US20110117213A1 - Treatment of acute exacerbation of asthma and reduction of likelihood of hospitalization of patients suffering therefrom - Google Patents

Treatment of acute exacerbation of asthma and reduction of likelihood of hospitalization of patients suffering therefrom Download PDF

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US20110117213A1
US20110117213A1 US12/948,545 US94854510A US2011117213A1 US 20110117213 A1 US20110117213 A1 US 20110117213A1 US 94854510 A US94854510 A US 94854510A US 2011117213 A1 US2011117213 A1 US 2011117213A1
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patient
administered
acute
fev
soc
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Kazuko Matsuda
Yuichi Iwaki
Kirk W. Johnson
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Medicinova Inc
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Medicinova Inc
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Assigned to MEDICINOVA, INC. reassignment MEDICINOVA, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: IWAKI, YUICHI, MATSUDA, KAZUKO, JOHNSON, KIRK W.
Publication of US20110117213A1 publication Critical patent/US20110117213A1/en
Priority to US13/525,181 priority patent/US8420697B2/en
Priority to US13/789,464 priority patent/US20140056999A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
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    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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Definitions

  • This invention relates to a method of treating severe episodes of asthma, preventing the manifestations of severe and long-lasting episodes of asthma from worsening, and reducing the likelihood of hospitalization (or other adverse clinical outcomes) of patients suffering from severe and long-lasting episodes of asthma, including without limitation, acute exacerbation of asthma.
  • this therapeutic approach with MN-221 provides additional bronchodilation and improved clinical outcomes including reduced hospitalization when used adjunctively to (that is, in combination with) recognized standard respiratory care for acute asthma exacerbations (i.e., nebulized albuterol, nebulized ipratropium, corticosteroids).
  • This invention is particularly well-suited for patients who fail to respond to this standard acute respiratory care or simply “standard of care” treatment regimen.
  • Acute exacerbation of asthma (AEA) or status asthmaticus is a long-lasting and severe asthma episode that is typically not responsive to bronchodilator or corticosteroid therapy.
  • An AEA may be diagnosed, for example and without limitation, by the symptoms of dyspnea and bronchospasm. Patients often experience progressively worsening breathlessness, cough, wheezing, and chest tightness, or some combination of these symptoms of AEA.
  • SOC Current standard of care
  • ⁇ -agonists e.g., albuterol
  • anticholinergics ipratropium
  • intravenous or oral corticosteroids e.g., prednisone and methylprednisolone
  • IV intravenous
  • IV or subcutaneous (SC) adrenoceptor agonists e.g., epinephrine in adults and terbutaline in children
  • IV aminophylline may also be administered, but are not generally recommended at least for adults according to the current NAEPP Asthma Guidelines (2007). See; also, S. C.
  • epinephrine or terbutaline should be considered in patients unresponsive to continuous nebulized ⁇ 2 -agonists, and in those patients unable to cooperate due to alteration of mental status or an inability to tolerate inhaled therapy.
  • Epinephrine may also be delivered in intubated patients not responding to inhaled therapy during mechanical ventilation.
  • Subcutaneously, 0.3-0.5 mL (1:1000) of epinephrine can be administered every 20 min. to a maximum of three doses.
  • Terbutaline can be administered subcutaneously (0.25-0.5 mg) and is the preferred treatment in pregnant females.
  • Intravenous infusion of terbutaline starting at 0.05-0.10 ⁇ g/kg per min has been utilized predominantly in pediatric patients. It may be considered in the treatment of patients with no response to inhaled or subcutaneous treatment, and in whom respiratory arrest is imminent, or in patients not adequately ventilated despite optimal setting of the ventilator.
  • a recent double blind, randomized controlled trial by Bogie et al. Pediatric Emergency Care (2007) 23(6) evaluated the benefit of intravenous terbutaline in 49 nonventilated children with acute severe asthma who were already on continuous high-dose nebulized albuterol. Although the use of intravenous terbutaline was associated with improvement in the clinical asthma severity score over the first 24 h, shorter use of continuous nebulized albuterol, and shorter ICU stay, the differences were not statistically significant.
  • the Applicants have identified novel methods for the treatment of severe asthma attacks, including AEA, especially in patients who fail to respond to current SOC.
  • AEA bronchodilation and the reduced hospitalization of patients suffering from such attacks can be achieved by administering MN-221 or pharmaceutically acceptable salts thereof (collectively, Active Agent, as described further below).
  • Active Agent is particularly beneficial in treating patients suffering from an acute severe respiratory attack could not have been predicted from the clinical experience of those of ordinary skill in the art using known beta-agonists.
  • a highly ⁇ 2 -selective adrenoceptor agonist in conjunction with a standard of care treatment regimen and thus preventing the manifestations of severe and long-lasting episodes of asthma from worsening, and reducing the likelihood of hospitalization of patients suffering from severe and long-lasting episodes of asthma, including without limitation, acute exacerbation of asthma.
  • methods for selecting patients that are likely or unlikely to undergo such treatment are also provided herein.
  • the present invention provides a method of treating AEA, comprising administering an effective amount of the Active Agent to a patient in need of such treatment.
  • the invention also provides novel methods of reducing the likelihood of hospitalization (e.g., a reduced hospitalization rate or a reduced stay in an intensive care unit) and/or worsening of one or more manifestations of AEA in a patient suffering from AEA comprising administering an effective amount of the Active Agent to such patient.
  • other methods of the present invention comprise determining that a patient is suffering from a long-lasting and severe asthma episode that is not responsive to initial standard of care treatment and administering to the patient an effective amount of the Active Agent.
  • the Active Agent is administered parenterally, more preferably, intravenously.
  • the Active Agent (MN-221 a/k/a bedoradrine or its pharmaceutically acceptable salts) administered intravenously allows it to distribute and partition into the congested lung tissue of AEA patients and allow bronchodilation without undue cardiovascular side effects.
  • the present invention provides a method of treating AEA by administering an effective amount of the Active Agent to a patient in need of such treatment wherein the AEA or one or more manifestations of the AEA are non-responsive or substantially non-responsive to treatment with SOC.
  • the present invention provides a method of treating a severe and long-lasting episode of asthma by administering an effective amount of the Active Agent to a patient in need of such treatment, wherein the severe and long-lasting episode of asthma or one or more manifestations of it are non-responsive or substantially non-responsive to treatment with SOC.
  • the Active Agent administered is MN-221 or pharmaceutically acceptable salts thereof.
  • patients suffering from AEA for example, those admitted to an emergency room because of an acute exacerbation of asthma
  • MN-221 in addition to having been treated with SOC
  • the hospitalization rate among those patients who were treated with SOC only was 54 percent (7 of 13, roughly half), compared to a hospitalization rate of 25 percent (4 of 16, roughly a quarter) among those patients who were treated with MN-221 and with SOC, demonstrating improved breathing ability (see, FIG. 1 ) and about a 50 percent reduction in hospitalization rate among AEA patients who were also treated with MN-221.
  • the invention also provides novel methods of reducing the likelihood of hospitalization of patients suffering from AEA, who are non-responsive to SOC.
  • the likelihood of hospitalization of a patient suffering from an acute exacerbation of asthma treated with MN-221 alone or in combination with SOC falls to substantially less than half or fifty percent, preferably, to about a quarter (or twenty-five percent) of all patients suffering from an acute respiratory attack.
  • FIG. 1 shows the improvement over baseline of FEV 1 between patients being treated with placebo and SOC versus patients being treated with a combination of SOC and MN-221.
  • FIG. 2 shows the absence of an adverse change in heart rate for patients receiving placebo and SOC versus patients receiving a combination of MN-221 and SOC.
  • FIG. 3 depicts the heart rate of dogs receiving vehicle, albuterol and three dosage levels of MN-221 adjunctive to albuterol.
  • the invention provides a method of improving one or more clinical outcomes of an individual experiencing an acute respiratory attack.
  • the acute respiratory attack is severe and usually requires that the individual present himself or herself to an emergency department (i.e., emergency room) of a hospital.
  • An acute respiratory attack may include an acute reversible bronchospasm, a severe acute bronchospasm, or an acute exacerbation of asthma.
  • the inventive method comprises administering to an individual suffering from an acute respiratory attack an effective amount of bedoradrine or a pharmaceutically acceptable salt thereof in combination with a standard of care (SOC) treatment regimen.
  • the bedoradrine or a pharmaceutically acceptable salt thereof can be administered after administration of the SOC treatment regimen, contemporaneously with the SOC treatment regimen, or before administration of the SOC treatment regimen.
  • a SOC treatment regimen comprises administration of one or more ⁇ -agonist bronchodilators, one or more anti-cholinergic drugs, one or more corticosteroids, or combinations thereof.
  • the SOC treatment regimen may also includes the
  • the one or more ⁇ -agonist bronchodilators, or one or more anti-cholinergic drugs are administered by inhalation, injection, or intravenous infusion.
  • the one or more ⁇ -agonist bronchodilators may be selected from albuterol, bitolterol, levalbuterol, pirbuterol, epinephrine, terbutaline, formoterol, or salmeterol, whereas the one or more anti-cholinergic drugs may, in turn, be selected from ipratropium or tiotropium.
  • the one or more corticosteroids may be selected from prednisone, methylprednisolone, or prednisolone.
  • the bedoradrine or a pharmaceutically acceptable salt thereof may be administered by any suitable route, but more preferably, intravenously, orally, or by inhalation.
  • the amount of bedoradrine or a pharmaceutically acceptable salt thereof administered to an individual typically falls in the range of 100 to 5,000 ⁇ g. More preferably, about 500 to about 1,500 ⁇ g of bedoradrine or a pharmaceutically acceptable salt thereof is administered intravenously over a period of about 5 to about 120 minutes.
  • the invention provides for one or more improved clinical outcomes.
  • Such improved clinical outcomes may include an increase in FEV 1 , a reduction in likelihood of hospitalization, an improvement in dyspnea scores, a reduction in incidence of intubation, a reduction in length of stay in an intensive care unit and an improvement in self-ambulation unaccompanied by respiratory distress.
  • the FEV 1 improves by 5% or more, 10% or more, or 15% or more.
  • the likelihood of hospitalization of an individual receiving the claimed combination (i.e., MN-221 plus SOC) treatment is reduced compared with an individual receiving only the SOC treatment regimen.
  • placebo is mentioned in this disclosure in combination with SOC, what it is meant is that an individual simply continues to receive the SOC treatment regimen and no test drug, such as MN-221 or a pharmaceutically acceptable salt thereof.
  • the likelihood of hospitalization of an individual receiving the claimed combination treatment is reduced to about 25% or less, about 20% or less, or about 15% or less.
  • An individual who will tend to benefit from the administration of bedoradrine or its pharmaceutically acceptable salt is an individual who is not responsive to an inhaled ⁇ -agonist bronchodilator, most typically albuterol. Such an individual is likely to experience an improvement from the acute respiratory attack for about 1 hour or more, about 2 hours or more, about 3 hours or more, about 4 hours or more, about 5 hours or more, about 6 hours or more, or about 8 hours or more after the claimed combination treatment.
  • the nature of the improvement may typically manifest itself in the form of an improvement in FEV 1 (L), FEV 1 (% predicted), PEFR, arterial blood oxygen saturation, respiratory rate, or combinations thereof after the claimed combination treatment, unaccompanied by one or more clinically observable adverse events.
  • Such clinically observable adverse events may include, but are not limited to, an increased heart rate, an increased blood glucose, tremor, headache, palpitations, or a jittery feeling.
  • the invention is also directed to a method of alleviating one or more negative effects of an acute respiratory attack selected from the group consisting of acute reversible bronchospasm, severe acute bronchospasm and acute exacerbation of asthma, comprising administering to a patient, who has been diagnosed as suffering from either acute reversible bronchospasm, severe acute bronchospasm, or acute exacerbation of asthma, an effective amount of bedoradrine or a pharmaceutically acceptable salt thereof. More specifically, the patient suffers from an acute, severe asthma attack, otherwise known as an acute exacerbation of asthma.
  • Target patients of the invention will be those who typically fail to respond to an SOC treatment regimen.
  • Such a patient experiences improved FEV 1 relative to the patient's pre-treatment FEV 1 and the improved FEV 1 persists on average for at least about 6 hours at a level that is about 50% or more of a peak effect.
  • a preferred daily amount of bedoradrine or a pharmaceutically acceptable salt thereof administered to a patient falls in the range of about 300 to 1500 ⁇ g.
  • Active Agent refers to an agent selected from the group consisting of MN-221, the free base form of MN-221, other pharmaceutically acceptable salts of the MN-221 free base (e.g., organic or inorganic acid addition salts), their pharmaceutically acceptable metabolites (e.g., a carboxylic acid), and pharmaceutically acceptable salts of their metabolites.
  • administering or “Administration of” a drug to a patient (and grammatical equivalents of this phrase) includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug.
  • direct administration including self-administration
  • indirect administration including the act of prescribing a drug.
  • a physician who instructs a patient to self-administer a drug and/or provides a patient with a prescription for a drug is administering the drug to the patient.
  • Effective amount of a drug is an amount of a drug that, when administered to a patient with AEA, will have the intended therapeutic effect, e.g., alleviation, amelioration, palliation or elimination of one or more manifestations of AEA in the patient.
  • the full therapeutic effect does not necessarily occur by administration of one dose (or dosage), and may occur only after administration of a series of doses.
  • a therapeutically effective amount may be administered in one or more administrations.
  • First line treatment refers to a treatment intended as an initial treatment of AEA. When first line treatment fails or is inadequate, subsequent treatments referred to as second line treatment and third line treatment may be used.
  • Manifestation of AEA refers to a symptom, sign, physiological state (e.g., heart rate, cough, shortness of breath and/or difficulty of breathing, hypoxia, or anxiety associated with inability to breathe), or report (e.g., FEV 1 , FEV 1 %, or PEER) characteristic of a patient with AEA.
  • physiological state e.g., heart rate, cough, shortness of breath and/or difficulty of breathing, hypoxia, or anxiety associated with inability to breathe
  • report e.g., FEV 1 , FEV 1 %, or PEER
  • MN-221 refers to the sulfate salt of formula: acetamide, N,N-dimethyl-2-[[(7S)-5,6,7,8-tetrahydro-7-[[(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl)phenyl]ethyl]amino]-2-naphthalenyl]oxy], sulfate (also known as bis[2-[[(7S)-7-[[(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl)phenyl]ethyl]amino]-5,6,7,8-tetrahydronaphthalen-2-yl]oxy]-N,N-dimethylacetamide] sulfate or ( ⁇ )-bis(2- ⁇ [(2S)-2-( ⁇ (2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl)phenyl]ethyl ⁇ amino)-1,
  • MN-221 is synthesized according to methods reported in literature. See, e.g., the references Yanagi et al. Chem. Pharm. Bull . (Tokyo) (2003) 51(2):221-23 and U.S. Pat. No. 6,133,266. Without being bound by mechanism, MN-221 may possess a greater selectivity for the human ⁇ 2 receptors than ⁇ -agonists commonly used to treat acute exacerbation of asthma (i.e., albuterol, levalbuterol, terbutaline). In addition, MN-221 may act as a full agonist at ⁇ 2 -adrenergic receptors and a partial agonist at the ⁇ 1 -adrenergic receptor.
  • the MN-221 may provide bronchodilation with a reduced risk of cardiovascular complications (e.g., tachycardia, arrhythmia).
  • a pharmaceutically acceptable metabolite of MN-221 includes, without limitation, a metabolite resulting from the hydrolysis of the amide moiety.
  • a carboxylic acid, representative of a hydrolysis product, is described in U.S. Pat. No. 6,136,852, the disclosure of which is incorporated herein by reference.
  • “Reduction” of a symptom or symptoms means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
  • a reduction in a likelihood of hospitalization means a lowering of a frequency of hospitalization or a reduction in a hospitalization rate, for example, from a 50% rate to a 25% rate, or lower, such as 15% or 10%.
  • Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results.
  • beneficial or desired clinical results include, but are not limited to, reduction, alleviation or amelioration of one or more manifestations of or negative effects of an acute respiratory attack (e.g., AEA), improvement in one or more clinical outcomes, diminishment of extent of disease, delay or slowing of disease progression, amelioration, palliation or stabilization of the disease state, and other beneficial results described herein.
  • AEA acute respiratory attack
  • the present invention provides a method of treating AEA, comprising administering an effective amount of the Active Agent to a patient in need of such treatment.
  • the invention also provides novel methods of preventing hospitalization, or reducing a rate of hospitalization and/or worsening of one or more manifestations of AEA in a patient suffering from AEA comprising administering an effective amount of the Active Agent to the patient in need of such prevention.
  • other methods of the present invention comprise determining that a patient is suffering from a long-lasting and severe asthma episode that is not responsive to initial standard of care treatment and administering to the non-responsive patient an effective amount of the Active Agent.
  • the present invention provides a method of treating AEA by administering an effective amount of the Active Agent to a patient in need of such treatment wherein the AEA or one or more manifestations of the AEA are non-responsive or substantially non-responsive to treatment with SOC.
  • an effective amount of the Active Agent to a patient in need of such treatment wherein the AEA or one or more manifestations of the AEA are non-responsive or substantially non-responsive to treatment with SOC.
  • the present invention provides a method of treating a severe and long-lasting episode of asthma by administering an effective amount of the Active Agent to a patient in need of such treatment, wherein the severe and long-lasting episode of asthma or one or more manifestations of it are non-responsive or substantially non-responsive to treatment with SOC.
  • the present invention provides methods of preventing hospitalization, or reducing the likelihood of hospitalization, of a patient suffering from an AEA, comprising administering to a patient, who has been diagnosed as suffering from AEA, an effective amount of the Active Agent.
  • the patient is suffering from a long-lasting and severe asthma episode that is not responsive to initial bronchodilator, or corticosteroid, or combination therapy thereof.
  • the long-lasting and severe asthma episodes include but is not limited to persistent cough secondary to asthma, shortness of breath and/or difficulty of breathing secondary to asthma, hypoxia secondary to asthma, or anxiety associated with inability to breathe or shortness of breath that is not responsive to initial bronchodilator or corticosteroid or combination therapy thereof.
  • the Active Agent administered is MN-221.
  • the patient treated shows as a symptom of AEA, a decreases in respiratory rate.
  • the patient has been admitted to an emergency room.
  • only about 20% to about 30% and only about 40% to about 50% of the patients treated with the Active Agent are hospitalized.
  • the patient in accordance to the present invention refers to patent that is not responsive to albuterol or methylprednisolone therapy, alone or in combination with one another.
  • the present invention provides methods of improving FEV 1 , FEV 1 %, peak expiratory flow rate (PEFR) or arterial blood oxygen saturation of a patient suffering from AEA, comprising: administering to the patient an effective amount of the Active Agent.
  • FEV 1 refers to the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, and may be measured by spirometry.
  • FEV 1 % refers to FEV 1 expressed as a percentage of the vital capacity, and is an index for assessing and quantifying airflow limitations.
  • Vital capacity refers to the volume change of the lung between a full inspiration and a maximal expiration.
  • the present invention provides methods of improving FEV 1 , FEV 1 %, PEFR, or arterial blood oxygen saturation, or decreasing a respiratory rate, of a patient suffering from AEA, comprising administering to a patient, who has been diagnosed as suffering from AEA, an effective amount of the Active Agent.
  • an improvement in FEV 1 or FEV 1 % or PEFR or arterial blood oxygen saturation, or a decrease in respiratory rate is achieved without observing clinically meaningful changes in heart rate, systolic, or diastolic blood pressure, or serum potassium when such administration is coupled to other standard of care treatments for acute exacerbation of asthma.
  • the improved FEV 1 is determined in comparison with a pre-treatment FEV 1 . In another embodiment, the improved FEV 1 persists on average for at least about 5 hours at a level that is about 50% or more of a peak effect.
  • peak effect refers to the highest, post-treatment percentage improvement in average FEV 1 . In another embodiment, the improved FEV 1 persists for about 2 hours to about 12 hours, about 4 hours to about 10 hours, and for about 6 hours to about 8 hours, at a level that is about 50%, about 60%, about 70%, or more of the maximum average FEV 1 increase observed after initiating administration of the Active Agent.
  • FIG. 1 An example of improved FEV 1 of patients suffering from an acute exacerbation of asthma attack who were treated with a combination of MN-221 and SOC is graphically shown in FIG. 1 .
  • the graphical representation also includes changes from baseline FEV 1 in patients receiving only SOC (that is, “Placebo+SOC,” which means patients received continuous SOC only; “MN-221+SOC” means patients received a combination of MN-221 and SOC).
  • Placebo+SOC which means patients received continuous SOC only
  • MN-221+SOC means patients received a combination of MN-221 and SOC
  • the present invention provides a method of treating a patient suffering from an acute exacerbation of asthma comprising administering an effective amount of a pharmaceutical composition comprising a solution of MN-221 or a solution of a pharmaceutically acceptable salt of MN-221 thereby treating the patient.
  • the patient experiences an improved FEV 1 , compared to a pre-treatment FEV 1 .
  • the improved FEV 1 persists on average for at least about 5 hours at a level that is about 50% or more of a peak effect.
  • the improved FEV 1 persists for about 2 hours to about 12 hours, about 4 hours to about 10 hours, and for about 6 hours to about 8 hours, at a level that is about 50%, about 60%, about 70%, or more of the maximum average FEV 1 increase observed after initiating administration of the pharmaceutical composition.
  • the Active Agent is administered in combination with administration of SOC.
  • the Active Agents is administered to an AEA patient in combination with other agents or procedures intended to treat AEA, ameliorate symptoms of AEA, potentiate the effects of the Active Agents, or provide other therapeutic benefit.
  • Administration of an agent “in combination with” includes parallel administration (administration of both the agents to the patient over a period-of time), co-administration (in which the agents are administered at approximately the same time, e.g., within about a few minutes to a few hours of one another, such as, administration of MN-221, and albuterol, ipratropium, and/or prednisone or prednisolone on same days), and co-formulation (in which the agents are combined or compounded into a single dosage form suitable for oral, inhaled or parenteral administration).
  • the SOC thus administered in combination comprises one or more of a ⁇ -agonist, anti-cholinergic agent, and a corticosteroid.
  • the ⁇ -agonist is an inhaled ⁇ -agonist.
  • the ⁇ -agonist is albuterol.
  • the albuterol is administered at a rate of from about 5 mg/hr to about 5 mg once every 20 minutes.
  • the albuterol administration is intermittent or continuous.
  • the anticholinergic agent is ipratropium.
  • the ⁇ -agonist or the anticholinergic agent is administered employing a nebulizer or an MDI (metered dose inhaler).
  • the corticosteroid is prednisone or methylprednisolone.
  • the corticosteroid is administered orally or parenterally.
  • the present invention provides a method of treating a patient suffering from an acute exacerbation of asthma comprising administering an effective amount of a pharmaceutical composition comprising a solution of MN-221 or a solution of a pharmaceutically acceptable salt of MN-221 and administering an effective amount of an inhalable pharmaceutical composition comprising a beta-agonist other than MN-221 or a pharmaceutically acceptable salt of the beta-agonist, thereby treating the patient.
  • the beta-agonist other than MN-221 is albuterol.
  • the solution of MN-221 is administered intravenously.
  • the MN-221 is administered in a daily amount of about 600 ⁇ g to about 1200 ⁇ g.
  • the effective amount of the pharmaceutical composition comprising a solution of MN-221 or a solution of a pharmaceutically acceptable salt of MN-221 is administered over a period of about 15 minutes to about 2 hours.
  • the present invention provides a method of treating a patient suffering from an acute exacerbation of asthma comprising:
  • step (b) determining if the patient exhibits a positive or negative response to said step (a);
  • step (c) discharging the patient if the patient exhibits a positive response to said step (a);
  • step (d) administering an effective amount of an injectable pharmaceutical composition comprising a solution of MN-221 or a solution of a pharmaceutically acceptable salt thereof, if the patient exhibits a negative response to said step (a);
  • step (e) determining if the patient exhibits a positive or negative response to said step (d);
  • step (f) discharging the patient if the patient exhibits a positive response to said step (d);
  • step (g) admitting the patient to a hospital if the patient exhibits a negative response to said step (d).
  • the patient discharged in step (f) remains symptom-free on average for at least about 3 hours after discharge.
  • the patient discharged in step (f) remains symptom-free on average for at least about 5 hours after discharge.
  • FEV1 denotes forced expiry volume in 1 second, ICU, intensive care unit, PaCO 2 , partial pressure of arterial oxygen pressure, PaO 2 , partial pressure of arterial oxygen, PFE, peak expiratory flow, and SaO 2 , arterial oxygen saturation.
  • the treatment methods provided herein are part of a first line treatment. In other embodiments, the treatment methods provided herein are part of a second line treatment or part of a third line treatment.
  • the present invention provides a method of selecting a patient suffering from acute exacerbation of asthma as likely or unlikely to be suitable for treatment comprising administration of MN-221 or a pharmaceutically acceptable salt thereof, the method comprising:
  • the patient is likely to undergo treatment comprising the administration of MN-221 or a pharmaceutically acceptable salt thereof, and if the FEV 1 is >55% of the predicted value, the patient is unlikely to undergo treatment comprising the administration of MN-221 or a pharmaceutically acceptable salt thereof, thereby selecting the patient.
  • the patient is likely to undergo treatment comprising the administration of MN-221 or a pharmaceutically acceptable salt thereof.
  • the “predicted value” of FEV 1 is a measure of FEV 1 which may be calculated following well known methods based on age, height, gender and race, and observed FVC, FEV 1 , and FEF25-75% values.
  • FVC refers to forced vital capacity, which is the total volume of air that can be exhaled from the lungs during a forced expiration following a maximal inspiration.
  • FEF25-75% refers to forced expiratory flow 25-75%, which is the average expired flow over the middle half of the FVC maneuver and may be considered a sensitive measure of small airways narrowing.
  • the patient is likely to be suitable for treatment comprising administration of MN-221 or a pharmaceutically acceptable salt thereof.
  • the method further comprising administering to the patient an effective amount of a pharmaceutical composition comprising a solution of MN-221 or a solution of a pharmaceutically acceptable salt of MN-221, thereby treating the acute exacerbation of asthma.
  • the MN-221 is administered in an amount of about 600 ⁇ g/patient to about 1200 ⁇ g/patient.
  • the effective amount of the pharmaceutical composition is administered over a period of about 15 minutes to about 2 hours.
  • the beta-agonist other than MN-221 is albuterol.
  • the patient may be selected from the following pool of potential patient for practicing the methods of the present invention: they may be male or female; may have self-reported history of physician-diagnosed and treated asthma for ⁇ 3 months; and may have a diagnosis of an acute exacerbation of asthma upon presentation at the ED as defined by dyspnea, evidence of bronchospasm, and by a known history of asthma.
  • such patients may have undergone: a brief physical examination that includes checking vital signs and auscultation, and assessing accessory respiratory muscle usage and the level of dyspnea the patient is experiencing; spirometry to measure the patient's FEV 1 (expressed as % of predicted); administration of supplemental oxygen to maintain oxygen saturation as measured by pulse oximetry of ⁇ 90%; administration of two doses of inhaled beta2-agonist (e.g., and without limitation, about 5 mg of albuterol) via nebulizer (each dose given sequentially once a hour or about once every 20 minutes), simultaneously with two doses of an inhaled anti-cholinergic agent (e.g., and without limitation, 0.5 mg ipratropium) via nebulizer (each dose given sequentially once about every 20 minutes) and a dose of corticosteroid of about 60 mg given orally (prednisone) or intravenously (methylprednisolone).
  • inhaled beta2-agonist e.g., and without limitation, about 5 mg
  • the number and amount of SOC administered may be altered as will be apparent to one skilled in the art.
  • the suitable patient may also have an FEV 1 ⁇ 55% within about 10 minutes of completing the SOC treatment as described immediately above; have ECG with no dysrhythmias (except sinus tachycardia); and have no clinical or electrocardiographic signs of ischemic heart disease.
  • the SOC administered as part of selecting patients and as part of treating patients, in accordance to the present invention may include standardized care consistent with the National Asthma Education and Prevention Program (NAEPP) guidelines.
  • NAEPP National Asthma Education and Prevention Program
  • the patient may receive standardized care consistent with the National Asthma Education and Prevention Program (NAEPP) guidelines.
  • NAEPP National Asthma Education and Prevention Program
  • the patient's FEV 1 is ⁇ 55% of predicted the patient may be suitable for treatment in accordance with the present methods. Throughout the screening process, the patient may continue to receive the appropriate medical care consistent with the NAEPP guidelines for the intended treatment of acute exacerbations of asthma.
  • the patient may continue to receive one or more of the following standard treatments and assessments until the patient's FEV 1 reaches ⁇ about 70%, of predicted.
  • standard treatments and assessments include: assessment of the patient's signs and symptoms; completion of a dyspnea index scale; supplemental oxygen to maintain oxygen saturation as measured by pulse oximetry of ⁇ about 90%; albuterol (2.5 mg) via nebulizer given hourly or once every 20 minutes; ipratropium (0.5 mg) via nebulizer may be given every hour; spirometry completed within 10 minutes of nebulizer treatments; followed by, reassessment of signs and symptoms.
  • the patient may continue to receive further treatment including hospital admission.
  • Safety, efficacy and PK parameters may be monitored throughout the treatment period.
  • An initial 24-hour follow-up visit may be completed to evaluate the patient's health status as well as for safety and PK parameters.
  • a second follow-up contact may be completed by telephone seven days post-randomization for safety purposes and to evaluate the patient's health status.
  • the occurrence of clinical signs, symptoms, laboratory abnormalities, ECG abnormalities suggesting toxicity, or results of efficacy analyses may result in a decision to modify the proposed planned dose escalations, to repeat a dose level, or to not evaluate any additional dose(s) of MN-221.
  • One or more of the following outcomes may be used to determine the usefulness of the present methods. They include: a change of FEV 1 expressed as percent of predicted after two doses of albuterol (e.g., and without limitation at about 2.5 mg to about 5 mg each) and ipratropium (e.g., and without limitation at about 0.5 mg each) when compared to FEV 1 2 hour after (“hour 2”) the start of MN-221 infusion; the safety, tolerability, and pharmacokinetic profile of MN-221 when administered after two doses of albuterol (e.g., and without limitation at about 5 mg each) and ipratropium (e.g., and without limitation at about 0.5 mg each) in patients with acute exacerbation of asthma; a measurement of FEV 1 % of predicted at time points other than about hour 2 (e.g., and without limitation at about hour 3, about hour 4, about hour 5, about hour 6, about hour 7, and about hour 8); a measurement of FEV 1 (L); a measurement of PEFR (L/sec
  • hour 2 refers to 2 hours after administration of MN-221, and includes 2 hours after stopping administration of MN-221.
  • the various aforementioned outcomes may be measured at time intervals of about hours 1, 2, 3, 4, 5, 6, 7, 8, and 24; additionally the dyspnea index scale may be measured at about day 8 also.
  • One or more of the following outcomes may also be used to determine the usefulness of the present methods: a measurement of the number of albuterol treatments in combination with MN-221 to achieve FEV 1 ⁇ 50%, ⁇ 60%, and ⁇ 70%; a measurement of time to achieve FEV1 ⁇ 50%, 60%, and ⁇ 70%; a measurement of the hospital admission rate; a measurement of the length of stay in hospital (in hours); and a measurement of the intensive care unit (ICU) admission rate.
  • ICU intensive care unit
  • the standard of care comprises one or more of about 2.5 mg to about 5 mg of albuterol administered by a nebulizer, or MDI about 1 mg of ipratropium administered by a nebulizer, or MDI; about 50 mg of prednisone administered orally, or about 50 mg of methylprednisolone administered intravenously; and about 2 gm of magnesium sulfate administered intravenously.
  • the Active Agent is administered i.v. in a daily amount of about 2400 ⁇ g (or 2.4 mg), about 1200 ⁇ g, about 1000 ⁇ g, about 800 ⁇ g, about 600 ⁇ g, about 450 ⁇ g, about 250 ⁇ g. In other embodiments, the Active Agent is administered in a single-dosed amount of about 200 ⁇ g to about 2000 ⁇ g.
  • the Active Agent is administered by infusion.
  • the infusion is performed at a rate of about 3 ⁇ g ( ⁇ gm or ⁇ g)/minute to about 60 ⁇ g/min; about 6 ⁇ g/minute to about 30 ⁇ g/minute; about 12/minute to about 15 ⁇ g/minute; about 7 ⁇ g/minute to about 18 ⁇ g/minute; about 9 ⁇ g/minute; about 13 ⁇ g/minute; and about 16 ⁇ g/minute.
  • the patient is administered intravenously for 15 minutes at about 40 ⁇ g/min and then about 45 minutes at about 13 ⁇ g/min.
  • the patients are those who have been admitted to an emergency room.
  • the patient may be treated in the vicinity of where the acute exacerbation of asthma occurred, or while being transported to a hospital (e.g., in an emergency rescue vehicle or ambulance).
  • the patient is administered an initial amount of the Active Agent in the range of about 3 ⁇ g/kg patient (or about 200 ⁇ g per patient) to about 60 ⁇ g/kg patient (or about 4 mg per patient).
  • the Active Agent may be administered over a period of about 1 minute to up to about 4 hours.
  • the Active Agent is administered for a period of time up to about 3 hours (h), up to about 2 h, up to about 1 h, up to about 45 min, up to about 30 min, and up to about 15 min.
  • the Active Agent may be administered at various rates of administration, for various periods of time.
  • the composition is administered as a formulation suitable for parenteral routes of administration, such as intravenous injection or infusion, intramuscular, percutaneous, and subcutaneous administration.
  • parenteral routes of administration such as intravenous injection or infusion, intramuscular, percutaneous, and subcutaneous administration.
  • suitable are solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories.
  • the intravenous formulation comprises approximately 0.20 mg to about 20 mg; or alternatively about 0.20 mg to about 10 mg; or alternatively about 0.20 mg to about 5 mg; or alternatively about 0.20 mg to about 3 mg; or alternatively about 0.20 mg to about 2 mg; or alternatively about 0.20 mg to about 1 mg; of the compound of the invention in an aqueous delivery system.
  • the aqueous delivery system may comprise about 0.02% to about 0.5% (w/v) of an acetate, phosphate, or citrate buffer.
  • the formulation has a pH of about 3.0 to about 7.0.
  • the concentration of the compound in the intravenous formulation falls in the range of about 0.15 ⁇ mol/mL to about 0.25 ⁇ mol/mL.
  • the subject is administered an amount of the compound of the invention in the range of about 3 ⁇ g/kg patient (or about 200 ⁇ g per patient) to about 60 ⁇ g/kg patient (or about 4 mg per patient).
  • the dosage may be administered intravenously as a single bolus injection to the subject, or as single bolus injection followed by a constant infusion for up to 24, 36, 48, or 72 hours, or as a constant infusion for up to 24, 36, 48, or 72 hours.
  • the dosage may be administered subcutaneously or intravenously at intervals not less than 4 hours and for up to 24, 36, 48, or 72 hours.
  • the subject is administered intravenously for 15 minutes at about 40 ⁇ g/min and then about 45 minutes at about 13 ⁇ g/min.
  • the intravenous formulation is reconstituted from a freeze-dried drug product comprising the compound of the invention.
  • the freeze-dried drug product further comprises carbohydrate and/or polyhydric alcohols.
  • the carbohydrate may be mannose, ribose, trehalose, maltose, inositol, lactose, or the like.
  • the polyhydric alcohols may be sorbitol, mannitol, or the like.
  • the pharmaceutical composition comprising the Active Agent can also be administered using a nebulizer (i.e., inhaled) or administered enterally, such as orally.
  • the liquid formulation comprises the Active Agent in an amount of about 3 ⁇ g/mL to about 60 ⁇ g/mL, about 6 ⁇ g/mL to about 30 ⁇ g/mL, and about 12 ⁇ g/mL to about 30 ⁇ g/mL, and about 15 ⁇ g/mL to about 20 ⁇ g/mL.
  • the liquid formulation further comprises dextrose.
  • MN-221 was tested at escalating doses of 240 ⁇ g to 1,080 ⁇ g in patients with AEA treated in emergency departments (EDs).
  • All patients were administered SOC treatment as follows: supplemental oxygen given to maintain oxygen saturation measured by pulse oximetry of ⁇ 90%; two doses of inhaled beta2-agonist (in this study, albuterol 5 mg) via nebulizer given approximately every 20 minutes; simultaneously with two doses of an inhaled anti-cholinergic agent (in this study, ipratropium 0.5 mg) via nebulizer given approximately every 20 minutes; one dose of corticosteroid given orally (in this study, prednisone 60 mg) or intravenously (in this study, methylprednisolone 125 mg), and intravenous magnesium sulfate (2 gm, diluted with 50-100 mL normal saline) and given over 10 minutes to patients with an FEV 1 ⁇ 25% of predicted upon ED presentation treatment.
  • supplemental oxygen given to maintain oxygen saturation measured by pulse oximetry of ⁇ 90%
  • two doses of inhaled beta2-agonist in this study, albuterol 5 mg
  • MN-221 was administered at the following doses: 16 ⁇ g/min for 15 minutes (total of 240 ⁇ g); 30 ⁇ g/min for 15 minutes (total of 450 ⁇ g); 16 ⁇ g/min for 15 minutes; 8 ⁇ g/min for 105 minutes (total of 1,080 ⁇ g).
  • a lyophilized unit dose for of MN-221, containing 2 mg MN-221 and lactose in a 10 mL vial was employed in the administration.
  • Vials containing 2 mg (2000 ⁇ g) of MN-221 and vials containing placebo were reconstituted as follows.
  • Patients were administered SOC treatment (inhaled albuterol, 2.5 mg via nebulizer up to every 20 minutes) and ipratropium (0.5 mg via nebulizer up to every 20 minutes) in addition to treatment with MN-221 or placebo.
  • SOC treatment inhaled albuterol, 2.5 mg via nebulizer up to every 20 minutes
  • ipratropium 0.5 mg via nebulizer up to every 20 minutes
  • a randomized, double-blind, placebo-controlled Phase II clinical trial is performed for demonstrating the efficacy and safety of administering MN-221 in accordance with the various aspects and embodiments of the methods of the present invention.
  • a patient is administered the following initial SOC treatment regimen (consistent with the National Asthma Education and Prevention Program and the Global Initiative for Asthma (GINA) guidelines).
  • the SOC includes the following: supplemental oxygen given to maintain oxygen saturation as measured by pulse oximetry of ⁇ 90% as needed; albuterol: 10 mg of albuterol via nebulizer prior to the qualifying spirometry evaluation; simultaneously with ipratropium: 1.0 mg of ipratropium via nebulizer prior to the qualifying spirometry evaluation (if a nebulizer is not used, albuterol and ipratropium may be administered using an MDI with spacer as follows; albuterol: 16 puffs of albuterol (90 ⁇ g/puff) via MDI with spacer prior to the qualifying spirometry evaluation, simultaneously with ipratropium: 16 puffs of ipratropium (18 ⁇ g/puff) via MDI with spacer prior to the qualifying spirometry evaluation); the patient is assessed for response to that treatment; one dose of at least 50 mg of a corticosteroid given either orally (prednisone) or intravenously (methylprednisolone) or
  • patients receive during a screening period the following standard treatment (in addition to the albuterol and ipratropium doses received during a pre-screening period): supplemental oxygen given to maintain oxygen saturation as measured by pulse oximetry of ⁇ 90% as needed; albuterol: a dose of at least 2.5 mg but not more than 7.5 mg of albuterol via nebulizer to be given during the screening period, simultaneously with ipratropium: a dose of 0.5 mg of ipratropium via nebulizer to be given during the screening period.
  • albuterol a dose of at least 6 puffs but not more than 18 puffs (90 ⁇ g/puff) via MDI with spacer to be given during the screening period
  • ipratropium a dose of 8 puffs (18 ⁇ g/puff) via MDI with spacer to be given during the screening period.
  • the patient's FEV 1 is less than or equal to 50 percent of predicted and the patient meets all other study entry criteria, the patient is randomized to receive either MN-221 or placebo. Patients enrolled in the study receive an intravenous 1-hour infusion of MN-221 study drug or placebo. Two (2) mg Lyophilized unit dose forms of MN-221 are used as dug product.
  • an aqueous formulation of 13.3 ⁇ g/mL MN-221 is administered to the patients.
  • Patients administered MN-221 receive a total dose of 1200 ⁇ g (40 ⁇ g/min for 15 min [600 ⁇ g]+13.3 ⁇ g/min for 45 min [600 ⁇ g]); i.e., patients receive 1200 ⁇ g over a period of 1 h.
  • SOC Patients enrolled in the study are administered SOC, as needed, in combination with MN-221 while being administered an intravenous infusion of MN-221, or with placebo.
  • the following SOC is administered.
  • Supplemental oxygen is optionally administered to maintain oxygen saturation as measured by pulse oximetry of ⁇ 90% as needed; albuterol: a dose of at least (2.5 mg) but not more than 7.5 mg of albuterol via nebulizer to be administered hourly during the treatment period;
  • ipratropium a dose of (0.5 mg) of ipratropium via nebulizer is optionally administered hourly during the treatment period. If nebulizers are not used, SOC may be administered by MDI.
  • the primary efficacy endpoint is improvement in FEV 1 .
  • MN-221 (2 mg) is formulated as an aseptically processed lyophilized product for injection, as tabulated below.
  • ED emergency department
  • MN-221 a prehospital setting
  • an SOC is administered or applied in combination.
  • albuterol about 10 mg
  • ipratropium about 1 mg
  • albuterol and ipatroprium are administered using an MDI with spacer as follows.
  • albuterol about 16 puffs of albuterol (90 ⁇ g/puff, and for ipratropium, about 16 puffs of ipratropium (18 ⁇ g/puff) are administered.
  • a corticosteroid given either orally (prednisone) or intravenously (methylprednisolone). Additionally, some patients are also administered about 2 gm of intravenous magnesium sulfate. Supplemental oxygen is also given to maintain oxygen saturation as measured by pulse oximetry of ⁇ 90%.

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US6136852A (en) * 1996-03-27 2000-10-24 Kissei Pharmaceutical Co., Ltd. 3,4-disubstituted phenylethanolaminotetralincarboxylic acid derivatives
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US6136852A (en) * 1996-03-27 2000-10-24 Kissei Pharmaceutical Co., Ltd. 3,4-disubstituted phenylethanolaminotetralincarboxylic acid derivatives
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