U.S. patent application number 17/705557 was filed with the patent office on 2022-07-14 for thromboxane receptor antagonists in aerd/asthma.
This patent application is currently assigned to Cumberland Pharmaceuticals Inc.. The applicant listed for this patent is Cumberland Pharmaceuticals Inc.. Invention is credited to Leo PAVLIV.
Application Number | 20220218672 17/705557 |
Document ID | / |
Family ID | 1000006227192 |
Filed Date | 2022-07-14 |
United States Patent
Application |
20220218672 |
Kind Code |
A1 |
PAVLIV; Leo |
July 14, 2022 |
Thromboxane Receptor Antagonists in AERD/Asthma
Abstract
The present invention is directed to methods of treating AERD
(aspirin exacerbated respiratory disease) and/or asthma via the
administration of a thromboxane receptor antagonist to a patient in
need thereof.
Inventors: |
PAVLIV; Leo; (Cary,
NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Cumberland Pharmaceuticals Inc. |
Nashville |
TN |
US |
|
|
Assignee: |
Cumberland Pharmaceuticals
Inc.
Nashville
TN
|
Family ID: |
1000006227192 |
Appl. No.: |
17/705557 |
Filed: |
March 28, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16687151 |
Nov 18, 2019 |
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17705557 |
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15195265 |
Jun 28, 2016 |
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16687151 |
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62186644 |
Jun 30, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/422
20130101 |
International
Class: |
A61K 31/422 20060101
A61K031/422 |
Claims
1-19. (canceled)
20. A method for treating and/or preventing asthma in a human
patient, comprising administering ifetroban or a pharmaceutically
acceptable salt thereof to the patient in a daily dose of about 200
mg, wherein the composition is administered orally.
21. The method of claim 20, wherein the daily dose is sufficient to
provide a plasma concentration of the ifetroban or pharmaceutically
acceptable salt thereof of about 1 ng/ml to about 1,000 ng/ml.
22. The method of claim 20, wherein the ifetroban or
pharmaceutically acceptable salt thereof is
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[4-[(Pentylamino)carbony-
l]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoic
acid, monosodium salt (ifetroban sodium).
23. A method of treating a symptom of aspirin desensitization in a
AERD patient, comprising administering ifetroban or a
pharmaceutically acceptable salt thereof to the patient in a daily
dose of about 200 mg, wherein the composition is administered
orally.
24. The method of claim 23, wherein the ifetroban is ifetroban
sodium.
25. The method of claim 23, wherein the daily dose of ifetroban
treats a symptom selected from the group consisting of nasal
polyps, 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.
26. The method of claim 23, wherein the dose of ifetroban provides
a plasma concentration of the thromboxane receptor antagonist of
about 40 ng/ml to about 3,500 ng/ml, wherein the desired plasma
concentration results in the patient experiencing a lessening of
said symptom.
27. A method of preventing a symptom of aspirin desensitization in
a AERD patient, comprising administering ifetroban or a
pharmaceutically acceptable salt thereof to the patient in a daily
dose of about 200 mg, wherein the composition is administered
orally.
28. The method of claim 27, wherein the ifetroban is ifetroban
sodium.
29. The method of claim 27, wherein the dose of ifetroban provides
a plasma concentration of the thromboxane receptor antagonist of
about 40 ng/ml to about 3,500 ng/ml, wherein the desired plasma
concentration results in the patient experiencing a lessening of
said symptom.
Description
FIELD OF THE INVENTION
[0001] 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.
BACKGROUND OF THE INVENTION
[0002] Aspirin Exacerbated Respiratory Disease (AERD) 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.
[0003] From a scientific perspective, 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.
[0004] 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.
[0005] It is typical that human patients who are suffering from
AERD also have asthma, nasal congestion, and nasal polyps. Such
patients often do not respond to conventional treatments.
[0006] AERD is also commonly referred to as Samter's Triad or
Aspirin Sensitive Asthma.
[0007] The most common treatment currently available for AERD is
aspirin desensitization. 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 325mg or 650 mg twice
daily). However, aspirin desensitization does not help many AERD
patients.
[0008] Other treatments include an antibiotic such as tobramycin or
biaxin, a salicylate-free diet, a corticosteroid such as
betamethasone, and/or acetylcysteine.
[0009] Aspirin challenge of subjects with aspirin exacerbated
respiratory disease (AERD) results in the activation of mast cells
(MCs), as evidenced by increases in the levels of tryptase in both
serum (Bochenek 2003) and nasal lavage fluid (Fischer 1994). In
addition, the levels of 9.alpha.-11.beta.-PGF2, a PGD2 metabolite,
increase in the plasma during the reaction to aspirin (Bochenek
2003). PGD2 has been shown to activate the thromboxane prostanoid
(TP) receptors found on bronchial smooth muscle thereby causing
bronchoconstriction (Armour 1989; Bochenek 2003; Pettipher 2007).
Administration of ifetroban in vitro has been shown to inhibit
contraction of guinea pig trachea elicited by PGD2 (Ogletree 1992)
and to both preempt and reverse TP receptor-induced bronchospasm in
rats and guinea pigs. Direct endobronchial application of lysine-
aspirin does not decrease the levels of PGD2 and PGD2 metabolites
recovered from bronchoalveolar lavage (BAL) fluids from AERD
patients. However, endobronchial application of lysine-aspirin does
reduce the concentration of other prostaglandins (Sladek 1994;
Szczeklik 1996). Thus, PGD2 production in AERD resists suppression
by aspirin.
[0010] The expression of COX-2, a relatively aspirin-resistant
enzyme, is expressed by a larger percentage of MCs in bronchial
biopsies from patients with AERD than in those of aspirin tolerant
controls (Sousa 1997). Since global expression of COX-2 in nasal
polyps is reduced in AERD relative to aspirin-tolerant controls
(Picado 1999), the selective upregulation of COX-2 expression by
MCs likely reflects cell-specific differences in the regulation of
the COX-2 isoform. Thus, the capacity for MCs to release PGD2 in
AERD during aspirin challenge may be due to their preferential
utilization of COX-2 for this function. 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.
[0011] Human studies demonstrate markedly impaired COX-2-dependent
synthesis of PGE2 in the sinonasal tissues of patients with AERD
compared with aspirin-tolerant controls (Picado 1999; Yoshimura
2008). Previous clinical studies also strongly support a critical
role of platelet-adherent granulocytes as a source of cysteinyl
leukotrienes (cys-LTs) in human subjects with AERD (Laidlaw 2012).
To further explore the pathogenetic consequences of a deficit in
COX-2-dependent PGE2 generation, sustained PGD2 generation, and the
role of platelets in AERD, mice lacking microsomal PGE2 synthase
(ptges-/- mice) were developed (Liu 2012; Liu 2013). PGE2 synthase
is the dominant terminal enzyme responsible for conversion of
COX-2-derived PGH2 to PGE2 (Murakami 2000).
[0012] To elicit the AERD phenotype in the ptges-/- mice, six doses
of an extract of allergens from the house dust mite
Dermatophagoides farina (Df) were administered and the animals
developed marked eosinophilic bronchovascular inflammation compared
with WT controls (Liu 2012). The blood and lungs of ptges-/- mice
contained markedly increased numbers of platelets adhering to
granulocytes, similar to the findings in humans. When challenged by
inhalation of Lysine aspirin, Df-treated ptges-/- mice exhibited
significant increases in airway resistance, accompanied by
increases in the levels of cys-LTs, histamine, and mouse MC
protease 1 in the BAL fluid. The increase in airway resistance was
sensitive to interference by zileuton or montelukast (Liu 2013),
consistent with the known pharmacology of AERD in humans. Exogenous
antibody-mediated platelet depletion prior to the Lys-ASA challenge
completely eliminated the increases in airway resistance and
cys-LTs. Moreover, deletion of TP receptors from ptges-/- mice or
the administration of SQ29,548, a selective antagonist of the TP
receptor, completely blocked the reaction to aspirin and the rise
in cys-LTs (FIG. 1). These findings imply that signaling through TP
receptors is critical for platelets to mediate the transcellular
synthesis of leukotriene C4 (LTC4) during challenge with aspirin.
These observations support the hypothesis that TP receptor blockade
will reduce the synthesis of cys-LTs in AERD and thereby provide a
new treatment modality for the disease and ease the desensitization
to aspirin.
SUMMARY OF THE INVENTION
[0013] It is an object of the present invention to provide new
methods of treating AERD and/or asthma.
[0014] It is an object of the invention to reduce rescue
medications needed as a result of an aspirin-induced reaction in a
human patient suffering from AERD.
[0015] It is another object of the invention to reduce the symptoms
of aspirin desensitization in AERD patients.
[0016] It accordance with the above object and others, 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. Preferably, 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.
[0017] In certain embodiments, the thromoboxane receptor antagonist
is a thromboxane A.sub.2 receptor antagonist to a human patient(s).
In preferred embodiments, the thromboxane A.sub.2 antagonist is
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[4-[(Pentylamino)carbony-
l]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoic
acid (Ifetroban), or pharmaceutically acceptable salts thereof In
certain preferred embodiments, the thromboxane A.sub.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. In such embodiments, the patient(s) will (preferably)
require a reduced amount of rescue medications as compared to human
patients who are not administered ifetroban. In certain preferred
embodiments, 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. In certain
preferred embodiments, the ifetroban is ifetroban sodium.
[0018] 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.alpha.,2.alpha.,3.alpha.,4.alpha.)]
-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-y-
l]methyl]-benzenepropanoic acid, monosodium salt (Ifetroban Sodium)
to a human patient(s). Preferably, 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. In certain preferred
embodiments, the thromboxane A.sub.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. In such embodiments, the patient(s) will (preferably)
require a reduced amount of rescue medications as compared to human
patients who are not administered ifetroban. In certain preferred
embodiments, 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. In certain
preferred embodiments, the ifetroban is ifetroban sodium.
[0019] In accordance with the above objects, 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.sub.2 receptor antagonist)
to a patient in need thereof In certain preferred embodiments, the
therapeutically effective amount of a thromboxane A.sub.2 receptor
antagonist provides a plasma concentration of the thromboxane
A.sub.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). In preferred
embodiments, the thromboxane A.sub.2 antagonist is
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[4-[(Pentylamino)carbony-
l]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoic
acid (Ifetroban), or pharmaceutically acceptable salts thereof. In
another preferred embodiment, the thromboxane receptor antagonist
is
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[4-[(Pentylamino)carbony-
l]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoic
acid, monosodium salt (Ifetroban Sodium). In certain preferred
embodiments, the thromboxane A.sub.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.sub.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.
[0020] 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. In such
embodiments, the patient(s) will (preferably) require a reduced
amount of rescue medications as compared to human patients who are
not administered ifetroban. In certain preferred embodiments, 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. In certain preferred
embodiments, the ifetroban is ifetroban sodium.
[0021] 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. In such embodiments, the patient(s) will (preferably)
require a reduced amount of rescue medications as compared to human
patients who are not administered ifetroban. In certain preferred
embodiments, 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. In certain
preferred embodiments, the ifetroban is ifetroban sodium.
[0022] In any of the above methods, the thromboxane A.sub.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.
[0023] The phrase "therapeutically 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.
[0024] The term "thromboxane A.sub.2 receptor antagonist" as used
herein 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. In certain
embodiments, a thromboxane A.sub.2 receptor antagonist inhibits
binding of thromboxane A.sub.2 to the receptor. Thromboxane A.sub.2
receptor antagonists include competitive antagonists (i.e.,
antagonists that compete with an agonist for the receptor) and
non-competitive antagonists. Thromboxane A.sub.2 receptor
antagonists include antibodies to the receptor. The antibodies may
be monoclonal. They may be human or humanized antibodies.
Thromboxane A.sub.2 receptor antagonists also include thromboxane
synthase inhibitors, as well as compounds that have both
thromboxane A.sub.2 receptor antagonist activity and thromboxane
synthase inhibitor activity.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] 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).
DETAILED DESCRIPTION OF THE INVENTION
[0026] The discovery and development of thromboxane A.sub.2
receptor antagonists has 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.sub.2 synthase inhibitory activity,
include ifetroban (BMS), ridogrel (Janssen), terbogrel (BI),
UK-147535 (Pfizer), GR 32191 (Glaxo), and S-18886 (Servier).
Preclinical pharmacology has established that this class of
compounds has effective antithrombotic activity obtained by
inhibition of the thromboxane pathway. These compounds also prevent
vasoconstriction induced by thromboxane A.sub.2 and other
prostanoids that act on the thromboxane A.sub.2 receptor within the
vascular bed, and thus may be beneficial for use in preventing
and/or treating hepatorenal syndrome and/or hepatic
encephalopathy.
[0027] Suitable thromboxane A.sub.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.alpha.,2.alpha.,3.alpha.,4.alpha.)]-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.
[0028] Additional thromboxane A.sub.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:
[0029] [1S-(1.alpha., 2.alpha., 3.alpha.,
4.alpha.)]-2-[[3-[4-[[(4-cyclo-hexylbutyl)amino]carbonyl]-2-oxazolyl]-7-o-
xabicyclo[2.2.1]-hept-2-yl]methyl]benzenepropanoic acid (SQ
33,961), or esters or salts thereof;
[0030] [1S-(1.alpha., 2.alpha., 3.alpha., 4.alpha.)] -2-
[[3-[4-[[[(4-chloro- phenyl)-butyl] amino] carbonyl]
-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic
acid or esters, or salts thereof;
[0031] [1S-(1.alpha., 2.alpha., 3.alpha.,
4.alpha.)]-[3-[[3-[4-[[(4-cycloh-exylbutyl)-amino]carbonyl]-2-oxazolyl]-7-
-oxabicyclo]2.2.1]hept-2-yl]benzene acetic acid, or esters or salts
thereof;
[0032] [1S-(1.alpha., 2.alpha., 3.alpha.,
4.alpha.)]-[2-[[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-2-oxazolyl]-7--
oxabicyclo[2.2.1]hept-2-yl]methyl]phenoxy]acetic acid, or esters or
salts thereof;
[0033] [1S-(1.alpha., 2.alpha., 3.alpha.,
4.alpha.]-2-[[3-[4-[[(7,7-dime-
thyloctyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-meth-
yl]benzenepropanoic acid, or esters or salts thereof.
[0034] 7-oxabicycloheptyl substituted heterocyclic amide
prostaglandin analogs as disclosed in U.S. Pat. No. 5,100,889,
issued Mar. 31, 1992, including [1S-[1.alpha., 2.alpha. (Z),
3.alpha., 4.alpha.)]-643-[4-[[(4-cyclohexylbutyl)amino] -carbonyl]
-2-oxazolyl] -7-oxabicyclo [2.2.1] hept-2-yl] -4-hexenoic acid, or
esters or salts thereof;
[0035] [1S-[1.alpha., 2.alpha. (Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-2-thiazolyl]-7--
oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts
thereof;
[0036] [1S-[1.alpha., 2.alpha. (Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[[(4-cyclohexyl-butyl)methylamino]carbonyl]-2-oxazoly-
l]-7-oxabicyclo-[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or
salts thereof;
[0037] [1S-[1.alpha., 2.alpha. (Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[(1-pyrrolidinyl)-carbonyl]-2-oxazolyl]-7-oxabicyclo[-
2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof;
[0038] [1S-[1.alpha., 2.alpha. (Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[(cyclohexylamino)-carbonyl]-2-oxazolyl]-7-oxabicyclo-
[2.2.1]hept-2-yl-4-hexenoic acid or esters or salts thereof;
[0039] [1S-[1.alpha., 2.alpha. (Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[[(2-cyclohexyl-ethyl)amino]carbonyl]-2-oxazolyl]-7-o-
xabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts
thereof;
[0040] [1S-[1.alpha., 2.alpha. (Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[[[2-(4-chloro-phenyl)ethyl]amino]carbonyl]-2-oxazoly-
l]-7-oxabicyclo-[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or
salts thereof;
[0041] [1S-[1.alpha., 2.alpha. (Z), 3.alpha.,
4.alpha.)]-6-[3-[4-[[(4-chlorophenyl)-amino]carbonyl]-2-oxazolyl]-7-oxabi-
cyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts
thereof;
[0042] [1S-[1.alpha., 2.alpha. (Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[[[4-(4-chloro-phenyl)butyl]amino]carbonyl]-2-oxazoly-
l]-7-oxabicyclo-[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or
salts thereof;
[0043] [1S-[1.alpha., 2.alpha. (Z), 3.alpha.,
4.alpha.)]]-6-[3-[4.alpha.-[[-(6-cyclohexyl-hexyl)amino]carbonyl]-2-oxazo-
lyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters, or
salts thereof;
[0044] [1S-[1.alpha., 2.alpha. (Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[[(6-cyclohexyl-hexyl)amino]carbonyl]-2-oxazolyl]-7-o-
xabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts
thereof;
[0045] [1S-[1.alpha., 2.alpha. (Z), 3.alpha.,
4.alpha.]]-6-[3-[4-[(propylamino)-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.-
1]hept-2-yl]-4-hexenoic acid, or esters or salts thereof;
[0046] [1S-[1.alpha., 2.alpha. (Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[[(4-butylphenyl)-amino]carbonyl]-2-oxazolyl]-7-oxabi-
cyclo[2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts
thereof;
[0047] [1S-[1.alpha., 2.alpha. (Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[(2,3-dihydro-1H-indol-1-yl)carbonyl]-2-oxazolyl]-7-o-
xabicyclo(2.2.1]hept-2-yl]-4-hexenoic acid, or esters or salts
thereof;
[0048] [1S-[1.alpha., 2.alpha. (Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-2-oxazolyl]-7-o-
xabicyclo[2.2.1]hept-2-yl]-N-(phenylsulfonyl)-4-hexenamide;
[0049] [1S-[1.alpha., 2.alpha. (Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-2-oxazolyl]-N-(-
methylsulfonyl)-7-oxabicyclo[2-.2.1]hept-2-yl]-4-hexenamide;
[0050] [1S-[1.alpha., 2.alpha. (Z), 3.alpha.,
4.alpha.)]]-7-[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-2-oxazolyl]-7-o-
xabicyclo (2.2.1]hept-2-yl]-5-heptenoic acid, or esters or salts
thereof;
[0051] [1S-[1.alpha., 2.alpha. (Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-1H-imidazol-2-y-
l]-7-oxabicyclo-[2.2.1]hept-2-yl]-4-hexenoic acid or esters or
salts thereof;
[0052] [1S-[1.alpha., 2.alpha., 3.alpha., 4.alpha.)]-6-[3-[4-[[(7,
7-dimethyloctyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl-
]-4-hexenoic acid, or esters or salts thereof;
[0053] [1S-[1.alpha., 2.alpha.(E), 3.alpha.,
4.alpha.)]]-6-[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-2-oxazolyl]-7-o-
xabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid;
[0054] [1S-[1.alpha., 2.alpha., 3.alpha.,
4.alpha.)]-3-[4-[[(4-(cyclohexylbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxab-
icyclo[2.2.1]heptane-2-hexanoic acid or esters or salts
thereof,
[0055] [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]]-6-[3-[4-[[(4-cyclohexyl-
butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-4-hexeno-
ic acid, or esters or salts thereof;
[0056] 7-oxabicycloheptane and 7-oxabicycloheptene compounds
disclosed in U.S. Pat. No. 4,537,981 to Snitman et al, the
disclosure of which is hereby incorporated by reference in its
entirety, such as [1S-(1.alpha., 2.alpha.(Z), 3.alpha.(1E, 3S*,
4R*),
4.alpha.)]]-7-[3-(3-hydroxy-4-phenyl-l-pentenyl)-7-oxabicyclo[2.2.1]hept--
2-yl]-5-heptenoic acid (SQ 29,548); the 7-oxabicycloheptane
substituted aminoprostaglandin analogs disclosed in U.S. Pat. No.
4,416,896 to Nakane et al, the disclosure of which is hereby
incorporated by reference in its entirety, such as [1S-[1.alpha.,
2.alpha.(Z), 3.alpha.,
4.alpha.)]]-7-[3-[[2-(phenylamino)carbonyl]-hydrazino]methyl]-7-oxabicycl-
o[2.2.1]hept-2-yl]-5-heptenoic acid; the 7-oxabicycloheptane
substituted diamide prostaglandin analogs disclosed in U.S. Pat.
No. 4,663,336 to Nakane et al, the disclosure of which is hereby
incorporated by reference in its entirety, such as, [1S-[1.alpha.,
2.alpha.(Z), 3.alpha.,
4.alpha.)]]-7-[3-[[[[(1-oxoheptyl)amino]-acetyl]amino]methyl]-7-oxabicycl-
o[2.2.1]hept-2-yl]-5-heptenoic acid and the corresponding
tetrazole, and [1S-[1.alpha., 2.alpha.(Z),
3.alpha.,4.alpha.)]]-7-[3-[[[[(4-cyclohexyl-1-oxobutyl)-amino]acetyl]amin-
o]methyl]-7-oxabicyclo]2.2.1]hept-2-yl]-5-heptenoic acid;
[0057] 7-oxabicycloheptane imidazole prostaglandin analogs as
disclosed in U.S. Pat. No. 4,977,174, the disclosure of which is
hereby incorporated by reference in its entirety, such as
[1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]]-6-[3-[[4-(4-cyclohexyl-1-hydroxybutyl)-1H-imidazole-
-1-yl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid or its
methyl ester;
[0058] [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]]-6-[3-[[4-(3-cyclohexyl-propyl)-1H-imidazol-1-yl]methyl]-7-oxa-
bicyclo[2.2.1]hept-2-yl]-4-hexenoic acid or its methyl ester;
[0059] [1S-[1.alpha., 2.alpha.(X(Z), 3.alpha.,
4.alpha.)]]-6-[3-[[4-(4-cyclohexyl-1-oxobutyl)-1H-imidazol-1-yl]methyl]-7-
-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid or its methyl
ester;
[0060] [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.]]-6-[3-(1H-imidazol-1-ylmethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-4--
hexenoic acid or its methyl ester; or
[0061] [1S-[1.alpha., 2.alpha.(Z), 3.alpha.,
4.alpha.)]]-6-[3-[[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-1H-imidazol-1--
yl]methyl-7-oxabicyclo-[2.2.1]-hept-2-yl]-4-hexenoic acid, or its
methyl ester;
[0062] The phenoxyalkyl carboxylic acids disclosed in U.S. Pat. No.
4,258,058 to Witte et al, the disclosure of which is hereby
incorporated by reference in its entirety, including
4-[2-(benzenesulfamido)ethyl]phenoxy- acetic acid (BM
13,177-Boehringer Mannheim), the sulphonamidophenyl carboxylic
acids disclosed in U.S. Pat. No. 4,443,477 to Witte et al, the
disclosure of which is hereby incorporated by reference in its
entirety, including
4-[2-(4-chlorobenzenesulfonamido)ethyl]-phenylacetic acid (BM
13,505, Boehringer Mannheim), the arylthioalkylphenyl carboxylic
acids disclosed in U.S. Pat. No. 4,752,616, the disclosure of which
is hereby incorporated by reference in its entirety, including
4-(3-((4-chlorophenyl)sulfonyl)propyl)benzene acetic acid.
[0063] Other examples of thromboxane A.sub.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]penta-
noic acid also referred to as R68,070-Janssen Research
Laboratories,
3-[1-(4-chlorophenylmethyl)-5-fluoro-3-methylindol-2-yl]-2,-2-dimethylpro-
panoic acid [(L-655240 Merck-Frosst) Eur. J. Pharmacol. 135(2):193,
Mar. 17, 87],
5(Z)-7-([2,4,5-cis]-4-(2-hydroxyphenyl)-2-trifl-uoromethyl-1,3-d-
ioxan-5-yl)heptenoic acid (ICI 185282, Brit. J. Pharmacol. 90
(Proc. Suppl):228 P-Abs, March 87),
5(Z)-7-[2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl]heptenoic acid
(ICI 159995, Brit. J. Pharmacol. 86 (Proc. Suppl):808 P-Abs.,
December 85),
N,N'-bis[7-(3-chlorobenzeneamino-sulfony-l)-1,2,3,4-tetrahydro-isoquinoly-
l]disulfonylimide (SKF 88046, Pharmacologist 25(3):116 Abs., 117
Abs, August 83), (1.alpha.(Z)-2.beta.,
5.alpha.]-(+)-7-[5-[[(1,1'-biphenyl)-4-yl]-methoxy]-2-(4-morpholinyl)-3-o-
xocyclopentyl]-4-heptenoic acid (AH 23848 -Glaxo, Circulation
72(6):1208, December 85, levallorphan allyl bromide (CM 32,191
Sanofi, Life Sci. 31 (20-21):2261, Nov. 15, 82),
(Z,2-endo-3-oxo)-7-(3-acetyl-2-bicyclo
[2.2.1]heptyl-5-hepta-3Z-enoic acid, 4-phenyl-thiosemicarbazone
(EP092-Univ. Edinburgh, Brit. J. Pharmacol. 84(3):595, March 85);
GR 32,191 (Vapiprost)-[1R-[1.alpha.(Z), 2.beta., 3.beta.,
5.alpha.]]-(+)-7-[5-([1,1'-biphenyl]-4-ylmethoxy)-3-hydroxy-2-(1-piperidi-
nyl)cyclopentyl]-4-heptenoic acid; ICI
192,605-4(Z)-6-[(2,4,5-cis)2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-1,3-dio-
xan-5-yl]hexenoic acid; BAY u 3405
(ramatroban)-3-[[(4-fluorophenyl)-sulfonyl]amino]-1,2,3,4-tetrahydro-9H-c-
- arbazole-9-propanoic acid; or ONO 3708-7-[2.alpha.,
4.alpha.-(dimethylmethano)-6.beta.-(2-cyclopentyl-2.beta.-hydroxyacetami-
do)-1.alpha.-cyclohexyl]-5(Z)-heptenoic acid;
(.+-.)(5Z)-7-[3-endo-((phenylsulfonyl)amino]-bicyclo[2.2.1]hept-2-exo-yl]-
-heptenoic acid (S-1452, Shionogi domitroban, Anboxan.RTM..);
(-)6,8-difluoro-9-p-methylsulfonylben-
zyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid (L670596, Merck)
and
(3-[1-(4-chlorobenzyl)-5-fluoro-3-methyl-indol-2-yl]-2,2-dimethylpropanoi-
c acid (L655240, Merck).
[0064] The preferred thromboxane A.sub.2 receptor antagonist of the
present invention is ifetroban or any pharmaceutically acceptable
salts thereof.
[0065] In certain preferred embodiments the preferred thromboxane
A.sub.2 receptor antagonist is ifetroban sodium (known chemically
as
[1S-(1.alpha.,2.alpha.,3.alpha.,4.alpha.)]-2-[[3-[4-[(Pentylamino)carbony-
l]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoic
acid, monosodium salt.
[0066] In certain embodiments, the AERD and/or asthma is treated
via the administration of a thromboxane receptor antagonist (e.g.,
a thromboxane A.sub.2 receptor antagonist) ranging from about 0.1
ng/ml to about 10,000 ng/ml. Preferably, 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.
[0067] In certain preferred embodiments, the thromboxane A.sub.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.sub.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.
[0068] When the thromboxane A.sub.2 receptor antagonist is
ifetroban, 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). Some
therapeutic effect of thromboxane A.sub.2 receptor antagonist,
e.g., ifetroban, may be seen at concentrations of greater than
about 1 ng/mL.
[0069] 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.
[0070] However, in order to obtain the desired plasma concentration
of thromboxane A.sub.2 receptor antagonists, daily doses of the
thromboxane A.sub.2 receptor antagonists ranging from about 0.1 mg
to about 5000 mg should be administered. Preferably, the daily dose
of thromboxane A.sub.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.
[0071] In certain preferred embodiments, a daily dose of ifetroban
sodium from about 10 mg to about 250 mg (ifetroban free acid
amounts) will produce effective plasma levels of ifetroban free
acid.
[0072] The thromboxane A.sub.2 receptor antagonists of the present
invention may be administered by any pharmaceutically effective
route. For example, the thromboxane A.sub.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.
[0073] In certain embodiments, the thromboxane A.sub.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.
[0074] 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.
[0075] 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.
[0076] Depending on the desired release profile, the oral solid
dosage forms of the present invention may contain a suitable amount
of controlled-release agents, extended-release agents,
modified-release agents.
[0077] 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.
[0078] In certain embodiments of the present invention, the
thromboxane A.sub.2 receptor antagonists may be formulated into a
dosage form suitable for parenteral use. For example, the dosage
form may be a lyophilized powder, a solution, suspension (e.g.,
depot suspension).
[0079] In other embodiments, 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.
[0080] 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.RTM.), montelukast (Singulair.RTM.), and
zileuton (Zyflo.RTM.)), and theophylline. Advair (a combination
drug that includes a steroid and a long-acting bronchodilator
drug). Inhaled steroid medications include but are not limited to
the following: Aerobid.RTM., Asmanex.RTM., Azmacort.RTM.,
Dulera.RTM. (a combination drug that also includes a long-acting
bronchodilator drug), Flovent.RTM., Pulmicort.RTM., Symbicort.RTM.
(a combination drug that includes a steroid and a long-acting
bronchodilator drug), Qvar.RTM., 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.RTM., 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. In
certain embodiments, 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.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0081] The following examples are not meant to be limiting and
represent certain embodiments of the present invention.
Example 1
[0082] In this example, ifetroban sodium tablets are prepared with
the following ingredients listed in Table 1:
TABLE-US-00001 TABLE 1 Ingredients Percent by weight Na salt of
Ifetroban 35 Mannitol 50 Microcrystalline Cellulose 8 Crospovidone
3.0 Magnesium Oxide 2.0 Magnesium Stearate 1.5 Colloidal Silica
0.3
[0083] 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.
[0084] The resulting homogeneous mixture is then compressed into
tablets each containing 35 mg, ifetroban sodium salt.
Example II
[0085] In this example, 1000 tablets each containing 400 mg of
Ifetroban sodium are produced from the following ingredients listed
in Table 2:
TABLE-US-00002 TABLE 2 Ingredients Amount Na salt of Ifetroban 400
gm Corn Starch 50 g Gelatin 7.5 g Microcrystalline Cellulose
(Avicel) 25 g Magnesium Stearate 2.5 g
Example III
[0086] In this example. An injectable solution of ifetroban sodium
is prepared for intravenous use with the following ingredients
listed in Table 3:
TABLE-US-00003 TABLE 3 Ingredients Amount Ifetroban Sodium 2500 mg
Methyl Paraben 5 mg Propyl Paraben 1 mg Sodium Chloride 25,000 mg
Water for injection q.s. 5 liter
[0087] 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
[0088] 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).
[0089] 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.
[0090] 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. In numerous trials, subjects with
asthma assigned to placebo have demonstrated improvement in
symptoms, quality of life, and even in lung function, such as FEV1.
In general, 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).
[0091] All individuals with AERD will experience a clinical
reaction to aspirin, most often at a dose of 81 mg or below. By
utilizing a modified Scripps Institute protocol (Hope, Woessner,
Simon, & Stevenson, 2009), limiting the study to individuals
with stable asthma and no history of life-threatening reaction to
COX inhibitors and administering the cysteinyl leukotriene receptor
1 (Cys-LT1) antagonist montelukast to all individuals undergoing
the challenge/desensitization, the procedure could safely be done
in an ambulatory/outpatient clinic setting. The results of a study
published in 2006 (White, Ludington, Mehra, Stevenson, & Simon,
2006), demonstrated that leukotriene modifier drugs, like
montelukast, had a significant effect in protecting the lower
airways from severe reactions (P=0.004) in subjects undergoing
aspirin challenge/desensitization. Thus, 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.
[0092] The primary objective of this study was to determine the
safety of oral ifetroban compared to placebo as measured by a
.gtoreq.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. 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 to oral aspirin
as measured by the change in NIFR compared to baseline during the
aspirin challenge; (vi) to determine the efficacy of oral ifetroban
compared to placebo in decreasing the respiratory reaction to oral
aspirin as measured by the change in TNSS compared to baseline
during the aspirin challenge; (vii) to determine the efficacy of
oral ifetroban compared to placebo in decreasing the respiratory
reaction to oral aspirin as measured by the amount of rescue
medication during the aspirin challenge; (viii) to determine the
efficacy of oral ifetroban compared to placebo in decreasing
respiratory sensitivity to COX-1 inhibition as measured by the
aspirin desensitization dose level; and (ix) to determine the
efficacy of oral ifetroban compared to placebo as measured by the
number of asthmatic reactions during the Treatment Period.
[0093] The main criteria for inclusion in the study were adults
with a history of physician-diagnosed stable asthma (FEV1 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 (at least 20 mg, twice per day, oral), with at least 1
week of therapy prior to receiving the first dose of the
investigational medicinal product (IMP).
[0094] Subjects were allowed to enter the trial on the following
medications: oral corticosteroids at a dose of .ltoreq.10 mg/day
prednisone or prednisone equivalent, inhaled/nasal corticosteroids,
inhaled long-acting .beta.-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 .beta.-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.
[0095] Oral, 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.
[0096] 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.
[0097] 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 .gtoreq.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 20 mg 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.
[0098] No subject met this primary endpoint therefore all subjects
continued to phase B of the study. No subject experienced a
.gtoreq.20% decrease in FEV1 during the aspirin challenge (phase
B). At baseline, FEV1 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. At
baseline, 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.
[0099] Safety evaluations included spirometry, NIFR, TNSS, adverse
events, & vital signs. No serious adverse events (SAE) or
treatment-emergent SAEs were reported.
[0100] Additional secondary objectives included evaluating the
treatment groups for the proportion of subjects with a .gtoreq.25%
decrease in peak NIFR (nasal inspiratory flow rate) and the
proportion of subjects with a .gtoreq.25%, 50% and 75% increase in
TNSS (total nasal symptom score) during phase A and phase B. The
results are further described in Table 4 below:
TABLE-US-00004 TABLE 4 Changes from Baseline in NIFR and TNSS
during Phase A and Phase B Phase A Phase B Phase C Ifetroban
Placebo Ifetroban Placebo Ifetroban Placebo No. of Subjects (%) n =
12 n = 4 n = 12 n = 4 n = 12 n = 4 NIFR .gtoreq.25% decrease 2(17)
1(25) 4(33) 1(25) 5(42) 1(25) .gtoreq.25% increase 3(25) 0 7(58)
2(50) 9(75) 2(50) TNSS .gtoreq.25% increase 0 0 3(25) 1(25) 3(25)
1(25) .gtoreq.25% decrease 1(8) 0 2(17) 0 2(17) 0 NIFR = nasal
inspiratory flow rate, TNSS = total nasal symptom score; *Overall
number of subjects may be less than the sum of subjects in phase A
and phase B columns since a subject that experienced an event
during phase A and phase B is counted twice. * Overall number of
subjects may be less than the sum of subjects in phase A and phase
B columns since a subject that experienced an event during phase A
and phase B is counted twice
[0101] Overall there were 6 (38%) subjects that experienced a
>25% decrease in peak NIFR, and 4 (25%) subjects that
experienced a .gtoreq.25% increase in TNSS during the study. As
expected, these events occurred mainly in phase B during the
aspirin desensitization process. Five (42%) subjects receiving
ifetroban and 1 (25%) subject receiving placebo experienced a
.gtoreq.25% decrease in peak NIFR during the study. One subject in
each treatment arm experienced a >25% decrease in peak NIFR
during both phase A and phase B. No one experienced a .gtoreq.50%
or 75% increase or decrease in TNSS during the study. No subject
experienced a .gtoreq.25% increase in TNSS during phase A.
[0102] Conversely, 1 (8%) subject during phase A and 2 (17%)
subjects during phase B experienced a .gtoreq.25% decrease in TNSS
but only in the ifetroban arm. No subject on placebo experienced a
.gtoreq.25% decrease in TNSS during the study. There were 9 (75%)
subjects receiving ifetroban and 2 (50%) subjects receiving placebo
that experienced a .gtoreq.25% increase in peak NIFR during the
study. These increases in peak NIFR occurred mainly in phase B
during the aspirin desensitization process. While no clear trends
were 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.
[0103] No asthmatic reactions were reported or rescue medications
used during phase A prior to aspirin initiation. For this reason,
all 16 subjects treated with IMP continued to phase B. Rescue
medication was only administered as a result of an aspirin-induced
reaction (AIR) during the aspirin desensitization process and no
subject required rescue medication outside the clinic for an
asthmatic reaction throughout the 7-day study period. Two (17%)
subjects on ifetroban and 1 (25%) subject on placebo did not
experience an AIR during the aspirin desensitization process hence
no rescue medication was administered to these 3 (19%) subjects. 1
(10%) subject on the ifetroban arm experienced an AIR yet required
no rescue medication to resolve symptoms. All 3 (100) subjects on
the placebo arm that experienced an AIR required rescue medications
and a greater number of medications on average were needed to
resolve their symptoms compared to subjects on ifetroban that
experienced an AIR. The amount of rescue medication required during
the aspirin challenge (phase B) was evaluated as a secondary
efficacy endpoint. Subjects on the placebo arm required, on
average, 7.33 rescue medications to resolve an aspirin-induced
reaction (AIR), while subjects on ifetroban required a mean of 2.90
rescue medications, a 2.5 fold difference. There is a trend toward
fewer rescue medications in favor of the ifetroban group. A summary
of AIRs and Rescue medication use is provided in Table 5 below:
TABLE-US-00005 TABLE 5 Summary of AERD Phase 2a Data: AIRs and
Rescue Medication Use Ifetroban Placebo All Subjects No. of
Subjects (%) n = 12 n = 4 n = 16 Aspirin-induced Reaction (AIR) Yes
10 (83) 3 (75) 13 (81) No 2 (17) 1 (25) 3 (19) Required Rescue
Medication* Yes 9 (90) 3 (100) 12 (92) No 1 (10) 0 1 (8) Total
Number of 29 22 51 Rescue Medications Mean (SD) 2.90 (2.02) 7.33
(3.79) 3.92 (3.04) Median* 3 9 3 Min, Max* 0, 7 3, 10 0, 10
[0104] There is a trend toward fewer rescue medications in favor of
the ifetroban group.
[0105] The incidence of the AIR provoked at each aspirin dose was
evaluated between treatment groups and summarized in this table.
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. Further information
concerning AERD Phase 2a AIRs by aspirin dose is presented in Table
6 below.
TABLE-US-00006 TABLE 6 Incidence of an AIR by Aspirin Dose No. of
Subjects (%)* Ifetroban Placebo All AIR Subjects Aspirin Dose (mg)
n = 10 n = 3** N = 13 30 0 0 0 60 5(50) 3(100) 8(62) 100 5(50)
1(25) 6(46) 150 0 0 0 325 0 0 0 *Based on AIR population only; **1
subject experienced 1 AIR at 60 mg and 1 AIR at 100 mg hence
counted twice. AIR = Aspirin-induced Reaction
[0106] 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.
[0107] 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.
TABLE-US-00007 TABLE 7 Severity of an AIR by Clinical Manifestation
Category/Feature Ifetroban Placebo All AIR Subjects n = 10 n = 3 N
= 13 All Symptoms* 43 20 63 Mean(SD) 4.3(1.34) 5.00(0.82)
4.50(1.22) Median 4 5 4 Min, Max 3.7 4.6 3.7 <20% decrease in 9
4 13 FEVI Mean 0.9 1 1 Upper Respiratory 25 11 36 Mean 2.5 2.8 2.6
Lower Respiratory 13 5 18 Mean 1.3 1.3 1.3 Ocular 5 4 9 Mean 0.5 1
0.6
[0108] In conclusion, in this clinical study, ifetroban at 200
mg/day was shown to be well tolerated and safe in subjects with a
history of AERD. There was no increase in AEs reported in the
ifetroban group compared to placebo. All subjects completed
treatment and aspirin desensitization. The primary endpoint was
met; ifetroban did not cause a .gtoreq.20% decrease in FEV1. The
results of this small safety study demonstrated that ifetroban was
safe when administered to patients with AERD. In addition, results
from the study suggest the symptoms of aspirin desensitization in
AERD patients may be diminished by the use of ifetroban at a dose
of 200 mg/day.
[0109] The primary endpoint was not met; ifetroban did not cause a
.gtoreq.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. Although the sample size is not sufficient to
demonstrate statistically significant treatment efficacy, these
data are encouraging. Larger studies with longer treatment duration
are needed to make formal conclusions about ifetroban efficacy in
AERD. The results of this small safety study support further
investigations of ifetroban at a therapeutic dose of 200 mg/day for
subjects with AERD.
CONCLUSION
[0110] In the preceding specification, the invention has been
described with reference to specific exemplary embodiments and
examples thereof. It will, however, be evident that various
modifications and changes may be made thereto without departing
from the broader spirit and scope of the invention as set forth in
the claims that follow. The specification and drawings are
accordingly to be regarded in an illustrative manner rather than a
restrictive sense.
REFERENCES
[0111] Armour C L, Johnson P R, Alfredson M L, Black J L.
Characterization of contractile prostanoid receptors on human
airway smooth muscle. Eur J Pharmacol 1989 Jun. 20;
165(2-3):215-22.
[0112] Bochenek G, Nagraba K, Nizankowska E, Szczeklik A. A
controlled study of 9alpha,11beta-PGF2 (a prostaglandin D2
metabolite) in plasma and urine of patients with bronchial asthma
and healthy controls after aspirin challenge. J Allergy Clin
Immunol 2003 April; 111(4):743-9.
[0113] Fischer A R, Rosenberg M A, Lilly C M, Callery J C, Rubin P,
Cohn J, et al. Direct evidence for a role of the mast cell in the
nasal response to aspirin in aspirin-sensitive asthma. J Allergy
Clin Immunol 1994 December; 94(6 Pt 1):1046-56.
[0114] Laidlaw T M, Kidder M S, Bhattacharyya N, Xing W, Shen S,
Milne G L, et al. Cysteinyl leukotriene overproduction in
aspirin-exacerbated respiratory disease is driven by
platelet-adherent leukocytes. Blood 2012 Apr. 19;
119(16):3790-8.
[0115] Liu T, Laidlaw T M, Feng C, Xing W, Shen S, Milne G L, et
al. Prostaglandin E2 deficiency uncovers a dominant role for
thromboxane A2 in house dust mite-induced allergic pulmonary
inflammation. Proc Natl Acad Sci USA 2012 Jul. 31;
109(31):12692-7.
[0116] Liu T, Laidlaw T M, Katz H R, Boyce J A. Prostaglandin E2
deficiency causes a phenotype of aspirin sensitivity that depends
on platelets and cysteinyl leukotrienes. Proc Natl Acad Sci USA
2013 Oct. 15; 110(42):16987-92.
[0117] Murakami M, Naraba H, Tanioka T, Semmyo N, Nakatani Y,
Kojima F, et al. Regulation of prostaglandin E2 biosynthesis by
inducible membrane-associated prostaglandin E2 synthase that acts
in concert with cyclooxygenase-2. J Biol Chem 2000 Oct. 20;
275(42):32783-92.
[0118] Ogletree M L, Allen G T. Interspecies differences in
thromboxane receptors: studies with thromboxane receptor
antagonists in rat and guinea pig smooth muscles. J Pharmacol Exp
Ther. 1992 February; 260(2):789-94.
[0119] Pettipher R, Hansel T T, Armer R. Antagonism of the
prostaglandin D2 receptors DP1 and CRTH2 as an approach to treat
allergic diseases. Nat Rev Drug Discov 2007 April; 6(4):313-25.
[0120] Picado C, Fernandez-Morata J C, Juan M, Roca-Ferrer J,
Fuentes M, Xaubet A, et al. Cyclooxygenase-2 mRNA is downexpressed
in nasal polyps from aspirin-sensitive asthmatics. Am J Respir Crit
Care Med 1999 July; 160(1):291-6.
[0121] Sladek K, Dworski R, Soja J, Sheller J R, Nizankowska E,
Oates J A, et al. Eicosanoids in bronchoalveolar lavage fluid of
aspirin-intolerant patients with asthma after aspirin challenge. Am
J Respir Crit Care Med 1994 April; 149(4 Pt 1):940-6.
[0122] Sousa A, Pfister R, Christie P E, Lane S J, Nasser S M,
Schmitz-Schumann M, et al Enhanced expression of cyclo-oxygenase
isoenzyme 2 (COX-2) in asthmatic airways and its cellular
distribution in aspirin-sensitive asthma. Thorax 1997 November;
52(11):940-5.
[0123] Szczeklik A, Sladek K, Dworski R, Nizankowska E, Soja J,
Sheller J, et al. Bronchial aspirin challenge causes specific
eicosanoid response in aspirin-sensitive asthmatics. Am J Respir
Crit Care Med 1996 December; 154(6 Pt 1):1608-14.
[0124] Yoshimura T, Yoshikawa M, Otori N, Haruna S, Moriyama H.
Correlation between the prostaglandin D(2)/E(2) ratio in nasal
polyps and the recalcitrant pathophysiology of chronic
rhinosinusitis associated with bronchial asthma. Allergol Int 2008
December; 57(4):429-36.
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