onset of rhinovirus symptoms.

6. The method of any one of the preceding claims, wherein the disease is asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, interstitial lung disease, cystic fibrosis, congestive heart failure, acute respiratory distress syndrome, acute lung injury, bronchiolitis, otitis media, sinusitis, acute bronchitis, a secondary bacterial infection, or pneumonia.

7. A method of treating a human rhinovirus (HRV) infection, the method comprising administering to a human subject in need thereof a compound of Formula (I):pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is administered at a dose of from about 0.5 mg to about 1.5 mg once daily for up to ten days, wherein treatment is initiated no more than 4 days after onset of rhino virus symptoms, and wherein the human subject is either a) elderly or immunocompromised, or b) has a disease whose symptoms are at risk of being exacerbated by an HRV infection.

8. The method of claim 7, wherein the human subject is elderly or immunocompromised.

9. The method of claim 7, wherein the human subject has a disease whose symptoms are at risk from being exacerbated by an HRV infection.

10. The method of claim 9, wherein the disease whose symptoms are at risk from being exacerbated by an HRV infection is an airways disease.

11. A method of reducing exacerbations of an airways disease, the method comprising administering to a human subject in need thereof a compound of Formula (I):(I), or a pharmaceutically acceptable salt thereof following onset of rhinovirus symptoms, wherein the compound of Formula (I) is administered at a dose of from about 0.5 mg to about 1.5 mg once daily for up to ten days, wherein treatment is initiated no more than 4 days after onset of rhinovirus symptoms.

12. The method of any one of claims 10 or 11, wherein the airways disease is asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis or acute lung injury.

13. The method of claim 10 or 11, wherein the airways disease is asthma.

14. The method of claim 10 or 11, wherein the airways disease is COPD.

15. A method of reducing exacerbations of a human rhino virus infection (HRV) in a human subject that is elderly or immunocompromised, the method comprising administering to the subject a compound of Formula (I):pharmaceutically acceptable salt thereof following onset of rhinovirus symptoms, wherein the compound of Formula (I) is administered at a dose of from about 0.5 mg to about 1.5 mg once daily for up to ten days, wherein treatment is initiated no more than 4 days after onset of rhinovirus symptoms.

16. The method of claim 7, 8 or 15, wherein the human subject has a lung transplant or stem cell transplant.

17. The method of any one of the preceding claims, wherein the treatment period is 10 days.

18. The method of any one of the preceding claims wherein treatment is initiated no more than 3 days after onset of symptoms.

19. The method of any one of the preceding claims, wherein the dose is about 0.5 mg.

20. The method of any one of claims 1 to 18, wherein the dose is about 1.5 mg.

21. The method of any one of claims 7 to 20, wherein the compound of Formula (I) is administered by inhalation.

22. The method of claim 21, wherein the compound of Formula (I) is in a dry powder formulation.

23. The method of any one of claims 1 to 6 or 22, wherein the dose is administered using a dry powder inhaler (DPI).

24. The method of claim 23, wherein the dry powder inhaler is an ELLIPTA device.

25. The method of any one of claims 1 to 6 or 22 to 24, wherein the dry powder formulation is present in one or more capsules, cartridges, or blister pockets.

26. The method of claim 25, wherein the dry powder formulation is present in a blister pocket.

27. The method of claim 26, wherein the dry powder formulation is present in two blister pockets, and wherein each of the two blister pockets contains a pre-metered dose of 0.75 mg of the compound of Formula (I) to administer simultaneously.

28. The method of claim 26, wherein the dry powder formulation is present in a single blister pocket that contains a pre-metered dose of 0.5 mg of the compound of Formula (I).

29. The method of any one of the preceding claims, wherein the method reduces the human subject’s respiratory tract symptom (LRTS) score and / or upper respiratory tract symptom (URTS) score after the treatment starts.

30. The method of claim 29, wherein the LRTS score and / or URTS score is reduced by at least 40%.

31. The method of any one of the preceding claims, wherein the compound of Formula (I) is administered in combination with one or more doses of a mild or moderate CYP3A4 inhibitor.

32. The method of any one of claims 1 to 6 and 21 to 31, wherein the inhalation is oral inhalation.

33. A compound for use in treating a human rhino virus (HRV) infection in a human subject, wherein the compound is used at a dose of about 0.1 mg, about 0.5 mg, or about 1.5 mg and is of Formula (I):or a pharmaceutically acceptable salt thereof, wherein the compound is in a dry powder formulation for inhalation, and wherein the human subject has a disease caused or exacerbated by the HRV infection.

34. Use of a compound for the manufacture of a medicament for the treatment of a human rhino virus (HRV) infection in a human subject, wherein the compound is used at a dose of about 0.1 mg, about 0.5 mg, or about 1.5 mg and is of Formula (I):or a pharmaceutically acceptable salt thereof, wherein the compound is in a dry powder formulation for inhalation, and wherein the human subject has a disease caused or exacerbated by the HRV infection.

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