US20170000771A1 - Thromboxane Receptor Antagonists in AERD/Asthma - Google Patents

Thromboxane Receptor Antagonists in AERD/Asthma Download PDF

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US20170000771A1
US20170000771A1 US15/195,265 US201615195265A US2017000771A1 US 20170000771 A1 US20170000771 A1 US 20170000771A1 US 201615195265 A US201615195265 A US 201615195265A US 2017000771 A1 US2017000771 A1 US 2017000771A1
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ifetroban
dose
day
aspirin
aerd
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Leo Pavliv
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Cumberland Pharmaceuticals Inc
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Cumberland Pharmaceuticals Inc
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Assigned to CUMBERLAND PHARMACEUTICALS, INC. reassignment CUMBERLAND PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PAVLIV, LEO
Priority to US16/687,151 priority patent/US11571412B2/en
Priority to US17/705,557 priority patent/US20220218672A1/en
Priority to US17/705,522 priority patent/US20220211674A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention is related to the use of thromboxane receptor antagonists (e.g., Ifetroban) in the treatment of AERD (aspirin exacerbated respiratory disease) and asthma; and pharmaceutical compositions for the treatment of the same.
  • thromboxane receptor antagonists e.g., Ifetroban
  • Aspirin Exacerbated Respiratory Disease is a chronic medical condition that consists of asthma, recurrent sinus disease with nasal polyps, as well as a sensitivity to aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs). Patients suffering from typically develop reactions triggered by aspirin or other NSAIDs. These reactions include, but are not limited to increased nasal congestion or stuffiness; eye watering or redness; cough, wheezing, or chest tightness; frontal headache or sensation of sinus pain; flushing and/or a rash; nausea and/or abdominal cramping; and a general feeling of malaise, sometimes accompanied by dizziness.
  • AERD is characterized by mast cell activation with overproduction of cysteinyl leukotrienes following inhibition of COX-1 by medications like aspirin or NSAIDs.
  • the cause of the mast cell activation that occurs following COX-1 inhibition is unknown.
  • AERD affects about 10% of adults who have asthma.
  • a large proportion (about 40%) of patients who have asthma and nasal polyps are sensitive to aspirin and NSAIDs.
  • AERD is also commonly referred to as Samter's Triad or Aspirin Sensitive Asthma.
  • Aspirin desensitization may be accomplished, for example, by hospitalizing the patient and instituting a regimen wherein the patient is initially given a very low dose (20-40 mg) of aspirin, with gradual higher doses given every 1.5-3 hours. Following an aspirin-induced reaction (and subsequent stabilization of the patient), further doses of aspirin are administered. The desensitization is considered to be complete once the patient has received a 325 mg dose of aspirin without further reaction. The patient is then discharged and continues treatment with aspirin (typically either 325 mg or 650 mg twice daily). However, aspirin desensitization does not help many AERD patients.
  • Other treatments include an antibiotic such as tobramycin or biaxin, a salicylate-free diet, a corticosteroid such as betamethasone, and/or acetylcysteine.
  • COX-2 a relatively aspirin-resistant enzyme
  • MCs bronchial biopsies from patients with AERD than in those of aspirin tolerant controls.
  • PGD2 The capacity of PGD2 to recruit and activate immune effector cells, induce vasodilation, and cause bronchoconstriction would fit well with a role in the pathophysiology of AERD, especially since its production resists suppression by low-dose aspirin.
  • the present invention is directed in part to providing a method of treating and/or preventing AERD or asthma in human patients by administration of a therapeutically effective amount of a thromboxane receptor antagonist.
  • the therapeutically effective amount of thromboxane receptor antagonist is sufficient to provide a plasma concentration of the thromboxane receptor antagonist of about 0.1 ng/ml to about 10,000 ng/ml, preferably from about 1.0 ng/ml to about 6000 ng/ml, or from about 40 ng/ml to about 3500 ng/ml, or from about 300 ng/ml to about 2500 ng/ml.
  • the thromoboxane receptor antagonist is a thromboxane A 2 receptor antagonist to a human patient(s).
  • the thromboxane A 2 antagonist is [1S-(1 ⁇ ,2 ⁇ ,3 ⁇ ,4 ⁇ )]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoic acid (Ifetroban), or pharmaceutically acceptable salts thereof.
  • the thromboxane A 2 receptor antagonist is ifetroban or a pharmaceutically acceptable salt thereof (e.g., ifetroban sodium) and the dose administered orally to human patients is from about in a daily dose from about 25 mg to about 400 mg.
  • the patient(s) will (preferably) require a reduced amount of rescue medications as compared to human patients who are not administered ifetroban.
  • the ifetroban is administered orally in an amount from about 150 mg to about 400 mg, from about 200 mg to about 300 mg, and in certain embodiments most preferably about 200 mg.
  • the ifetroban is ifetroban sodium.
  • the present invention is further directed in part to providing a method for treating and/or preventing AERD or asthma by administration of a therapeutically effective amount of [1S-(1 ⁇ ,2 ⁇ ,3 ⁇ ,4 ⁇ )]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoic acid, monosodium salt (Ifetroban Sodium) to a human patient(s).
  • the therapeutically effective amount provides a plasma concentration of the Ifetroban of about 0.1 ng/ml to about 10,000 ng/ml, preferably from about 1.0 ng/ml to about 6000 ng/ml, or from about 40 ng/ml to about 3500 ng/ml, or from about 300 ng/ml to about 2500 ng/ml.
  • the thromboxane A 2 receptor antagonist is ifetroban or a pharmaceutically acceptable salt thereof (e.g., ifetroban sodium) and the dose administered orally to human patients is from about in a daily dose from about 25 mg to about 400 mg.
  • the patient(s) will (preferably) require a reduced amount of rescue medications as compared to human patients who are not administered ifetroban.
  • the ifetroban is administered orally in an amount from about 150 mg to about 400 mg, from about 200 mg to about 300 mg, and in certain embodiments most preferably about 200 mg.
  • the ifetroban is ifetroban sodium.
  • the present invention provides for methods of preventing, reversing or treating a symptom associated with AERD or asthma including but not limited to nasal congestion (or stuffiness), eye watering, eye redness, coughing, wheezing, chest tightness; frontal headache, sensation of sinus pain, flushing, rash, hives, nausea, abdominal cramping, a general feeling of malaise, dizziness, difficulty breathing, and combinations of any of the foregoing by the administration of a therapeutically effective amount of a thromboxane receptor antagonist (preferably, a thromboxane A 2 receptor antagonist) to a patient in need thereof.
  • a thromboxane receptor antagonist preferably, a thromboxane A 2 receptor antagonist
  • the therapeutically effective amount of a thromboxane A 2 receptor antagonist provides a plasma concentration of the thromboxane A 2 receptor antagonist of about 0.1 ng/ml to about 10,000 ng/ml, wherein the desired plasma concentration results in the patient experiencing a lessening of said symptom(s).
  • the thromboxane A 2 antagonist is [1S-(1 ⁇ ,2 ⁇ ,3 ⁇ ,4 ⁇ )]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoic acid (Ifetroban), or pharmaceutically acceptable salts thereof.
  • the thromboxane receptor antagonist is [1S-(1 ⁇ ,2 ⁇ ,3 ⁇ ,4 ⁇ )]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoic acid, monosodium salt (Ifetroban Sodium).
  • the thromboxane A 2 receptor antagonist is ifetroban or a pharmaceutically acceptable salt thereof (e.g., ifetroban sodium) and the dose administered orally to human patients is from about 150 mg/day to about 400 mg/day, administered in one dose or divided doses.
  • the thromboxane A 2 receptor antagonist is ifetroban sodium and the dose is about 200 mg/day when administered orally to a human patient(s) suffering from AERD and/or asthma.
  • the invention is also directed in part to a method of reducing rescue medications as a result of an aspirin-induced reaction in a human patient(s) suffering from AERD, comprising administering ifetroban or a pharmaceutically acceptable salt thereof in a daily dose from about 25 mg to about 400 mg.
  • the patient(s) will (preferably) require a reduced amount of rescue medications as compared to human patients who are not administered ifetroban.
  • the ifetroban is administered orally in an amount from about 150 mg to about 400 mg, from about 200 mg to about 300 mg, and in certain embodiments most preferably about 200 mg.
  • the ifetroban is ifetroban sodium.
  • the invention is also directed in part to a method of reducing the symptoms of aspirin desensitization in a human AERD patient(s), comprising rescue medications as a result of an aspirin-induced reaction in a human patient(s) suffering from AERD, comprising orally administering ifetroban or a pharmaceutically acceptable salt thereof in a daily dose from about 25 mg to about 400 mg.
  • the patient(s) will (preferably) require a reduced amount of rescue medications as compared to human patients who are not administered ifetroban.
  • the ifetroban is administered orally in an amount from about 150 mg to about 400 mg, from about 200 mg to about 300 mg, and in certain embodiments most preferably about 200 mg.
  • the ifetroban is ifetroban sodium.
  • the thromboxane A 2 receptor antagonist may be ifetroban or a pharmaceutically acceptable salt thereof (e.g., ifetroban sodium) in a daily dose of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, and about 400 mg.
  • the daily dose may be administered once daily, twice daily, three times daily, or four times daily.
  • terapéuticaally effective amount refers to that amount of a substance that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment.
  • the effective amount of such substance will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • thromboxane A 2 receptor antagonist refers to a compound that inhibits the expression or activity of a thromboxane receptor by at least or at least about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% in a standard bioassay or in vivo or when used in a therapeutically effective dose.
  • a thromboxane A 2 receptor antagonist inhibits binding of thromboxane A 2 to the receptor.
  • Thromboxane A 2 receptor antagonists include competitive antagonists (i.e., antagonists that compete with an agonist for the receptor) and non-competitive antagonists.
  • Thromboxane A 2 receptor antagonists include antibodies to the receptor. The antibodies may be monoclonal. They may be human or humanized antibodies.
  • Thromboxane A 2 receptor antagonists also include thromboxane synthase inhibitors, as well as compounds that have both thromboxane A 2 receptor antagonist activity and thromboxane synthase inhibitor activity.
  • FIG. 1 depicts the deletion or blockade of TP receptors attenuates aspirin sensitivity in PGE2-deficient mice.
  • A Peak change in RL occurring in response to Lys-ASA challenge of ptges ⁇ / ⁇ or ptges/tpr ⁇ / ⁇ (DKO) mice 24 h after their final treatment with PBS or Df.
  • B Peak change in RL in ptges ⁇ / ⁇ mice receiving two doses of the TP receptor selective antagonist SQ29.548 prior to challenge with Lys-ASA.
  • C Levels of cys-LTs, mMCP-1, and histamine in BAL fluids from the same mice as in (B). Results are from 10 mice/group. (Adapted from Liu 2013).
  • thromboxane A 2 receptor antagonists have been an objective of many pharmaceutical companies for approximately 30 years (see, Dogne J-M, et al., Exp. Opin. Ther. Patents 11: 1663-1675 (2001)).
  • Certain individual compounds identified by these companies, either with or without concomitant thromboxane A 2 synthase inhibitory activity, include ifetroban (BMS), ridogrel (Janssen), terbogrel (BI), UK-147535 (Pfizer), GR 32191 (Glaxo), and S-18886 (Servier).
  • BMS ifetroban
  • ridogrel Jikker
  • BI terbogrel
  • UK-147535 Pfizer
  • GR 32191 Gaxo
  • S-18886 Servier
  • These compounds also prevent vasoconstriction induced by thromboxane A 2 and other prostanoids that act on the thromboxane A 2 receptor within the vascular bed, and thus may be beneficial for use in preventing and/or treating hepatorenal syndrome and/or hepatic encephalopathy.
  • Suitable thromboxane A 2 receptor antagonists for use in the present invention may include, for example, but are not limited to small molecules such as ifetroban (BMS; [1S-(1 ⁇ ,2 ⁇ ,3 ⁇ ,4 ⁇ )]-2-[[3-[4-[(pentylamino)carbony-1]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2 yl]methyl]benzenepropanoic acid), as well as others described in U.S. Patent Application Publication No. 2009/0012115, the disclosure of which is hereby incorporated by reference in its entirety.
  • BMS ifetroban
  • Additional thromboxane A 2 receptor antagonists suitable for use herein are also described in U.S. Pat. No. 4,839,384 (Ogletree); U.S. Pat. No. 5,066,480 (Ogletree, et al.); U.S. Pat. No. 5,100,889 (Misra, et al.); U.S. Pat. No. 5,312,818 (Rubin, et al.); U.S. Pat. No. 5,399,725 (Poss, et al.); and U.S. Pat. No. 6,509,348 (Ogletree), the disclosures of which are hereby incorporated by reference in their entireties. These may include, but are not limited to, interphenylene 7-oxabicyclo-heptyl substituted heterocyclic amide prostaglandin analogs as disclosed in U.S. Pat. No. 5,100,889, including:
  • thromboxane A 2 receptor antagonists suitable for use herein include, but are not limited to vapiprost (which is a preferred example), (E)-5-[[[(pyridinyl)]3-(trifluoromethyl)phenyl]methylene]amino]-oxy]pentanoic acid also referred to as R68,070-Janssen Research Laboratories, 3-[1-(4-chlorophenylmethyl)-5-fluoro-3-methylindol-2-yl]-2,-2-dimethylpropanoic acid [(L-655240 Merck-Frosst) Eur. J. Pharmacol.
  • the preferred thromboxane A 2 receptor antagonist of the present invention is ifetroban or any pharmaceutically acceptable salts thereof.
  • the preferred thromboxane A 2 receptor antagonist is ifetroban sodium (known chemically as [1S-(1 ⁇ ,2 ⁇ ,3 ⁇ ,4 ⁇ )]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoic acid, monosodium salt.
  • the AERD and/or asthma is treated via the administration of a thromboxane receptor antagonist (e.g., a thromboxane A 2 receptor antagonist) ranging from about 0.1 ng/ml to about 10,000 ng/ml.
  • a thromboxane receptor antagonist e.g., a thromboxane A 2 receptor antagonist
  • the plasma concentration of thromboxane receptor antagonist ranges from about 1 ng/ml to about 1,000 ng/ml, preferably from about 1.0 ng/ml to about 6000 ng/ml, or from about 40 ng/ml to about 3500 ng/ml, or from about 300 ng/ml to about 2500 ng/ml.
  • the thromboxane A 2 receptor antagonist is ifetroban or a pharmaceutically acceptable salt thereof (e.g., ifetroban sodium) and the dose administered orally to human patients is from about 150 mg/day to about 400 mg/day, administered in one dose or divided doses. In certain preferred embodiments, the thromboxane A 2 receptor antagonist is ifetroban sodium and the dose is about 200 mg/day when administered orally to a human patient(s) suffering from AERD and/or asthma.
  • a pharmaceutically acceptable salt thereof e.g., ifetroban sodium
  • the desired plasma concentration for providing a therapeutic effect for the treatment of AERD and/or asthma should be greater than about 10 ng/mL (ifetroban free acid).
  • the dose administered must be carefully adjusted according to age, weight and condition of the patient, as well as the route of administration, dosage form and regimen and the desired result.
  • daily doses of the thromboxane A 2 receptor antagonists ranging from about 0.1 mg to about 5000 mg should be administered.
  • the daily dose of thromboxane A 2 receptor antagonists ranges from about 1 mg to about 1000 mg; about 10 mg to about 1000 mg; about 50 mg to about 500 mg; about 100 mg to about 500 mg; about 200 mg to about 500 mg; about 300 mg to about 500 mg; and about 400 mg to about 500 mg per day.
  • a daily dose of ifetroban sodium from about 10 mg to about 250 mg will produce effective plasma levels of ifetroban free acid.
  • the thromboxane A 2 receptor antagonists of the present invention may be administered by any pharmaceutically effective route.
  • the thromboxane A 2 receptor antagonists may be formulated in a manner such that they can be administered orally, intranasally, rectally, vaginally, sublingually, buccally, parenterally, or transdermally, and, thus, be formulated accordingly.
  • the thromboxane A 2 receptor antagonists may be formulated in a pharmaceutically acceptable oral dosage form.
  • Oral dosage forms may include, but are not limited to, oral solid dosage forms and oral liquid dosage forms.
  • Oral solid dosage forms may include, but are not limited to, tablets, capsules, caplets, powders, pellets, multiparticulates, beads, spheres and any combinations thereof. These oral solid dosage forms may be formulated as immediate release, controlled release, sustained (extended) release or modified release formulations.
  • the oral solid dosage forms of the present invention may also contain pharmaceutically acceptable excipients such as fillers, diluents, lubricants, surfactants, glidants, binders, dispersing agents, suspending agents, disintegrants, viscosity-increasing agents, film-forming agents, granulation aid, flavoring agents, sweetener, coating agents, solubilizing agents, and combinations thereof.
  • pharmaceutically acceptable excipients such as fillers, diluents, lubricants, surfactants, glidants, binders, dispersing agents, suspending agents, disintegrants, viscosity-increasing agents, film-forming agents, granulation aid, flavoring agents, sweetener, coating agents, solubilizing agents, and combinations thereof.
  • the oral solid dosage forms of the present invention may contain a suitable amount of controlled-release agents, extended-release agents, modified-release agents.
  • Oral liquid dosage forms include, but are not limited to, solutions, emulsions, suspensions, and syrups. These oral liquid dosage forms may be formulated with any pharmaceutically acceptable excipient known to those of skill in the art for the preparation of liquid dosage forms. For example, water, glycerin, simple syrup, alcohol and combinations thereof.
  • the thromboxane A 2 receptor antagonists may be formulated into a dosage form suitable for parenteral use.
  • the dosage form may be a lyophilized powder, a solution, suspension (e.g., depot suspension).
  • the thromboxane receptor antagonists may be formulated into a topical dosage form such as, but not limited to, a patch, a gel, a paste, a cream, an emulsion, liniment, balm, lotion, and ointment.
  • a significant proportion of patients that suffer from asthma take one or more medications on a daily (chronic) basis in order to prevent or attenuate symptoms of asthma.
  • Such drugs include corticosteroids (including but not limited to inhaled corticosteroids), Cromolyn, Omalizumab, short or long-acting beta-2 agonists (typically inhaled), leukotriene modifiers (e.g., zafirlukast (Accolate®), montelukast (Singulair®), and zileuton (Zyflo®)), and theophylline Advair (a combination drug that includes a steroid and a long-acting bronchodilator drug).
  • corticosteroids including but not limited to inhaled corticosteroids
  • Cromolyn Cromolyn
  • Omalizumab short or long-acting beta-2 agonists (typically inhaled)
  • leukotriene modifiers e.g., zafirluk
  • Inhaled steroid medications include but are not limited to the following: Aerobid®, Asmanex®, Azmacort®, Dulera® (a combination drug that also includes a long-acting bronchodilator drug), Flovent®, Pulmicort®, Symbicort® (a combination drug that includes a steroid and a long-acting bronchodilator drug), Qvar®, and the like.
  • Inhaled steroids come in three forms: the metered dose inhaler (MDI), dry powder inhaler (DPI), and nebulizer solutions.
  • Omalizumab (trade name Xolair®, Roche/Genentech and Novartis) is a humanized antibody originally designed to reduce sensitivity to inhaled or ingested allergens, especially in the control of moderate to severe allergic asthma, which does not respond to high doses of corticosteroids.
  • the present method of treatment further contemplates combination therapy comprising administering a thromboxane receptor antagonist and one or more of the above drugs to a human patient suffering from AERD and/or asthma.
  • ifetroban sodium tablets are prepared with the following ingredients listed in Table 1:
  • the sodium salt of ifetroban, magnesium oxide, mannitol, microcrystalline cellulose, and crospovidone is mixed together for about 2 to about 10 minutes employing a suitable mixer.
  • the resulting mixture is passed through a #12 to #40 mesh size screen. Thereafter, magnesium stearate and colloidal silica are added and mixing is continued for about 1 to about 3 minutes.
  • the resulting homogeneous mixture is then compressed into tablets each containing 35 mg, ifetroban sodium salt.
  • the sodium salt of ifetroban, preservatives and sodium chloride are dissolved in 3 liters of water for injection and then the volume is brought up to 5 liters.
  • the solution is filtered through a sterile filter and aseptically filled into pre-sterilized vials which are then closed with pre-sterilized rubber closures.
  • Each vial contains a concentration of 75 mg of active ingredient per 150 ml of solution.
  • Example IV is a multicenter, double-blind, randomized, placebo-controlled trial to determine the safety of oral ifetroban in patients with a history of aspirin exacerbated respiratory disease (AERD).
  • AERD aspirin exacerbated respiratory disease
  • the eligible subjects were randomized (3:1 active to placebo) in this 7-day study which consisted of a screening, treatment and follow-up period. Any subject receiving at least a partial dose of IMP were not replaced and included in the study analysis. Of 19 subjects enrolled and randomized to study treatment, 14 (74%) were randomized to the ifetroban group and 5 (26%) to the placebo group. Of those 14 randomized to ifetroban, 12 (86%) subjects were treated and 100% of those treated completed treatment. Of 5 subjects randomized to placebo, 4 (80%) started treatment and 100% completed treatment. All treated subjects were analyzed for safety and efficacy variables.
  • a placebo treatment arm was included in this study to provide data on the spontaneous response rate of AERD subjects, as well as to help identify any safety or efficacy signals in the subjects receiving ifetroban.
  • subjects with asthma assigned to placebo have demonstrated improvement in symptoms, quality of life, and even in lung function, such as FEV 1.
  • the placebo effect in asthma can be as great as 30 to 50% depending on which endpoint is chosen (Castro, 2007; Placebo versus Best - Available - Therapy Control Group in Clinical Trials for Pharmacologic Therapies. Proceedings of the American Thoracic Society, 570-573).
  • montelukast substantially increases the safety of aspirin challenge/desensitization and it is the standard of care to use montelukast as a pre-treatment for subjects with AERD undergoing a planned aspirin challenge/desensitization. Because montelukast does not inhibit CYP2C9 or CYP3A4, montelukast was not expected to affect the elimination of ifetroban.
  • the primary objective of this study was to determine the safety of oral ifetroban compared to placebo as measured by a >20% decrease in Forced Expiratory Volume in 1 second (FEV1) compared to baseline following a dose of Investigational Medicinal Product (IMP) (Study Day 1) or following a dose of IMP but prior to initiation of the aspirin challenge.
  • FEV1 Forced Expiratory Volume in 1 second
  • Secondary objectives were: (i) to determine the safety of oral ifetroban compared to placebo as measured by peak Nasal Inspiratory Flow Rate (NIFR) compared to baseline following a dose of IMP (Study Day 1) or following a dose of IMP but prior to initiation of the aspirin challenge; (ii) to determine the safety of oral ifetroban compared to placebo as measured by the change in Total Nasal Symptom Score (TNSS) compared to baseline following a dose of IMP (Study Day 1) or following a dose of IMP but prior to initiation of the aspirin challenge; (iii) to determine the safety and tolerability of oral ifetroban compared to placebo as measured by treatment-emergent adverse events; (iv) to determine the efficacy of oral ifetroban compared to placebo in decreasing the respiratory reaction to oral aspirin as measured by the change in FEV1 compared to baseline during the aspirin challenge; (v) to determine the efficacy of oral ifetroban compared to placebo in decreasing the respiratory reaction
  • the main criteria for inclusion in the study were adults with a history of physician-diagnosed stable asthma (FEV 1 of at least 1.25 Liters (L) and 60% or better than predicted (calculated by spirometer based on gender, age, etc.) on two previous visits with no more than a 10% variation in those values, no increase in baseline dose of oral glucocorticoids for asthma for at least three months, and no history of hospitalization or emergency room visits for asthma for at least the prior six months), who have a history of nasal polyposis and have a history of at least one clinical reaction to oral aspirin or other nonselective cyclooxygenase (COX) inhibitor with features of lower (cough, chest tightness, wheezing, dyspnea) and/or upper (rhinorrhea, sneezing, nasal obstruction, conjunctival itching and discharge) airway involvement, and who are currently receiving montelukast (at least 10 mg per day, oral) or zafirlukast (
  • Subjects were allowed to enter the trial on the following medications: oral corticosteroids at a dose of ⁇ 10 mg/day prednisone or prednisone equivalent, inhaled/nasal corticosteroids, inhaled long-acting ⁇ -adrenergic agonists and inhaled ipratropium; however, no modifications were allowed during the study except for a temporary increase in the dose of oral corticosteroids if asthma worsened requiring such intervention. Subjects were required to stop using short-acting ⁇ -adrenergic agonists 24 hours prior, nasal decongestants and antihistamines 48 hours prior to first dose of IMP and throughout the study unless asthma worsened requiring such intervention.
  • nasal, inhaled corticosteroids and inhaled long acting beta-adrenergic agonists and inhaled ipratropium were allowed to be used during the study without modification to the subject's dosing regimen if the subject entered the trial on such medications. It is believed that these medications would not mask a potential response to the aspirin challenge.
  • Inhaled short acting beta-adrenergic agonists, nasal decongestants, and antihistamines were not allowed for specified periods prior to the study and through the initiation of the aspirin challenge as these medications may mask a potential response and thus affect the study efficacy endpoints. Warfarin, antiplatelet, or anticoagulant medications were prohibited 2 weeks prior to enrollment and during the course of the study.
  • the primary efficacy variable assessed was FEV1 measured by spirometry.
  • Secondary efficacy variables included the NIFR using a Youlten meter (or similar), and the subject-completed questionnaire, Total Nasal Symptom Score (TNSS). Additional efficacy variables were the incidence of asthmatic reactions, the incidence of respiratory reactions to oral aspirin, the amount of medications used to manage an aspirin-induced reaction and the aspirin dose at which a reaction was provoked during the desensitization process.
  • the treatment period consisted of a phase A assessing safety and efficacy of IMP administered Day 1 and Day 2 followed by a phase B assessing safety and efficacy of IMP during the aspirin challenge on Day 2 and Day 3. Subjects experiencing a decrease in FEV1 of ⁇ 20% during phase A would not continue to phase B of the study.
  • the follow-up period started upon completion of the aspirin challenge and ended on Day 7 with a phone call to assess for safety. All subjects were required to be taking either oral montelukast or zafirlukast (at least 10 mg/day or 20mg twice per day, respectively) one week prior to the study and for the duration of the study.
  • Ifetroban was supplied as 50-mg ifetroban sodium capsules and orally administered at a dose of 200 mg every 24 hours for three consecutive days. Identically appearing placebo capsules were provided for blinding purposes and 4 capsules administered orally every 24 hours for 3 consecutive days. The duration of IMP treatment was 3 days. The study duration was 7 days.
  • phase B No subject met this primary endpoint therefore all subjects continued to phase B of the study.
  • FEV 1 was comparable between treatment groups (Table 8 and Table 10). Mean changes from baseline FEV1 remained well below 20% throughout the treatment period in both treatment groups. No clear trends were observed between treatment groups.
  • FEV1 was comparable between treatment groups. Mean changes from baseline FEV1 remained well below 20% throughout the treatment period in both treatment groups. No clear trends were observed between treatment groups.
  • NIFR peak inspiratory flow rate
  • TNSS total nasal symptom score
  • the incidence of the AIR provoked at each aspirin dose was evaluated between treatment groups and summarized in Table 6. All subjects who experienced an AIR reacted to a provoking dose of 60 and/or 100 mg. No reaction occurred after the 100-mg provoking dose. All initial reactions in the placebo arm occurred at the 60-mg dose while in the ifetroban arm, 50% of the initial reactions occurred at 60-mg and the other half at 100-mg. One subject on placebo experienced a provoking dose reaction at 60 mg on Day 2 and another AIR on Day 3 at 100 mg. The severity of the 2 AIRs were comparable to one another. All other subjects experienced a single AIR during the aspirin desensitization process.
  • the severity of the AIRs were compared between treatment groups by the number of separate symptoms that manifested during the aspirin challenge. The total number of symptoms are based on 14 AIRs that occurred in 13 subjects, 10 ifetroban-treated subjects and 3 placebo-treated subjects. As mentioned previously, 1 subject on the placebo arm experienced 2 AIRs. The average number of symptoms per AIR was comparable between treatment groups. Both arms experienced a bronchial reaction ( ⁇ 20% decrease in FEV1, wheezing, chest tightness) as part of the AIR at a similar rate. While an upper respiratory effect (rhinorrhea, nasal obstruction, sneezing) was equally as common between treatment groups, an ocular manifestation seems to trend toward the placebo arm more often than on the ifetroban arm. AIR severity in the study is reported in Table 7 below.
  • the primary endpoint was not met; ifetroban did not cause a ⁇ 20% decrease in FEV1 during the course of IMP treatment or the aspirin desensitization process. Mean changes from baseline FEV1 remained well below 20% throughout the treatment period in both groups with no clear trends observed. While no appreciable difference was observed in the proportion of subjects with worsening NIFR or TNSS between treatment groups, there is an observed trend in favor of the ifetroban group toward greater improvements to NIFR and TNSS during phase A and phase B. Moreover, there is an apparent trend toward fewer rescue medications in favor of the ifetroban group and, while an upper respiratory effect was equally as common between treatment groups, an ocular manifestation seems to trend toward the placebo arm more often than on the ifetroban arm.

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