WO2010009288A1

WO2010009288A1 - Compositions and uses of antiviral active pharmaceutical agents

Info

Publication number: WO2010009288A1
Application number: PCT/US2009/050794
Authority: WO
Inventors: Jonathan S. Sadeh; Heribert W. Staudinger
Original assignee: Schering Corporation
Priority date: 2008-07-17
Filing date: 2009-07-16
Publication date: 2010-01-21
Also published as: TW201016215A; AR072815A1

Abstract

Several embodiments of the present invention provide for a method of treating, reducing or minimizing asthma exacerbations in humans that are PCR+ for a rhinovirus, which includes orally inhaling or intranasally administering a therapeutically effective amount of pleconaril.

Description

COMPOSITIONS AND USES OF ANTIVIRAL ACTIVE

PHARMACEUTICAL AGENTS

FIELD OF THE INVENTION

[0001] The present invention relates to treatment, reduction, minimization or prevention of asthma exacerbations in patients by orally inhaling or intranasally administering an antiviral active pharmaceutical agent.

BACKGROUND OF THE INVENTION

[0002] The picornavirus family of viruses includes the rhinoviruses and enteroviruses. Rhinoviruses are the leading cause of viral respiratory infection (VRI), including the common cold. There are approximately 1 billion colds per year in the United States (US). ^<2) The age distribution of patients with the common cold skews toward younger persons. Adults average two to four colds a year, although the range varies widely. Women, especially those age 20 to 30 years, have more colds than men, probably because of their closer contact with children. On average, individuals older than 60 years experience less than one cold per year. Colds are most prevalent among younger children, who experience about six to ten colds per year.

[0003] Pleconaril is an antiviral active pharmaceutical agent that selectively inhibits picornaviruses by preventing these viruses from uncoating once inside the cell; pleconaril also prevents some picornaviruses from attaching to host cells by integrating into a specific hydrophobic site within the viral capsid. Currently there are no other compounds on the market with the same mechanism of action as pleconaril.

[0004] Pleconaril is known as 1 ,2,4-oxadiazole3-[3,5-Dimethyl-4-[3-(3-methyl-

5-isoxazolyl)propoxyJphenyl]-5-(trifluoromethyl). It has other names such as PICOVIR®, VP 63843 and Win 63843. Pleconaril is a picornavirus replication inhibitor useful in the treatment of, amongst other things, viral induced infections of the upper and lower airways, viral meningitis, and life-threatening diseases such as chronic meningoencephalitis, neonatal enteroviral disease, polio and myocarditis. According to the Merck Index, it may be prepared in accordance with U.S. Patent No. 5,464,848, which is incorporated by reference.

[0005] An oral formulation of pleconaril was developed and clinical trials were conducted with the oral formulation which confirmed the ability of pleconaril to reduce the severity and duration of common cold symptoms. Pleconaril reduced the time to resolution of cold symptoms by 25% compared to placebo, and met the predefined goal set prior to these phase III studies. Among adult patients who received 5 or 7 days of treatment with a tablet formulation, pleconaril was generally well tolerated; the most commonly reported adverse events were headache (24%), diarrhea (8%), and nausea (6%).

[0006] Asthma exacerbations may be associated with the common cold.

Asthma exacerbations include coughing, wheezing and shortness of breath. For those people that are subject to asthma exacerbations, the common cold can be particularly problematic and possibly life threatening.

[0007] Orally administered pleconaril, such as oral tablets, was studied for the prevention of asthma exacerbations. In this study asthmatic patients were given pleconaril at two dosage forms or placebo after presenting common cold symptoms. Subjects were treated for 1 week and followed for another 2 weeks with the primary end point being asthma exacerbations, defined as a 15% reduction in FEVl during the 3 week study period. Subjects were asthmatics >14 years of age with an FEVl 50-85% of predicted value, presenting with no more than 18 hours of symptoms suggestive of the common cold. Two-hundred fifty four subjects enrolled in the study. The pleconaril and placebo groups did not appear to differ in the primary efficacy endpoint. Sixty three subjects tested positive for rhinovirus and only 5 subjects experienced an asthma exacerbation, making it difficult to differentiate between the groups. Thus, it was determined that pleconaril administered orally did not have an effect on asthma exacerbations.

[0008] Thus, there is a need for a method or composition that is able to prevent, reduce, treat or minimize asthma exacerbations in humans that have a picornavirus, such as the rhino virus.

SUMMARY OF THE INVENTION

[0009] It has been surprisingly found that antiviral active pharmaceutical agents when administered via oral inhalation or intranasally have a significant effect on asthma symptoms. In particular, it has been found that inhalation of an anti-rhinoviral active pharmaceutically active agent, such as pleconaril, is effective at preventing, treating, reducing or minimizing asthma related symptoms such as asthma exacerbations associated with viral or cold symptoms.

[0010] Several embodiments of the present invention provide for methods of treating, reducing or minimizing asthma exacerbations in patients that are PCR+ for a rhinovirus, comprising intranasally administering a therapeutically effective amount of pleconaril to the patient. Typical patients in need of such treating, reducing or minimizing asthma exacerbations include those patients that have a history of or are prone to asthma exacerbations. Pleconaril can be administered by a nasal spray, nebulizer or a pressurized metered dose inhaler or any other acceptable deliver device. Therapeutically effective amount of pleconaril is an amount ranging from about 1 mg to about 600 mg; from about 1 mg to about 100 mg from about 10 mg to about 50 mg; from about 20 to about 30 mg; or about 24 mg.

[0011] In various embodiments of the present invention, pleconaril treated patients that are PCR+ for the rhinovirus are three times less likely to have an asthma exacerbation than patients that are PCR- for the rhinovirus. Thus, various methods of the present invention provide for a three times reduction in the likelihood of having an asthma exacerbation in patients that PCR+ for the rhinovirus than patients that are PCR- for the rhinovirus.

[0012] The exacerbation is either diagnosed by a physician or as a significant change in the asthma control questionnaire (ACQ) which is made up of 6 questions which assess changes in subjective symptoms during the day and night, increase in rescue medication use, activity limitation; changes in lung function (peak flow or FEV l) are also factored into the ACQ score.

[0013] Pleconaril may be administered at about 1.5 mg/spray; 4 sprays per nostril; two times per day. Thus, a total of 16 sprays may be administered per day. Pleconaril may be administered for a period of at least 7 days or a period of at least 14 days and may be administered once daily or twice daily.

[0014] Further embodiments provide for methods of treating, reducing or minimizing asthma exacerbations in patients that are PCR+ for a rhinovirus, comprising administering twice daily about 24 mg of pleconaril. The pleconaril may be administered by applying 4 sprays per nostril.

[0015] Still further embodiments provide for methods of treating, reducing or minimizing asthma exacerbations in a patient that is PCR+ for a rhinovirus, comprising administering an orally inhaled therapeutically effective amount of pleconaril to the patient. Patients in need of such treating, reducing or minimizing asthma exacerbations are typically those patients that have a history of or are prone to asthma exacerbations. Pleconaril nasal spray, given as prophylaxis, has a meaningful effect on asthma symptoms and lung function. The pleconaril can be administered by a dry powder inhaler, nebulizer or a pressurized metered dose inhaler.

[0016] For oral inhalation, the amount of a pleconaril dose per day is from about 200 mg to about 500 mg; from about 300 mg to about 400 mg; from about 350 mg to about 450 mg; or about 400 mg. For oral inhalation administration, pleconaril may be administered either two times per day or three times per day.

[0017] Various other embodiments provide for methods of treating, reducing or minimizing asthma exacerbations in patients that are PCR+ for a rhinovirus, comprising orally inhaling or intranasally administering a therapeutically effective amount of an anti-rhinovirus active pharmaceutical agent to a patient in need of such treating, reducing or minimizing asthma exacerbations. These methods are useful for patients that have a history of or are prone to asthma exacerbations.

[0018] Various embodiments of the present invention will result in the prevention, reduction of treatment or minimization of symptoms or exacerbations associated with chronic obstructive pulmonary disease (COPD) in PCR+ subjects.

[0019] Additional embodiments provide compositions useful in treating, reducing or minimizing asthma exacerbations in patients that are PCR+ for a rhinovirus, wherein the compositions comprise a therapeutically effective amount of pleconaril in an amount ranging from about 1 mg to about 600 mg. Further embodiments provide a drug product that comprises a nasal spray, dry powder inhaler, nebulizer or a pressurized metered dose inhaler and the pleconaril composition.

[0020] Several embodiments of the present invention provide for a method of treating, reducing or minimizing asthma exacerbations in humans that are PCR+ for the rhinovirus, which includes administering an inhaled composition that comprises a therapeutically effective amount of pleconaril. The human subjects may be prone to, susceptible to or have a history of asthma symptoms and/or asthma exacerbations. The composition may be intranasally or orally inhaled. The composition may be in a formulation that can be administered by a nasal spray, dry powder inhaler, nebulized or a pressurized metered dose inhaler. Pleconaril may be in a present in a range from about 1 mg to about 600 mg or from about 200 mg to about 400 mg. [0021] Other embodiments provide for a method of treating, reducing or minimizing asthma exacerbations in patients that are PCR+ for the rhinovirus that includes administering twice daily an inhaled composition that comprises a therapeutically effective amount of pleconaril in an amount in the range from about 1 mg to about 600 mg. Further embodiments provide for a method of treating, reducing or minimizing asthma exacerbations in patients that are PCR+ for the rhinovirus, which includes administering twice daily an intranasally inhaled composition that comprises a therapeutically effective amount of pleconaril in an amount in the range from about 1 mg to about 600 mg.

[0022] Still further embodiments, have a method of treating, reducing or minimizing asthma exacerbations in patients that are PCR+ for the rhinovirus, comprising administering twice daily an orally inhaled composition that comprises a therapeutically effective amount of pleconaril in an amount in the range from about 1 mg to about 600 mg. Other embodiments provide a method of treating, reducing or minimizing asthma exacerbations in patients that are PCR+ for the rhinovirus, including administering twice daily an inhaled composition that includes a therapeutically effective amount of pleconaril for a period of at least 7 days.

[0023] Still further embodiments provide a method of treating, reducing or minimizing asthma exacerbations in patients that are PCR+ for the rhinovirus, by administering an inhaled composition that comprises a therapeutically effective amount of an anti-rhinovirus active pharmaceutically agent.

[0024] Additional embodiments provide a composition useful in treating, reducing or minimizing asthma exacerbations in patients that are PCR+ for a rhinovirus, which includes administering an inhaled composition that comprises a therapeutically effective amount of pleconaril is an amount ranging from about 1 mg to about 600 mg or an amount ranging from about 200 mg to about 400 mg. The composition may be in a formulation that can be administered by a nasal spray, dry powder inhaler or a pressurized metered dose inhaler. BRIEF DESCRIPTION OF DRAWINGS

[0025] FIGURE 1 FEVl Changes from Baseline

[0026] FIGURE 2 Total Asthma Symptom Score

[0027] FIGURE 3 Asthma Exacerbations in PCR+ and PCR- subjects

DETAILED DESCRIPTION

[0028] In contrast to earlier studies, it has been surprisingly found that an antiviral active pharmaceutical agent when administered as an inhalation product has a significant effect on asthma symptoms. The antiviral active pharmaceutical agent may be an anti-picornavirus agent, such as an anti-rhinovirus agent. In particular, it has been found that inhalation of an anti-rhinovirus active pharmaceutically active agent, such as pleconaril, is effective at treating, reducing and minimizing asthma related symptoms such as asthma exacerbations associated with viral or cold symptoms. More particularly, it has been found that inhalation of pleconaril is useful for the prevention, treatment, reduction or minimization of exacerbation of symptoms associated with asthma.

[0029J Thus, various embodiments of the present invention provide for methods of preventing, treating, reducing or minimizing asthma symptoms such as asthma exacerbations by administering by inhalation or intranasally a formulation that includes an therapeutically effective amount of pleconaril.

[0030] Populations that can be treated according to the present invention include subjects 12 years and older, 6 years of age and older as well as subjects less than 6 years old. Various embodiments of the present invention also provide for the common cold in adults and children.

[0031] Various embodiments of the present invention may be used in the prevention, reduction treatment or minimization of asthma exacerbations associated with the common cold.

[0032] Desirably, various embodiments of the present invention may result in the prevention, reduction treatment or minimization of symptoms or exacerbations associated with chronic obstructive pulmonary disease (COPD) in PCR+ subjects. [0033] Useful treatment regimens include once daily or twice daily dosing. The treatment may last as long as necessary, such as at least 3 days, at least 5 days, at least 7 days, or about 5 days or about 7 days or about 10 days or about 14 days. A dosing regimen may be twice daily (BID) for 7 to 14 days or 7 days.

[0034] Various embodiments of the present invention may advantageously result in reduced rescue therapy utilization, fewer physician and emergency room visits, improved asthma control and reduced hospitalization.

[0035] Pleconaril may be administered in an amount ranging from about 1 mg to about 600 mg in single or multiple doses daily.

[0036] For oral inhalation, the amount of a pleconaril dose per day is from about 200 mg to about 500 mg; from about 300 mg to about 400 mg; from about 350 mg to about 450 mg;or about 400 mg. For oral inhalation administration, pleconaril may be administered either two times per day or three times per day. Useful oral administration devices include a dry powder inhaler (DPI), metered dose inhaler (MDI) or a nebulizer.

[0037] For intranasal administration, the amount of a pleconaril dose per day is about 1 mg to about 100 mg; from about 10 mg to about 50 mg; from about 20 to about 30 mg; or about 24 mg. Pleconaril may be administered at about 1.5 mg/spray; 4 sprays per nostril; two times per day. Thus, a total of 16 sprays are administered per day.

[0038] The phrase "therapeutically effective amount" means that amount of the pleconaril and one or more pharmaceutically active agents which provides a therapeutic benefit in the treatment or management of the disease or disease states. [0039] The term "patients" means any subject that may be administered an active pharmaceutical agent, such as pleconaril, and is not limited to subjects that may have or display symptoms of an illness or disease.

[0040] Various dosage forms may be used. Dosage form refers to the administrable form of a composition provided in a measured or unit amount, and includes at least one therapeutic agent in association with one or more other excipients comprising a delivery system, for example, a carrier, a diluent, and a coloring agent. Examples of dosage forms include gels, nasal sprays, nasal drops, creams, powders, a measured amount of aerosol presented for inhalation, and a measured amount of liquid.

[0041] Administration may be accomplished utilizing a device selected from a nebulizer, a metered pump-spray device, dry powder inhaler and a pressurized metered dosing inhaler. A single pressurized metered dose inhaler may be adapted for nasal inhalation routes simply by switching between an actuator that is designed for nasal delivery and an actuator designed for oral delivery. The type of device to deliver pleconaril will depend on the type of targeted inhalation. Useful devices desirably provide consistent measured amounts of aerosolized pharmaceutical compositions thereof for delivery to the oral airway passages and lungs by oral inhalation or intranasally by inhalation.

[0042] Any suitable pump spray may be used, such as pump sprays used for

NASONEX ® as sold by Schering-Plough or AFRIN ® as sold by Schering-Plough. Aqueous compositions, such as those useful in nasal sprays, may contain, inter alia, water, auxiliaries and/or one or more of the excipients, such as: suspending agents, e.g., microcrystalline cellulose, sodium carboxymethylcellulose, hydroxpropyl-methyl cellulose; humectants, e.g. glycerin and propylene glycol; acids, bases or buffer substances for adjusting the pH, e.g., citric acid, sodium citrate, phosphoric acid, sodium phospate as well as mixtures of citrate and phosphate buffers; surfactants, e.g. polysorbate 80; and antimicrobial preservatives, e.g., benzalkonium chloride, phenylethyl alcohol and potassium sorbate. [0043] Useful devices include pressurized metered-dose inhalers ("MDI") which deliver aerosolized particles suspended in chlorofluorocarbon propellants such as CFC- 1 1 , CFC- 12, or the non-chlorofluorocarbons or alternate propellants such as the fluorocarbons, HFC- 134A or HFC-227 with or without other excipients. As is known to one of skill in the art, the product may contain two interchangeable actuators. For instance, it could contain one actuator for nasal administration and one actuator for oral administration.

[0044] In another embodiment of the present invention, the delivery device may comprise two interchangeable actuators, respectively, for both oral and nasal delivery to treat both the oral and nasal sites of viral activity. A typical actuator for nasal delivery may be circular with an orifice diameter of about one millimeter. An actuator for use in oral delivery can be enclosed within a mouthpiece and the actuator typically has an orifice diameter of about 0.5 millimeters.

[0045] Useful formulations may also be administered via a dry powder inhaler, such as the TWISTHALER ® by Schering-Plough and is described in US 6,240,918, which is incorporated herein in its entirety.

[0046] Useful formulations may also be administered via a nebulizer device.

Typical commercial nebulizer devices produce dispersions of droplets in gas streams by one of two methods. Jet nebulizers use a compressed air supply to draw up a fluid by venturi action and introduce it into a flowing gas stream, after which the fluid is caused to impact one or more stationary baffles to remove excessively large droplets. Ultrasonic nebulizers use an electrically driven transducer to subject a fluid to high- frequency oscillations, producing a cloud of droplets which can be entrained in a moving gas stream; these devices are less preferred for delivering suspensions. There are hand-held nebulizers which atomize the fluid with a squeeze bulb air supply, but the more widely used equipment incorporates an electrically powered compressor or connects to a cylinder of compressed gas. Although the various devices which are commercially available vary considerably in their delivery efficiency for a given medicament, they all are useful for the treatment of the present invention; it is necessary for the prescriber to specify an exact amount of medicament formulation which is to be charged to each particular device, since their respective outputs of respirable droplets are far from identical.

[0047] Suspension formulations suitable for nebulization contain solid particles of a respirable size (e.g., preferably averaging less than about 5 microns in the largest dimension and more preferably averaging less than about 2 microns) and desirably maintain their suspended particle size distribution during storage. In addition, the particle-containing droplets formed during nebulization of the formulations desirably have appropriate sizes for deposition in the desired area of the respiratory system.

[0048] Also available are hand-held nebulizers which atomize a liquid with a squeeze bulb air supply, but the more widely used equipment incorporates an electrically powered compressor or connects to a cylinder of compressed gas. Although the various devices which are commercially available vary considerably in their delivery efficiency for a given medicament since their respective outputs of respirable droplets are far from identical, any may be used for delivery of the medicaments of the present invention when a prescriber specifies an exact amount of medicament formulation which is to be charged to each particular device.

[0049] Suitable medicaments that may be added to the compositions of various embodiments of the present invention include, but are not limited to, antivirals, antihistamines, such as histamine H₁, H₂, H₃ receptor antagonists, expectorants, nonsteroidal anti-inflammatory agents, anti-cholinergics, pharmaceutically acceptable zinc salts, antibiotics, leukotriene D₄ antagonists, leukotriene inhibitors, P₂Y agonists, syk kinase analogues, echinaceia, vitamin C, and vitamin E. For instance, the formulation may contain pleconaril in combination with a decongestant or a corticosteroid. Pleconaril with the additional active pharmaceutically agent may be administered concurrently or sequentially, i.e. they may be administered in combination either concurrently or by the sequential administration of the ingredients in a suitable order.

[0050] The compositions may contain any of a number of optional components, such as humectants, preservatives, antioxidants, chelating agents and aromatic substances. Humectants, which are hygroscopic materials such as glycerin, a polyethylene or other glycol, a polysaccharide and the like act to inhibit water loss from the composition and may add moisturizing qualities. Useful aromatic substances include camphor, menthol, eucalyptol and the like, and fragrances. Preservatives are typically incorporated to establish and maintain a freedom from pathogenic organisms; representative components include benzyl alcohol, methylparaben, propylparaben, butylparaben, chlorobutanol, phenethyl alcohol (which also is a fragrance additive), phenyl mercuric acetate and benzalkonium chloride.

[0051] The foregoing descriptions of various embodiments of the invention are representative of various aspects of the invention, and are not intended to be exhaustive or limiting to the precise forms disclosed. Many modifications and variations undoubtedly will occur to those having skill in the art. It is intended that the scope of the invention shall be fully defined solely by the appended claims.

EXAMPLE

[0052] The following example demonstrates the surprising usefulness of pleconaril when administered via inhalation to subjects that are PCR+. The target end point on the trial was post-exposure prophylaxis of the common cold to reduce the incidence of asthma exacerbations in adults and children (6 years and over).

[0053] A proof-of-concept study was conducted to evaluate a pleconaril containing nasal spray in asthmatic subjects with a history of presumed upper respiratory infection (URI) induced asthma exacerbations in the past two years. The primary objective of the study was to assess the efficacy of pleconaril nasal spray in preventing asthma exacerbation and common cold symptoms in asthmatic subjects exposed to a household member exhibiting symptoms consistent with a picornavirus respiratory infection.

[0054] A total of 31 1 subjects were randomized to this study (pleconaril group,

154 subjects and placebo group, 157 subjects); 129 men and 182 women; aged 6 to 65. Subjects were enrolled in the summer/fall seasons when they were asymptomatic and followed until they were exposed to a household member with cold symptoms. Once exposed, subjects would be randomized to drug or placebo, which they already had in their possession and thus could start taking a pleconaril nasal spray immediately. The pleconaril nasal spray had about 1.5 mg/spray. Each subject receiving pleconaril administered 4 sprays per nostril; two times per day. Thus, a total of 16 sprays are administered per day and about 24 mg of pleconaril were administered.

[0055] The rate of asthma exacerbations, which were defined as a change in asthma regimen by a physician or a significant change in the ACQ score (Asthma Control Questionnaire). Subjects were also tested as being PCR+ or PCR- for the rhino virus. [0056] For disorders of the lower airways, the severity of the disease state in a patient can be quantified by objective pulmonary function tests, including a measurement of the subjects' forced expiratory volume in 1 second (FEVi). When this result is about 65 to 79 percent of the predicted value (determined using a formula that takes into account the patient's age, sex, race and size), the airway obstruction is considered to be mild. For an FEVi value about 50 to 64 percent of predicted, the airway obstruction is classified as moderate; if the value is less than 50 percent of predicted, the airway obstruction is considered to be severe; and if the value is less than 30 percent the airway obstruction is considered to be very severe.

RESULTS

[0057] A difference between the groups was seen in terms of asthma symptoms and lung function when all randomized patients were evaluated. In both treatment groups, the FEVl decreased at each time point it was measured. The pleconaril group, however, consistently had less of a decrease in FEVl at each time point than the placebo group. The greatest difference in FEVl occurred on Day 4 (pleconaril group 1.5% and placebo group 5.1 %, p=0.035), see FIGURES 1 -3.

[0058] Most of the efficacy was seen in subjects who were PCR+ for rhinovirus. In particular, the PCR positive pleconaril-treated subjects had fewer asthma exacerbations. More particularly, the pleconaril treated patients that are PCR+ for the rhinovirus were three times less likely to have an asthma exacerbation than patients that are PCR- for the rhinovirus.

[0059] Pleconaril nasal spray had a meaningful effect on asthma symptoms and lung function. In particular, pleconaril nasal spray, given as prophylaxis, has a meaningful effect on asthma symptoms and lung function. Pleconaril improves asthma symptoms and lung function compared to placebo. Such efficacy was observed regardless of the efficacy of pleconaril on cold symptoms. The efficacy was observed in the fall (during peak rhinovirus season), in PCR+ patients and during the first week U

of treatment. Pleconaril was extremely safe and well tolerated. The study showed there was a meaningful reduction in asthma symptoms and lung function in subjects treated with pleconaril nasal spray.

Claims

WHAT IS CLAIMED IS:

1. A method of treating, reducing or minimizing asthma exacerbations in patients that are PCR+ for a rhinovirus, comprising intranasally administering a therapeutically effective amount of pleconaril to the patient.

2. The method of claim 1 , wherein the pleconaril is administered by a nasal spray.

3. The method of claim 1 , wherein the pleconaril is administered by a pressurized metered dose inhaler.

4. The method of claim 1 , wherein the therapeutically effective amount of pleconaril per day is an amount ranging from about 1 mg to about 600 mg.

5. The method of claim 1, wherein the therapeutically effective amount of pleconaril per day is an amount ranging from about 1 mg to about 100 mg.

6. The method of claim 1 , wherein the therapeutically effective amount of pleconaril per day is an amount ranging from about 10 mg to about 50 mg.

7. The method of claim 1, wherein the therapeutically effective amount of pleconaril per day is an amount ranging from about 20 to about 30 mg.

8. The method of claim 1, wherein the therapeutically effective amount of pleconaril per day is about 24 mg.

9. The method of claim 1, wherein the method provides a three times reduction in the likelihood of having an asthma exacerbation in patients that PCR+ for the rhinovirus than patients that are PCR- for the rhinovirus.

10. The method of claim 1, wherein the composition is administered for a period of at least 7 days.

1 1. The method of claim 1, wherein the composition is administered for a period of at least 14 days.

12. The method of claim 1 , wherein the composition is administered twice daily.

13. A method of treating, reducing or minimizing asthma exacerbations in patients that are PCR+ for a rhinovirus, comprising administering twice daily about 24 mg of pleconaril.

14. The method of claim 13; wherein the pleconaril is administered by applying 4 sprays per nostril twice daily.

15. A method of treating, reducing or minimizing asthma exacerbations in a patient that is PCR+ for a rhinovirus, comprising administering an orally inhaled therapeutically effective amount of pleconaril to the patient.

16. The method of claim 15, wherein the pleconaril is administered by a dry powder inhaler.

17. The method of claim 15, wherein the pleconaril is administered by a pressurized metered dose inhaler.

18. The method of claim 15, wherein the therapeutically effective amount of pleconaril is an amount ranging from about 1 mg to about 600 mg.

19. The method of claim 15, wherein the therapeutically effective amount of pleconaril is an amount ranging from about 200 mg to about 500 mg.

20. The method of claim 15, wherein the therapeutically effective amount of pleconaril is an amount ranging from about 300 mg to about 400 mg.

21. The method of claim 15, wherein the therapeutically effective amount of pieconaril is an amount ranging from about 350 mg to about 450 mg

22. The method of claim 15, wherein the therapeutically effective amount of pleconaril is about 400 mg.

23. The method of claim 15, wherein the composition is administered three times daily.

24. A method of treating, reducing or minimizing asthma exacerbations in patients that are PCR+ for a rhinovirus, comprising orally inhaling or intranasally administering a therapeutically effective amount of an anti-rhinovirus active pharmaceutical agent to a patient in need of such treating, reducing or minimizing asthma exacerbations.

25. The method of claim 24, wherein the patient has a history of or is prone to asthma exacerbations.