U.S. patent application number 17/314251 was filed with the patent office on 2021-12-09 for methods for treating or preventing asthma by administering an il-4r antagonist.
The applicant listed for this patent is REGENERON PHARMACEUTICALS, INC., SANOFI BIOTECHNOLOGY. Invention is credited to Nikhil Amin, Neil Graham, Gianluca Pirozzi, Ariel Teper.
Application Number | 20210380705 17/314251 |
Document ID | / |
Family ID | 1000005784729 |
Filed Date | 2021-12-09 |
United States Patent
Application |
20210380705 |
Kind Code |
A1 |
Amin; Nikhil ; et
al. |
December 9, 2021 |
METHODS FOR TREATING OR PREVENTING ASTHMA BY ADMINISTERING AN IL-4R
ANTAGONIST
Abstract
The invention provides methods for treating or preventing asthma
and associated conditions in a patient. The methods featured in the
invention comprise administering to a subject in need thereof a
therapeutic composition comprising an interleukin-4 receptor
(IL-4R) antagonist, such as an anti-IL-4R antibody.
Inventors: |
Amin; Nikhil; (Chappaqua,
NY) ; Graham; Neil; (Croton-on-Hudson, NY) ;
Pirozzi; Gianluca; (Berkeley Heights, NJ) ; Teper;
Ariel; (Bridgewater, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SANOFI BIOTECHNOLOGY
REGENERON PHARMACEUTICALS, INC. |
Paris
Tarrytown |
NY |
FR
US |
|
|
Family ID: |
1000005784729 |
Appl. No.: |
17/314251 |
Filed: |
May 7, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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16173848 |
Oct 29, 2018 |
11034768 |
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17314251 |
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62742736 |
Oct 8, 2018 |
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62647368 |
Mar 23, 2018 |
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62710381 |
Feb 16, 2018 |
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62579120 |
Oct 30, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07K 16/2866 20130101;
A61K 2039/545 20130101; C07K 2317/76 20130101; A61K 2039/505
20130101; C07K 2317/21 20130101; A61K 31/573 20130101; A61K 39/3955
20130101; A61K 2039/54 20130101; A61P 11/06 20180101; C07K 2317/565
20130101 |
International
Class: |
C07K 16/28 20060101
C07K016/28; A61P 11/06 20060101 A61P011/06; A61K 39/395 20060101
A61K039/395; A61K 31/573 20060101 A61K031/573 |
Foreign Application Data
Date |
Code |
Application Number |
May 4, 2018 |
EP |
18305566.4 |
Claims
1-84. (canceled)
85. A method for treating a subject having moderate-to-severe
asthma and co-morbid moderate-to-severe atopic dermatitis
comprising: administering to the subject a loading dose of an
antibody or an antigen-binding fragment thereof that specifically
binds to interleukin-4 receptor (IL-4R); and administering to the
subject a plurality of maintenance doses of the antibody or the
antigen-binding fragment thereof, wherein the loading dose and the
plurality of maintenance doses are administered as an add-on
maintenance asthma therapy, and wherein the antibody or
antigen-binding fragment thereof comprises three heavy chain CDR
sequences comprising SEQ ID NOs: 3, 4 and 5 respectively, and three
light chain CDR sequences comprising SEQ ID NOs: 6, 7 and 8
respectively.
86-94. (canceled)
95. The method of claim 85, wherein the plurality of maintenance
doses are administered once every other week (q2w).
96. The method of claim 85, wherein the loading dose is about 600
mg of the antibody or the antigen-binding fragment thereof, and
wherein each maintenance dose of antibody or antigen-binding
fragment thereof is about 300 mg.
97. The method of claim 85, wherein the loading dose is about 400
mg of the antibody or the antigen-binding fragment thereof, and
wherein each maintenance dose of antibody or antigen-binding
fragment thereof is about 200 mg.
98. The method of claim 85, wherein the maintenance doses of
antibody or antigen-binding fragment thereof are administered for
at least 24 weeks.
99. The method of claim 85, wherein the subject is 12 years of age
or older.
100. The method of claim 85, wherein the subject has a blood
eosinophil count of greater than about 300 cells/.mu.l.
101. The method of claim 85, wherein the moderate-to-severe asthma
is uncontrolled with ICS and one or two controller medications.
102. The method of claim 101, wherein the controller medications
are selected from a long-acting .beta..sub.2 agonist and a
leukotriene receptor antagonist.
103. The method of claim 85, wherein the antibody or
antigen-binding fragment thereof comprises a heavy chain variable
region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1
and a light chain variable region (LCVR) comprising the amino acid
sequence of SEQ ID NO: 2.
104. The method of claim 103, wherein the antibody is
dupilumab.
105. The method of claim 85, wherein the antibody or
antigen-binding fragment thereof is administered by a prefilled
needle and syringe, a prefilled autoinjector delivery device or a
prefilled pen delivery device.
106. A method for improving one or more asthma-associated
parameter(s) in a subject having moderate-to-severe asthma and
co-morbid moderate-to-severe atopic dermatitis comprising:
administering to the subject a loading dose of an antibody or an
antigen-binding fragment thereof that specifically binds to
interleukin-4 receptor (TL-4R); and administering to the subject a
plurality of maintenance doses of the antibody or the
antigen-binding fragment thereof, wherein the loading dose and the
plurality of maintenance doses are administered as an add-on
maintenance asthma therapy, and wherein the antibody or
antigen-binding fragment thereof comprises three heavy chain CDR
sequences comprising SEQ ID NOs: 3, 4 and 5 respectively, and three
light chain CDR sequences comprising SEQ ID NOs: 6, 7 and 8
respectively.
107. The method of claim 106, wherein the improvement in an
asthma-associated parameter is selected from the group consisting
of: (a) an improvement in lung function as measured by forced
expiratory volume (FEV.sub.1) or by forced expiratory flow at
25-75% of the pulmonary volume (FEF25-75), (b) a decrease in daily
albuterol or levalbuterol use, (c) a decrease in daily oral
corticosteroids (OCS) use, (d) a decrease of five-item Asthma
Control Questionnaire (ACQ5) score, and (e) a decrease of 22-item
Sinonasal Outcome Test (SNOT-22) score.
108. The method of claim 106, wherein the loading dose is about 600
mg of the antibody or the antigen-binding fragment thereof, and
wherein each maintenance dose of antibody or antigen-binding
fragment thereof is about 300 mg.
109. The method of claim 106, wherein the loading dose is about 400
mg of the antibody or the antigen-binding fragment thereof, and
wherein each maintenance dose of antibody or antigen-binding
fragment thereof is about 200 mg.
110. A method for reducing the incidence of asthma exacerbations in
a subject having moderate-to-severe asthma and co-morbid
moderate-to-severe atopic dermatitis comprising: administering to
the subject a loading dose of an antibody or an antigen-binding
fragment thereof that specifically binds to interleukin-4 receptor
(TL-4R); and administering to the subject a plurality of
maintenance doses of the antibody or the antigen-binding fragment
thereof, wherein the loading dose and the plurality of maintenance
doses are administered as an add-on maintenance asthma therapy, and
wherein the antibody or antigen-binding fragment thereof comprises
three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4 and 5
respectively, and three light chain CDR sequences comprising SEQ ID
NOs: 6, 7 and 8 respectively.
111. The method of claim 110, wherein the subject experiences a
reduction in annualized severe asthma exacerbations.
112. The method of claim 110, wherein the loading dose is about 600
mg of the antibody or the antigen-binding fragment thereof, and
wherein each maintenance dose of antibody or antigen-binding
fragment thereof is about 300 mg.
113. The method of claim 100, wherein the loading dose is about 400
mg of the antibody or the antigen-binding fragment thereof, and
wherein each maintenance dose of antibody or antigen-binding
fragment thereof is about 200 mg.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/173,848 filed Oct. 29, 2018 which claims
the benefit of U.S. Provisional Application Nos. 62/579,120 filed
Oct. 30, 2017; 62/710,381 filed Feb. 16, 2018; 62/647,368 filed
Mar. 23, 2018 and 62/742,736 filed Oct. 8, 2018 and EP Application
No. EP18305566.4 filed May 4, 2018 each of which is incorporated
herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The invention relates to the treatment and/or prevention of
asthma and related conditions. More specifically, the invention
relates to the administration of an interleukin-4 receptor (IL-4R)
antagonist to treat or prevent asthma in a patient in need
thereof.
BACKGROUND
[0003] Asthma is a chronic inflammatory disease of the airways
characterized by airway hyper responsiveness, acute and chronic
bronchoconstriction, airway edema, and mucus plugging. The
inflammation component of asthma is thought to involve many cell
types, including mast cells, eosinophils, T lymphocytes,
neutrophils, and epithelial cells, and their biological products.
Patients with asthma most often present with symptoms of wheezing,
shortness of breath, cough, and chest tightness. For most asthma
patients, a regimen of controller therapy and bronchodilator
therapy provides adequate long-term control. Inhaled
corticosteroids (ICS) are considered the "gold standard" in
controlling asthma symptoms, and inhaled beta2-agonists are the
most effective bronchodilators currently available. Studies have
shown that combination therapy of an ICS with an inhaled
long-acting beta2-agonist (LABA) provides better asthma control
than high doses of ICS alone. Consequently, combination therapy has
been the recommended treatment for subjects who are not controlled
on low doses of ICS alone.
[0004] Nonetheless, it is estimated that 5% to 10% of the
population with asthma has symptomatic disease despite maximum
recommended treatment with combinations of anti-inflammatory and
bronchodilator drugs. Furthermore, this severe asthma population
accounts for up to 50% of the total health cost through hospital
admissions, use of emergency services, and unscheduled physician
visits. There is an unmet need for a new therapy in this severe
asthma population as many of these patients are poorly responsive
to ICS due to a number of cellular and molecular mechanisms. In
addition, the long term adverse effects of systemic and inhaled
corticosteroids on bone metabolism, adrenal function, and growth in
children lead to attempts to minimize the amount of corticosteroid
usage. Although a large portion of asthma patients are managed
reasonably well with current treatments, patients with severe
uncontrolled asthma (e.g., severe corticosteroid-refractory asthma
or steroid-intolerant asthma) have few therapeutic treatment
options that can adequately control the disease. The consequence of
unresponsiveness to therapy or lack of compliance with therapy is
loss of asthma control and ultimately asthma exacerbation.
[0005] An estimated 45% of patients with severe asthma require
systemic glucocorticoids to control their disease, and to prevent
life-threatening exacerbations associated with increased risk of
permanent damage to lung tissue, progressive fixed airway
obstruction, and accelerated decline in lung function. However,
systemic glucocorticoids act non-selectively and are associated
with significant multi-organ toxicities and broad
immunosuppression. There is a need for safer and more effective
targeted therapies that prevent exacerbations and lung function
impairment, improve asthma symptoms and control, and reduce or
obviate the need for oral glucocorticoids.
[0006] Approximately 20% of patients with asthma have uncontrolled,
moderate-to-severe disease with recurrent exacerbations and
persistent symptoms despite maximized standard-of-care controller
therapy. This population is at an increased risk of morbidity
(especially exacerbations) and accounts for significant healthcare
resources. These patients have substantially reduced lung function,
despite maximum treatment, and are destined to inexorably further
lose lung function. No currently approved treatments have been
shown to slow this inexorable decline in these patients, or to
consistently and meaningfully increase lung function.
[0007] Accordingly, a need exists in the art for novel targeted
therapies for the treatment and/or prevention of asthma.
BRIEF SUMMARY OF THE INVENTION
[0008] According to one aspect, a method for treating a subject
having severe uncontrolled asthma (e.g., severe steroid-dependent
asthma) comprising administering to the subject a loading dose of
an antibody or an antigen-binding fragment thereof that
specifically binds to interleukin-4 receptor (IL-4R), and
administering to the subject a plurality of maintenance doses of
the antibody or the antigen-binding fragment thereof, wherein the
plurality of maintenance doses are administered during a treatment
phase comprising an induction phase, an oral corticosteroid (OCS)
reduction phase, and an OCS maintenance phase is provided.
[0009] In certain exemplary embodiments, a maintenance dose of
antibody or antigen-binding fragment thereof is administered once
every other week (q2w). In certain exemplary embodiments, a
maintenance dose of antibody or antigen-binding fragment thereof is
administered every fourth week (q4w).
[0010] In certain embodiments, the subject is administered a
loading dose, and the subject is administered a maintenance dose
having a dose regimen of 500 mg q4w or 750 mg q4w.
[0011] In certain embodiments, the loading dose is eliminated. In
certain embodiments, the subject is administered a dose regimen of
500 mg q4w or 750 mg q4w.
[0012] In certain exemplary embodiments, the loading dose is about
600 mg of the antibody or the antigen-binding fragment thereof,
and/or each maintenance dose of antibody or antigen-binding
fragment thereof is about 300 mg of the antibody or the
antigen-binding fragment thereof.
[0013] In certain exemplary embodiments, the maintenance doses of
antibody or antigen-binding fragment thereof are administered for
at least 24 weeks.
[0014] In certain exemplary embodiments, a first maintenance dose
of antibody or antigen-binding fragment thereof is administered two
weeks after the loading dose of antibody or antigen-binding
fragment thereof.
[0015] In certain exemplary embodiments, the OCS reduction phase is
about 16 weeks in length.
[0016] In certain exemplary embodiments, OCS use by the subject is
reduced during the OCS reduction phase. In certain exemplary
embodiments, the subject uses 50% or less, 75% or less or 90% or
less OCS in the maintenance phase compared to the induction phase.
In certain exemplary embodiments, OCS use by the subject is reduced
to about 5 mg/day or less in the maintenance phase. In other
exemplary embodiments, the OCS is reduced and/or eliminated, for
example the subject is weaned off of the previous OCS dose. In
certain exemplary embodiments, the administration of the OCS is
completely eliminated from a treatment regimen.
[0017] In certain exemplary embodiments, the subject has a blood
eosinophil count of less than or equal to about 150 cells/.mu.l. In
certain exemplary embodiments, the subject has a blood eosinophil
count of greater than about 150 cells/.mu.l. In certain exemplary
embodiments, the subject has a blood eosinophil count of greater
than about 300 cells/.mu.l.
[0018] In certain exemplary embodiments, the subject experiences a
reduction in annualized severe asthma exacerbations. In certain
exemplary embodiments, the subject experiences an improvement in
lung function as measured by forced expiratory volume (FEV.sub.1).
In other embodiments, the subject exhibits an improvement in small
airway lung function and/or a reduction in small airway
inflammation. In certain embodiments, the improvement in lung
function and reduction in inflammation is measured by forced
expiratory flow at 25-75% of the pulmonary volume (FEF25-75).
[0019] In certain exemplary embodiments, OCS use by the subject is
optimized prior to treatment with the antibody or antigen-binding
fragment thereof. In certain exemplary embodiments, the OCS is
prednisone or prednisolone.
[0020] In certain exemplary embodiments, the antibody or
antigen-binding fragment thereof comprises heavy and light chain
complementary determining region (CDR) sequences from the heavy
chain variable region (HCVR)/light chain variable region (LCVR)
sequence pair comprising SEQ ID NOs: 1 and 2 In certain exemplary
embodiments, the antibody or antigen-binding fragment thereof
comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3,
4 and 5 respectively, and three light chain CDR sequences
comprising SEQ ID NOs: 6, 7 and 8 respectively. In certain
exemplary embodiments, the antibody or antigen-binding fragment
thereof comprises a HCVR comprising the amino acid sequence of SEQ
ID NO: 1 and a LCVR comprising the amino acid sequence of SEQ ID
NO: 2.
[0021] In certain exemplary embodiments, the subject is an adult.
In certain exemplary embodiments, the subject is an adolescent. In
certain exemplary embodiments, the subject is an adult or an
adolescent, e.g., is 12 years or older.
[0022] In another aspect, a method for treating a subject having
severe uncontrolled asthma (e.g., severe steroid-dependent asthma)
comprising administering to the subject a loading dose of an
antibody or an antigen-binding fragment thereof that specifically
binds to interleukin-4 receptor (IL-4R), and administering to the
subject a plurality of maintenance doses of the antibody or the
antigen-binding fragment thereof, wherein the plurality of
maintenance doses are administered during a treatment phase
comprising an induction phase, an oral corticosteroid (OCS)
reduction phase, and a maintenance phase, and wherein the antibody
or antigen-binding fragment thereof comprises heavy and light chain
CDR sequences from the HCVR/LCVR sequence pair comprising SEQ ID
NOs: 1 and 2 is provided.
[0023] In another aspect, a method for treating a subject having
severe uncontrolled asthma, e.g., severe steroid-dependent asthma,
comprising administering to the subject a loading dose of about 600
mg of an antibody or an antigen-binding fragment thereof that
specifically binds to interleukin-4 receptor (IL-4R), and
administering to the subject a plurality of maintenance doses of
the antibody or the antigen-binding fragment thereof, wherein each
maintenance dose is about 300 mg of the antibody or antigen-binding
fragment thereof, wherein the plurality of maintenance doses are
administered during a treatment phase comprising an induction
phase, an oral corticosteroid (OCS) reduction phase, and a
maintenance phase, and wherein the antibody or antigen-binding
fragment thereof comprises heavy and light chain CDR sequences from
the HCVR/LCVR sequence pair comprising SEQ ID NOs: 1 and 2 is
provided.
[0024] In another aspect, a method for reducing an annualized
severe exacerbation rate in a subject having moderate-to-severe
uncontrolled asthma, comprising administering to the subject q2w or
q4w an antibody or an antigen-binding fragment thereof that
specifically binds to IL-4R, is provided.
[0025] In certain exemplary embodiments, the dosage is 200 mg q2w,
or 300 mg q2w.
[0026] In certain exemplary embodiments, a maintenance dose of
antibody or antigen-binding fragment thereof is administered every
fourth week (q4w).
[0027] In certain embodiments, the subject is administered a
loading dose and maintenance doses, and the subject is administered
a dose regimen of 500 mg q4w or 750 mg q4w.
[0028] In certain embodiments, the loading dose is eliminated. In
certain embodiments, the subject is administered a dose regimen of
500 mg q4w or 750 mg q4w.
[0029] In certain exemplary embodiments, the subject has a blood
eosinophil count of less than about 150 cells/.mu.l, of greater
than or equal to about 150 cells/.mu.l, or of greater than about
300 cells/.mu.l.
[0030] In certain exemplary embodiments, the subject has a
fractional exhaled nitric oxide (FeNO) level of greater than or
equal to about 25 parts per billion (ppb), has an FeNO level of
greater than or equal to about 50 ppb, or has an FeNO level of
between greater than or equal to about 25 ppb and about 50 ppb.
[0031] In another aspect, a method for improving an FEV.sub.1 score
in a subject having uncontrolled moderate-to-severe asthma,
comprising administering to the subject q2w or q4w an antibody or
an antigen-binding fragment thereof that specifically binds to
IL-4R, is provided.
[0032] In certain exemplary embodiments, the dosage is administered
at 200 mg q2w or 300 mg q2w. In certain exemplary embodiments, the
dosage is administered at 500 mg q4w or 750 mg q4w.
[0033] In certain exemplary embodiments, the subject has a blood
eosinophil count of less than about 150 cells/.mu.l, of greater
than or equal to about 150 cells/.mu.l, or of greater than about
300 cells/.mu.l.
[0034] In certain exemplary embodiments, the subject has a
fractional exhaled nitric oxide (FeNO) level of greater than or
equal to about 25 parts per billion (ppb), has an FeNO level of
greater than or equal to about 50 ppb, or has an FeNO level of
between greater than or equal to about 25 ppb and about 50 ppb.
[0035] In another embodiment, the subject exhibits at least a 10%,
15%, 20% or 25% reduction in a biomarker selected from the group
consisting of FeNO, eotaxin-3 total IgE, periostin and thymus and
activation regulated chemokine (TARC) at week 4 week 12 or week 24
following administration of the IL-4R antibody or fragment
thereof.
[0036] In certain exemplary embodiments, the subject is an adult.
In certain exemplary embodiments, the subject is an adolescent. In
certain exemplary embodiments, the subject is an adult or an
adolescent, e.g., is 12 years or older.
[0037] In other aspects, the disclosure provides a method for
improving a forced expiratory flow at 25-75% of the pulmonary
volume (FEF25-75) score in a subject having uncontrolled
moderate-to-severe asthma, comprising administering to the subject
q2w or q4w an antibody or an antigen-binding fragment thereof that
specifically binds to IL-4R.
[0038] In one embodiment, the dosage is 200 mg q2w or 300 mg q2w.
In one embodiment, the dosage is 500 mg q4w or 750 mg q4w.
[0039] In one embodiment, the subject has a blood eosinophil count
of less than about 150 cells/.mu.l. In one embodiment, the subject
has a blood eosinophil count of greater than or equal to about 150
cells/.mu.l. In one embodiment, the subject has a blood eosinophil
count of greater than about 300 cells/.mu.l.
[0040] In another embodiment, the subject has an FeNO level of
greater than or equal to about 25 ppb. In another embodiment, the
subject has an FeNO level of greater than or equal to about 50 ppb.
In another embodiment, the subject has an FeNO level of between
greater than or equal to about 25 ppb and about 50 ppb.
[0041] In another embodiment, the subject exhibits at least a 10%,
at least a 15%, at least a 20%, or at least a 25% reduction in a
biomarker selected from the group consisting of FeNO, eotaxin-3
total IgE, periostin and thymus and activation regulated chemokine
(TARC) at week 4 week 12 or 24 following administration of the IL4R
antibody or fragment thereof.
[0042] In certain exemplary embodiments, the subject is an adult.
In certain exemplary embodiments, the subject is an adolescent. In
certain exemplary embodiments, the subject is an adult or an
adolescent, e.g., is 12 years or older.
[0043] In another aspect, the disclosure provides a method of
reducing or eliminating OCS use in a subject suffering from steroid
dependent severe asthma, the method comprising administering to the
subject a loading dose of an antibody or an antigen-binding
fragment thereof that specifically binds to an IL-4R; and
administering to the subject a plurality of maintenance doses of
the antibody or the antigen-binding fragment thereof, wherein a
reduction of at least 50% or greater, of at least 75% or greater,
or of at least 90% or greater in OCS use is achieved at week 24
following administration of the loading dose.
[0044] In one embodiment, the OCS use is reduced to less than 5 mg
per day at week 24 following administration of the loading dose. In
another embodiment, the OCS is substantially eliminated after a
period of time (e.g., 1 year) following administration of the
loading dose. In certain embodiments, the OCS is substantially
eliminated after 40 weeks, 45 weeks, 50 weeks, 52 weeks or greater
after first dose following administration of the loading dose.
[0045] In one embodiment, the maintenance dose of antibody or
antigen-binding fragment thereof is administered once every other
week (q2w). In one embodiment, the loading dose is about 600 mg of
the antibody or the antigen-binding fragment thereof. In one
embodiment, each maintenance dose of antibody or antigen-binding
fragment thereof is about 300 mg of the antibody or the
antigen-binding fragment thereof. In another embodiment, the
maintenance doses of antibody or antigen-binding fragment thereof
are administered for at least 24 weeks. In one embodiment, a first
maintenance dose of antibody or antigen-binding fragment thereof is
administered two weeks after the loading dose of antibody or
antigen-binding fragment thereof. In one embodiment, the OCS is
prednisone or prednisolone.
[0046] In one embodiment, the antibody or antigen-binding fragment
thereof comprises heavy and light chain complementary determining
region (CDR) sequences from the heavy chain variable region
(HCVR)/light chain variable region (LCVR) sequence pair comprising
SEQ ID NOs: 1 and 2 In one embodiment, the antibody or
antigen-binding fragment thereof comprises three heavy chain CDR
sequences comprising SEQ ID NOs: 3, 4 and 5 respectively, and three
light chain CDR sequences comprising SEQ ID NOs: 6, 7 and 8
respectively. In one embodiment, the antibody or antigen-binding
fragment thereof comprises a HCVR comprising the amino acid
sequence of SEQ ID NO: 1 and a LCVR comprising the amino acid
sequence of SEQ ID NO: 2.
[0047] In certain exemplary embodiments, a maintenance dose of
antibody or antigen-binding fragment thereof is administered every
fourth week (q4w).
[0048] In certain embodiments, the subject is administered a
loading dose is administered, and the subject is administered a
dose regimen of 500 mg q4w, and 750 mg q4w.
[0049] In certain embodiments, the loading dose is eliminated. In
certain embodiments, the subject is administered a dose regimen of
500 mg q4w, and 750 mg q4w.
[0050] In certain exemplary embodiments, the subject is an adult.
In certain exemplary embodiments, the subject is an adolescent. In
certain exemplary embodiments, the subject is an adult or an
adolescent, e.g., is 12 years or older.
[0051] In another aspect, a method for treating a subject having
oral corticosteroid (OCS)-dependent, moderate-to-severe asthma is
provided, comprising administering to the subject a loading dose of
an antibody or an antigen-binding fragment thereof that
specifically binds to interleukin-4 receptor (IL-4R), and
administering to the subject a plurality of maintenance doses of
the antibody or the antigen-binding fragment thereof, wherein the
loading dose and the plurality of maintenance doses are
administered as an add-on maintenance asthma therapy.
[0052] In certain exemplary embodiments, the antibody or
antigen-binding fragment thereof comprises heavy and light chain
complementary determining region (CDR) sequences from the heavy
chain variable region (HCVR)/light chain variable region (LCVR)
sequence pair comprising SEQ ID NOs: 1 and 2 In certain exemplary
embodiments, the antibody or antigen-binding fragment thereof
comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3,
4 and 5 respectively, and three light chain CDR sequences
comprising SEQ ID NOs: 6, 7 and 8 respectively. In certain
exemplary embodiments, the antibody or antigen-binding fragment
thereof comprises a HCVR comprising the amino acid sequence of SEQ
ID NO: 1 and a LCVR comprising the amino acid sequence of SEQ ID
NO: 2.
[0053] In certain exemplary embodiments, the loading dose is about
600 mg of the antibody or the antigen-binding fragment thereof. In
certain exemplary embodiments, each maintenance dose of antibody or
antigen-binding fragment thereof is about 300 mg of the antibody or
the antigen-binding fragment thereof.
[0054] In certain exemplary embodiments, the loading dose is about
400 mg of the antibody or the antigen-binding fragment thereof. In
certain exemplary embodiments, each maintenance dose of antibody or
antigen-binding fragment thereof is about 200 mg of the antibody or
the antigen-binding fragment thereof.
[0055] In certain exemplary embodiments, the subject is 12 years of
age or older.
[0056] In certain exemplary embodiments, the OCS is prednisone or
prednisolone.
[0057] In another aspect, a method for treating a subject having
moderate-to-severe asthma and co-morbid moderate-to-severe atopic
dermatitis is provided, comprising administering to the subject a
loading dose of an antibody or an antigen-binding fragment thereof
that specifically binds to interleukin-4 receptor (IL-4R), and
administering to the subject a plurality of maintenance doses of
the antibody or the antigen-binding fragment thereof, wherein the
loading dose and the plurality of maintenance doses are
administered as an add-on maintenance asthma therapy.
[0058] In another aspect, a method for treating a subject having
moderate-to-severe uncontrolled asthma wherein onset of asthma
occurred when the subject was greater than 40 years of age is
provided, comprising administering to the subject a loading dose of
an antibody or an antigen-binding fragment thereof that
specifically binds to interleukin-4 receptor (IL-4R), and
administering to the subject a plurality of maintenance doses of
the antibody or the antigen-binding fragment thereof, wherein the
loading dose and the plurality of maintenance doses are
administered as an add-on maintenance asthma therapy.
[0059] In another aspect, a method for treating a subject having
moderate-to-severe uncontrolled asthma and one or both of co-morbid
chronic rhinosinusitis and nasal polyposis is provided, comprising
administering to the subject a loading dose of an antibody or an
antigen-binding fragment thereof that specifically binds to
interleukin-4 receptor (IL-4R), and administering to the subject a
plurality of maintenance doses of the antibody or the
antigen-binding fragment thereof, wherein the loading dose and the
plurality of maintenance doses are administered as an add-on
maintenance asthma therapy.
[0060] In another aspect, a method for treating a subject having
moderate-to-severe uncontrolled asthma and co-morbid allergic
rhinitis is provided, comprising administering to the subject a
loading dose of an antibody or an antigen-binding fragment thereof
that specifically binds to interleukin-4 receptor (IL-4R), and
administering to the subject a plurality of maintenance doses of
the antibody or the antigen-binding fragment thereof, wherein the
loading dose and the plurality of maintenance doses are
administered as an add-on maintenance asthma therapy.
[0061] In another aspect, a method for improving allergic
rhinitis-related quality of life of a subject having
moderate-to-severe uncontrolled asthma and co-morbid allergic
rhinitis is provided, comprising administering to the subject a
loading dose of an antibody or an antigen-binding fragment thereof
that specifically binds to interleukin-4 receptor (IL-4R), and
administering to the subject a plurality of maintenance doses of
the antibody or the antigen-binding fragment thereof, wherein the
loading dose and the plurality of maintenance doses are
administered as an add-on maintenance asthma therapy.
[0062] In another aspect, a method for improving allergic
rhinitis-related quality of life in a subject having oral
corticosteroid-dependent asthma is provided, comprising
administering to the subject a loading dose of an antibody or an
antigen-binding fragment thereof that specifically binds to
interleukin-4 receptor (IL-4R), and administering to the subject a
plurality of maintenance doses of the antibody or the
antigen-binding fragment thereof, wherein the loading dose and the
plurality of maintenance doses are administered as an add-on
maintenance asthma therapy.
[0063] In certain exemplary embodiments, morning and evening daily
asthma symptoms are improved.
[0064] In certain exemplary embodiments, the oral
corticosteroid-dependent asthma is oral corticosteroid-dependent
severe asthma.
[0065] In another aspect, a method for improving asthma control in
a subject having oral corticosteroid-dependent asthma is provided,
comprising administering to the subject a loading dose of an
antibody or an antigen-binding fragment thereof that specifically
binds to interleukin-4 receptor (IL-4R), and administering to the
subject a plurality of maintenance doses of the antibody or the
antigen-binding fragment thereof, wherein the loading dose and the
plurality of maintenance doses are administered as an add-on
maintenance asthma therapy.
[0066] In certain exemplary embodiments, health related quality of
life is improved.
[0067] In certain exemplary embodiments, the oral
corticosteroid-dependent asthma is oral corticosteroid-dependent
severe asthma.
[0068] Other embodiments will become apparent from a review of the
ensuing detailed description, drawings, tables and accompanying
claims.
BRIEF DESCRIPTION OF THE FIGURES
[0069] The foregoing and other features and advantages of the
present invention will be more fully understood from the following
detailed description of illustrative embodiments taken in
conjunction with the accompanying drawings. The file of this patent
contains at least one drawing/photograph executed in color. Copies
of this patent with color drawing(s)/photograph(s) will be provided
by the Office upon request and payment of the necessary fee.
[0070] FIG. 1 depicts the Venture (EFC13691) study design for the
phase 3 trial. EOS denotes end of study, EOT end of treatment, OCS
oral glucocorticoid, q2w every 2 weeks, R Randomization visit.
.sup.a600 mg (or matching placebo) loading dose on day 1;
.sup.brandomization and first investigational medicinal product
administration occurred at this visit; .sup.cthe screening period
could be increased to 10 weeks for patients experiencing an asthma
exacerbation that required a change in glucocorticoid dose to allow
for 2 weeks of stabilization prior to randomization.
[0071] FIG. 2 depicts a CONSORT diagram showing the patient
disposition for the Venture (EFC13691) study.
[0072] FIG. 3 is a chart showing the baseline demographics for the
patient population.
[0073] FIG. 4A FIG. 4D graphically depict primary and secondary
endpoints during the 24-week treatment period in an intent to treat
(ITT) population. FIG. 4A depicts primary and secondary oral
glucocorticoid endpoints at week 24 FIG. 4B depicts the annualized
rate of severe exacerbations. FIG. 4C depicts change in
pre-bronchodilator FEV.sub.1 (in L). FIG. 4D depicts and change in
FeNO (in ppb).
[0074] FIG. 5A FIG. 5B depict week 24 results by baseline blood
eosinophil subgroups. FIG. 5A depicts primary endpoint data. FIG.
5B depicts secondary oral glucocorticoid endpoint data.
[0075] FIG. 6A FIG. 6B depict severe Asthma Exacerbations (FIG. 6A)
and pre-bronchodilator FEV.sub.1 (L) (FIG. 6B) during the 24-week
treatment period by baseline blood eosinophil subgroups.
[0076] FIG. 7 depicts the Quest study design for the phase 3
trial.
[0077] FIG. 8 is the patient disposition for the Quest study.
[0078] FIG. 9A FIG. 9B graphically depict severe asthma
exacerbations in the ITT population and in subgroups defined by
baseline blood eosinophils .gtoreq.150 and .gtoreq.300 cells/.mu.l
(FIG. 9A) and subgroups defined by baseline FeNO Levels <25 ppb,
.gtoreq.25 to 50 ppb and .gtoreq.50 ppb (FIG. B).
[0079] FIG. 10A FIG. 10C depict change from baseline in FEV.sub.1
over time in the ITT population (FIG. 10 A), at week 12 in
subgroups defined by baseline blood eosinophils .gtoreq.150 and
.gtoreq.300 cells/.mu.l (FIG. 10 B), and subgroups defined by
baseline FeNO Levels <25 ppb, .gtoreq.25 to 50 ppb, and
.gtoreq.50 ppb (FIG. 10 C).
[0080] FIG. 11A FIG. 11B graphically depict post hoc analysis of
severe asthma exacerbations (FIG. 11 A) and change from baseline in
FEV.sub.1 (FIG. 11 B) in patients with high (.gtoreq.25 ppb) or low
(<25 ppb) baseline FeNO levels and high (.gtoreq.150
cells/.mu.l) or low (<150 cells/.mu.l) baseline blood
eosinophils.
[0081] FIG. 12 depicts baseline demographics and clinical
characteristics of adolescents (n=107) and adults (n=1795). Bold
text highlights key differences between subgroups. FeNO,
fractionated exhaled nitric oxide; LABA, long-acting
.beta.-agonist; SD, standard deviation.
[0082] FIG. 13A FIG. 13B graphically depict a reduction in severe
exacerbations and improved FEV.sub.1 in the overall intent-to-treat
(ITT) population. Light grey circles, 1.14 mL placebo; dark grey
circles, 2 mL placebo; triangles, 200 mg q2w dupilumab; Xs, 300 mg
q2w dupilumab. ***P<0.001 vs. placebo. CI, confidence interval;
LS, least squares; SE, standard error; arrow, primary endpoint.
[0083] FIG. 14A FIG. 14B graphically depict a reduction in severe
exacerbation rates in adolescents and adults. Light grey circles,
1.14 mL placebo; dark grey circles, 2 mL placebo; orange, 200 mg
q2w dupilumab; blue, 300 mg q2w dupilumab. ***P<0.001 vs.
placebo; NS, non-significant.
[0084] FIG. 15A FIG. 15B graphically depict improved FEV.sub.1 at
week 12 and at week 52 in adolescents and adults. Despite higher
baseline levels, adolescents had a greater increase in FEV.sub.1
*P<0.05, **P<0.01 ***P<0.001 vs. placebo.
[0085] FIG. 16A FIG. 16B graphically depict improved FEV.sub.1
during the 52-week treatment period in adolescents and adults.
*P<0.05 **P<0.01 vs. placebo.
[0086] FIG. 17 depicts that the adverse event profiled was
comparable between subgroups (safety population). Eosinophilia is
identified as AE with HLT as eosinophilic disorders, or PT as
eosinophil count increased. HLT, high-level term; PT, preferred
term; SAE, severe adverse event; TEAE, treatment-emergent adverse
event.
[0087] FIG. 18A FIG. 18B graphically depicts an improvement in
percent predicted FEV.sub.1 during the 52-week treatment period in
adolescents and adults. Light grey circles, 1.14 mL placebo; dark
grey circles, 2 mL placebo; triangles, 200 mg q2w dupilumab; Xs,
300 mg q2w dupilumab. *P<0.05, **P<0.01 vs. placebo.
[0088] FIG. 19A FIG. 19B graphically depict FeNO levels during the
52-week treatment period in adolescents and adults. Light grey
circles, 1.14 mL placebo; dark grey circles, 2 mL placebo;
triangles, 200 mg q2w dupilumab; Xs, 300 mg q2w dupilumab.
*P<0.05 **P<0.01 ***P<0.001 vs. placebo.
[0089] FIG. 20A FIG. 20B graphically depict ACQ-5 scores during the
52-week treatment period in adolescents and adults. Light grey
circles, 1.14 mL placebo; dark grey circles, 2 mL placebo;
triangles, 200 mg q2w dupilumab; Xs, 300 mg q2w dupilumab.
*P<0.05 **P<0.01 ***P<0.001 vs. placebo.
[0090] FIG. 21A FIG. 21B graphically depict AQLQ scores during the
52-week treatment period in adolescents and adults. Light grey
circles, 1.14 mL placebo; dark grey circles, 2 mL placebo;
triangles, 200 mg q2w dupilumab; Xs, 300 mg q2w dupilumab.
*P<0.05 **P<0.01 ***P<0.001 vs. placebo.
[0091] FIG. 22 depicts TEAEs (PT) occurring in .gtoreq.10% of
patients according to adolescent and adult subgroups (safety
population).
[0092] FIG. 23 depicts conjunctivitis TEAE information (safety
population).
[0093] FIG. 24 depicts eosinophilia TEAE information (safety
population). Eosinophilia is identified as AE with HLT as
eosinophilic disorders, or PT as eosinophil count increased.
[0094] FIG. 25A FIG. 25D depict the effect of dupilumab during the
24-week treatment period on AM symptom scores in the ITT population
(FIG. 25A) and the subgroup of patients who reduced OCS use by 100%
by week 24 (FIG. 25B), as well as on PM symptom scores in the ITT
population (FIG. 25C) and the subgroup of patients who reduced OCS
use by 100% by week 24 (FIG. 25D). *P<0.05, ***P<0.001 SE,
standard error. Triangles, placebo; circles, 300 mg q2w
dupilumab.
[0095] FIG. 26A FIG. 26B depict the effect of dupilumab on asthma
control and HRQoL in patients with OCS-dependent severe asthma,
showing ACQ-5 score (FIG. 26A) and AQLQ global score (FIG. 26B).
*P<0.05 *P<0.01 ***P<0.001 SE, standard error. The minimum
clinically important difference is 0.5 for all scales. Triangles,
placebo; circles, 300 mg q2w dupilumab.
[0096] FIG. 27A FIG. 27B depict the effect of dupilumab on severe
exacerbation rate, FEV1 and FEV1/FVC ratio in patients with
uncontrolled, moderate-severe-asthma who were >40 years old at
the onset of asthma, and had baseline post-bronchodilator
FEV1/FVC<0.7 or .gtoreq.0.7.
DETAILED DESCRIPTION
[0097] Before the invention is described, it is to be understood
that this invention is not limited to particular methods and
experimental conditions described, as such methods and conditions
may vary. It is also to be understood that the terminology used
herein is for the purpose of describing particular embodiments
only, and is not intended to be limiting, because the scope of the
invention will be limited only by the appended claims.
[0098] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs.
[0099] As used herein, the term "about," when used in reference to
a particular recited numerical value, means that the value may vary
from the recited value by no more than 1%. For example, as used
herein, the expression "about 100" includes 99 and 101 and all
values in between (e.g., 99.1, 99.2, 99.3, 99.4 etc.).
[0100] As used herein, the terms "treat," "treating," or the like,
mean to alleviate symptoms, eliminate the causation of symptoms
either on a temporary or permanent basis, or to prevent or slow the
appearance of symptoms of the named disorder or condition.
[0101] Although any methods and materials similar or equivalent to
those described herein can be used in the practice of the
invention, the typical methods and materials are now described. All
publications mentioned herein are incorporated herein by reference
in their entirety.
Methods for Reducing the Incidence of Asthma Exacerbations
[0102] The invention includes methods for reducing the incidence of
asthma exacerbations in a subject in need thereof comprising
administering a pharmaceutical composition comprising an IL-4R
antagonist to the subject. According to certain embodiments, the
IL-4R antagonist is an antibody or antigen-binding fragment thereof
that specifically binds IL-4R. Exemplary anti-IL-4R antibodies that
can be used in the context of the methods featured in the invention
are described elsewhere herein. As used herein, the expression
"asthma exacerbation" means an increase in the severity and/or
frequency and/or duration of one or more symptoms or indicia of
asthma. An "asthma exacerbation" also includes any deterioration in
the respiratory health of a subject that requires and or is
treatable by a therapeutic intervention for asthma (such as, e.g.,
steroid treatment, inhaled corticosteroid treatment,
hospitalization, etc.). There are two types of asthma exacerbation
events: a loss of asthma control (LOAC) event and a severe
exacerbation event.
[0103] According to certain embodiments, a loss of asthma control
(LOAC) event is defined as one or more of the following: (a)
greater than or equal to 6 additional reliever puffs of
salbutamol/albuterol or levosalbutamol/levalbuterol in a 24 hour
period (compared to baseline) on 2 consecutive days; (b) an
increase in ICS greater than or equal to 4 times the dose at visit
2 and (c) use of systemic corticosteroids for greater than or equal
to 3 days; or (d) hospitalization or emergency room visit because
of asthma, requiring systemic corticosteroids.
[0104] In certain instances, an asthma exacerbation may be
categorized as a "severe asthma exacerbation event." A severe
asthma exacerbation event means an incident requiring immediate
intervention in the form of treatment with either systemic
corticosteroids or with inhaled corticosteroids at four or more
times the dose taken prior to the incident. According to certain
embodiments, a severe asthma exacerbation event is defined as a
deterioration of asthma requiring: use of systemic corticosteroids
for greater than or equal to 3 days; or hospitalization or
emergency room visit because of asthma, requiring systemic
corticosteroids. The general expression "asthma exacerbation"
therefore includes and encompasses the more specific subcategory of
"severe asthma exacerbations." Accordingly, methods for reducing
the incidence of severe asthma exacerbations in a patient in need
thereof are included.
[0105] A "reduction in the incidence" of an asthma exacerbation
means that a subject who has received a pharmaceutical composition
comprising an IL-4R antagonist experiences fewer asthma
exacerbations (i.e., at least one fewer exacerbation) after
treatment than before treatment, or experiences no asthma
exacerbations for at least 4 weeks (e.g., 4, 6, 8, 12, 14 or more
weeks) following initiation of treatment with the pharmaceutical
composition. A "reduction in the incidence" of an asthma
exacerbation alternatively means that, following administration of
the pharmaceutical composition, the likelihood that a subject
experiences an asthma exacerbation is decreased by at least 10%
(e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more) as
compared to a subject who has not received the pharmaceutical
composition.
[0106] The invention includes methods for reducing the incidence of
asthma exacerbations in a subject in need thereof comprising
administering a pharmaceutical composition comprising an IL-4R
antagonist to the subject as well as administering to the subject
one or more maintenance doses of an inhaled corticosteroid (ICS)
and/or one or more maintenance doses of a second controller, e.g.,
a long-acting beta-agonist (LABA) or a leukotriene receptor
antagonist (LTA). Suitable ICSs include, but are not limited to,
fluticasone (e.g., fluticasone propionate, e.g., Flovent.TM.),
budesonide, mometasone (e.g., mometasone furoate, e.g.,
Asmanex.TM.), flunisolide (e.g., Aerobid.TM.), dexamethasone
acetate/phenobarbital/theophylline (e.g., Azmacort.TM.),
beclomethasone dipropionate HFA (Qvar.TM.), and the like. Suitable
LABAs include, but are not limited to, salmeterol (e.g.,
Serevent.TM.), formoterol (e.g., Foradil.TM.), and the like.
Suitable LTAs include, but are not limited to, montelukast (e.g.,
Singulaire.TM.), zafirlukast (e.g., Accolate.TM.), and the
like.
[0107] The invention includes methods for reducing the incidence of
asthma exacerbations in a subject in need thereof comprising
administering a pharmaceutical composition comprising an IL-4R
antagonist to the subject as well as administering to the subject
one or more reliever medications to eliminate or reduce one or more
asthma-associated symptoms. Suitable reliever medications include,
but are not limited to, quick-acting beta2-adrenergic receptor
agonists such as, e.g., albuterol (i.e., salbutamol, e.g.,
Proventil.TM., Ventolin.TM., Xopenex.TM. and the like), pirbuterol
(e.g., Maxair.TM.) metaproterenol (e.g., Alupent.TM.) and the
like.
Methods for Improving Asthma-Associated Parameters
[0108] The invention also includes methods for improving one or
more asthma-associated parameters in a subject in need thereof,
wherein the methods comprise administering a pharmaceutical
composition comprising an IL-4R antagonist to the subject. A
reduction in the incidence of an asthma exacerbation (as described
above) may correlate with an improvement in one or more
asthma-associated parameters; however, such a correlation is not
necessarily observed in all cases.
[0109] Examples of "asthma-associated parameters" include: (1)
relative percent change from baseline (e.g., at week 12) in forced
expiratory volume in 1 second (FEV.sub.1); (2) a relative percent
change from baseline (e.g., at week 12) as measured by forced
expiratory flow at 25-75% of the pulmonary volume (FEF25-75); (3)
annualized rate of loss of asthma control events during the
treatment period; (4) annualized rate of severe exacerbation events
during the treatment period; (5) time to loss of asthma control
events during the treatment period; (6) time to severe exacerbation
events during the treatment period; (7) time to loss of asthma
control events during overall study period; (8) time to severe
exacerbation events during overall study period; (9) health care
resource utilization; (10) change from baseline at week 12 in: i)
morning and evening asthma symptom scores, ii) ACQ-5 score, iii)
AQLQ score, iv) morning and evening PEF, v) number of
inhalations/day of salbutamol/albuterol or
levosalbutamol/levalbuterol for symptom relief, vi) nocturnal
awakenings; (11) change from baseline at week 12 and week 24 in: i)
22-item Sino Nasal Outcome Test (SNOT-22), ii) Hospital Anxiety and
Depression Score (HADS), iii) EuroQual questionnaire (EQ-5D-3 L or
EQ-5D-5 L). An "improvement in an asthma-associated parameter"
means an increase from baseline of one or more of FEV.sub.1, AM PEF
or PM PEF, and/or a decrease from baseline of one or more of daily
albuterol/levalbuterol use, ACQ5 score, average nighttime
awakenings or SNOT-22 score. As used herein, the term "baseline,"
with regard to an asthma-associated parameter, means the numerical
value of the asthma-associated parameter for a patient prior to or
at the time of administration of a pharmaceutical composition
comprising an IL-4R antagonist.
[0110] To determine whether an asthma-associated parameter has
"improved," the parameter is quantified at baseline and at a time
point after administration of the pharmaceutical composition
described herein. For example, an asthma-associated parameter may
be measured at day 1 day 2, day 3 day 4 day 5 day 6 day 7 day 8 day
9 day 10 day 11 day 12 day 14 or at week 3 week 4, week 5 week 6
week 7 week 8 week 9 week 10 week 11 week 12 week 13 week 14 week
15, week 16 week 17 week 18 week 19 week 20 week 21 week 22 week 23
week 24 or longer, after the initial treatment with the
pharmaceutical composition. The difference between the value of the
parameter at a particular time point following initiation of
treatment and the value of the parameter at baseline is used to
establish whether there has been an "improvement" in the asthma
associated parameter (e.g., an increase or decrease, as the case
may be, depending on the specific parameter being measured).
[0111] The terms "acquire" or "acquiring" as used herein, refer to
obtaining possession of a physical entity, or a value, e.g., a
numerical value, by "directly acquiring" or "indirectly acquiring"
the physical entity or value, such as an asthma-associated
parameter. "Directly acquiring" means performing a process (e.g.,
performing a synthetic or analytical method) to obtain the physical
entity or value. "Indirectly acquiring" refers to receiving the
physical entity or value from another party or source (e.g., a
third-party laboratory that directly acquired the physical entity
or value). Directly acquiring a physical entity includes performing
a process that includes a physical change in a physical substance,
e.g., a starting material. Exemplary changes include making a
physical entity from two or more starting materials, shearing or
fragmenting a substance, separating or purifying a substance,
combining two or more separate entities into a mixture, performing
a chemical reaction that includes breaking or forming a covalent or
non-covalent bond. Directly acquiring a value includes performing a
process that includes a physical change in a sample or another
substance, e.g., performing an analytical process which includes a
physical change in a substance, e.g., a sample, analyte, or reagent
(sometimes referred to herein as "physical analysis").
[0112] Information that is acquired indirectly can be provided in
the form of a report, e.g., supplied in paper or electronic form,
such as from an online database or application (an "App"). The
report or information can be provided by, for example, a healthcare
institution, such as a hospital or clinic; or a healthcare
provider, such as a doctor or nurse.
[0113] Forced Expiratory Volume in 1 Second (FEV.sub.1). According
to certain embodiments, administration of an IL-4R antagonist to a
patient results in an increase from baseline of forced expiratory
volume in 1 second (FEV.sub.1). Methods for measuring FEV.sub.1 are
known in the art. For example, a spirometer that meets the 2005
American Thoracic Society (ATS)/European Respiratory Society (ERS)
recommendations can be used to measure FEV.sub.1 in a patient. The
ATS/ERS Standardization of Spirometry may be used as a guideline.
Spirometry is generally performed between 6 and 10 AM after an
albuterol withhold of at least 6 hours. Pulmonary function tests
are generally measured in the sitting position, and the highest
measure is recorded for FEV.sub.1 (in liters).
[0114] The invention includes therapeutic methods that result in an
increase of FEV.sub.1 from baseline of at least 0.05 L at week 12
following initiation of treatment with a pharmaceutical composition
comprising an anti-IL-4R antagonist. For example, administration of
an IL-4R antagonist to a subject in need thereof causes an increase
of FEV.sub.1 from baseline of about 0.05 L, 0.10 L, 0.12 L, 0.14 L,
0.16 L, 0.18 L, 0.20 L, 0.22 L, 0.24 L, 0.26 L, 0.28 L, 0.30 L,
0.32 L, 0.34 L, 0.36 L, 0.38 L, 0.40 L, 0.42 L, 0.44 L, 0.46 L,
0.48 L, 0.50 L, or more at week 12.
[0115] FEF25-75%. According to certain embodiments, administration
of an IL-4R antagonist to a patient results in an increase from
baseline of FEF25-75%. Methods for measuring FEF are known in the
art. For example, a spirometer that meets the 2005 American
Thoracic Society (ATS)/European Respiratory Society (ERS)
recommendations can be used to measure FEV.sub.1 in a patient. The
FEF25-75 (forced expiratory flow between 25% and 75%) is the speed
(in liters per second) at which a person can empty the middle half
of his or her air during a maximum expiration (i.e., Forced Vital
Capacity or FVC). The parameter relates to the average flow from
the point at which 25 percent of the FVC has been exhaled to the
point at which 75 percent of the FVC has been exhaled. The
FEF25-75% of a subject provides information regarding small airway
function, such that the extent of mall airway disease and/or
inflammation. A change in FEF25-75 is an early indicator of
obstructive lung disease. In certain embodiments, an improvement
and/or increase in the FEF25-75% parameter is an improvement of at
least 10%, 25%, 50% or more as compared to baseline. In certain
embodiments, the methods of the invention result in normal
FEF25-75% values in a subject (e.g., values ranging from 50-60% and
up to 130% of the average).
[0116] Morning and Evening Peak Expiratory Flow (AM PEF and PM
PEF). According to certain embodiments, administration of an IL-4R
antagonist to a patient results in an increase from baseline of
morning (AM) and/or evening (PM) peak expiratory flow (AM PEF
and/or PM PEF). Methods for measuring PEF are known in the art. For
example, according to one method for measuring PEF, patients are
issued an electronic PEF meter for recording morning (AM) and
evening (PM) PEF (as well as daily albuterol use, morning and
evening asthma symptom scores, and number of nighttime awakenings
due to asthma symptoms that require rescue medications). Patients
are instructed on the use of the device, and written instructions
on the use of the electronic PEF meter are provided to the
patients. In addition, a medical professional may instruct the
patients on how to record pertinent variables in the electronic PEF
meter. AM PEF is generally performed within 15 minutes after
arising (between 6 am and 10 am) prior to taking any albuterol. PM
PEF is generally performed in the evening (between 6 pm and 10 pm)
prior to taking any albuterol. Subjects should try to withhold
albuterol for at least 6 hours prior to measuring their PEF. Three
PEF efforts are performed by the patient and all 3 values are
recorded by the electronic PEF meter. Usually the highest value is
used for evaluation. Baseline AM PEF may be calculated as the mean
AM measurement recorded for the 7 days prior to administration of
the first dose of pharmaceutical composition comprising the IL-4R
antagonist, and baseline PM PEF may be calculated as the mean PM
measurement recorded for the 7 days prior to administration of the
first dose of pharmaceutical composition comprising the IL-4R
antagonist.
[0117] The invention includes therapeutic methods that result in an
increase in AM PEF and/or PM PEF from baseline of at least 1.0
L/min at week 12 following initiation of treatment with a
pharmaceutical composition comprising an anti-IL-4R antagonist. For
example, according to the invention, administration of an IL-4R
antagonist to a subject in need thereof causes an increase in PEF
from baseline of about 0.5 L/min, 1.0 L/min, 1.5 L/min, 2.0 L/min,
2.5 L/min, 3.0 L/min, 3.5 L/min, 4.0 L/min, 4.5 L/min, 5.0 L/min,
5.5 L/min, 6.0 L/min, 6.5 L/min, 7.0 L/min, 7.5 L/min, 8.0 L/min,
8.5 L/min, 9.0 L/min, 9.5 L/min, 10.0 L/min, 10.5 L/min, 11.0
L/min, 12.0 L/min, 15 L/min, 20 L/min, or more at week 12.
[0118] Albuterol/Levalbuterol Use. According to certain
embodiments, administration of an IL-4R antagonist to a patient
results in a decrease from baseline of daily albuterol or
levalbuterol use. The number of albuterol/levalbuterol inhalations
can be recorded daily by the patients in a diary, PEF meter, or
other recording device. During treatment with the pharmaceutical
composition described herein, use of albuterol/levalbuterol
typically may be on an as-needed basis for symptoms, not on a
regular basis or prophylactically. The baseline number of
albuterol/levalbuterol inhalations/day may be calculated based on
the mean for the 7 days prior to administration of the first dose
of pharmaceutical composition comprising the IL-4R antagonist.
[0119] The invention includes therapeutic methods that result in a
decrease in albuterol/levalbuterol use from baseline of at least
0.25 puffs per day at week 12 following initiation of treatment
with a pharmaceutical composition comprising an anti-IL-4R
antagonist. For example, administration of an IL-4R antagonist to a
subject in need thereof causes a decrease in albuterol/levalbuterol
use from baseline of about 0.25 puffs per day, 0.50 puffs per day,
0.75 puffs per day, 1.00 puff per day, 1.25 puffs per day, 1.5
puffs per day, 1.75 puffs per day, 2.00 puffs per day, 2.25 puffs
per day, 2.5 puffs per day, 2.75 puffs per day, 3.00 puffs per day,
or more at week 12.
[0120] OCS Use. According to certain embodiments, administration of
an IL-4R antagonist to a patient can be used in conjunction with an
OCS such as oral prednisone. The number of OCS administrations can
be recorded daily by the patients in a diary, PEF meter, or other
recording device. During treatment with the pharmaceutical
composition described herein, occasional short-term use of
prednisone typically can be used to control acute asthmatic
episodes, e.g., episodes in which bronchodilators and other
anti-inflammatory agents fail to control symptoms. In other
aspects, prednisone is used concurrent with or as a substitution
for ICS. Oral prednisone may be administered in dosages of about 5
mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg or 40 mg. OCS can
optionally be administered once a day or multiple times a day
(e.g., twice a day, three times a day, four times a day, etc.)
[0121] In certain exemplary embodiments, the invention provides
methods for reducing or eliminating the dependency of the subject
on OCS use. The reduction or elimination of steroid dependency is
highly advantageous and desirable. In certain embodiments, a
reduction of 50% or greater (e.g., 50%, 60%, 70%, 80%, 90% or more)
in the OCS dose is achieved after administration of IL-4R antibody
therapy at a period of time (e.g., at week 24 In certain
embodiments, the OCS is substantially eliminated after 40 weeks, 45
weeks, 50 weeks, 52 weeks, or greater after first dose following
administration of the loading dose. In other embodiments, the level
of OCS use is reduced to less than 5 mg per day (e.g., less than 5
mg, 4 mg, 3 mg, 2 mg or less per day). In other embodiments, the
dependency on OCS use is substantially eliminated after 3 months, 6
months, 9 months or 1 year following treatment with IL4R antibody
or fragment thereof.
[0122] 5-Item Asthma Control Questionnaire (ACQ) Score. According
to certain embodiments, administration of an IL-4R antagonist to a
patient results in a decrease from baseline of five-item Asthma
Control Questionnaire (ACQ5) score. The ACQ5 is a validated
questionnaire to evaluate asthma control.
[0123] The invention includes therapeutic methods that result in a
decrease in ACQ5 score from baseline of at least 0.10 points at
week 12 following initiation of treatment with a pharmaceutical
composition comprising an anti-IL-4R antagonist. For example,
administration of an IL-4R antagonist to a subject in need thereof
causes a decrease in ACQ score from baseline of about 0.10 points,
0.15 points, 0.20 points, 0.25 points, 0.30 points, 0.35 points,
0.40 points, 0.45 points, 0.50 points, 0.55 points, 0.60 points,
0.65 points, 0.70 points, 0.75 points, 0.80 points, 0.85 points, or
more at week 12.
[0124] Night-Time Awakenings. According to certain embodiments,
administration of an IL-4R antagonist to a patient results in a
decrease from baseline of average number of nighttime
awakenings.
[0125] In certain embodiments, the methods decrease the average
number of nighttime awakenings from baseline by at least about 0.10
times per night at week 12 following initiation of treatment. For
example, administration of an IL-4R antagonist to a subject in need
thereof can cause a decrease in average number of nighttime
awakenings from baseline of about 0.10 times per night, 0.15 times
per night, 0.20 times per night, 0.25 times per night, 0.30 times
per night, 0.35 times per night, 0.40 times per night, 0.45 times
per night, 0.50 times per night, 0.55 times per night, 0.60 times
per night, 0.65 times per night, 0.70 times per night, 0.75 times
per night, 0.80 times per night, 0.85 times per night, 0.90 times
per night, 0.95 times per night, 1.0 times per night, 2.0 times per
night, or more at week 12.
[0126] 22-Item Sinonasal Outcome Test (SNOT-22) Score. According to
certain embodiments, administration of an IL-4R antagonist to a
patient results in a decrease from baseline of 22-item Sinonasal
Outcome Test (SNOT-22). The SNOT-22 is a validated questionnaire to
assess the impact of chronic rhinosinusitis on quality of life
(Hopkins et al 2009 Clin. Otolaryngol. 34: 447-454).
[0127] The invention includes therapeutic methods that result in a
decrease in SNOT-22 score from baseline of at least 1 point at week
12 following initiation of treatment with a pharmaceutical
composition comprising an anti-IL-4R antagonist. For example,
administration of an IL-4R antagonist to a subject in need thereof
can cause a decrease in SNOT-22 score from baseline of about 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 points, or more at week 12.
[0128] Biomarkers. In certain embodiments, the subject experiences
an improvement in lung function as measured by a biomarker, e.g., a
biomarker associated with severe steroid-dependent asthma or severe
uncontrolled asthma. For example, the biomarker may be fractional
exhaled nitric oxide (FeNO), Eotaxin-3 total IgE, Periostin, or
thymus and activation-regulated chemokine (TARC). In certain
embodiments, an improvement in lung function is indicated by a
reduction or increase (as appropriate) at week 4 week 12 or week 24
following treatment.
Methods for Treating Asthma
[0129] In some embodiments, the invention provides methods for
treating asthma, including, e.g., moderate-to-severe uncontrolled
asthma or inadequately controlled asthma, in a subject in need
thereof, wherein the methods comprise administering a
pharmaceutical composition comprising an IL-4R antagonist to the
subject. In certain embodiments, the methods are useful for
treating moderate-to-severe uncontrolled asthma in a subject.
[0130] As used herein, the term "asthma" can be used
interchangeably with "intermittent asthma," or "bronchial asthma."
"Asthma," "bronchial asthma" and "intermittent asthma" refer to
asthma in which one or any combination of the following are true:
symptoms occur 2 or fewer days per week; symptoms do not interfere
with normal activities; nighttime symptoms occur fewer than 2 days
per month; or one or more lung function tests (e.g., forced
expiratory volume in one second (FEV.sub.1) and/or peak expiratory
flow (PEF) of greater than 80%) are normal when the subject is not
suffering from an asthma attack.
[0131] As used herein, the term "persistent asthma" or "persistent
bronchial asthma" refers to asthma that is more severe than
(bronchial) asthma/intermittent (bronchial) asthma. A subject
suffering from persistent asthma or persistent bronchial asthma
experiences one or more of the following: symptoms more than 2 days
per week; symptoms that interfere with normal activities; nighttime
symptoms that occur more than 2 days per month; or one or more lung
function tests (e.g., forced expiratory volume in one second
(FEV.sub.1) and/or peak expiratory flow (PEF) of less than 80%)
that are not normal when the subject is not suffering from an
asthma attack; the subject relies on daily asthma control
medication; the subject has taken a systemic steroid more than once
in the last year after a severe asthma flare-up; or use of a
short-acting beta-2 agonist more than two days per week for relief
of asthma symptoms.
[0132] Asthma/intermittent asthma, bronchial asthma/intermittent
bronchial asthma, and persistent asthma/persistent bronchial asthma
can be categorized as "mild," "moderate," "severe" or
"moderate-to-severe." "Mild intermittent asthma" or "mild
intermittent bronchial asthma" is defined as having symptoms less
than once a week, and having forced expiratory volume in one second
(FEV.sub.1) or peak expiratory flow (PEF).gtoreq.80%. "Mild
persistent asthma" or "mild persistent bronchial asthma" differs in
that symptoms frequency is greater than once per week but less than
once per day, and variability in FEV.sub.1 or PEF is <20%-30%.
"Moderate intermittent asthma" or "moderate intermittent bronchial
asthma" is defined as having symptoms less than once a week, and
having forced expiratory volume in one second (FEV.sub.1) or peak
expiratory flow (PEF) of 60-80%. "Moderate persistent asthma" or
"moderate persistent bronchial asthma" is defined as having daily
symptoms, exacerbations that may affect activity and/or sleep,
nocturnal symptoms more than once a week, daily use of inhaled
short-acting beta-2 agonist and having forced expiratory volume in
one second (FEV.sub.1) or peak expiratory flow (PEF) of 60-80%.
"Severe intermittent asthma" or "severe intermittent bronchial
asthma" is defined as having symptoms less than once a week, and
having forced expiratory volume in one second (FEV.sub.1) or peak
expiratory flow (PEF) of 60%. "Severe persistent asthma" or "severe
persistent bronchial asthma" is defined as having daily symptoms,
frequent exacerbations that may affect activity and/or sleep,
frequent nocturnal symptoms, limitation of physical activities,
daily use of inhaled short-acting beta-2 agonist, and having forced
expiratory volume in one second (FEV.sub.1) or peak expiratory flow
(PEF) of 60%. "Moderate-to-severe intermittent asthma" or
"moderate-to-severe intermittent bronchial asthma" is defined as
having symptoms between those of moderate intermittent
asthma/moderate intermittent bronchial asthma and severe
intermittent asthma/severe intermittent bronchial asthma.
"Moderate-to-severe persistent asthma" or "moderate-to-severe
persistent bronchial asthma" is defined as having symptoms between
those of moderate persistent asthma/moderate persistent bronchial
asthma and severe persistent asthma/severe persistent bronchial
asthma.
[0133] As used herein, the term "inadequately controlled asthma"
refers to patients whose asthma is either "not well controlled" or
"very poorly controlled" as defined by the "Expert Panel Report 3:
Guidelines for the Diagnosis and Management of Asthma," National
Heart, Blood and Lung Institute, NIH, Aug. 28, 2007 "Not well
controlled asthma" is defined as having symptoms greater than two
days per week, nighttime awakenings one to three times per week,
some limitations on normal activity, short-acting beta2-agonist use
for symptom control greater than two days per week, FEV.sub.1 of
60-80% of predicted and/or personal best, an ATAQ score of 1-2 an
ACQ score of 1.5 or greater, and an ACT score of 16-19 "Very poorly
controlled asthma" is defined as having symptoms throughout the
day, nighttime awakenings four times or more per week, extreme
limitations on normal activity, short-acting beta2-agonist use for
symptom control several times per day, FEV.sub.1 of less than 60%
of predicted and/or personal best, an ATAQ score of 3-4 an ACQ
score of N/A, and an ACT score of less than or equal to 15.
[0134] In some embodiments, a subject is identified as having
"moderate-to-severe uncontrolled" asthma if the subject receives
such a diagnosis from a physician, based on the Global Initiative
for Asthma (GINA) 2009 Guidelines, and one or more of the following
criteria: i) Existing treatment with moderate- or high-dose
ICS/LABA (2 fluticasone propionate 250 .mu.g twice daily or
equipotent ICS daily dosage) with a stable dose of ICS/LABA for
greater than or equal to 1 month prior to administration of the
loading dose of IL-4R antagonist; ii) FEV.sub.1 40 to 80% predicted
normal prior to administration of the loading dose of IL-4R
antagonist; iii) ACQ-5 score greater than or equal to 1.5 prior to
administration of the loading dose of IL-4R antagonist; iv)
reversibility of at least 12% and 200 mL in FEV.sub.1 after 200
.mu.g to 400 .mu.g (2 to 4 inhalations) of salbutamol/albuterol
prior to administration of the loading dose of IL-4R antagonist; or
v) has experienced, within 1 year prior to administration of the
loading dose of IL-4R antagonist, any of the following events: (a)
treatment with greater than or equal to 1 systemic (oral or
parenteral) steroid burst for worsening asthma, (b) hospitalization
or an emergency/urgent medical care visit for worsening asthma.
[0135] "Severe asthma" refers to asthma in which adequate control
cannot be achieved by high-dose treatment with inhaled
corticosteroids and additional controllers (e.g., long-acting
inhaled beta 2 agonists, montelukast, and/or theophylline) or by
oral corticosteroid treatment (e.g., for at least six months per
year), or is lost when the treatment is reduced. In certain
embodiments, severe asthma includes asthma that is treated with
high-dose ICS and at least one additional controller (e.g., LABA,
montelukast, or theophylline) or oral corticosteroids .gtoreq.6
months/year, wherein at least one of the following occurs or would
occur if treatment is reduced: ACT<20 or ACQ.gtoreq.1.5 at least
2 exacerbations in the last 12 months; at least 1 exacerbation
treated in hospital or requiring mechanical ventilation in the last
12 months; or FEV1<80% (if FEV1/FVC below the lower limit of
normal).
[0136] "Steroid-dependent asthma" refers to asthma which requires
one or more of the following treatments: frequent, short term oral
corticosteroid treatment bursts in the past 12 months; regular use
of high dose inhaled corticosteroids in the past 12 months; regular
use of injected long acting corticosteroids; daily use of oral
corticosteroids; alternate-day oral corticosteroids; or prolonged
use of oral corticosteroids in the past year.
[0137] "Oral corticosteroid-dependent asthma" refers to a subject
having .gtoreq.3 30-day oral corticosteroid (OCS) fills over a
12-month period and a primary asthma diagnosis within 12 months of
the first OCS fill. Subjects with OCS-dependent asthma may also
experience one or any combination of the following: have received
physician prescribed LABA and high dose ICS (total daily dose
.gtoreq.500 g fluticasone propionate dry powder formulation
equivalent) for at least 3 months (the ICS and LABA can be parts of
a combination product, or given by separate inhalers); have
received additional maintenance asthma controller medications
according to standard practice of care e.g., leukotriene receptor
antagonists (LTRAs), theophylline, long-acting muscarinic
antagonists (LAMAs), secondary ICS and cromones; received OCS for
the treatment of asthma at a dose of between .gtoreq.7.5 to <30
mg (prednisone or prednisolone equivalent); have received an OCS
dose administered every other day (or different doses every other
day); morning pre-bronchodilator (BD) FEV1 of <80% predicted
normal; have evidence of asthma as documented by post-BD
(albuterol/salbutatomol) reversibility of FEV1.gtoreq.12% and
.gtoreq.200 mL (15-30 min after administration of 4 puffs of
albuterol/salbutamol); or have a history of at least one asthma
exacerbation event within 12 months.
[0138] In one aspect, methods for treating asthma are provided
comprising: (a) selecting a patient that exhibits a blood
eosinophil level of at least 300 cells per microliter; and (b)
administering to the patient a pharmaceutical composition
comprising an IL-4R antagonist.
[0139] In another aspect, methods for treating asthma are provided
comprising: (a) selecting a patient that exhibits a blood
eosinophil level of 200-299 cells per microliter; and (b)
administering to the patient a pharmaceutical composition
comprising an IL-4R antagonist.
[0140] In another aspect, methods for treating asthma are provided
comprising: (a) selecting a patient that exhibits a blood
eosinophil level of less than 200 cells per microliter; and (b)
administering to the patient a pharmaceutical composition
comprising an IL-4R antagonist.
[0141] In a related aspect, methods for treating asthma comprising
an add-on therapy to background therapy are provided. In certain
embodiments, an IL-4R antagonist is administered as an add-on
therapy to an asthma patient who is on background therapy for a
certain period of time (e.g., 1 week, 2 weeks, 3 weeks, 1 month, 2
months, 5 months, 12 months, 18 months, 24 months, or longer) (also
called the "stable phase"). In some embodiments, the background
therapy comprises a ICS and/or a LABA.
[0142] In some embodiments, the invention includes a method for
reducing an asthma patient's dependence on ICS and/or LABA for the
treatment of one or more asthma exacerbations comprising: (a)
selecting a patient who has moderate-to-severe asthma that is
uncontrolled with a background asthma therapy comprising an ICS, a
LABA, or a combination thereof; and administering to the patient a
pharmaceutical composition comprising an IL-4R antagonist.
[0143] In some embodiments, the invention encompasses methods to
treat or alleviate conditions or complications associated with
asthma, such as chronic rhino sinusitis, allergic rhinitis,
allergic fungal rhino sinusitis, allergic broncho-pulmonary
aspergillosis, unified airway disease, Churg-Strauss syndrome,
vasculitis, chronic obstructive pulmonary disease (COPD), and
exercise induced bronchospasm.
[0144] The invention also includes methods for treating persistent
asthma. As used herein, the term "persistent asthma" means that the
subject has symptoms at least once a week at day and/or at night,
with the symptoms lasting a few hours to a few days. In certain
alternative embodiments, the persistent asthma is "mildly
persistent" (e.g., more than twice a week but less than daily with
symptoms severe enough to interfere with daily activities or sleep
and/or where pulmonary function is normal or reversible with
inhalation of a bronchodilator), "moderately persistent" (e.g.,
symptoms occurring daily with sleep interrupted at least weekly
and/or with pulmonary function moderately abnormal), or "severely
persistent" (e.g., continuous symptoms despite the correct use of
approved medications and/or where pulmonary function is severely
affected).
Interleukin-4 Receptor Antagonists
[0145] The methods featured in the invention comprise administering
to a subject in need thereof a therapeutic composition comprising
an IL-4R antagonist. As used herein, an "IL-4R antagonist" is any
agent that binds to or interacts with IL-4R and inhibits the normal
biological signaling function of IL-4R when IL-4R is expressed on a
cell in vitro or in vivo. Non-limiting examples of categories of
IL-4R antagonists include small molecule IL-4R antagonists,
anti-IL-4R aptamers, peptide-based IL-4R antagonists (e.g.,
"peptibody" molecules), and antibodies or antigen-binding fragments
of antibodies that specifically bind human IL-4R. According to
certain embodiments, the IL-4R antagonist comprises an anti-IL-4R
antibody that can be used in the context of the methods featured in
the invention are described elsewhere herein. For example, in one
embodiment, the IL-4R antagonist is an antibody or antigen-binding
fragment thereof that specifically binds to an IL-4R, and comprises
the heavy chain and light chain (Complementarity Determining
Region) CDR sequences from the Heavy Chain Variable Region (HCVR)
and Light Chain Variable Region (LCVR) of SEQ ID NOs:1 and 2
respectively.
[0146] The term "human IL4R" (hIL-4R) refers to a human cytokine
receptor that specifically binds to interleukin-4 (IL-4), such as
IL-4R.alpha..
[0147] The term "antibody" refers to immunoglobulin molecules
comprising four polypeptide chains, two heavy (H) chains and two
light (L) chains inter-connected by disulfide bonds, as well as
multimers thereof (e.g., IgM). Each heavy chain comprises a heavy
chain variable region (abbreviated herein as HCVR or V.sub.H) and a
heavy chain constant region. The heavy chain constant region
comprises three domains, C.sub.H1 C.sub.H2 and C.sub.H3. Each light
chain comprises a light chain variable region (abbreviated herein
as LCVR or V.sub.L) and a light chain constant region. The light
chain constant region comprises one domain (C.sub.L1). The V.sub.H
and V.sub.L regions can be further subdivided into regions of
hypervariability, termed complementarity determining regions
(CDRs), interspersed with regions that are more conserved, termed
framework regions (FR). Each V.sub.H and V.sub.L is composed of
three CDRs and four FRs, arranged from amino-terminus to
carboxy-terminus in the following order: FR1, CDR1 FR2 CDR2 FR3
CDR3 FR4 In different embodiments, the FRs of the anti-IL-4R
antibody (or antigen-binding portion thereof) may be identical to
the human germline sequences, or may be naturally or artificially
modified. An amino acid consensus sequence may be defined based on
a side-by-side analysis of two or more CDRs.
[0148] The term "antibody" also includes antigen-binding fragments
of full antibody molecules. The terms "antigen-binding portion" of
an antibody, "antigen-binding fragment" of an antibody, and the
like, as used herein, include any naturally occurring,
enzymatically obtainable, synthetic, or genetically engineered
polypeptide or glycoprotein that specifically binds to an antigen
to form a complex. Antigen-binding fragments of an antibody may be
derived, e.g., from full antibody molecules using any suitable
standard techniques, such as proteolytic digestion or recombinant
genetic engineering techniques involving the manipulation and
expression of DNA encoding antibody variable and optionally
constant domains. Such DNA is known and/or is readily available
from, e.g., commercial sources, DNA libraries (including, e.g.,
phage-antibody libraries), or can be synthesized. The DNA may be
sequenced and manipulated chemically or by using molecular biology
techniques, for example, to arrange one or more variable and/or
constant domains into a suitable configuration, or to introduce
codons, create cysteine residues, modify, add or delete amino
acids, etc.
[0149] Non-limiting examples of antigen-binding fragments include:
(i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv)
Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb
fragments; and (vii) minimal recognition units consisting of the
amino acid residues that mimic the hypervariable region of an
antibody (e.g., an isolated complementarity determining region
(CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4
peptide. Other engineered molecules, such as domain-specific
antibodies, single domain antibodies, domain-deleted antibodies,
chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies,
tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies,
bivalent nanobodies, etc.), small modular immunopharmaceuticals
(SMIPs), and shark variable IgNAR domains, are also encompassed
within the expression "antigen-binding fragment."
[0150] An antigen-binding fragment of an antibody will typically
comprise at least one variable domain. The variable domain may be
of any size or amino acid composition and will generally comprise
at least one CDR that is adjacent to or in frame with one or more
framework sequences. In antigen-binding fragments having a V.sub.H
domain associated with a V.sub.L domain, the V.sub.H and V.sub.L
domains may be situated relative to one another in any suitable
arrangement. For example, the variable region may be dimeric and
contain V.sub.H-V.sub.H V.sub.H-V.sub.L or V.sub.L-V.sub.L dimers.
Alternatively, the antigen-binding fragment of an antibody may
contain a monomeric V.sub.H or V.sub.L domain.
[0151] In certain embodiments, an antigen-binding fragment of an
antibody may contain at least one variable domain covalently linked
to at least one constant domain. Non-limiting, exemplary
configurations of variable and constant domains that may be found
within an antigen-binding fragment of an antibody described herein
include: (i) V.sub.H-C.sub.H1 (ii) V.sub.H-C.sub.H2 (iii)
V.sub.H-C.sub.H3 (iv) V.sub.H-C.sub.H1-C.sub.H2 (v)
V.sub.H-C.sub.H1-C.sub.H2-C.sub.H3 (vi) V.sub.H-C.sub.H2-C.sub.H3
(vii) V.sub.H-C.sub.L (viii) V.sub.L-C.sub.H1 (ix) V.sub.L-C.sub.H2
(x) V.sub.L-C.sub.H3 (xi) V.sub.L-C.sub.H1-C.sub.H2 (xii)
V.sub.L-C.sub.H1-C.sub.H2-C.sub.H3 (xiii) V.sub.L-C.sub.H2-C.sub.H3
and (Xiv) V.sub.L-C.sub.L In any configuration of variable and
constant domains, including any of the exemplary configurations
listed above, the variable and constant domains may be either
directly linked to one another or may be linked by a full or
partial hinge or linker region. A hinge region may consist of at
least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that
result in a flexible or semi-flexible linkage between adjacent
variable and/or constant domains in a single polypeptide molecule,
typically the hinge region may consist of between 2 to 60 amino
acids, typically between 5 to 50 or typically between 10 to 40
amino acids. Moreover, an antigen-binding fragment of an antibody
described herein may comprise a homo-dimer or hetero-dimer (or
other multimer) of any of the variable and constant domain
configurations listed above in non-covalent association with one
another and/or with one or more monomeric V.sub.H or V.sub.L domain
(e.g., by disulfide bond(s)).
[0152] As with full antibody molecules, antigen-binding fragments
may be monospecific or multispecific (e.g., bispecific). A
multispecific antigen-binding fragment of an antibody will
typically comprise at least two different variable domains, wherein
each variable domain is capable of specifically binding to a
separate antigen or to a different epitope on the same antigen. Any
multispecific antibody format, may be adapted for use in the
context of an antigen-binding fragment of an antibody described
herein using routine techniques available in the art.
[0153] The constant region of an antibody is important in the
ability of an antibody to fix complement and mediate cell-dependent
cytotoxicity. Thus, the isotype of an antibody may be selected on
the basis of whether it is desirable for the antibody to mediate
cytotoxicity.
[0154] The term "human antibody" includes antibodies having
variable and constant regions derived from human germline
immunoglobulin sequences. The human antibodies featured in the
invention may nonetheless include amino acid residues not encoded
by human germline immunoglobulin sequences (e.g., mutations
introduced by random or site-specific mutagenesis in vitro or by
somatic mutation in vivo), for example in the CDRs and in
particular CDR3 However, the term "human antibody" does not include
antibodies in which CDR sequences derived from the germline of
another mammalian species, such as a mouse, have been grafted onto
human framework sequences.
[0155] The term "recombinant human antibody" includes all human
antibodies that are prepared, expressed, created or isolated by
recombinant means, such as antibodies expressed using a recombinant
expression vector transfected into a host cell (described further
below), antibodies isolated from a recombinant, combinatorial human
antibody library (described further below), antibodies isolated
from an animal (e.g., a mouse) that is transgenic for human
immunoglobulin genes (see e.g., Taylor et al. (1992) Nucl. Acids
Res. 20:6287-6295) or antibodies prepared, expressed, created or
isolated by any other means that involves splicing of human
immunoglobulin gene sequences to other DNA sequences. Such
recombinant human antibodies have variable and constant regions
derived from human germline immunoglobulin sequences. In certain
embodiments, however, such recombinant human antibodies are
subjected to in vitro mutagenesis (or, when an animal transgenic
for human Ig sequences is used, in vivo somatic mutagenesis) and
thus the amino acid sequences of the V.sub.H and V.sub.L regions of
the recombinant antibodies are sequences that, while derived from
and related to human germline V.sub.H and V.sub.L sequences, may
not naturally exist within the human antibody germline repertoire
in vivo.
[0156] Human antibodies can exist in two forms that are associated
with hinge heterogeneity. In one form, an immunoglobulin molecule
comprises a stable four chain construct of approximately 150-160
kDa in which the dimers are held together by an interchain heavy
chain disulfide bond. In a second form, the dimers are not linked
via inter-chain disulfide bonds and a molecule of about 75-80 kDa
is formed composed of a covalently coupled light and heavy chain
(half-antibody). These forms have been extremely difficult to
separate, even after affinity purification.
[0157] The frequency of appearance of the second form in various
intact IgG isotypes is due to, but not limited to, structural
differences associated with the hinge region isotype of the
antibody. A single amino acid substitution in the hinge region of
the human IgG4 hinge can significantly reduce the appearance of the
second form (Angal et al. (1993) Molecular Immunology 30:105) to
levels typically observed using a human IgG1 hinge. The invention
encompasses antibodies having one or more mutations in the hinge,
C.sub.H2 or C.sub.H3 region, which may be desirable, for example,
in production, to improve the yield of the desired antibody
form.
[0158] An "isolated antibody" means an antibody that has been
identified and separated and/or recovered from at least one
component of its natural environment. For example, an antibody that
has been separated or removed from at least one component of an
organism, or from a tissue or cell in which the antibody naturally
exists or is naturally produced, is an "isolated antibody". An
isolated antibody also includes an antibody in situ within a
recombinant cell. Isolated antibodies are antibodies that have been
subjected to at least one purification or isolation step. According
to certain embodiments, an isolated antibody may be substantially
free of other cellular material and/or chemicals.
[0159] The term "specifically binds," or the like, means that an
antibody or antigen-binding fragment thereof forms a complex with
an antigen that is relatively stable under physiologic conditions.
Methods for determining whether an antibody specifically binds to
an antigen are well known in the art and include, for example,
equilibrium dialysis, surface plasmon resonance, and the like. For
example, an antibody that "specifically binds" IL-4R, as featured
in the invention, includes antibodies that bind IL-4R or portion
thereof with a K.sub.D of less than about 1000 nM, less than about
500 nM, less than about 300 nM, less than about 200 nM, less than
about 100 nM, less than about 90 nM, less than about 80 nM, less
than about 70 nM, less than about 60 nM, less than about 50 nM,
less than about 40 nM, less than about 30 nM, less than about 20
nM, less than about 10 nM, less than about 5 nM, less than about 4
nM, less than about 3 nM, less than about 2 nM, less than about 1
nM, or less than about 0.5 nM, as measured in a surface plasmon
resonance assay. An isolated antibody that specifically binds human
IL-4R may, however, have cross-reactivity to other antigens, such
as IL-4R molecules from other (non-human) species.
[0160] The anti-IL-4R antibodies useful for the methods may
comprise one or more amino acid substitutions, insertions, and/or
deletions (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 substitutions
and/or 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 insertions and/or 1, 2, 3,
4, 5, 6, 7, 8, 9 or 10 deletions) in the framework and/or CDR
regions of the heavy and light chain variable domains as compared
to the corresponding germline sequences from which the antibodies
were derived. Such mutations can be readily ascertained by
comparing the amino acid sequences disclosed herein to germline
sequences available from, for example, public antibody sequence
databases. The invention includes methods involving the use of
antibodies, and antigen-binding fragments thereof, that are derived
from any of the amino acid sequences disclosed herein, wherein one
or more amino acids (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino
acids) within one or more framework and/or one or more (e.g. 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 with respect to the tetrameric
antibody or 1, 2, 3, 4, 5 or 6 with respect to the HCVR and LCVR of
an antibody) CDR regions are mutated to the corresponding
residue(s) of the germline sequence from which the antibody was
derived, or to the corresponding residue(s) of another human
germline sequence, or to a conservative amino acid substitution of
the corresponding germline residue(s) (such sequence changes are
referred to herein collectively as "germline mutations"). A person
of ordinary skill in the art, starting with the heavy and light
chain variable region sequences disclosed herein, can easily
produce numerous antibodies and antigen-binding fragments that
comprise one or more individual germline mutations or combinations
thereof. In certain embodiments, all of the framework and/or CDR
residues within the V.sub.H and/or V.sub.L domains are mutated back
to the residues found in the original germline sequence from which
the antibody was derived. In other embodiments, only certain
residues are mutated back to the original germline sequence, e.g.,
only the mutated residues found within the first 8 amino acids of
FR1 or within the last 8 amino acids of FR4 or only the mutated
residues found within CDR1 CDR2 or CDR3 In other embodiments, one
or more of the framework and/or CDR residue(s) are mutated to the
corresponding residue(s) of a different germline sequence (i.e., a
germline sequence that is different from the germline sequence from
which the antibody was originally derived). Furthermore, the
antibodies may contain any combination of two or more germline
mutations within the framework and/or CDR regions, e.g., wherein
certain individual residues are mutated to the corresponding
residue of a particular germline sequence while certain other
residues that differ from the original germline sequence are
maintained or are mutated to the corresponding residue of a
different germline sequence. Once obtained, antibodies and
antigen-binding fragments that contain one or more germline
mutations can be easily tested for one or more desired property
such as, improved binding specificity, increased binding affinity,
improved or enhanced antagonistic or agonistic biological
properties (as the case may be), reduced immunogenicity, etc. The
use of antibodies and antigen-binding fragments obtained in this
general manner are encompassed within the invention.
[0161] The invention also includes methods involving the use of
anti-IL-4R antibodies comprising variants of any of the HCVR, LCVR,
and/or CDR amino acid sequences disclosed herein having one or more
conservative substitutions. For example, the invention includes the
use of anti-IL-4R antibodies having HCVR, LCVR, and/or CDR amino
acid sequences with, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4
or fewer, etc. conservative amino acid substitutions relative to
any of the HCVR, LCVR, and/or CDR amino acid sequences disclosed
herein.
[0162] The term "surface plasmon resonance" refers to an optical
phenomenon that allows for the analysis of real-time interactions
by detection of alterations in protein concentrations within a
biosensor matrix, for example using the BIAcore.TM. system (Biacore
Life Sciences division of GE Healthcare, Piscataway, N.J.).
[0163] The term "K.sub.D" refers to the equilibrium dissociation
constant of a particular antibody-antigen interaction.
[0164] The term "epitope" refers to an antigenic determinant that
interacts with a specific antigen binding site in the variable
region of an antibody molecule known as a paratope. A single
antigen may have more than one epitope. Thus, different antibodies
may bind to different areas on an antigen and may have different
biological effects. Epitopes may be either conformational or
linear. A conformational epitope is produced by spatially
juxtaposed amino acids from different segments of the linear
polypeptide chain. A linear epitope is one produced by adjacent
amino acid residues in a polypeptide chain. In certain
circumstance, an epitope may include moieties of saccharides,
phosphoryl groups, or sulfonyl groups on the antigen.
Preparation of Human Antibodies
[0165] Methods for generating human antibodies in transgenic mice
are known in the art. Any such known methods can be used to make
human antibodies that specifically bind to human IL-4R.
[0166] Using VELOCIMMUNE.RTM. technology (see, for example, U.S.
Pat. No. 6,596,541 Regeneron Pharmaceuticals) or any other known
method for generating monoclonal antibodies, high affinity chimeric
antibodies to IL-4R are initially isolated having a human variable
region and a mouse constant region. The VELOCIMMUNE.RTM. technology
involves generation of a transgenic mouse having a genome
comprising human heavy and light chain variable regions operably
linked to endogenous mouse constant region loci such that the mouse
produces an antibody comprising a human variable region and a mouse
constant region in response to antigenic stimulation. The DNA
encoding the variable regions of the heavy and light chains of the
antibody are isolated and operably linked to DNA encoding the human
heavy and light chain constant regions. The DNA is then expressed
in a cell capable of expressing the fully human antibody.
[0167] Generally, a VELOCIMMUNE.RTM. mouse is challenged with the
antigen of interest, and lymphatic cells (such as B-cells) are
recovered from the mice that express antibodies. The lymphatic
cells may be fused with a myeloma cell line to prepare immortal
hybridoma cell lines, and such hybridoma cell lines are screened
and selected to identify hybridoma cell lines that produce
antibodies specific to the antigen of interest. DNA encoding the
variable regions of the heavy chain and light chain may be isolated
and linked to desirable isotypic constant regions of the heavy
chain and light chain. Such an antibody protein may be produced in
a cell, such as a CHO cell. Alternatively, DNA encoding the
antigen-specific chimeric antibodies or the variable domains of the
light and heavy chains may be isolated directly from
antigen-specific lymphocytes.
[0168] Initially, high affinity chimeric antibodies are isolated
having a human variable region and a mouse constant region. The
antibodies are characterized and selected for desirable
characteristics, including affinity, selectivity, epitope, etc.,
using standard procedures known to those skilled in the art. The
mouse constant regions are replaced with a desired human constant
region to generate a fully human antibody featured in the
invention, for example wild-type or modified IgG1 or IgG4 While the
constant region selected may vary according to specific use, high
affinity antigen-binding and target specificity characteristics
reside in the variable region.
[0169] In general, the antibodies that can be used in the methods
possess high affinities, as described above, when measured by
binding to antigen either immobilized on solid phase or in solution
phase. The mouse constant regions are replaced with desired human
constant regions to generate the fully human antibodies featured in
the invention. While the constant region selected may vary
according to specific use, high affinity antigen-binding and target
specificity characteristics reside in the variable region.
[0170] In one embodiment, human antibody or antigen-binding
fragment thereof that specifically binds IL-4R that can be used in
the context of the methods featured in the invention comprises the
three heavy chain CDRs (HCDR1 HCDR2 and HCDR3) contained within a
heavy chain variable region (HCVR) having an amino acid sequence of
SEQ ID NO: 1 The antibody or antigen-binding fragment may comprise
the three light chain CDRs (LCVR1 LCVR2 LCVR3) contained within a
light chain variable region (LCVR) having an amino acid sequence of
SEQ ID NO: 2 Methods and techniques for identifying CDRs within
HCVR and LCVR amino acid sequences are well known in the art and
can be used to identify CDRs within the specified HCVR and/or LCVR
amino acid sequences disclosed herein. Exemplary conventions that
can be used to identify the boundaries of CDRs include, e.g., the
Kabat definition, the Chothia definition, and the AbM definition.
In general terms, the Kabat definition is based on sequence
variability, the Chothia definition is based on the location of the
structural loop regions, and the AbM definition is a compromise
between the Kabat and Chothia approaches. See, e.g., Kabat,
"Sequences of Proteins of Immunological Interest," National
Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et al., J.
Mol. Biol. 273:927-948 (1997); and Martin et al., Proc. Natl. Acad.
Sci. USA 86:9268-9272 (1989). Public databases are also available
for identifying CDR sequences within an antibody.
[0171] In certain embodiments, the antibody or antigen-binding
fragment thereof comprises the six CDRs (HCDR1 HCDR2 HCDR3 LCDR1
LCDR2 and LCDR3) from the heavy and light chain variable region
amino acid sequence pairs (HCVR/LCVR) of SEQ ID NOs: 1 and 2.
[0172] In certain embodiments, the antibody or antigen-binding
fragment thereof comprises six CDRs
(HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3) having the amino acid
sequences of SEQ ID NOs: 3/4/5/6/7/8.
[0173] In certain embodiments, the antibody or antigen-binding
fragment thereof comprises HCVR/LCVR amino acid sequence pairs of
SEQ ID NOs: 1 and 2.
[0174] In one embodiment, the antibody is dupilumab, which
comprises the HCVR/LCVR amino acid sequence pairs of SEQ ID NOs: 1
and 2.
Pharmaceutical Compositions
[0175] The invention includes methods that comprise administering
an IL-4R antagonist to a patient, wherein the IL-4R antagonist is
contained within a pharmaceutical composition. The pharmaceutical
compositions featured in the invention are formulated with suitable
carriers, excipients, and other agents that provide suitable
transfer, delivery, tolerance, and the like. A multitude of
appropriate formulations can be found in the formulary known to all
pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack
Publishing Company, Easton, Pa. These formulations include, for
example, powders, pastes, ointments, jellies, waxes, oils, lipids,
lipid (cationic or anionic) containing vesicles (such as
LIPOFECTIN.TM.), DNA conjugates, anhydrous absorption pastes,
oil-in-water and water-in-oil emulsions, emulsions carbowax
(polyethylene glycols of various molecular weights), semi-solid
gels, and semi-solid mixtures containing carbowax. See also Powell
et al. "Compendium of excipients for parenteral formulations" PDA
(1998) J Pharm Sci Technol 52:238-311.
[0176] The dose of antibody administered to a patient may vary
depending upon the age and the size of the patient, symptoms,
conditions, route of administration, and the like. The dose is
typically calculated according to body weight or body surface area.
Depending on the severity of the condition, the frequency and the
duration of the treatment can be adjusted. Effective dosages and
schedules for administering pharmaceutical compositions comprising
anti-IL-4R antibodies may be determined empirically; for example,
patient progress can be monitored by periodic assessment, and the
dose adjusted accordingly. Moreover, interspecies scaling of
dosages can be performed using well-known methods in the art (e.g.,
Mordenti et al., 1991Pharmaceut. Res. 8:1351).
[0177] Various delivery systems are known and can be used to
administer the pharmaceutical compositions featured in the
invention, e.g., encapsulation in liposomes, microparticles,
microcapsules, recombinant cells capable of expressing the mutant
viruses, receptor mediated endocytosis (see, e.g., Wu et al., 1987
J. Biol. Chem. 262:4429-4432). Methods of administration include,
but are not limited to, intradermal, intramuscular,
intraperitoneal, intravenous, subcutaneous, intranasal,
intra-tracheal, epidural, and oral routes. The composition may be
administered by any convenient route, for example by infusion or
bolus injection, by absorption through epithelial or mucocutaneous
linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and
may be administered together with other biologically active
agents.
[0178] A pharmaceutical composition featured in the invention can
be delivered subcutaneously or intravenously with a standard needle
and syringe. In addition, with respect to subcutaneous delivery, a
pen delivery device (e.g., an autoinjector pen) readily has
applications in delivering a pharmaceutical composition featured in
the invention. Such a pen delivery device can be reusable or
disposable. A reusable pen delivery device generally utilizes a
replaceable cartridge that contains a pharmaceutical composition.
Once all of the pharmaceutical composition within the cartridge has
been administered and the cartridge is empty, the empty cartridge
can readily be discarded and replaced with a new cartridge that
contains the pharmaceutical composition. The pen delivery device
can then be reused. In a disposable pen delivery device, there is
no replaceable cartridge. Rather, the disposable pen delivery
device comes prefilled with the pharmaceutical composition held in
a reservoir within the device. Once the reservoir is emptied of the
pharmaceutical composition, the entire device is discarded.
[0179] Numerous reusable pen and autoinjector delivery devices have
applications in the subcutaneous delivery of a pharmaceutical
composition. Examples include, but are not limited to AUTOPEN.TM.
(Owen Mumford, Inc., Woodstock, UK), DISETRONIC.TM. pen (Disetronic
Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75/25.TM. pen,
HUMALOG.TM. pen, HUMALIN 70/30.TM. pen (Eli Lilly and Co.,
Indianapolis, Ind.), NOVOPEN.TM. I, II and III (Novo Nordisk,
Copenhagen, Denmark), NOVOPEN JUNIOR.TM. (Novo Nordisk, Copenhagen,
Denmark), BD.TM. pen (Becton Dickinson, Franklin Lakes, N.J.),
OPTIPEN.TM., OPTIPEN PRO.TM., OPTIPEN STARLET.TM., and OPTICLIK.TM.
(Sanofi-Aventis, Frankfurt, Germany), to name only a few. Examples
of disposable pen delivery devices having applications in
subcutaneous delivery of a pharmaceutical composition featured in
the invention include, but are not limited to the SOLOSTAR.TM. pen
(Sanofi-Aventis), the FLEXPEN.TM. (Novo Nordisk), and the
KWIKPEN.TM. (Eli Lilly), the SURECLICK.TM. Autoinjector (Amgen,
Thousand Oaks, Calif.), the PENLET.TM. (Haselmeier, Stuttgart,
Germany), the EPIPEN (Dey, L. P.), and the HUMIRA.TM. Pen (Abbott
Labs, Abbott Park Ill.), to name only a few. Examples of
large-volume delivery devices (e.g., large-volume injectors)
include, but are not limited to, bolus injectors such as, e.g., BD
Libertas West SmartDose, Enable Injections, SteadyMed PatchPump,
Sensile SenseTrial, YPsomed YpsoDose, Bespak Lapas, and the
like.
[0180] For direct administration to the sinuses, the pharmaceutical
compositions featured in the invention may be administered using,
e.g., a microcatheter (e.g., an endoscope and microcatheter), an
aerosolizer, a powder dispenser, a nebulizer or an inhaler. The
methods include administration of an IL-4R antagonist to a subject
in need thereof, in an aerosolized formulation. For example,
aerosolized antibodies to IL-4R may be administered to treat asthma
in a patient. Aerosolized antibodies can be prepared as described
in, for example, U.S. Pat. No. 8,178,098 incorporated herein by
reference in its entirety.
[0181] In certain situations, the pharmaceutical composition can be
delivered in a controlled release system. In one embodiment, a pump
may be used (see Langer, supra; Sefton, 1987 CRC Crit. Ref. Biomed.
Eng. 14:201). In another embodiment, polymeric materials can be
used; see, Medical Applications of Controlled Release, Langer and
Wise (eds.), 1974 CRC Pres., Boca Raton, Fla. In yet another
embodiment, a controlled release system can be placed in proximity
of the composition's target, thus requiring only a fraction of the
systemic dose (see, e.g., Goodson, 1984 in Medical Applications of
Controlled Release, supra, vol. 2 pp. 115-138). Other controlled
release systems are discussed in the review by Langer, 1990 Science
249:1527-1533.
[0182] The injectable preparations may include dosage forms for
intravenous, subcutaneous, intracutaneous and intramuscular
injections, drip infusions, etc. These injectable preparations may
be prepared by known methods. For example, the injectable
preparations may be prepared, e.g., by dissolving, suspending or
emulsifying the antibody or its salt described above in a sterile
aqueous medium or an oily medium conventionally used for
injections. As the aqueous medium for injections, there are, for
example, physiological saline, an isotonic solution containing
glucose and other auxiliary agents, etc., which may be used in
combination with an appropriate solubilizing agent such as an
alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol,
polyethylene glycol), a nonionic surfactant (e.g., polysorbate 80
HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor
oil)), etc. As the oily medium, there are employed, e.g., sesame
oil, soybean oil, etc., which may be used in combination with a
solubilizing agent such as benzyl benzoate, benzyl alcohol, etc.
The injection thus prepared is typically filled in an appropriate
ampoule.
[0183] Advantageously, the pharmaceutical compositions for oral or
parenteral use described above are prepared into dosage forms in a
unit dose suited to fit a dose of the active ingredients. Such
dosage forms in a unit dose include, for example, tablets, pills,
capsules, injections (ampoules), suppositories, etc.
[0184] Exemplary pharmaceutical compositions comprising an
anti-IL-4R antibody that can be used in the invention are
disclosed, e.g., in US Patent Application Publication No.
2012/0097565.
Dosage
[0185] The amount of IL-4R antagonist (e.g., anti-IL-4R antibody)
administered to a subject according to the methods featured in the
invention is, generally, a therapeutically effective amount. As
used herein, the phrase "therapeutically effective amount" means an
amount of IL-4R antagonist that results in one or more of: (a) a
reduction in the incidence of asthma exacerbations; (b) an
improvement in one or more asthma-associated parameters (as defined
elsewhere herein); and/or (c) a detectable improvement in one or
more symptoms or indicia of an upper airway inflammatory condition.
A "therapeutically effective amount" also includes an amount of
IL-4R antagonist that inhibits, prevents, lessens, or delays the
progression of asthma in a subject.
[0186] In the case of an anti-IL-4R antibody, a therapeutically
effective amount can be from about 0.05 mg to about 700 mg, e.g.,
about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0
mg, about 3.0 mg, about 5.0 mg, about 7.0 mg, about 10 mg, about 20
mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70
mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120
mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about
170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg,
about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260
mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about
310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg,
about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400
mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about
450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg,
about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540
mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about
590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg,
about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680
mg, about 690 mg, or about 700 mg of the anti-IL-4R antibody. In
certain embodiments, 300 mg of an anti-IL-4R antibody is
administered.
[0187] The amount of IL-4R antagonist contained within the
individual doses may be expressed in terms of milligrams of
antibody per kilogram of patient body weight (i.e., mg/kg). For
example, the IL-4R antagonist may be administered to a patient at a
dose of about 0.0001 to about 10 mg/kg of patient body weight. For
example, the IL-4R antagonist can be administered at a dose of 1
mg/kg, 2 mg/kg, 3 mg/kg, or 4 mg/kg.
[0188] In some embodiments, the dose of IL-4R antagonist may vary
according to eosinophil count. For example, the subject may have a
blood eosinophil count (high blood eosinophils) .gtoreq.300
cells/.mu.L, or 300-499 cells/.mu.L or .gtoreq.500 cells/.mu.L
(HEos); a blood eosinophil count of 200 to 299 cells/.mu.L
(moderate blood eosinophils); or a blood eosinophil count <200
cells/.mu.L (low blood eosinophils).
[0189] In certain embodiments, the methods comprise a loading dose
of about 400 to about 600 mg of an IL-4R antagonist.
[0190] In certain embodiments, the methods comprise one or more
maintenance doses of about 200 to about 300 mg of the IL-4R
antagonist.
[0191] In certain embodiments, the ICS and LABA are administered
for the duration of administration of the IL-4R antagonist.
[0192] In certain embodiments, the loading dose comprises 600 mg of
an anti-IL-4R antibody or antigen-binding fragment thereof, and the
one or more maintenance doses comprises 300 mg of the antibody or
antigen-binding fragment thereof administered every other week.
[0193] In certain embodiments, the loading dose comprises 400 mg of
an anti-IL-4R antibody or antigen-binding fragment thereof, and the
one or more maintenance dose comprises 200 mg of the antibody or
antigen-binding fragment thereof administered every other week.
[0194] In certain embodiments, the loading dose comprises 400 mg of
an anti-IL-4R antibody or antigen-binding fragment thereof, and the
one or more maintenance dose comprises 200 mg of the antibody or
antigen-binding fragment thereof administered every other week,
which may be increased to 300 mg of the antibody or antigen-binding
fragment thereof administered every other week.
[0195] In other embodiments, the loading dose comprises 600 mg of
an anti-IL-4R antibody or antigen-binding fragment thereof, and the
one or more maintenance doses comprises 300 mg of the antibody or
antigen-binding fragment thereof administered every fourth
week.
[0196] In other embodiments, the loading dose comprises 400 mg of
an anti-IL-4R antibody or antigen-binding fragment thereof, and the
one or more maintenance doses comprises 200 mg of the antibody or
antigen-binding fragment thereof administered every fourth
week.
[0197] In other embodiments, the loading dose comprises 600 mg of
an anti-IL-4R antibody or antigen-binding fragment thereof, and the
one or more maintenance doses comprises 300 mg of the antibody or
antigen-binding fragment thereof administered once a week.
[0198] In other embodiments, the loading dose comprises 400 mg of
an anti-IL-4R antibody or antigen-binding fragment thereof, and the
one or more maintenance doses comprises 200 mg of the antibody or
antigen-binding fragment thereof administered once a week.
[0199] In other embodiments, the loading dose comprises 600 mg of
an anti-IL-4R antibody or antigen-binding fragment thereof, and the
one or more maintenance doses comprises 300 mg of the antibody or
antigen-binding fragment thereof administered every third week.
[0200] In other embodiments, the loading dose comprises 400 mg of
an anti-IL-4R antibody or antigen-binding fragment thereof, and the
one or more maintenance doses comprises 200 mg of the antibody or
antigen-binding fragment thereof administered every third week.
[0201] In one embodiment, the subject is 6 to <18 years old and
the IL-4R antibody or antigen binding fragment thereof is
administered at 2 mg/kg or 4 mg/kg.
[0202] In another embodiment, the subject is 12 to <18 years old
and the IL-4R antibody or antigen binding fragment thereof is
administered at 2 mg/kg or 4 mg/kg.
[0203] In another embodiment, the subject is 6 to <12 years old
and the IL-4R antibody or antigen binding fragment thereof is
administered at 2 mg/kg or 4 mg/kg.
[0204] In another embodiment, the subject is 2 to <6 years old
and the IL-4R antibody or antigen binding fragment thereof is
administered at 2 mg/kg or 4 mg/kg.
[0205] In yet another embodiment, the subject is <2 years old
and the IL-4R antibody or antigen binding fragment thereof is
administered at 2 mg/kg or 4 mg/kg.
Combination Therapies
[0206] Certain embodiments of the methods featured in the invention
comprise administering to the subject one or more additional
therapeutic agents in combination with the IL-4R antagonist. As
used herein, the expression "in combination with" means that the
additional therapeutic agents are administered before, after, or
concurrent with the pharmaceutical composition comprising the IL-4R
antagonist. In some embodiments, the term "in combination with"
includes sequential or concomitant administration of an IL-4R
antagonist and a second therapeutic agent. The invention includes
methods to treat asthma or an associated condition or complication
or to reduce at least one exacerbation, comprising administration
of an IL-4R antagonist in combination with a second therapeutic
agent for additive or synergistic activity.
[0207] For example, when administered "before" the pharmaceutical
composition comprising the IL-4R antagonist, the additional
therapeutic agent may be administered about 72 hours, about 60
hours, about 48 hours, about 36 hours, about 24 hours, about 12
hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours,
about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or
about 10 minutes prior to the administration of the pharmaceutical
composition comprising the IL-4R antagonist. When administered
"after" the pharmaceutical composition comprising the IL-4R
antagonist, the additional therapeutic agent may be administered
about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour,
about 2 hours, about 4 hours, about 6 hours, about 8 hours, about
10 hours, about 12 hours, about 24 hours, about 36 hours, about 48
hours, about 60 hours, or about 72 hours after the administration
of the pharmaceutical composition comprising the IL-4R antagonist.
Administration "concurrent" with the pharmaceutical composition
comprising the IL-4R antagonist means that the additional
therapeutic agent is administered to the subject in a separate
dosage form within less than 5 minutes (before, after, or at the
same time) of administration of the pharmaceutical composition
comprising the IL-4R antagonist, or administered to the subject as
a single combined dosage formulation comprising both the additional
therapeutic agent and the IL-4R antagonist.
[0208] The additional therapeutic agent may be, e.g., another IL-4R
antagonist, an IL-1 antagonist (including, e.g., an IL-1 antagonist
as set forth in U.S. Pat. No. 6,927,044), an IL-6 antagonist, an
IL-6R antagonist (including, e.g., an anti-IL-6R antibody as set
forth in U.S. Pat. No. 7,582,298), a TNF antagonist, an IL-8
antagonist, an IL-9 antagonist, an IL-17 antagonist, an IL-5
antagonist, an IgE antagonist, a CD48 antagonist, a leukotriene
inhibitor, an anti-fungal agent, an NSAID, a long-acting beta2
agonist (e.g., salmeterol or formoterol), an inhaled corticosteroid
(e.g., fluticasone or budesonide), a systemic corticosteroid (e.g.,
oral or intravenous), methylxanthine, nedocromil sodium, cromolyn
sodium, or combinations thereof. For example, in certain
embodiments, the pharmaceutical composition comprising an IL-4R
antagonist is administered in combination with a combination
comprising a long-acting beta2 agonist and an inhaled
corticosteroid (e.g., fluticasone+salmeterol [e.g., Advair.RTM.
(GlaxoSmithKline)] or budesonide+formoterol [e.g., SYMBICORT.RTM.
(Astra Zeneca)]).
Administration Regimens
[0209] According to certain embodiments, multiple doses of an IL-4R
antagonist may be administered to a subject over a defined time
course. Such methods comprise sequentially administering to a
subject multiple doses of an IL-4R antagonist. As used herein,
"sequentially administering" means that each dose of IL-4R
antagonist is administered to the subject at a different point in
time, e.g., on different days separated by a predetermined interval
(e.g., hours, days, weeks, or months). The invention includes
methods that comprise sequentially administering to the patient a
single initial dose of an IL-4R antagonist, followed by one or more
secondary doses of the IL-4R antagonist, and optionally followed by
one or more tertiary doses of the IL-4R antagonist.
[0210] The invention includes methods comprising administering to a
subject a pharmaceutical composition comprising an IL-4R antagonist
at a dosing frequency of about four times a week, twice a week,
once a week (qlw), once every two weeks (bi-weekly or q2w), once
every three weeks (tri-weekly or q3w), once every four weeks
(monthly or q4w), once every five weeks (q5w), once every six weeks
(q6w), once every eight weeks (q8w), once every twelve weeks
(q12w), or less frequently so long as a therapeutic response is
achieved. In certain embodiments involving the administration of a
pharmaceutical composition comprising an anti-IL-4R antibody, once
a week dosing of an amount of about 75 mg, 100 mg, 150 mg, 200 mg,
or 300 mg, can be employed. In other embodiments involving the
administration of a pharmaceutical composition comprising an
anti-IL-4R antibody, once every two weeks dosing (bi-weekly dosing)
of an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg, can
be employed. In other embodiments involving the administration of a
pharmaceutical composition comprising an anti-IL-4R antibody, once
every three weeks dosing of an amount of about 75 mg, 100 mg, 150
mg, 200 mg, or 300 mg, can be employed. In other embodiments
involving the administration of a pharmaceutical composition
comprising an anti-IL-4R antibody, once every four weeks dosing
(monthly dosing) of an amount of about 75 mg, 100 mg, 150 mg, 200
mg, or 300 mg, can be employed. In other embodiments involving the
administration of a pharmaceutical composition comprising an
anti-IL-4R antibody, once every five weeks dosing of an amount of
about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg, can be employed. In
other embodiments involving the administration of a pharmaceutical
composition comprising an anti-IL-4R antibody, once every six weeks
dosing of an amount of about 75 mg, 100 mg, 150 mg, 200 mg, or 300
mg, can be employed. In other embodiments involving the
administration of a pharmaceutical composition comprising an
anti-IL-4R antibody, once every eight weeks dosing of an amount of
about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg, can be employed. In
other embodiments involving the administration of a pharmaceutical
composition comprising an anti-IL-4R antibody, once every twelve
weeks dosing of an amount of about 75 mg, 100 mg, 150 mg, 200 mg,
or 300 mg, can be employed. In one embodiment, the route of
administration is subcutaneous.
[0211] The term "week" or "weeks" refers to a period of (n.times.7
days) .+-.2 days, e.g. (n.times.7 days) .+-.1 day, or (n.times.7
days), wherein "n" designates the number of weeks, e.g. 1, 2, 3, 4,
5, 6, 8, 12 or more.
[0212] The terms "initial dose," "secondary doses," and "tertiary
doses," refer to the temporal sequence of administration of the
IL-4R antagonist. Thus, the "initial dose" is the dose that is
administered at the beginning of the treatment regimen (also
referred to as the "baseline dose"); the "secondary doses" are the
doses that are administered after the initial dose; and the
"tertiary doses" are the doses that are administered after the
secondary doses. The initial, secondary, and tertiary doses may all
contain the same amount of IL-4R antagonist, but generally may
differ from one another in terms of frequency of administration. In
certain embodiments, however, the amount of IL-4R antagonist
contained in the initial, secondary and/or tertiary doses varies
from one another (e.g., adjusted up or down as appropriate) during
the course of treatment. In certain embodiments, two or more (e.g.,
2, 3, 4 or 5) doses are administered at the beginning of the
treatment regimen as "loading doses" followed by subsequent doses
that are administered on a less frequent basis (e.g., "maintenance
doses"). In one embodiment, the maintenance dose may be lower than
the loading dose. For example, one or more loading doses of 600 mg
of IL-4R antagonist may be administered followed by maintenance
doses of about 75 mg to about 300 mg.
[0213] In certain embodiments, the loading dose is about 400 to
about 600 mg of the IL-4R antagonist. In one embodiment, the
loading dose is 400 mg of the IL-4R antagonist. In another
embodiment, the loading dose is 600 mg of the IL-4R antagonist.
[0214] In certain embodiments, the maintenance dose is about 200 to
about 300 mg of the IL-4R antagonist. In one embodiment, the
maintenance dose is 200 mg of the IL-4R antagonist. In another
embodiment, the maintenance dose is 300 mg of the IL-4R
antagonist.
[0215] In certain embodiments, the loading dose is two times the
maintenance dose.
[0216] In some embodiments, the loading dose comprises 600 mg of
the antibody or antigen-binding fragment thereof, and the one or
more maintenance doses comprises 300 mg of the antibody or
antigen-binding fragment thereof administered every other week.
[0217] In some embodiments, a subject has OCS-dependent asthma, and
the loading dose comprises 600 mg of the antibody or
antigen-binding fragment thereof, and the one or more maintenance
doses comprises 300 mg of the antibody or antigen-binding fragment
thereof administered every other week.
[0218] In some embodiments, a subject has co-morbid
moderate-to-severe atopic dermatitis, and the loading dose
comprises 600 mg of the antibody or antigen-binding fragment
thereof, and the one or more maintenance doses comprises 300 mg of
the antibody or antigen-binding fragment thereof administered every
other week.
[0219] In some embodiments, the loading dose comprises 400 mg of
the antibody or antigen-binding fragment thereof, and the one or
more maintenance dose comprises 200 mg of the antibody or
antigen-binding fragment thereof administered every other week.
[0220] In some embodiments, a subject has OCS-dependent asthma, and
the loading dose comprises 400 mg of the antibody or
antigen-binding fragment thereof, and the one or more maintenance
doses comprises 200 mg of the antibody or antigen-binding fragment
thereof administered every other week.
[0221] In some embodiments, a subject has co-morbid
moderate-to-severe atopic dermatitis, and the loading dose
comprises 400 mg of the antibody or antigen-binding fragment
thereof, and the one or more maintenance doses comprises 200 mg of
the antibody or antigen-binding fragment thereof administered every
other week.
[0222] In some embodiments, the loading dose comprises 600 mg of
the antibody or antigen-binding fragment thereof, and the one or
more maintenance doses comprises 300 mg of the antibody or
antigen-binding fragment thereof administered every fourth
week.
[0223] In some embodiments, a subject has OCS-dependent asthma, and
the loading dose comprises 600 mg of the antibody or
antigen-binding fragment thereof, and the one or more maintenance
doses comprises 300 mg of the antibody or antigen-binding fragment
thereof administered every fourth week.
[0224] In some embodiments, a subject has co-morbid
moderate-to-severe atopic dermatitis, and the loading dose
comprises 600 mg of the antibody or antigen-binding fragment
thereof, and the one or more maintenance doses comprises 300 mg of
the antibody or antigen-binding fragment thereof administered every
fourth week.
[0225] In some embodiments, the loading dose comprises 400 mg of
the antibody or antigen-binding fragment thereof, and the one or
more maintenance doses comprises 200 mg of the antibody or
antigen-binding fragment thereof administered every fourth
week.
[0226] In some embodiments, a subject has OCS-dependent asthma, and
the loading dose comprises 400 mg of the antibody or
antigen-binding fragment thereof, and the one or more maintenance
doses comprises 200 mg of the antibody or antigen-binding fragment
thereof administered every fourth week.
[0227] In some embodiments, a subject has co-morbid
moderate-to-severe atopic dermatitis, and the loading dose
comprises 400 mg of the antibody or antigen-binding fragment
thereof, and the one or more maintenance doses comprises 200 mg of
the antibody or antigen-binding fragment thereof administered every
fourth week.
[0228] In one exemplary embodiment, each secondary and/or tertiary
dose is administered 1 to 14 (e.g., 1, 11/22, 21/23, 31/24, 41/25,
51/26, 61/27, 71/28, 81/29, 91/210, 101/211, 111/212, 121/213,
131/214, 141/2 or more) weeks after the immediately preceding dose.
The phrase "the immediately preceding dose" means, in a sequence of
multiple administrations, the dose of IL-4R antagonist that is
administered to a patient prior to the administration of the very
next dose in the sequence with no intervening doses.
[0229] The methods may include administering to a patient any
number of secondary and/or tertiary doses of an IL-4R antagonist.
For example, in certain embodiments, only a single secondary dose
is administered to the patient. In other embodiments, two or more
(e.g., 2, 3, 4, 5, 6, 7, 8 or more) secondary doses are
administered to the patient. Likewise, in certain embodiments, only
a single tertiary dose is administered to the patient. In other
embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more)
tertiary doses are administered to the patient.
[0230] In embodiments involving multiple secondary doses, each
secondary dose may be administered at the same frequency as the
other secondary doses. For example, each secondary dose may be
administered to the patient 1 to 2 weeks after the immediately
preceding dose. Similarly, in embodiments involving multiple
tertiary doses, each tertiary dose may be administered at the same
frequency as the other tertiary doses. For example, each tertiary
dose may be administered to the patient 2 to 4 weeks after the
immediately preceding dose. Alternatively, the frequency at which
the secondary and/or tertiary doses are administered to a patient
can vary over the course of the treatment regimen. The frequency of
administration may also be adjusted during the course of treatment
by a physician depending on the needs of the individual patient
following clinical examination.
[0231] The invention includes methods comprising sequential
administration of an IL-4R antagonist and a second therapeutic
agent, to a patient to treat asthma or an associated condition. In
some embodiments, the methods comprise administering one or more
doses of an IL-4R antagonist followed by one or more doses (e.g.,
2, 3, 4, 5, 6, 7, 8 or more) of a second therapeutic agent. For
example, one or more doses of about 75 mg to about 300 mg of the
IL-4R antagonist may be administered after which one or more doses
(e.g., 2, 3, 4, 5, 6, 7, 8 or more) of a second therapeutic agent
(e.g., an inhaled corticosteroid or a beta2-agonist or any other
therapeutic agent, as described elsewhere herein) may be
administered to treat, alleviate, reduce or ameliorate one or more
symptoms of asthma. In some embodiments, the IL-4R antagonist is
administered at one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8 or
more) resulting in an improvement in one or more asthma-associated
parameters followed by the administration of a second therapeutic
agent to prevent recurrence of at least one symptom of asthma.
Alternative embodiments pertain to concomitant administration of an
IL-4R antagonist and a second therapeutic agent. For example, one
or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, or more) of an IL-4R
antagonist are administered and a second therapeutic agent is
administered at a separate dosage at a similar or different
frequency relative to the IL-4R antagonist. In some embodiments,
the second therapeutic agent is administered before, after or
concurrently with the IL-4R antagonist.
[0232] In certain embodiments, the IL-4R antagonist is administered
every other week for 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20
weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks,
34 weeks, 36 weeks, 38 weeks, 40 weeks, 42 weeks, 44 weeks, 46
weeks, 48 weeks or more. In other embodiments, the IL-4R antagonist
is administered every four weeks for 12 weeks, 16 weeks, 20 weeks,
24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48
weeks or more. In specific embodiments, the IL-4R antagonist is
administered for at least 24 weeks.
[0233] The invention includes methods for treating a subject having
severe uncontrolled asthma (e.g., severe steroid-dependent asthma)
comprising administering to the subject a loading dose of an
antibody or an antigen-binding fragment thereof that specifically
binds to IL-4R. In certain embodiments, the methods comprise
administering to the subject a plurality of maintenance doses of
the antibody or the antigen-binding fragment thereof, wherein the
plurality of maintenance doses are administered during a treatment
phase. The treatment phase comprises an induction phase, an OCS
reduction phase, and an OCS maintenance phase.
[0234] In certain exemplary embodiments, the induction phase
comprises a period during which subjects continuously receive their
OCS dose(s). In certain exemplary embodiments, the reduction phase
comprises a period during which subjects receive a lower OCS dose
relative to the dose received during the induction phase. In
certain exemplary embodiments, the maintenance phase comprises a
period during which a subject receives a certain stable amount or
dose(s) of OCS. Alternatively, the maintenance phase comprises a
period in which OCS therapy/administration is reduced or
eliminated. In certain embodiments, OCS use by the patient is
completely eliminated and the patient is steroid free within less
than 1 year of treatment with the IL4R antibody or fragment thereof
(e.g., within 1 year, 6 months, 3 months or 1 month of initial
treatment).
[0235] In another aspect, a method for treating a subject having
severe steroid-dependent asthma and/or severe uncontrolled asthma
comprises administering to the subject a loading dose of about 600
mg of an antibody or an antigen-binding fragment thereof that
specifically binds to interleukin-4 receptor (IL-4R), and
administering to the subject a plurality of maintenance doses of
the antibody or the antigen-binding fragment thereof. Each
maintenance dose is about 300 mg of the antibody or antigen-binding
fragment thereof, wherein the plurality of maintenance doses are
administered during a treatment phase comprising an induction
phase, an oral corticosteroid (OCS) reduction phase, and a
maintenance phase, and wherein the antibody or antigen-binding
fragment thereof comprises heavy and light chain CDR sequences from
the HCVR/LCVR sequence pair comprises SEQ ID NOs: 1 and 2.
Treatment Populations
[0236] The methods featured in the invention include administering
to a subject in need thereof a therapeutic composition comprising
an IL-4R antagonist. The expression "a subject in need thereof"
means a human or non-human animal that exhibits one or more
symptoms or indicia of asthma (e.g., moderate-to-severe
uncontrolled asthma), or who has been diagnosed with asthma. For
example, "a subject in need thereof" may include, e.g., subjects
who, prior to treatment, exhibit (or have exhibited) one or more
asthma-associated parameter, such as, e.g., impaired FEV.sub.1
(e.g., less than 2.0 L), impaired FEF25-75%; impaired AM PEF (e.g.,
less than 400 L/min), impaired PM PEF (e.g., less than 400 L/min),
an ACQ5 score of at least 2.5 at least 1 nighttime awakenings per
night, and/or a SNOT-22 score of at least 20 In various
embodiments, the methods may be used to treat mild,
moderate-to-severe, and severe asthma in patients in need thereof.
In certain embodiments, the methods may be used to treat mild,
moderate-to-severe, and severe asthma in patients in need thereof,
wherein the patients further exhibit comorbid moderate-to-severe
atopic dermatitis.
[0237] In a related embodiment, a "subject in need thereof" may be
a subject who, prior to receiving an IL-4R antagonist, has been
prescribed or is currently taking a combination of ICS/LABA.
Examples of ICS include mometasone furoate, budesonide, and
fluticasone propionate. Examples of LABA include formoterol and
salmeterol. Examples of ICS/LABA therapies include
fluticasone/salmeterol combination therapy and
budesonide/formoterol combination therapy. For example, the
invention includes methods that comprise administering an IL-4R
antagonist to a patient who has been taking a regular course of
ICS/LABA for two or more weeks immediately preceding the
administration of the IL-4R antagonist (such prior treatments are
referred to herein as "background treatments"). The invention
includes therapeutic methods in which background treatments are
continued in combination with administration of the IL-4R
antagonist. In yet other embodiments, the amount of the ICS
component, the LABA component, or both, is gradually decreased
prior to or after the start of IL-4R antagonist administration. In
some embodiments, the invention includes methods to treat patients
with persistent asthma for at least .gtoreq.12 months. In one
embodiment, a patient with persistent asthma may be resistant to
treatment by a therapeutic agent, such as a corticosteroid, and may
be administered an IL-4R antagonist according to the present
methods.
[0238] In some embodiments, a "subject in need thereof" may be a
subject with elevated levels of an asthma-associated biomarker.
Examples of asthma-associated biomarkers include, but are not
limited to, IgE, thymus and activation regulated chemokine (TARC),
eotaxin-3 CEA, YKL-40 and periostin. In some embodiments, a
"subject in need thereof" may be a subject with blood eosinophils
.gtoreq.300 cells/.mu.L, 200-299 cells/.mu.L, or <200
cells/.mu.L. In one embodiment, a "subject in need thereof" may be
a subject with elevated level of bronchial or airway inflammation
as measured by the fraction of exhaled nitric oxide (FeNO).
[0239] In some embodiments, a "subject in need thereof" is selected
from the group consisting of: a subject age 18 years old or older,
a subject 12 years or older, a subject age 12 to 17 years old (12
to <18 years old), a subject age 6 to 11 years old (6 to <12
years old), and a subject age 2 to 5 years old (2 to <6 years
old). In some embodiments, a "subject in need thereof" is selected
from the group consisting of: an adult, an adolescent, and a child.
In some embodiments, a "subject in need thereof" is selected from
the group consisting of: an adult age 18 years of age or older, an
adolescent age 12 to 17 years old (12 to <18 years old), a child
age 6 to 11 years old (6 to <12 years old), and a child age 2 to
5 years old (2 to <6 years old). The subject can be less than 2
years of age, e.g., 12 to 23 months, or 6 to 11 months.
[0240] A normal IgE level in healthy subjects is less than about
100 kU/L (e.g., as measured using the IMMUNOCAP.RTM. assay [Phadia,
Inc. Portage, Mich.]). Thus, the invention includes methods
comprising selecting a subject who exhibits an elevated serum IgE
level, which is a serum IgE level greater than about 100 kU/L,
greater than about 150 kU/L, greater than about 500 kU/L, greater
than about 1000 kU/L, greater than about 1500 kU/L, greater than
about 2000 kU/L, greater than about 2500 kU/L, greater than about
3000 kU/L, greater than about 3500 kU/L, greater than about 4000
kU/L, greater than about 4500 kU/L, or greater than about 5000
kU/L, and administering to the subject a pharmaceutical composition
comprising a therapeutically effective amount of an IL-4R
antagonist.
[0241] TARC levels in healthy subjects are in the range of 106 ng/L
to 431 ng/L, with a mean of about 239 ng/L. (An exemplary assay
system for measuring TARC level is the TARC quantitative ELISA kit
offered as Cat. No. DDN00 by R&D Systems, Minneapolis, Minn.)
Thus, the invention involves methods comprising selecting a subject
who exhibits an elevated TARC level, which is a serum TARC level
greater than about 431 ng/L, greater than about 500 ng/L, greater
than about 1000 ng/L, greater than about 1500 ng/L, greater than
about 2000 ng/L, greater than about 2500 ng/L, greater than about
3000 ng/L, greater than about 3500 ng/L, greater than about 4000
ng/L, greater than about 4500 ng/L, or greater than about 5000
ng/L, and administering to the subject a pharmaceutical composition
comprising a therapeutically effective amount of an IL-4R
antagonist.
[0242] Eotaxin-3 belongs to a group of chemokines released by
airway epithelial cells, which is up-regulated by the Th2 cytokines
IL-4 and IL-13 (Lilly et al 1999 J. Allergy Clin. Immunol. 104:
786-790). The invention includes methods comprising administering
an IL-4R antagonist to treat patients with elevated levels of
eotaxin-3 such as more than about 100 pg/ml, more than about 150
pg/ml, more than about 200 pg/ml, more than about 300 pg/ml, or
more than about 350 pg/ml. Serum eotaxin-3 levels may be measured,
for example, by ELISA.
[0243] Periostin is an extracellular matrix protein involved in the
Th2-mediated inflammatory processes. Periostin levels are found to
be up-regulated in patients with asthma (Jia et al 2012 J Allergy
Clin Immunol. 130:647-654.e10 doi: 10.1016/j.jaci.2012.06.025 Epub
2012 Aug. 1). The invention includes methods comprising
administering an IL-4R antagonist to treat patients with elevated
levels of periostin.
[0244] Fractional exhaled NO (FeNO) is a biomarker of bronchial or
airway inflammation. FeNO is produced by airway epithelial cells in
response to inflammatory cytokines including IL-4 and IL-13 (Alwing
et al 1993 Eur. Respir. J. 6: 1368-1370). FeNO levels in healthy
adults range from 2 to 30 parts per billion (ppb). An exemplary
assay for measuring FeNO is by using a NIOX instrument by Aerocrine
AB, Solna, Sweden. The assessment may be conducted prior to
spirometry and following a fast of at least an hour. The invention
includes methods comprising administering an IL-4R antagonist to
patients with elevated levels of exhaled NO (FeNO), such as more
than about 30 ppb, more than about 31 ppb, more than about 32 ppb,
more than about 33 ppb, more than about 34 ppb, or more than about
35 ppb.
[0245] Carcinoembryogenic antigen (CEA) (also known as CEA cell
adhesion molecule 5 [CEACAM5]) is a tumor marker that is found
correlated to non-neoplastic diseases of the lung (Marechal et al
1988 Anticancer Res. 8: 677-680). CEA levels in serum may be
measured by ELISA. The invention includes methods comprising
administering an IL-4R antagonist to patients with elevated levels
of CEA, such as more than about 1.0 ng/ml, more than about 1.5
ng/ml, more than about 2.0 ng/ml, more than about 2.5 ng/ml, more
than about 3.0 ng/ml, more than about 4.0 ng/ml, or more than about
5.0 ng/ml.
[0246] YKL-40 (named for its N-terminal amino acids tyrosine (Y),
lysine (K) and leucine (L) and its molecular mass of 40 kD) is a
chitinase-like protein found to be up regulated and correlated to
asthma exacerbation, IgE, and eosinophils (Tang et al 2010 Eur.
Respir. J. 35: 757-760). Serum YKL-40 levels are measured by, for
example, ELISA. The invention includes methods comprising
administering an IL-4R antagonist to patients with elevated levels
of YKL-40 such as more than about 40 ng/ml, more than about 50
ng/ml, more than about 100 ng/ml, more than about 150 ng/ml, more
than about 200 ng/ml, or more than about 250 ng/ml.
[0247] Periostin is a secreted matricellular protein associated
with fibrosis, and its expression is upregulated by recombinant
IL-4 and IL-13 in cultured bronchial epithelial cells and bronchial
fibroblasts (Jia et al. (2012) J. Allergy Clin. Immunol. 130:647).
In human asthmatic patients periostin expression levels correlate
with reticular basement membrane thickness, an indicator of
subepithelial fibrosis. Id. The invention includes methods
comprising administering an IL-4R antagonist to patients with
elevated levels of periostin.
[0248] Induced sputum eosinophils and neutrophils are
well-established direct markers of airway inflammation (Djukanovic
et al 2002 Eur. Respire. J. 37: 1S-2S). Sputum is induced with
inhalation of hypertonic saline solution and processed for cell
counts according to methods known in the art, for example, the
guidelines of European Respiratory Society.
[0249] In some embodiments, the subjects are stratified into the
following groups: a blood eosinophil count (high blood eosinophils)
.gtoreq.300 cells/.mu.L (HEos) or 300-499 cells/.mu.L or
.gtoreq.500 cells/.mu.L, a blood eosinophil count of 200 to 299
cells/.mu.L (moderate blood eosinophils), or a blood eosinophil
count <200 cells/.mu.L (low blood eosinophils), and are
administered an anti-IL-4R antibody or antigen binding fragment
thereof at a dose or dosing regimen based upon the eosinophil
level.
[0250] In some embodiments, the subjects are stratified into the
following groups: a blood eosinophil count of .gtoreq.300
cells/.mu.L, of 300-499 cells/.mu.L, or of .gtoreq.500 cells/.mu.L
(high blood eosinophils); a blood eosinophil count of .gtoreq.150
cells/.mu.L (moderate blood eosinophils); or a blood eosinophil
count of <150 cells/.mu.L (low blood eosinophils), and are
administered an anti-IL-4R antibody or antigen binding fragment
thereof at a dose or dosing regimen based upon the eosinophil
level.
[0251] In some embodiments, a subject has "eosinophilic phenotype"
asthma defined by a blood eosinophil count of .gtoreq.150
cells/.mu.L, a blood eosinophil count of .gtoreq.300 cells/.mu.L, a
blood eosinophil count of 300-499 cells/.mu.L, or a blood
eosinophil count of .gtoreq.500 cells/.mu.L, and are administered
an anti-IL-4R antibody or antigen binding fragment thereof.
Methods for Assessing Pharmacodynamic Asthma-Associated
Parameters
[0252] The invention also includes methods for assessing one or
more pharmacodynamic asthma-associated parameters a subject in need
thereof, caused by administration of a pharmaceutical composition
comprising an IL-4R antagonist. A reduction in the incidence of an
asthma exacerbation (as described above) or an improvement in one
or more asthma-associated parameters (as described above) may
correlate with an improvement in one or more pharmacodynamic
asthma-associated parameters; however, such a correlation is not
necessarily observed in all cases.
[0253] Examples of "pharmacodynamic asthma-associated parameters"
include, for example, the following: (a) biomarker expression
levels; (b) serum protein and RNA analysis; (c) induced sputum
eosinophils and neutrophil levels; (d) exhaled nitric oxide (FeNO);
and (e) blood eosinophil count. An "improvement in a
pharmacodynamic asthma-associated parameter" means, for example, a
decrease from baseline of one or more biomarkers, such as TARC,
eotaxin-3 or IgE, a decrease in sputum eosinophils or neutrophils,
FeNO, periostin or blood eosinophil count. As used herein, the term
"baseline," with regard to a pharmacodynamic asthma-associated
parameter, means the numerical value of the pharmacodynamic
asthma-associated parameter for a patient prior to or at the time
of administration of a pharmaceutical composition described
herein.
[0254] To assess a pharmacodynamic asthma-associated parameter, the
parameter is quantified at baseline and at a time point after
administration of the pharmaceutical composition. For example, a
pharmacodynamic asthma-associated parameter may be measured at day
1 day 2 day 3 day 4 day 5 day 6 day 7 day 8 day 9 day 10 day 11 day
12 day 14 or at week 3 week 4 week 5 week 6, week 7 week 8 week 9
week 10 week 11 week 12 week 13 week 14 week 15 week 16 week 17
week 18 week 19 week 20 week 21 week 22 week 23 week 24 or longer,
after the initial treatment with the pharmaceutical composition.
The difference between the value of the parameter at a particular
time point following initiation of treatment and the value of the
parameter at baseline is used to establish whether there has been
change, such as an "improvement," in the pharmacodynamic
asthma-associated parameter (e.g., an increase or decrease, as the
case may be, depending on the specific parameter being
measured).
[0255] In certain embodiments, administration of an IL-4R
antagonist to a patient causes a change, such as a decrease or
increase, in expression of a particular biomarker.
Asthma-associated biomarkers include, but are not limited to, the
following: (a) total IgE; (b) thymus and activation-regulated
chemokine (TARC); (c) YKL-40 (d) carcinoembryonic antigen in serum;
(e) eotaxin-3 in plasma; and (f) periostin in serum. For example,
administration of an IL-4R antagonist to an asthma patient can
cause one or more of a decrease in TARC or eotaxin-3 levels, or a
decrease in total serum IgE levels. The decrease can be detected at
week 1 week 2 week 3 week 4 week 5 or longer following
administration of the IL-4R antagonist. Biomarker expression can be
assayed by methods known in the art. For example, protein levels
can be measured by ELISA (Enzyme Linked Immunosorbent Assay). RNA
levels can be measured, for example, by reverse transcription
coupled to polymerase chain reaction (RT-PCR).
[0256] Biomarker expression, as discussed above, can be assayed by
detection of protein or RNA in serum. The serum samples can also be
used to monitor additional protein or RNA biomarkers related to
response to treatment with an IL-4R antagonist, IL-4/IL-13
signaling, asthma, atopy or eosinophilic diseases (e.g., by
measuring soluble IL-4R.alpha.IL-4 IL-13 periostin). In some
embodiments, RNA samples are used to determine RNA levels
(non-genetic analysis), e.g., RNA levels of biomarkers; and in
other embodiments, RNA samples are used for transcriptome
sequencing (e.g., genetic analysis).
Formulations
[0257] In some embodiments, the antibody or antigen binding
fragment thereof is formulated in a composition comprising: i)
about 150 mg/mL of antibody or an antigen-binding fragment thereof
that specifically binds to IL-4R, ii) about 20 mM histidine, iii)
about 12.5 mM acetate, iv) about 5% (w/v) sucrose, v) about 25 mM
arginine hydrochloride, vi) about 0.2% (w/v) polysorbate 80 wherein
the pH of the formulation is about 5.9 and wherein the viscosity of
the formulation is about 8.5 cPoise.
[0258] In alternative embodiments, the antibody or antigen binding
fragment thereof is formulated in a composition comprising: i)
about 175 mg/mL of antibody or an antigen-binding fragment thereof
that specifically binds to IL-4R, ii) about 20 mM histidine, iii)
about 12.5 mM acetate, iv) about 5% (w/v) sucrose, v) about 50 mM
arginine hydrochloride, vi) about 0.2% (w/v) polysorbate 80 wherein
the pH of the formulation is about 5.9 and wherein the viscosity of
the formulation is about 8.5 cPoise.
[0259] In specific embodiments, the antibody or antigen-binding
fragment thereof comprises an HCVR comprising the amino acid
sequence of SEQ ID NO: 1 and an LCVR comprising the amino acid
sequence of SEQ ID NO: 2.
[0260] The present invention is further illustrated by the
following examples which should not be construed as further
limiting. The contents of the figures and all references, patents
and published patent applications cited throughout this application
are expressly incorporated herein by reference for all
purposes.
[0261] Furthermore, in accordance with the present invention there
may be employed conventional molecular biology, microbiology, and
recombinant DNA techniques within the skill of the art. Such
techniques are explained fully in the literature. See, e.g., Green
& Sambrook, Molecular Cloning: A Laboratory Manual Fourth
Edition (2012) Cold Spring Harbor Laboratory Press, Cold Spring
Harbor, N.Y.; DNA Cloning: A Practical Approach Volumes I and II
(D. N. Glover ed. 1985); Oligonucleotide Synthesis (M. J. Gait ed.
1984); Nucleic Acid Hybridization [B. D. Hames & S. J. Higgins
eds. (1985)]Transcription And Translation [B. D. Hames & S. J.
Higgins, eds. (1984)]; Animal Cell Culture [R. I. Freshney, ed.
(1986)]Immobilized Cells And Enzymes [IRL Press, (1986)]B. Perbal,
A Practical Guide To Molecular Cloning (1984); F. M. Ausubel et al.
(eds.), Current Protocols in Molecular Biology John Wiley &
Sons, Inc. (1994).
EXAMPLES
[0262] The following examples are put forth so as to provide those
of ordinary skill in the art with a complete disclosure and
description of how to make and use the methods and compositions
featured in the invention, and are not intended to limit the scope
of what the inventors regard as their invention. Efforts have been
made to ensure accuracy with respect to numbers used (e.g.,
amounts, temperature, etc.) but some experimental errors and
deviations should be accounted for. Unless indicated otherwise,
parts are parts by weight, molecular weight is average molecular
weight, temperature is in degrees Centigrade, and pressure is at or
near atmospheric.
[0263] The exemplary IL-4R antagonist used in the following
Examples is the human anti-IL-4R antibody named dupilumab (also
referred to herein as "mAb1").
Example 1 VENTURE Phase III Trial Study (NCT02528214)
[0264] Severe uncontrolled asthma can lead to a dependence on oral
corticosteroids, with systemic steroid exposure. This can
potentially lead to serious short-term and long-term adverse
effects, including weight gain, diabetes, osteoporosis, glaucoma,
anxiety, depression, cardiovascular disease and immunosuppression.
Patients with severe chronic asthma live with a profound decrease
in their lung function, approximately 52 percent of predicted
normal for those in this study at baseline. The decrease in lung
function impacts their ability to breathe normally and may lead to
frequent exacerbations that require acute treatment and
hospitalization. These problems occur even in patients who are
treated with chronic OCS.
[0265] A phase 3 trial/study was performed to evaluate
investigational dupilumab in adults and adolescents with severe
steroid-dependent asthma, without minimum blood eosinophil
requirement, to receive add-on dupilumab 300 mg or placebo every 2
weeks for 24 weeks. The Phase 3 trial (VENTURE) enrolled 210
patients (203 completed the randomized treatment period, with 101
in the dupilumab group and 102 in the placebo group) with severe
asthma and regular use of maintenance OCS in the six months prior
to the study (FIG. 1). In the study, the prescribed OCS was
prednisone or prednisolone. Patients were randomized using a 1:1
randomization ratio and treated with either dupilumab, 300 mg every
other week with a loading dose of 600 mg, or placebo (FIG. 2). The
median baseline eosinophil count in the study was 260
eosinophils/microliter. Primary endpoint was reduction in
glucocorticoid dose at week 24 Key secondary endpoints included
proportion of patients achieving .gtoreq.50% reduction in
glucocorticoid-dose, and reduction to <5 mg/day in
glucocorticoid-dose at week 24 Severe exacerbation rates and
pre-bronchodilator forced expiratory volume in 1 second (FEV.sub.1)
were assessed in overall population and in patients with blood
eosinophils .gtoreq.300 cells/.mu.L. Safety was assessed
overall.
[0266] Inclusion criteria for the study are shown below in Table 1
Baseline demographics for the study are shown in FIG. 3.
TABLE-US-00001 TABLE 1 Inclusion criteria. VENTURE study Age Adults
& adolescents, >=12 years Asthma At least 6 m of documented
OCS requirement history (equivalent to GINA 5 - severe) Existing
High dose ICS asthma OCS daily dose: 5 mg minimum to 35 mg
treatment maximum Up to 3 controllers are eligible. Pre-BD <=80%
for adults; <=90% for adolescents FEV.sub.1 ACQ-5 None specified
FEV.sub.1 Documented history within prior year Reversibility #
severe None specified exacerbations in prior year
Exclusion criteria for the Venture study were also used; the
criteria for exclusion of patients was EOS<150 restricted to no
more than 25% of total population.
[0267] The primary endpoint analyzed was the percent reduction of
the OCS dose at week 24 Key secondary endpoints analyzed included a
reduction of 50% or greater in the OCS dose and a reduction of OCS
dose to <5 mg/day. Other secondary endpoints investigated
included achieving patient's maximum possible reduction per
protocol, and a patient no longer requiring OCS. Disease-specific
efficacy measures were used. The measures were a reduction in
annualized severe exacerbation and improvement in lung function
(FEV.sub.1). FIG. 2 shows the overall disposition of the patients
in the study.
Primary Outcome
[0268] In the intent to treat (ITT) population, dupilumab treatment
significantly reduced oral glucocorticoid dose compared with
placebo, while maintaining asthma control: least squares (LS) mean
(standard error [SE]) percentage change from baseline to week 24
(-70.1% (4.90) versus -41.9% (4.57) from baseline, respectively
(P<0.001 FIG. 4A; Table 2)). The observed median change from
baseline to week 24 in dupilumab-treated patients was 100%
(interquartile range (IQR), 62.5% to 100%) versus 50% (IQR, 0% to
100%) in the placebo group.
TABLE-US-00002 TABLE 2 Summary of outcomes at week 24 - ITT
population. Dupilumab Placebo 300 mg q2w (N = 107) (N = 103)
Percentage reduction in oral glucocorticoid dose from baseline at
Week 24 LS mean change (SE) -41.85 (4.57) -70.09 (4.90) LS mean
difference versus placebo (95% CI) -28.24 (-40.67 to -15.81) P
value versus placebo <0.001 Median reduction (IQR).sup.a -50
(-100 to 0) -100 (-100 to -62.50) 100% 29.0 52.4 .gtoreq.90% 30.8
55.3 .gtoreq.75% 39.3 68.9 .gtoreq.50% 53.3 79.6 0% 68.2 86.4 No
reduction or increase in glucocorticoid dose, 31.8 13.6 or dropped
out of study Reduction in oral glucocorticoid dose from baseline
(mg/day) at Week 24 LS mean change (SE) -4.77 (0.54) -7.58 (0.58)
LS mean difference versus placebo (95% CI) -2.81 (-4.29 to -1.33) P
value versus placebo <0.001 Proportion of patients with
.gtoreq.50% reduction in oral glucocorticoid dose at Week 24 Yes -
no. (%) 57 (53.3) 82 (79.6) Estimate (95% CI) 0.50 (0.40 to 0.61)
0.80 (0.70 to 0.87) Odds ratio versus placebo (95% CI) 3.98 (2.06
to 7.67) P value versus placebo <0.001 Proportion of patients
with oral glucocorticoid reduced to <5 mg/day at Week 24 Yes -
no. (%) 40 (37.4) 74 (71.8) Estimate (95% CI) 0.33 (0.24 to 0.44)
0.69 (0.58 to 0.79) Odds ratio versus placebo (95% CI) 4.48 (2.39
to 8.39) P value versus placebo <0.001 Proportion of patients no
longer requiring oral glucocorticoid at Week 24 Yes - no. (%) 31
(29.2) 54 (52.4) Estimate (95% CI) 0.25 (0.17 to 0.35) 0.48 (0.36
to 0.59) Odds ratio versus placebo (95% CI) 2.74 (1.47 to 5.10) P
value versus placebo 0.002 Proportion of patients with maximum
possible oral glucocorticoid dose at Week 24 Yes - no. (%) 32
(29.9) 54 (52.4) Estimate (95% CI) 0.26 (0.18 to 0.36) 0.48 (0.36
to 0.59) Odds ratio versus placebo (95% CI) 2.57 (1.40 to 4.73) P
value versus placebo 0.002 Adjusted annualized rate of severe
exacerbation events during the 24-week treatment period Estimate
(95% CI) 1.597 (1.248 to 2.043) 0.649 (0.442 to 0.955) Relative
risk versus placebo (95% CI) 0.407 (0.263 to 0.630) P value versus
placebo <0.001 Change from baseline in pre-bronchodilator
FEV.sub.1 (L) at Week 24 LS mean change (SE) - L 0.01 (0.05) 0.22
(0.05) LS mean difference versus placebo (95% CI) 0.22 (0.09 to
0.34) P value versus placebo <0.001 Change from baseline in FeNO
(ppb) at Week 24 Mean change (SE) - ppb 0.3 (27.9) -17.3 (27.9) P
value versus placebo.sup.b <0.001 CI denotes confidence
interval, FeNO Fractional exhaled nitric oxide, FEV.sub.1 forced
expiratory volume in 1 second, IQR interquartile range, LS,
least-squares, ppb parts per billion, q2w every 2 weeks, SD
standard deviation, and SE standard error. .sup.aCalculated from
observed data only. .sup.bFeNO was tested non-parametrically.
Secondary Outcomes
Glucocorticoid Reduction Outcomes
[0269] For the primary endpoint, at 24 weeks in the overall
population, dupilumab added to standard therapies significantly
reduced the use of maintenance oral corticosteroids (OCS) by 70.1%
(median 100 percent) compared to 41.9% with placebo (median 50
percent) (p<0.001).
[0270] In pre-specified analyses of patients with baseline
eosinophil counts greater than or equal to 300 cells/microliter,
adding dupilumab significantly reduced OCS use by 80 percent on
average (median 100 percent) compared to 43 percent for placebo
(median 50 percent).
[0271] The proportion of patients achieving .gtoreq.50% reduction
in oral glucocorticoid dose relative to baseline at week 24 was
significantly greater with dupilumab versus placebo (80% vs. 50%;
P<0.001; Observed values: 80% for dupilumab, 53% for placebo)
(FIG. 4A; Table 2). Sensitivity analyses also demonstrated greater
proportion of patients with 50%, 75%, and 90% reductions in oral
glucocorticoids with dupilumab (Table 3). Significantly more
patients treated with dupilumab versus placebo achieved a reduction
of oral glucocorticoid dose to <5 mg/day (69% vs. 33%;
P<0.001; Observed values: 72% for dupilumab, 37% for placebo)
(FIG. 4A; Table 2).
TABLE-US-00003 TABLE 3 Sensitivity analyses: percentage reduction
of oral glucocorticoid dose (mg/day) at week 24 analyzed by
proportional odds model - ITT population. Percentage Dupilumab
reduction in oral glucocorticoid Placebo 300 mg q2w dose from
baseline at Week 24 (N = 107) (N = 103) .gtoreq.90% 33 (30.8) 57
(55.3) .gtoreq.75% 42 (39.3) 71 (68.9) .gtoreq.50% 57 (53.3) 82
(79.6) >0% 73 (68.2) 89 (86.4) No reduction or any increase in
34 (31.8) 14 (13.6) oral glucocorticoid dose, or dropped out of
study Odds ratio versus placebo .sup. 3.25 (1.90 to 5.55) (95% CI)
P value versus placebo <0.001 Data are mean (SD), or no. (%). CI
denotes confidence interval, q2w every 2 weeks, and ITT
intent-to-treat. The percentage reduction of oral glucocorticoid
dose at week 24 was classified into five ordinal categories (90% to
100%, 75% to <90%, 50% to <75%, >0% to <50%, no
reduction or any increase in oral glucocorticoid dose or dropped
out from study). The model used the endpoint category as the
response variable, and treatment groups, optimized oral
glucocorticoid dose at baseline, regions, and baseline blood
eosinophil level subgroups (.gtoreq.150 cells/.mu.L or <150
cells/.mu.L) as covariates.
[0272] Notably, 48% of the dupilumab-treated patients versus 26% of
placebo-treated patients achieved their maximum possible
glucocorticoid dose reduction at week 24 (P=0.002 observed values:
52% for dupilumab, 30% for placebo) (FIG. 4A; Table 2). Similarly,
48% of dupilumab-treated patients versus 25% of placebo-treated
patients no longer required oral glucocorticoids at week 24
(P=0.002 Observed values: 52% for dupilumab, 29% for placebo) (FIG.
4A; Table 2). Dupilumab consistently reduced oral glucocorticoid
outcome measures irrespective of baseline blood eosinophil count
(FIG. 5A and FIG. 5B; Table 4).
TABLE-US-00004 TABLE 4 Subgroup analyses of oral glucocorticoid
endpoints at week 24 by baseline blood eosinophil subgroups.
Dupilumab Placebo 300 mg q2w (N = 107) (N = 103) Percentage
reduction in oral glucocorticoid dose from baseline (mg/day)
Baseline blood eosinophils .gtoreq.300 cells/.mu.L - no. 41 47 LS
mean change (SE) -42.71 (6.77) -79.54 (6.36) LS mean difference
versus placebo (95% CI) -36.83 (-54.71 to -18.94) Baseline blood
eosinophils <300 cells/.mu.L - no. 65 54 LS mean change (SE)
-44.98 (6.00) -66.31 (6.47) LS mean difference versus placebo (95%
CI) -21.33 (-38.75 to -3.90) Overall P value for interaction 0.238
Baseline blood eosinophils .gtoreq.150 cells/.mu.L 69 80 LS mean
change (SE) -46.51 (5.21) -75.91 (4.76) LS mean difference versus
placebo (95% CI) -29.39 (-43.12 to -15.67) Baseline blood
eosinophils <150 cells/.mu.L - no. 37 21 LS mean change (SE)
-36.87 (8.60) -63.77 (11.14) LS mean difference versus placebo (95%
CI) -26.89 (-54.52 to 0.73) Overall P value for interaction 0.708
Patients with .gtoreq.50% reduction in oral glucocorticoid dose
Baseline blood eosinophils .gtoreq.300 cells/.mu.L - no. 41 48
Estimate (95% CI) 0.52 (0.36 to 0.68) 0.88 (0.74 to 0.95) Odds
ratio versus placebo (95% CI) 6.59 (2.13 to 20.42) Baseline blood
eosinophils <300 cells/.mu.L - no. 66 55 Estimate (95% CI) 0.52
(0.40 to 0.65) 0.76 (0.63 to 0.86) Odds ratio versus placebo (95%
CI) 2.91 (1.28 to 6.63) Overall P value for interaction 0.296
Baseline blood eosinophils .gtoreq.150 cells/.mu.L - no. 69 81
Estimate (95% CI) 0.53 (0.41 to 0.65) 0.84 (0.74 to 0.90) Odds
ratio versus placebo (95% CI) 4.49 (2.04 to 9.85) Baseline blood
eosinophils <150 cells/.mu.L - no. 38 22 Estimate (95% CI) 0.47
(0.31 to 0.64) 0.75 (0.52 to 0.89) Odds ratio versus placebo (95%
CI) 3.33 (0.97 to 11.48) Overall P value for interaction 0.493
Patients with oral glucocorticoid reduced to <5 mg/day Baseline
blood eosinophils .gtoreq.300 cells/.mu.L - no. 41 48 Estimate (95%
CI) 0.40 (0.25 to 0.57) 0.84 (0.70 to 0.92) Odds ratio versus
placebo (95% CI) 8.04 (2.71 to 23.82) Baseline blood eosinophils
<300 cells/.mu.L - no. 66 55 Estimate (95% CI) 0.35 (0.24 to
0.48) 0.63 (0.49 to 0.75) Odds ratio versus placebo (95% CI) 3.12
(1.41 to 6.93) Overall P value for interaction 0.226 Baseline blood
eosinophils .gtoreq.150 cells/.mu.L - no. 69 81 Estimate (95% CI)
0.44 (0.32 to 0.57) 0.77 (0.66 to 0.85) Odds ratio versus placebo
(95% CI) 4.29 (2.04 to 9.04) Baseline blood eosinophils <150
cells/.mu.L - no. 38 22 Estimate (95% CI) 0.21 (0.10 to 0.38) 0.62
(0.39 to 0.80) Odds ratio versus placebo (95% CI) 6.03 (1.70 to
21.44) Overall P value for interaction 0.826 Proportion of patients
no longer requiring oral glucocorticoid Baseline blood eosinophils
.gtoreq.300 cells/.mu.L - no. 40 48 Estimate (95% CI) 0.26 (0.13 to
0.44) 0.59 (0.41 to 0.74) Odds ratio versus placebo (95% CI) 4.07
(1.46 to 11.33) Baseline blood eosinophils <300 cells/.mu.L -
no. 66 55 Estimate (95% CI) 0.26 (0.16 to 0.38) 0.43 (0.30 to 0.57)
Odds ratio versus placebo 2.15 (0.96 to 4.81) Overall P value for
interaction 0.413 Baseline blood eosinophils .gtoreq.150
cells/.mu.L - no. 68 81 Estimate (95% CI) 0.30 (0.19 to 0.43) 0.54
(0.42 to 0.66) Odds ratio versus placebo (95% CI) 2.73 (1.31 to
5.70) Baseline blood eosinophils <150 cells/.mu.L - no. 38 22
Estimate (95% CI) 0.19 (0.09 to 0.35) 0.42 (0.23 to 0.65) Odds
ratio versus placebo (95% CI) 3.15 (0.93 to 10.73) Overall P value
for interaction 0.966 Proportion of patients with maximum possible
oral glucocorticoid dose Baseline blood eosinophils .gtoreq.300
cells/.mu.L - no. 41 48 Estimate (95% CI) 0.31 (0.18 to 0.48) 0.59
(0.43 to 0.74) Odds ratio versus placebo (95% CI) 3.26 (1.26 to
8.43) Baseline blood eosinophils <300 cells/.mu.L - no. 66 55
Estimate (95% CI) 0.26 (0.16 to 0.38) 0.43 (0.30 to 0.57) Odds
ratio versus placebo (95% CI) 2.15 (0.96 to 4.81) Overall P value
for interaction 0.544 Baseline blood eosinophils .gtoreq.150
cells/.mu.L - no. 69 81 Estimate (95% CI) 0.32 (0.21 to 0.45) 0.54
(0.42 to 0.65) Odds ratio versus placebo (95% CI) 2.47 (1.21 to
5.02) Baseline blood eosinophils <150 cells/.mu.L - no. 38 22
Estimate (95% CI) 0.19 (0.09 to 0.35) 0.42 (0.23 to 0.65) Odds
ratio versus placebo (95% CI) 3.15 (0.93 to 10.73) Overall P value
for interaction 0.842 CI denotes confidence interval, LS
least-squares, SE standard error, and q2w every 2 weeks.
[0273] While improvements were observed in all baseline blood
eosinophil subgroups, the magnitude of the treatment effect was
largest in those with higher baseline eosinophil counts (e.g., odds
ratio versus placebo in patients with .gtoreq.50% reduction in oral
glucocorticoid dose was 6.59 (95% CI, 2.1 to 20.4) for patients
with .gtoreq.300 cells/.mu.L and 2.91 (95% CI, 1.3 to 6.6) for
those with <300 cells/.mu.L at baseline). In the overall
population, 69 percent of patients who received dupilumab were able
to reduce their OCS dose to less than 5 mg per day while
maintaining asthma control compared to 33 percent of patients who
received placebo (p less than 0.0001); in the high EOS group, 84
percent of dupilumab patients were able to reduce their OCS dose to
less than 5 mg per day compared to 40 percent for placebo. (p
equals 0.0002.) Half of the patients completely eliminated oral
glucocorticoid use. Despite glucocorticoid reductions, dupilumab
versus placebo in the overall population and .gtoreq.300
cells/.mu.L Eos subgroup decreased severe exacerbations by 59.3%
(P<0.001) and 71.1%, and improved FEV.sub.1 by 0.22 L
(P<0.001) and 0.32 L, respectively.
Exacerbations and FEV.sub.1
[0274] In addition to significant reductions in oral glucocorticoid
use during the 24-week treatment period, dupilumab significantly
(P<0.001) reduced severe asthma exacerbations versus placebo by
59.3% in the overall population (FIG. 4B and Table 7), and also
improved FEV.sub.1 by LS mean (SE) 0.22 L (0.05) (vs. 0.01 L [0.05]
by placebo, P<0.001) at week 24 in the overall population.
Though dupilumab reduced the rate of annualized severe asthma
exacerbations and improved FEV.sub.1 versus placebo regardless of
baseline eosinophil count (FIG. 6A and FIG. 6B, Table 5), these
benefits were more pronounced in patients with higher baseline
blood eosinophil counts. For example, dupilumab decreased severe
exacerbations by 71.1% and improved FEV.sub.1 by LS mean (SE) 0.32
L (95% CI 0.10 to 0.54) (both P<0.001 vs. placebo) in patients
with baseline blood eosinophils .gtoreq.300 cells/.mu.L.
TABLE-US-00005 TABLE 5 Subgroup analyses of exacerbations and
change in pre-bronchodilator FEV.sub.1 at week 24 by baseline blood
eosinophil subgroups. Dupilumab Placebo 300 mg q2w (N = 107) (N =
103) Annualized event rate of severe exacerbations Baseline blood
eosinophils .gtoreq.300 cells/.mu.L - no. 41 48 Estimate (95% CI)
1.742 (1.202 to 2.525) 0.504 (0.260 to 0.975) Relative risk versus
placebo (95% CI) 0.289 (0.139 to 0.601) Baseline blood eosinophils
<300 cells/.mu.L - no. 66 55 Estimate (95% CI) 1.440 (1.045 to
1.984) 0.784 (0.502 to 1.226) Relative risk versus placebo (95% CI)
0.545 (0.315 to 0.940) Overall P value for interaction 0.143
Baseline blood eosinophils .gtoreq.150 cells/.mu.L - no. 69 81
Estimate (95% CI) 1.536 (1.139 to 2.071) 0.642 (0.425 to 0.971)
Relative risk versus placebo (95% CI) 0.418 (0.254 to 0.689)
Baseline blood eosinophils <150 cells/.mu.L - no. 38 22 Estimate
(95% CI) 1.537 (1.009 to 2.342) 0.609 (0.276 to 1.340) Relative
risk versus placebo (95% CI) 0.396 (0.166 to 0.946) Overall P value
for interaction 0.824 Pre-bronchodilator FEV.sub.1 (L) Baseline
blood eosinophils .gtoreq.300 cells/.mu.L Baseline - no. 41 48 Mean
baseline (SD) - L 1.57 (0.59) 1.55 (0.49) Week 24 - no. 39 45 LS
mean change (SE) - L 0.12 (0.09) 0.44 (0.09) LS mean difference
versus placebo (95% CI) 0.32 (0.10 to 0.54) Baseline blood
eosinophils <300 cells/.mu.L Baseline - no. 66 55 Mean baseline
(SD) - L 1.66 (0.62) 1.52 (0.56) Week 24 - no. 65 52 LS mean change
(SE) - L 0.00 (0.05) 0.13 (0.05) LS mean difference versus placebo
(95% CI) 0.13 (-0.02 to 0.28) Overall P value for interaction 0.174
Baseline blood eosinophils .gtoreq.150 cells/.mu.L Baseline - no.
69 81 Mean baseline (SD) - L 1.68 (0.61) 1.56 (0.55) Week 24 - no.
66 76 LS mean change (SE) - L 0.09 (0.06) 0.32 (0.06) LS mean
difference versus placebo (95% CI) 0.22 (0.06 to 0.38) Baseline
blood eosinophils <150 cells/.mu.L Baseline - no. 38 22 Mean
baseline (SD) - L 1.53 (0.61) 1.45 (0.45) Week 24 - no. 38 21 LS
mean change (SE) - L -0.08 (0.06) 0.16 (0.08) LS mean difference
versus placebo (95% CI) 0.24 (0.05 to 0.44) Overall P value for
interaction 0.949 CI denotes confidence interval, FEV.sub.1 forced
expiratory volume in 1 second, LS least-squares, q2w every 2 weeks,
SD standard deviation and SE standard error.
[0275] Improvements in FEV.sub.1 were rapid and sustained, as early
as week two (LS mean change 0.15 L; 95% CI 0.04 to 0.26), and
further increased through week 24 (P<0.05 at all time points)
(FIG. 4C and Table 2). At 24 weeks, dupilumab improved lung
function, as assessed by forced expiratory volume over one second
(FEV.sub.1) by 220 ml (15 percent) in the overall population (p
equals 0.0007) compared with 10 ml for placebo, and by 320 ml (25
percent) compared with 120 ml for placebo in patients with
eosinophil counts equal to or greater than 300 cells/microliter (p
equals 0.0049).
Other Secondary and Exploratory Outcomes
[0276] The Phase 3 study enrolled steroid-dependent severe asthma
patients regardless of eosinophil levels or other biomarkers, and
the results showed improvements compared to placebo on lung
function and exacerbations across patient subgroups: those with
baseline eosinophil counts above 300 cells/microliter; above 150
cells/microliter; and below 150 cells/microliter. Dupilumab
demonstrated a consistent improvement in lung function across the
asthma program for patients with severe asthma struggling with
declines in their everyday breathing ability.
[0277] ACQ-5 scores at week 24 indicated a significant improvement
(P=0.002) in asthma control with dupilumab versus placebo (LS mean
difference in change from baseline: -0.47 [95% CI, -0.76 to
-0.18]). With dupilumab, the LS mean improvement from baseline
(-1.05) at week 24 was twice the minimally clinically important
difference of 0.5 for the ACQ-5 instrument.
[0278] Dupilumab treatment suppressed FeNO by week two and was
sustained during the 24-week treatment period (P<0.001 versus
placebo at all time points; FIG. 4D). The percentage of patients
with FeNO<25 ppb (upper limit of normal) (Table 6) was increased
from 43.6% at baseline to 84.4% in dupilumab group, while no change
was observed in the placebo group (44.7% to 45.1%).
TABLE-US-00006 TABLE 6 Proportion of patients achieving a FeNO
suppression of <25 ppb at baseline and week 24. Dupilumab
Placebo 300 mg q2w (N = 107) (N = 103) Baseline, n 103 101 Median
(IQR) 29.0 (17.0 to 56.0) 28.0 (14.0 to 48.0) <25 ppb - no. (%)
46 (44.7) 44 (43.6) Week 24, n 91 90 Median (IQR) 27.0 (16.0 to
45.0) 15.0 (11.0 to 21.0) Change from baseline, 0.3 (27.9) -17.3
(27.9) mean (SD) <25 ppb - no. (%) 41 (45.1) 76 (84.4) P value
versus placebo <0.001 FeNO denotes fractional exhaled nitric
oxide, IQR interquartile range, ppb parts per billion, q2w every 2
weeks, and SD standard deviation.
Morning and Evening Daily Asthma Symptoms in Patients with
Oral-Corticosteroid-Dependent Severe Asthma
[0279] Patients' asthma symptoms were recorded as scores in an
e-diary, in the morning for symptoms during the night (AM
symptoms), and in the evening (PM symptoms) for symptoms during the
day, scoring their severity 0 (mildest) to 4 (most severe). Change
from baseline in asthma-symptom scores during 24-week treatment
period was analyzed by using mixed-effect models with repeated
measures.
[0280] Mean baseline AM/PM symptom scores in the dupilumab and
placebo groups, respectively, were 1.37/1.37 and 1.50/1.52 in the
ITT population (n=210), and 1.45/1.49 and 1.50/1.52 in patients who
reduced OCS use 100% by week 24 (40.5%). In the dupilumab group,
symptoms improved rapidly (LS mean change from baseline in AM/PM
symptom scores at week 2, -0.18/-0.23 both P<0.05 vs placebo),
with continued improvement through week 16 (-0.47/-0.47 both
P<0.05 vs placebo), and a maintained positive effect until week
24 (FIG. 25A and FIG. 25C). Patients in the dupilumab group who
reduced OCS use 100% by week 24 demonstrated a similar pattern
response with a greater magnitude of symptom improvements (FIG. 25B
and FIG. 25D). Overall, the most frequent treatment-emergent
adverse event occurring in dupilumab- vs. placebo-treated patients
was eosinophilia (14% vs 1%). Injection-site reactions occurred in
9% of dupilumab-treated vs. 4% of placebo-treated patients.
[0281] Dupilumab improved morning and evening daily asthma symptoms
in a rapid and sustained manner, despite OCS withdrawal, in
patients with OCS-dependent, severe asthma. Symptom improvements
were greatest in patients who reduced OCS use 100% by week 24
Dupilumab was generally well tolerated.
[0282] Population: ITT; 100% OCS reduction subgroup. Endpoints: LS
mean change from baseline in AM/PM asthma symptoms during the
treatment period. Treatment arms: Dupilumab 300 mg q2w;
placebo.
Asthma Control and Health-Related Quality of Life
[0283] Asthma control was assessed by weekly recording in an
e-diary of the validated 5-item Asthma Control Questionnaire
(ACQ-5), on which higher scores (range 0-6) indicated less control.
Health-related quality of life (HRQoL) was assessed by using the
self-administered 7-item asthma quality of life questionnaire
(AQLQ), on which higher global scores (range 0-7) indicated better
HRQoL. Change from baseline in ACQ-5 and AQLQ scores during the
24-week treatment period were analyzed by using mixed-effect models
with repeated measures.
[0284] In the dupilumab and placebo groups, respectively, mean
baseline ACQ-5 scores were 2.42 and 2.58 and mean baseline AQLQ
scores were 4.38 and 4.31 In the dupilumab group, asthma control
rapidly improved (week 2 LS mean change from baseline in ACQ-5
score, 0.57; P=0.002 vs. placebo), further improved at week 12
(1.01; P=0.001 vs. placebo), and remained stable through week 24
(1.05; P=0.002 vs. placebo) (FIG. 26A). In patients receiving
dupilumab treatment, an LS mean improvement from baseline in AQLQ
score of 0.76 was observed at week 12 (P=0.14 vs. placebo), which
was further improved to 0.89 at week 24 (P=0.008 vs placebo) (FIG.
26B). Overall, the most frequent treatment-emergent adverse event
occurring in dupilumab- vs. placebo-treated patients was
eosinophilia (14% vs 1%). Injection-site reactions occurred in 9%
of dupilumab-treated vs. 4% of placebo-treated patients.
[0285] Add-on dupilumab vs. placebo significantly improved asthma
control and improved HRQoL in patients with OCS-dependent, severe
asthma. Improvement in asthma control occurred as early as week 2
and was maintained for 24 weeks. Dupilumab was generally
well-tolerated.
[0286] Population: ITT. Endpoints: LS mean change from baseline in
ACQ-5 at weeks 2, 12 and 24 LS mean change from baseline in AQLQ at
weeks 12 and 24 safety during treatment period. Treatment arms:
Dupilumab 300 mg q2w; placebo.
Safety
[0287] The incidence of TEAEs was similar across treatment groups
(62.1% vs. 64.5% for dupilumab vs. placebo) in the safety
population. The TEAEs by Medical Dictionary for Regulatory
Activities (MedDRA) Preferred Term most frequently occurring in
.gtoreq.5% of patients treated with dupilumab versus placebo were
viral upper respiratory tract infection (8.7% vs. 17.8%),
bronchitis (6.8% vs. 5.6%), sinusitis (6.8% vs. 3.7%), influenza
(2.9% vs. 5.6%), injection-site reactions (8.7% vs. 3.7%) and the
laboratory measure of eosinophilia (grouped `Eosinophil count
increase` and `eosinophilia` Preferred terms) (13.6% vs. 0.9%). Per
study protocol, all cases of eosinophil counts .gtoreq.3,000
cells/.mu.L on treatment were to be reported as AEs and occurred in
12.6% of dupilumab-treated patients versus 0.9% in the placebo
group. The reported eosinophilia TEAEs were all exclusively
laboratory findings without any clinical consequences or associated
AEs.
[0288] Serious TEAEs were reported in 9 (8.7%) dupilumab- and 6
(5.6%) placebo-treated patients; serious TEAEs were not related to
the investigational medicinal product. There were no deaths in the
study. Treatment-emergent anti-drug antibody responses were
observed in 5 patients in each group (dupilumab 5.0%; placebo 4.7%)
and had no meaningful impact on efficacy or safety.
TABLE-US-00007 TABLE 7 Changes in FEV.sub.1 and inflammatory
biomarkers at weeks 4 and 24 in dupilumab vs placebo treated
patients. DPL PBO 300 mg q2w (N = 107) (N = 103) Pre-bronchodilator
FEV.sub.1 BL, L, mean (SD) 1.63 (0.61) 1.53 (0.53) Change from BL
at 0.04 (0.04) 0.18 (0.04)* Week 4, LS mean (SE) Change from BL at
0.01 (0.05) 0.22 (0.05)*** Week 24, LS mean (SE) FeNO BL, ppb, mean
(SD) 39.6 (34.1) 35.6 (28.3) Change from BL at -0.7 (25.4) -14.6
(23.0) Week 4, ppb, mean (SD) Change from BL at 0.3 (27.9) -17.3
(27.9) Week 24, ppb, mean (SD) Percentage mean change 8.05 (74.96)
-28.19 (38.99)*** from BL at Week 4 (SD) Percentage mean change
11.07 (51.93) -30.36 (46.00)*** from BL at Week 24 (SD) Eotaxin-3
BL, PG/ML, mean (SD) 50.62 (40.75) 47.86 (52.18) Percentage mean
change 64.68 (231.22) -1.46 (176.66)*** from BL at Week 4 (SD)
Percentage mean change 57.13 (187.87) 4.90 (181.84)*** from BL at
Week 24 (SD) Total IgE BL, IU/ML, mean (SD) 426.62 (881.22) 434.65
(654.54) Percentage mean change -0.02 (86.60) -19.97 (18.01)***
from BL at Week 4 (SD) Percentage mean change 7.98 (92.76) -56.21
(19.91)*** from BL at Week 24 (SD) Periostin- Shino test BL, PG/ML,
mean (SD) 69.10 (24.96) 78.88 (34.72) Percentage mean change 3.50
(20.97) -14.41 (25.79)*** from BL at Week 4 (SD) Percentage mean
change 8.60 (36.81) -19.03 (25.35)*** from BL at Week 24 (SD) TARC
BL, PG/ML, mean (SD) 428.03 (663.07) 369.81 (298.11) Percentage
mean change 22.46 (121.05) -25.03 (54.16)*** from BL at Week 4 (SD)
Percentage mean change 12.63 (65.52) -22.96 (44.94)*** from BL at
Week 24 (SD) *P < 0.05, **P < 0.01, ***P < 0.001 vs
placebo. CI, confidence interval, SE, standard error, SD, standard
deviation, forced expiratory volume in 1 second, FEV.sub.1,
Fractional exhaled nitric oxide, FeNO, Thymus and Activation
Regulated Chemokine, TARC.
Methods
Study Design and Oversight
[0289] This Phase 3 multinational, randomized, double-blind,
placebo-controlled study assessed efficacy and safety of dupilumab
in patients with oral glucocorticoid-dependent severe asthma.
Patients completed an 8 to 10-week oral glucocorticoid dose
optimization period followed by 1:1 randomization to dupilumab or
placebo for a 24-week treatment period. This treatment period
consisted of a 4-week induction period, during which optimized oral
glucocorticoid dose was continued; a 16-week oral glucocorticoid
reduction period (weeks 4 to 20), during which the glucocorticoid
dose was down-titrated every 4 weeks according to a protocol
pre-specified algorithm; a 4-week maintenance period, during which
patients remained on the glucocorticoid dose established at week 20
and a 12-week post-treatment evaluation period. Eligible patients
who completed treatment were permitted to enter a long-term,
open-label extension study.
[0290] The study was conducted in accordance with the Declaration
of Helsinki, International Conference on Harmonization Good
Clinical Practice guidelines, and applicable regulatory
requirements. An independent data and safety monitoring committee
conducted blinded monitoring of patient safety data. The local
institutional review board or ethics committee at each study center
oversaw trial conduct and documentation. All patients provided
written informed consent before participating in the trial.
Patients
[0291] Patients aged .gtoreq.12 years with physician-diagnosed
asthma for .gtoreq.12 months based on the Global Initiative for
Asthma 2014 Guidelines were eligible to participate. Patients were
required to be on regular systemic glucocorticoids in the previous
6 months (5 to 35 mg/day of prednisone or prednisolone or
equivalent) for 4 weeks prior to screening, and a high-dose inhaled
glucocorticoid (fluticasone propionate .gtoreq.500 .mu.g total
daily dose or equipotent equivalent) in combination with up to two
controllers (e.g. long-acting .beta.2-agonist or leukotriene
receptor antagonist) for .gtoreq.3 months. Eligible patients had to
have pre-bronchodilator forced expiratory volume in 1 second
(FEV.sub.1)<80% of predicted normal (<90% for adolescents),
17 FEV.sub.1 reversibility .gtoreq.12% and 200 mL, or airway hyper
responsiveness documented in the 12 months prior to screening visit
1 Patients were recruited with no minimum requirement for baseline
blood or sputum eosinophil count or any other Type 2 biomarkers
(e.g. FeNO or IgE). Key exclusion criteria included lung diseases
other than asthma, deterioration of asthma requiring emergency
treatment or hospitalization within 4 weeks of Visit 1, and current
smokers or smokers who had stopped within 6 months before screening
or who had a smoking history of .gtoreq.10 pack-years.
Treatment and Procedures
[0292] Patients were randomized (1:1) to receive subcutaneous
dupilumab 300 mg (following 600 mg loading dose on Day 1) as add-on
therapy or matched placebo every 2 weeks (q2w). Randomization was
conducted by interactive voice/web response technology and patients
were stratified according to optimized oral glucocorticoid dose
(<10 mg/day or .gtoreq.10 mg/day of prednisone/prednisolone) and
country. Patients using other oral glucocorticoids were switched to
a clinically comparable dose of prednisone or prednisolone during
the screening period.
[0293] Optimized oral glucocorticoid dose was defined as the lowest
dose a patient could tolerate without experiencing .gtoreq.0.5
increase in 5-Item Asthma Control Questionnaire (ACQ-5) score,
severe exacerbation or any clinically significant event requiring
oral glucocorticoid dose adjustment. During the dose-reduction
phase, oral glucocorticoid dose was reduced every 4 weeks to
minimize risk of clinically significant events and carryover
effects from the previous dose. No dose adjustments were allowed
beyond week 20 except for safety reasons. Background asthma
controllers were continued at a stable dose and short-acting
.beta.2-agonist use was permitted as needed for asthma
symptoms.
Endpoints
[0294] The primary efficacy endpoint was the percentage reduction
in oral glucocorticoid dose from baseline to week 24 while
maintaining asthma control. A patient was considered as having
maintained asthma control between weeks 20 and 24 if no clinically
significant event (based on investigator judgment) required oral
glucocorticoid dose adjustment. For patients experiencing an
exacerbation, the final oral glucocorticoid dose was considered to
be one step higher than the dose they were receiving at the time of
the exacerbation.
[0295] Key secondary efficacy endpoints assessed in patients
maintaining asthma control were proportion of patients achieving
.gtoreq.50% reduction from baseline in oral glucocorticoid dose and
proportion of patients achieving a reduction in oral glucocorticoid
dose to <5 mg/day. Other secondary endpoints included absolute
reduction in oral glucocorticoid dose, proportion of patients
achieving maximum possible oral glucocorticoid dose reduction, and
proportion of patients no longer requiring oral
glucocorticoids.
[0296] Additional efficacy endpoints included annualized rate of
severe exacerbation events during the treatment period (defined as
requiring hospitalization, emergency room visit, or treatment for
.gtoreq.3 days with systemic glucocorticoids at least 2 times the
current dose); absolute change from baseline in pre-bronchodilator
FEV.sub.1 at weeks 2, 4, 8, 12, 16, 20 and 24 and change from
baseline in ACQ-5 score at week 24.
[0297] An exploratory endpoint of absolute change from baseline in
FeNO (ppb) was assessed using a NIOX instrument (Aerocrine AB,
Solna, Sweden) at weeks 2, 4, 8, 12, 16, 20 and 24.
Statistical Analysis
[0298] It was estimated that 90 randomized patients per treatment
group would give the study 94% power (2 tailed test at
.alpha.=0.05) to detect a treatment difference of 27% in daily
glucocorticoid dose 18 assuming a common standard deviation of
50%.
[0299] The primary endpoint was analyzed using an analysis of
covariance (ANCOVA) model. The model included percentage reduction
of oral glucocorticoid dose at week 24 as the response variable,
and treatment groups, optimized oral glucocorticoid dose at
baseline, regions (pooled countries), and baseline eosinophil
subgroups (.gtoreq.150 cells/.mu.L, <150 cells/.mu.L) as
covariates. The treatment difference was tested at the 2-sided
significance level of .alpha.=0.05 For patients who discontinued
the study or had missing oral glucocorticoid dose data at week 24
(2 patients in the dupilumab group and 1 in the placebo group), the
primary missing data handling approach was a pattern mixture model
by multiple imputations (PMM by MI).
[0300] The key secondary and other binary secondary endpoints were
analyzed using logistic regression models. Annualized rate of
severe exacerbation events during the 24-week treatment period was
analyzed using a negative binomial regression model. Mixed-effect
models with repeated measures approach was used to analyze
pre-bronchodilator FEV.sub.1 changes from baseline at various time
points during the 24-week treatment period and 5-Item Asthma
Control Questionnaire (ACQ-5) change from baseline at week 24.
[0301] Efficacy analyses were performed on the intent-to-treat
(ITT) population, defined as all randomized patients analyzed
according to treatment allocated, regardless of treatment received.
Primary and key secondary endpoints, FEV.sub.1 and severe asthma
exacerbation rates were also analyzed in subgroups of patients
defined by baseline blood eosinophil levels (.gtoreq.300
cells/.mu.L, <300 cells/.mu.L, .gtoreq.150 cells/.mu.L and
<150 cells/.mu.L). The safety population included all patients
who received .gtoreq.1 dose or a partial dose of investigational
treatment, analyzed according to treatment received.
[0302] All analyses were conducted using SAS software, version 9.4
(SAS Institute).
CONCLUSION
[0303] This study demonstrated that dupilumab as an add-on therapy
significantly reduced oral glucocorticoid use in patients with oral
glucocorticoid-dependent severe asthma, reduced severe asthma
exacerbations by 59.3% and improved FEV.sub.1 by 0.22 L in the
overall population, with a 71% reduction in exacerbations and 0.32
L improvement in FEV.sub.1 in "eosinophilic" patients with baseline
blood eosinophils .gtoreq.300 cells/.mu.L. Dupilumab treatment also
improved asthma control and reduced FeNO levels, a marker of airway
Type 2 inflammation.
[0304] Add-on dupilumab 300 mg every 2 weeks (q2w) (vs. placebo)
significantly reduced oral corticosteroid (OCS) use at week 24
(least squares [LS] mean 70.1% vs. 41.9%, median 100% vs. 50%),
while simultaneously reducing the severe asthma exacerbation rate
during the 24-week treatment period (59%) and improving the forced
expiratory volume in 1 second (FEV1) at week 24 (LS mean difference
0.22 L), and was generally well tolerated in patients with
OCS-dependent, severe asthma.
[0305] Dupilumab is the first biologic to show positive efficacy
based on multiple asthma outcome measures in the overall study
population irrespective of baseline blood eosinophil count (i.e.
.gtoreq.300, <300, .gtoreq.150 and <150 cells/.mu.L). Indeed,
28.6% of the patients enrolled had baseline blood eosinophils of
<150 cells/.mu.L. In this subgroup, 75% of dupilumab-treated
patients reduced their oral glucocorticoid doses by 50% and 62% of
patients reduced their oral glucocorticoid doses to <5 mg/day.
These data are in contrast to previous studies with
anti-interleukin-5 monoclonal antibodies including mepolizumab and
benralizumab that showed a treatment effect exclusively in patients
with high baseline blood eosinophils.
[0306] In this study, placebo-treated patients also showed a 41.9%
reduction in oral glucocorticoid-dependence. Better adherence to
drug regimens in a clinical study setting may have contributed to
this observation. However, towards the end of the study, these
placebo-treated patients demonstrated mild deterioration of lung
function (FEV.sub.1), further highlighting the need for a treatment
that improves lung function in patients with oral
glucocorticoid-dependent severe asthma. The ability of dupilumab to
increase lung function as markedly as it did in this study, even in
the face of glucocorticoid withdrawal, indicates that it appears to
be inhibiting key drivers of lung inflammation that lead to reduced
lung function.
[0307] Dupilumab reduced FeNO levels in the setting of significant
withdrawal of oral glucocorticoid in a study population with
persistent Type 2 inflammation (determined by elevated FeNO) in
spite of chronic glucocorticoid use.
[0308] Dupilumab reduced the oral glucocorticoid dose by an
observed mean of 74% (observed median of 100%) in a broader
population without requiring a minimum baseline blood eosinophils
count. Without intending to be bound by scientific theory, these
findings indicate that dupilumab, with its dual blockade of the
interleukin-4 and interleukin-13 signaling pathways by way of
interleukin-4 receptor-alpha blockade, inhibits Type 2 inflammation
more broadly than targeting eosinophils alone. While interleukin-4
is central to the differentiation and proliferation of T-helper 2
cells, inducing cytokine production and IgE synthesis,
interleukin-13 plays a pivotal role in pathological features of the
disease such as goblet cell hyperplasia, mucus production, smooth
muscle contractility, and airway hyper-responsiveness.
[0309] In patients with glucocorticoid-dependent severe asthma,
dupilumab was generally well tolerated, with a safety profile
consistent with previous studies in asthma and other indications,
such as eosinophilic esophagitis, nasal polyposis, and atopic
dermatitis. Dupilumab-treated patients showed a greater mean
transient increase from baseline in blood eosinophil counts
compared with placebo, with increased proportion of patients
(12.6%) with eosinophil counts .gtoreq.3,000 cells/.mu.L. Patients
with transient elevations in blood eosinophils did not have
concomitant clinical AEs or consequences. The increase in blood
eosinophil counts is consistent with the hypothesis that dupilumab
blocks interleukin-4 and interleukin-13 function in eosinophil
survival, activation and recruitment to tissues, but not regress
from bone marrow, resulting in transient increase in circulating
eosinophil counts. Since glucocorticoids suppress circulating
eosinophils, the greater reduction in oral glucocorticoids in the
dupilumab group could also be contributing to the eosinophil
elevations. No treatment-related conjunctivitis AEs were observed
between dupilumab and placebo groups, in contrast to dupilumab
atopic dermatitis studies.
[0310] In conclusion, add-on therapy with dupilumab significantly
reduced the need for oral glucocorticoids, while simultaneously
reducing severe exacerbations and improving lung function
(FEV.sub.1) in glucocorticoid-dependent severe asthma patients
regardless of baseline blood eosinophil counts, and was generally
well tolerated.
Example 2 QUEST Phase III Trial Study (NCT02414854)
Methods
[0311] Asthma patients, .gtoreq.12 years with moderate-to-severe
asthma, uncontrolled with ICS and one or two controllers, were
randomized 2:1 to add-on subcutaneous dupilumab 200 or 300 mg every
2 weeks (q2w), or matched placebos, for 52 weeks in a double-blind,
placebo-controlled phase 3 study (NCT02414854). Primary endpoints
were annualized rate of severe asthma exacerbations and absolute
change from baseline to week 12 in pre-bronchodilator forced
expiratory volume in 1 second (FEV.sub.1) in the overall study
population. Secondary endpoints included exacerbations and
FEV.sub.1 in patients with .gtoreq.300 eosinophils/.mu.L. Asthma
control and dupilumab safety were also assessed. Co-primary
endpoints were annualized severe exacerbation rate over 52 weeks,
and change from baseline to week 12 in FEV.sub.1 (L).
[0312] The specific details of the study are described below. This
randomized, double-blind, placebo-controlled, parallel-group trial
assessed the efficacy of dupilumab in patients with uncontrolled
moderate-to-severe asthma. Patients completed a 4.+-.1-week
screening period, followed by randomization to dupilumab and
matched-volume placebo, a 52-week randomized treatment period, and
a 12-week post-treatment follow-up period (see FIG. 7).
Patients
[0313] Patients aged .gtoreq.12 years with physician-diagnosed
persistent asthma for .gtoreq.12 months, based on the Global
Initiative for Asthma 2014 Guidelines were eligible to participate,
meeting the following key criteria: current treatment with
medium-to-high dose inhaled glucocorticoid (fluticasone propionate
.gtoreq.500 .mu.g total daily dose or equipotent equivalent) plus
up to two additional controllers (e.g., long-acting .beta..sub.2
agonist or leukotriene receptor antagonist); pre-bronchodilator
(BD) forced expiratory volume in 1 second (FEV.sub.1)<80%
predicted normal (<90% for those aged 12 to 17 years); FEV.sub.1
reversibility .gtoreq.12% and 200 ml; 5-item asthma control
questionnaire (ACQ-5) score .gtoreq.1.5; a worsening of asthma in
the previous year that required hospitalization, emergency medical
care, or treatment with systemic glucocorticoids for .gtoreq.3
days. Patients were recruited irrespective of baseline blood
eosinophil count or Type 2 biomarkers. (See FIG. 8.)
Treatment and Procedures
[0314] Patients were randomized (2:2:1:1) to receive 52 weeks of
add-on therapy with subcutaneous dupilumab 200 mg (loading dose 400
mg) or 300 mg (loading dose 600 mg) every 2 weeks (q2w) or a
matched-volume placebo for each active dose (supplied in prefilled
syringes, 1.14 ml for 200 mg dupilumab and 2.0 ml for 300 mg
dupilumab). Randomization was conducted by interactive voice/web
response technology and was stratified by age (<18 years,
.gtoreq.18 years), peripheral blood eosinophil count (<300
cells/.mu.L, .gtoreq.300 cells/.mu.L) at screening, inhaled
glucocorticoid dose level (medium/high), and country. Background
asthma controller medicines were continued at a stable dose
throughout the study and recorded daily by patients in an
electronic diary. Use of inhaled glucocorticoids, long-acting
.beta..sub.2 agonists, long-acting muscarinic antagonists,
anti-leukotrienes, and methylxanthines was permitted. Throughout
the study, patients were permitted to use a short-acting
.beta..sub.2-adrenergic receptor agonist as necessary for symptom
relief. Type 2 biomarkers were measured; the biomarkers included
blood eosinophils, FeNO, serum IgE, periostin, TARC, and plasma
eotaxin-3.
Endpoints
[0315] The primary efficacy endpoints were annualized rate of
severe exacerbation events during the 52-week treatment period and
absolute change from baseline in pre-BD FEV.sub.1 at week 12 in the
overall study population. These endpoints were also included as
secondary study endpoints for those with blood eosinophil counts
.gtoreq.300 eosinophils/.mu.L. Additional secondary study endpoints
are summarized in Table 8. A severe asthma exacerbation was defined
as a deterioration of asthma requiring treatment for .gtoreq.3 days
with systemic glucocorticoids or hospitalization or an emergency
room visit requiring systemic glucocorticoids. Safety and
tolerability were reported according to incidence of
treatment-emergent adverse events (TEAEs) and serious TEAEs.
TABLE-US-00008 TABLE 8 Summary of study outcome measures per
hierarchical testing procedure. Time Outcome Measure Frame Primary
Efficacy Endpoints Annualized rate of severe asthma exacerbations
52 weeks Absolute change from baseline in pre-bronchodilator
FEV.sub.1 Week 12 Secondary Efficacy Endpoints Percentage change
from baseline in pre-bronchodilator FEV.sub.1 Week 12 Annualized
rate of severe asthma exacerbations in patients with .gtoreq.150
eosinophils/.mu.l 52 weeks Absolute change from baseline in
pre-bronchodilator FEV.sub.1 in pts with .gtoreq.150
eosinophils/.mu.l Week 12 Annualized rate of severe asthma
exacerbations in patients with .gtoreq.300 eosinophils/.mu.l 52
weeks Absolute change from baseline in pre-bronchodilator FEV.sub.1
in patients with .gtoreq.300 eosinophils/.mu.l Week 12 Annualized
rate of severe asthma exacerbations in patients with <300
eosinophils/.mu.l 52 weeks Annualized rate of severe asthma
exacerbations in patients on high-dose inhaled 52 weeks
glucocorticoids Absolute change from baseline in pre-bronchodilator
FEV.sub.1 in patients on high-dose Week 12 inhaled
glucocorticoids/long-acting .beta..sub.2 agonists Change from
baseline in AQLQ [S] global score Week 24 Change from baseline in
AQLQ [S] global score in patients with .gtoreq.300
eosinophils/.mu.l Week 24 Change from baseline in ACQ-5 score Week
24 Annualized rate of severe asthma exacerbations resulting in
hospitalization or emergency 52 weeks room visit Absolute change
from baseline in pre-bronchodilator FEV.sub.1 in patients with Week
12 <300 eosinophils/.mu.l ACQ-5 denotes Asthma Control
Questionnaire 5-item version, and AQLQ (S) asthma quality of life
questionnaire (standardized version).
Statistical Analysis
[0316] It was estimated that a sample size of approximately 1638
patients would give the study 99% power (2-tailed test at
.alpha.=0.05) to detect a 55% relative risk reduction (i.e.,
annualized rate of 0.6 and 0.27 for placebo and dupilumab groups,
respectively) in the annualized rate of severe exacerbations. This
sample size was also expected to provide 98% power to detect a 0.15
L treatment difference in pre-BD FEV.sub.1 change from baseline to
week 12 Efficacy analyses were performed on the intent-to-treat
(ITT) population, defined as all randomized patients by allocated
treatment whether or not treatment was received. The annualized
rate of severe exacerbations was analyzed using a negative binomial
regression model, including the four treatment groups, age, region,
baseline eosinophil strata, baseline inhaled glucocorticoid dose
level, and 1-year prior exacerbations were included as covariates.
Change from baseline in continuous endpoints such as FEV.sub.1 and
patient-reported outcomes were analyzed using a mixed-effects model
with repeated measures (MMRM), including treatment, age, baseline
eosinophil strata, baseline inhaled glucocorticoid dose level,
visit, treatment-by-visit interaction, baseline value, and
baseline-by-visit interaction as covariates. Sex and baseline
height were included as covariates only in the models for
spirometry parameters.
Results
[0317] Baseline demographics and clinical characteristics of the
ITT population are shown in Table 4 and were generally similar
across the four treatment groups (Table 10). In 1,902 patients,
dupilumab 200/300 mg q2w as compared to placebo reduced annualized
severe exacerbation rates during the 52-week treatment period by
48%/46%, (both P<0.0001) (FIG. 9A). Improved FEV.sub.1 was
observed at week 12 (LS mean difference vs placebo 0.14 L/0.13 L;
both P<0.0001) in the overall population.
[0318] Pre-specified subgroup analyses by baseline blood eosinophil
count showed significant reductions in exacerbation rates
(P<0.001) with dupilumab 200 and 300 mg compared with
matched-volume placebo in patients with .gtoreq.300
eosinophils/.mu.L (65.8% and 67.4% reduction vs. placebo), and
patients with .gtoreq.150 eosinophils/.mu.L (55.8% and 59.8%
reduction vs. placebo). There were consistent trends but a lack of
significance in exacerbations and FEV.sub.1 outcomes in patients
with <300 eosinophils/.mu.L. Pre-specified subgroup analyses by
baseline FeNO levels showed similar effect (P<0.001). (See FIG.
9B and Table 9)
TABLE-US-00009 TABLE 9 Summary of primary efficacy and secondary
endpoints. Randomized treatment group to overall population
Dupilumab Dupilumab Placebo 200 mg q2w Placebo 300 mg q2w (N = 317)
(N = 631) (N = 321) (N = 633) Adjusted annualized rate of severe
asthma exacerbations Estimate (95% CI) 0.871 (0.724 to 1.048) 0.456
(0.389 to 0.534) 0.970 (0.810 to 1.160) 0.524 (0.450 to 0.611)
Relative risk versus matching placebo.sup..dagger. -- 0.523 (0.413
to 0.662) -- 0.540 (0.430 to 0.680) (95% CI) P value versus
matching placebo.sup..dagger. <0.001 <0.001 Mean baseline
(SD) pre-bronchodilator 1.76 (0.61) 1.78 (0.62) 1.75 (0.57) 1.78
(0.60) FEV.sub.1 - L Change from baseline in FEV.sub.1 at Week 12
LS mean (SE) change - L 0.18 (0.02) 0.32 (0.02) 0.21 (0.02) 0.34
(0.02) LS mean difference versus matching -- 0.14 (0.08 to 0.19) --
0.13 (0.08 to 0.18) placebo (95% CI).dagger-dbl. P value versus
matching placebo.dagger-dbl. <0.001 <0.001 Percent change
from baseline in FEV.sub.1 at Week 12 LS mean (SE) 12.11 (1.56)
21.34 (1.13) 13.67 (1.56) 23.08 (1.13) LS mean difference versus
matching -- 9.23 (5.54 to 12.92) -- 9.41 (5.74 to 13.07) placebo
(95% CI).dagger-dbl. P value versus matching placebo.dagger-dbl.
<0.001 <0.001 Adjusted annualized rate of severe asthma N =
148 N = 264 N = 142 N = 277 exacerbations in patients with
.gtoreq.300 eosinophils/.mu.l Estimate (95% CI) 1.081 (0.846 to
1.382) 0.370 (0.289 to 0.475) 1.236 (0.972 to 1.571) 0.403 (0.317
to 0.512) Relative risk versus matching placebo.sup..dagger. --
0.342 (0.244 to 0.480) -- 0.326 (0.234 to 0.454) (95% CI) P value
versus matching placebo.sup..dagger. <0.001 <0.001 Change
from baseline in FEV.sub.1 in patients N = 144 N = 256 N = 139 N =
266 with .gtoreq.300 eosinophils/.mu.l at Week 12 LS mean (SE)
change 0.21 (0.03) 0.43 (0.03) 0.22 (0.03) 0.47 (0.02) LS mean
difference versus -- 0.21 (0.13 to 0.29) -- 0.24 (0.16 to 0.32)
matching placebo (95% CI).dagger-dbl. P value versus matching
placebo.dagger-dbl. <0.001 <0.001 Adjusted annualized rate of
severe asthma N = 232 N = 437 N = 237 N = 452 exacerbations in
patients with .gtoreq.150 eosinophils/.mu.l Estimate (95% CI) 1.007
(0.814 to 1.245) 0.445 (0.368 to 0.538) 1.081 (0.879 to 1.329)
0.434 (0.359 to 0.525) Relative risk versus matching
placebo.sup..dagger. -- 0.442 (0.337 to 0.581) -- 0.402 (0.307 to
0.526) P value versus matching placebo.sup..dagger. <0.001
<0.001 Change from baseline in FEV.sub.1 in patients N = 224 N =
425 N = 229 N = 434 with .gtoreq.150 eosinophils/.mu.l at Week 12
LS mean (SE) change 0.18 (0.03) 0.36 (0.02) 0.22 (0.03) 0.37 (0.02)
LS mean difference versus 0.17 (0.11 to 0.23) 0.15 (0.09 to 0.21)
matching placebo (95% CI).dagger-dbl. P value versus matching
placebo.dagger-dbl. <0.001 <0.001
[0319] In the overall study population, dupilumab 200 and 300 mg
q2w improved pre-BD FEV.sub.1 at week 12 by 0.32 L and 0.34 L,
respectively (0.14 and 0.13 L difference vs. matched-placebos,
P<0.001) (FIG. 10A). In patients with .gtoreq.300
eosinophils/.mu.L the FEV improvements were larger, with dupilumab
improving FEV.sub.1 at week 12 by 0.43 L and 0.47 L, respectively
(0.21 to 0.24 L difference as compared to matched-placebos,
P<0.001). (See FIG. 10B.) Improvement in FEV.sub.1 was rapid
(with significant differences as compared to placebo evident by the
first evaluation at week 2 for both regimens) and was sustained
throughout the 52-week treatment period (P<0.001 for both
regimens at week 52). In addition, a post-bronchodilator FEV.sub.1
slope analysis between weeks 8 and 52 showed a loss of lung
function on placebo of 0.04 L/year, with no loss on either
dupilumab dose (P<0.05).
[0320] FEV.sub.1 improvements at week 12 (P<0.05) with both dose
regimens were greater in subgroup of patients with higher baseline
FeNO levels (0.19 and 0.12 L for FeNO.gtoreq.25 to 50; 0.30 and
0.39 L for FeNO.gtoreq.50 ppb). (See FIG. 10C and Table 8.)
[0321] In addition, dupilumab 200 and 300 mg significantly improved
percentage change from baseline to week 12 in pre-bronchodilator
FEV.sub.1 versus placebo: 21.34% versus 12.11% and 23.08% versus
13.67%, respectively (P<0.001). The rate of severe exacerbation
events resulting in hospitalization or emergency room visit during
the 52-week treatment period was 0.035 versus 0.065 (P=0.004),
comparing combined dupilumab-treated with combined placebo-treated
patients. This produced a relative risk reduction for dupilumab
versus placebo of 46.8%. (See Table 9.)
[0322] Dupilumab significantly improved ACQ-5 as early as week 2
and the effect was sustained over the course of treatment
(P<0.01). Likewise, Asthma Quality of Life Questionnaire,
Standardized Version score, AM and PM asthma symptom scores, and AM
and PM peak expiratory flow were improved at week 24 and week 52
(See Table 9.)
[0323] Patients treated with dupilumab showed greater reduction
from baseline over the course of treatment in FeNO, total IgE,
periostin, eotaxin-3 and TARC versus placebo (Table 13). Transient
elevations in blood eosinophil counts were observed in both
treatment groups that decreased to close to baseline levels by week
52.
[0324] In order to better understand the effect of dupilumab on
patients with evidence of type 2 inflammation, analyses were
conducted to evaluate biomarker efficacy relationships. Each
biomarker was tested in an un-penalized spline model for
biomarker-by treatment interactions with respect to exacerbations
and FEV.sub.1. In these analyses, the interactions for eosinophils
and FeNO were significant (P<0.05) when exacerbations were the
outcome measure, while eosinophils, FeNO, periostin, ECP, IgE, and
eotaxin-3 were significant for FEV.sub.1 at week 12 (Table 11).
Dupilumab effect on exacerbations was similar for IgE levels above
and below the median value at baseline (167 IU/mL), and greater for
FEV.sub.1 improvement for IgE levels above the median.
[0325] Dupilumab-treated patients with baseline blood eosinophils
.gtoreq.150 cells/.mu.L and FeNO.gtoreq.25 ppb (Type 2-high)
experienced greater treatment benefit versus placebo for both
severe exacerbation rate reduction and FEV.sub.1 improvement. (See
FIG. 11A and FIG. 11B.) No treatment effect was observed in
patients with baseline eosinophils <150 cells/.mu.L and
FeNO<25 ppb (Type 2-low). However, dupilumab-treated patients
with either baseline blood eosinophils <150 cells/.mu.L and
FeNO.gtoreq.25 ppb or .gtoreq.150 cells/.mu.L and <FeNO 25 ppb
experienced numerical reduction in severe exacerbation rates.
[0326] The most frequent adverse event in the dupilumab-treated
groups vs placebo was injection site reactions (15%/18% vs 5%/10%,
respectively). In contrast to dupilumab studies in atopic
dermatitis, conjunctivitis rates were similar between dupilumab and
placebo.
TABLE-US-00010 TABLE 10 Baseline Demographic and Clinical
Characteristics (ITT Population). Dupilumab Dupilumab Overall
Placebo 200 mg q2w Placebo 300 mg q2w Population N = 317 N = 631 N
= 321 N = 633 N = 1902 Mean (SD) age - yr 48.2 (15.6) 47.9 (15.3)
48.2 (14.7) 47.7 (15.6) 47.9 (15.3) <18 yr - no. of patients (%)
21 (6.6) 34 (5.4) 18 (5.6) 34 (5.4) 107 (5.6) Female sex - no. of
patients (%) 198 (62.5) 387 (61.3) 218 (67.9) 394 (62.2) 1197
(62.9) Mean (SD) BMI - kg/m.sup.2 29.76 (7.25) 29.05 (6.52) 29.21
(6.95) 29.07 (6.68) 29.20 (6.77) Mean (SD) pre-bronchodilator 1.76
(0.61) 1.78 (0.62) 1.75 (0.57) 1.78 (0.60) 1.78 (0.60) FEV.sub.1 -
L Mean (SD) pre-bronchodilator 58.43 (13.22) 58.38 (13.52) 58.35
(13.87) 58.51 (13.52) 58.43 (13.52) FEV.sub.1 - % predicted Mean
(SD) FEV.sub.1 reversibility - % 25.06 (18.76) 27.39 (22.79) 26.45
(17.65) 25.73 (23.79) 26.29 (21.73) Mean (SD) exacerbations in past
2.07 (1.58) 2.07 (2.66) 2.31 (2.07) 2.02 (1.86) 2.09 (2.15) year -
no. High-dose inhaled 172 (54.3) 317 (50.2) 167 (52.0) 323 (51.0)
979 (51.5) glucocorticoid/LABA use - no. of patients (%) Mean (SD)
ACQ-5.sup..dagger. score 2.71 (0.73) 2.76 (0.80) 2.77 (0.77) 2.77
(0.76) 2.76 (0.77) Mean (SD) AQLQ.dagger-dbl. global score 4.26
(1.02) 4.31 (1.08) 4.30 (1.03) 4.28 (1.05) 4.29 (1.05) Mean (SD) AM
asthma symptom 1.16 (0.81) 1.14 (0.85) 1.12 (0.84) 1.12 (0.87) 1.14
(0.85) score.sctn. Mean (SD) PM asthma symptom 1.27 (0.82) 1.26
(0.85) 1.23 (0.82) 1.27 (0.84) 1.26 (0.84) score.sctn.
Atopic/allergic ongoing condition - 266 (83.9) 509 (80.7) 266
(82.9) 524 (82.8) 1565 (82.3) no. of patients (%) Atopic dermatitis
35 (11.0) 61 (9.7) 38 (11.8) 62 (9.8) 196 (10.3) Allergic rhinitis
221 (69.7) 421 (66.7) 225 (70.1) 438 (69.2) 1305 (68.6) Nasal
polyposis and/or chronic 63 (19.9) 126 (20.0) 70 (21.8) 123 (19.4)
382 (20.1) rhinosinusitis Former smoker - no. of patients 59 (18.6)
126 (20.0) 67 (20.9) 116 (18.3) 368 (19.3) (%) Mean (SD) pack-years
- no. 3.96 (2.81) 3.89 (2.69) 4.07 (3.12) 4.15 (3.04) 4.02 (2.89)
Biomarker levels Mean (SD) blood eosinophil 370 (338) 349 (345) 391
(419) 351 (369) 360 (366) count - cells/.mu.l Median (min-max)
blood 270 250 265 250 255 eosinophil count - cells/.mu.l (0-2200)
(0-3610) (0-3580) (0-4330) (0-4330) Mean (SD) FeNO - ppb 34.47
(28.54) 34.45 (34.91) 38.39 (38.00) 34.01 (29.74) 34.97 (32.85)
Median (min-max) FeNO - ppb 26.00 23.00 27.00 24.00 25.00
(3.0-197.0) (3.0-387.0) (5.0-351.0) (4.0-202.0) (3.0-387.0) Mean
(SD) total IgE - IU/ml 393.90 (624.70) 460.96 (817.75) 448.47
(796.66) 415.08 (701.40) 432.40 (746.66) Median (min-max) total IgE
- IU/ml 174.50 154.00 178.50 174.00 167.00 (1.0-5000.0)
(1.0-5000.0) (3.0-5000.0) (1.0-5000.0) (1.0-5000.0) Mean (SD) TARC
- pg/ml 377.88 (288.22) 394.12 (457.89) 398.00 (344.16) 364.35
(295.58) 382.22 (364.25) Median (min-max) TARC - pg/ml 296.00
314.50 300.00 295.00 302.00 (33.1 to 1970.0) (15.6 to 8600.0) (34.0
to 3210.0) (15.6 to 3170.0) (15.6 to 8600.0) Mean (SD) periostin -
ng/ml 79.62 (36.58) 79.88 (39.18) 80.94 (40.73) 78.49 (37.90) 79.55
(38.58) Median (min-max) periostin - ng/ml 71.70 70.60 71.00 69.70
70.60 (27.8 to 244.9) (20.5 to 368.2) (25.1 to 312.8) (19.2 to
298.5) (19.2 to 368.2) Mean (SD) eotaxin-3 - pg/ml 52.11 (86.35)
78.30 (340.04) 50.89 (57.85) 69.53 (481.53) 66.36 (342.53) Median
(min-max) eotaxin-3 - pg/ml 36.50 39.15 37.45 38.30 38.20 (2.0 to
1180.0) (2.0 to 6430.0) (2.0 to 723.0) (2.0 to 12000.0) (2.0 to
12000.0) ACQ-5 denotes 5-item Asthma Control Questionnaire, AQLQ
(S) Asthma Quality of Life Questionnaire (Standardized Version),
BMI body mass index, FeNO fractional exhaled nitric oxide,
FEV.sub.1 forced expiratory volume in 1 second, LABA long-acting
.beta..sub.2-agonist, min to max minimum to maximum, ppb parts per
billion, q2w every 2 weeks, q4w every 4 weeks, SD standard
deviation, and TARC thymus and activation-regulated chemokine.
.sup..dagger.ACQ-5 is a patient-reported measure of the adequacy of
asthma control and change in asthma control that occurs either
spontaneously or as a result of treatment. Higher scores indicate
less control; a global score ranging from 0 to 6 is calculated.
.dagger-dbl.AQLQ (S) is a patient-reported measure of the impact of
asthma on quality of life. Higher scores indicate better quality of
life; a global score ranging from 1 to 7 is calculated.
.sctn.Asthma symptom scores are patient-reported measures, taken
upon waking and in the evening, of asthma symptoms and their
effects on activities (PM) and sleep (AM). Higher scores indicate
greater disruption; symptoms are scored on a range from 0 to 4.
TABLE-US-00011 TABLE 11 Subgroup Analyses of Primary Endpoints by
Baseline Blood Eosinophil Count and FeNO Levels Randomized
treatment group - ITT population Dupilumab Dupilumab Placebo 200 mg
q2w Placebo 300 mg q2w Subgroup/Endpoint (N = 317) (N = 631) (N =
321) (N = 633) Baseline EOS .gtoreq.300 cells/.mu.l Annualized rate
of severe exacerbations at N = 148 N = 264 N = 142 N = 277 Week 52
Estimate (95% CI) 1.081 (0.846 to 1.382) 0.370 (0.289 to 0.475)
1.236 (0.972 to 1.571) 0.403 (0.317 to 0.512) Relative risk versus
matching placebo.sup..dagger. -- 0.342 (0.244 to 0.480) -- 0.326
(0.234 to 0.454) P value versus matching placebo.sup..dagger.
<0.001 <0.001 Change from baseline in FEV.sub.1 (I) at N =
144 N = 256 N = 139 N = 266 Week 12 LS mean (SE) change 0.21 (0.03)
0.43 (0.03) 0.22 (0.03) 0.47 (0.02) LS mean difference versus
matching -- 0.21 (0.13 to 0.29) -- 0.24 (0.16 to 0.32) placebo (95%
CI).dagger-dbl. P value versus matching placebo.dagger-dbl.
<0.001 <0.001 Baseline EOS .gtoreq.150 cells/.mu.l Annualized
rate of severe exacerbations at N = 232 N = 437 N = 237 N = 452
Week 52 Estimate (95% CI) 1.007 (0.814 to 1.245) 0.445 (0.368 to
0.538) 1.081 (0.879 to 1.329) 0.434 (0.359 to 0.525) Relative risk
versus matching placebo.sup..dagger. -- 0.442 (0.337 to 0.581) --
0.402 (0.307 to 0.526) P value versus matching placebo.sup..dagger.
<0.001 <0.001 Change from baseline in FEV.sub.1 (I) at N =
224 N = 425 N = 229 N = 434 Week 12 LS mean (SE) change 0.18 (0.03)
0.36 (0.02) 0.22 (0.03) 0.37 (0.02) LS mean difference versus
matching 0.17 (0.11 to 0.23) 0.15 (0.09 to 0.21) placebo (95%
CI).dagger-dbl. P value versus matching placebo.dagger-dbl.
<0.001 <0.001 Baseline EOS <300 cells/.mu.l Annualized
rate of severe exacerbations at N = 169 N = 366 N = 178 N = 356
Week 52.sup..dagger. Estimate (95% CI) 0.675 (0.515 to 0.884) 0.512
(0.418 to 0.628) 0.732 (0.562 to 0.954) 0.610 (0.502 to 0.742)
Relative risk versus matching placebo.sup..dagger. -- 0.759 (0.548
to 1.052) -- 0.834 (0.608 to 1.144) P value versus matching
placebo.sup..dagger. 0.10 0.26 Change from baseline in FEV.sub.1
(I) at N = 163 N = 354 N = 173 N = 344 Week 12.dagger-dbl. LS mean
(SE) change 0.15 (0.03) 0.23 (0.02) 0.18 (0.03) 0.22 (0.02) LS mean
difference versus matching -- 0.08 (0.01 to 0.15) -- 0.04 (-0.03 to
0.11) placebo (95% CI).dagger-dbl. P value versus matching
placebo.dagger-dbl. 0.02 0.25 Baseline EOS <150 cells/.mu.l
Annualized rate of severe exacerbations at N = 85 N = 193 N = 83 N
= 181 Week 52.sup..dagger. Estimate (95% CI) 0.511 (0.346 to 0.755)
0.472 (0.358 to 0.623) 0.642 (0.445 to 0.927) 0.737 (0.575 to
0.946) Relative risk versus matching placebo.sup..dagger. -- 0.925
(0.580 to 1.474) -- 1.149 (0.747 to 1.767) P value versus matching
placebo.sup..dagger. 0.74 0.53 Change from baseline in FEV.sub.1
(I) at N = 83 N = 185 N = 83 N = 176 Week 12.dagger-dbl. LS mean
(SE) change 0.13 (0.04) 0.19 (0.03) 0.11 (0.04) 0.20 (0.03) LS mean
difference versus matching -- 0.06 (-0.04 to 0.15) -- 0.09 (-0.01
to 0.18) placebo (95% CI).dagger-dbl. P value versus matching
placebo.dagger-dbl. 0.26 0.08 Baseline FeNO .gtoreq.50 ppb
Annualized rate of severe exacerbations at N = 71 N = 119 N = 75 N
= 124 Week 52 Estimate (95% CI) 1.057 (0.722 to 1.547) 0.326 (0.221
to 0.480) 1.274 (0.901 to 1.801) 0.388 (0.270 to 0.558) Relative
risk versus matching placebo.sup..dagger. -- 0.308 (0.183 to 0.519)
-- 0.305 (0.188 to 0.494) P value versus matching
placebo.sup..dagger. <0.001 <0.001 Change from baseline in
FEV.sub.1 (I) at N = 69 N = 114 N = 73 N = 113 Week 12 LS mean (SE)
change 0.23 (0.05) 0.53 (0.04) 0.19 (0.05) 0.59 (0.04) LS mean
difference versus matching -- 0.30 (0.17 to 0.44) -- 0.39 (0.26 to
0.52) placebo (95% CI).dagger-dbl. P value versus matching
placebo.dagger-dbl. <0.001 <0.001 Baseline FeNO .gtoreq.25 to
50 ppb Annualized rate of severe exacerbations at N = 91 N = 180 N
= 97 N = 186 Week 52 Estimate (95% CI) 0.925 (0.648 to 1.322) 0.358
(0.258 to 0.495) 1.045 (0.739 to 1.478) 0.462 (0.343 to 0.622)
Relative risk versus matching placebo.sup..dagger. -- 0.386 (0.243
to 0.616) -- 0.442 (0.282 to 0.693) P value versus matching
placebo.sup..dagger. <0.001 <0.001 Change from baseline in
FEV.sub.1 (I) at N = 88 N = 174 N = 94 N = 182 Week 12 LS mean (SE)
change 0.21 (0.04) 0.39 (0.03) 0.23 (0.04) 0.35 (0.03) LS mean
difference versus matching -- 0.19 (0.09 to 0.28) -- 0.12 (0.03 to
0.21) placebo (95% CI).dagger-dbl. P value versus matching
placebo.dagger-dbl. <0.001 0.01 Baseline FeNO <25 ppb
Annualized rate of severe exacerbations at N = 149 N = 325 N = 144
N = 317 Week 52 Estimate (95% CI) 0.693 (0.525 to 0.916) 0.521
(0.418 to 0.650) 0.748 (0.565 to 0.992) 0.593 (0.478 to 0.735)
Relative risk versus matching placebo.sup..dagger. -- 0.752 (0.541
to 1.046) -- 0.792 (0.572 to 1.098) P value versus matching
placebo.sup..dagger. 0.09 0.16 Change from baseline in FEV.sub.1
(I) at N = 144 N = 316 N = 141 N = 309 Week 12 LS mean (SE) change
0.15 (0.03) 0.20 (0.02) 0.20 (0.03) 0.23 (0.02) LS mean difference
versus matching -- 0.05 (-0.02 to 0.12) -- 0.03 (-0.04 to 0.10)
placebo (95% CI).dagger-dbl. P value versus matching
placebo.dagger-dbl. 0.14 0.39 *CI denotes confidence interval, EOS
eosinophils, FeNO fractional exhaled nitric oxide, FEV.sub.1 forced
expiratory volume in 1 second, LS least square, NA not applicable,
ppb parts per billion, q2w every 2 weeks, q4w every 4 weeks, and SE
standard error. .sup..dagger.Derived using a negative binomial
model with the total number of events starting from randomization
up to Visit 18 or last contact date as the response variable; the
four treatment groups, age, region (pooled country), baseline
eosinophil strata, baseline ICS dose level, and number of severe
exacerbations in the year prior to the study as covariates; and
log-transformed standardized observation duration as an offset
variable. .dagger-dbl.Week 12 changes from baseline were derived
using an MMRM approach, with change from baseline in
pre-bronchodilator FEV.sub.1 values at Week 12 as the response
variable, and treatment, age, sex, baseline height, region (pooled
country), baseline eosinophil strata, baseline ICS dose level,
visit, treatment-by-visit interaction, baseline pre-bronchodilator
FEV.sub.1 value, and baseline-by-visit interaction as
covariates.
TABLE-US-00012 TABLE 12 Summary of Additional Secondary Endpoints.
Randomized treatment group Dupilumab Dupilumab Placebo 200 mg q2w
Placebo 300 mg q2w Endpoint (N = 317) (N = 631) (N = 321) (N = 633)
Change from baseline in AQLQ (S) global score at Week 24 LS mean
(SE) change 0.94 (0.06) 1.14 (0.04) 1.00 (0.06) 1.15 (0.04) LS mean
difference versus matching -- 0.20 (0.06 to 0.34) -- 0.15 (0.01 to
0.28) placebo (95% CI).sup..dagger. P value versus matching
placebo.sup..dagger. 0.004 0.03 Change from baseline in AQLQ (S)
global score at Week 52 LS mean (SE) change 0.99 (0.06) 1.28 (0.04)
1.03 (0.06) 1.29 (0.04) LS mean difference versus matching -- 0.29
(0.15, 0.44) -- 0.26 (0.12, 0.40) placebo (95% CI).sup..dagger. P
value versus matching placebo.sup..dagger. <0.001 <0.001
Change from baseline in AQLQ (S) global score at Week 24 in
patients with .gtoreq.300 eosinophils/.mu.L LS mean (SE) change
0.96 (0.09) 1.37 (0.06) 0.98 (0.09) 1.32 (0.06) LS mean difference
versus matching -- 0.41 (0.20 to 0.62) -- 0.34 (0.13 to 0.54)
placebo (95% CI).sup..dagger. P value versus matching
placebo.sup..dagger. <0.001 0.001 Change from baseline in ACQ-5
score at Week 2 LS mean (SE) change -0.56 (0.05) -0.89 (0.04) -0.61
(0.05) -0.92 (0.04) LS mean difference versus matching -- -0.34
(-0.46, -0.22) -- -0.31 (-0.42, -0.19) placebo (95% CI).dagger-dbl.
P value versus matching placebo.dagger-dbl. <0.001 <0.001
Change from baseline in ACQ-5 score at Week 24 LS mean (SE) change
-1.10 (0.06) -1.44 (0.04) -1.21 (0.06) -1.40 (0.04) LS mean
difference versus matching -- -0.35 (-0.48 to -0.21) -- -0.19
(-0.32 to -0.05) placebo (95% CI).dagger-dbl. P value versus
matching placebo.dagger-dbl. <0.001 0.007 Change from baseline
in ACQ-5 score at Week 52 LS mean (SE) change -1.15 (0.06) -1.54
(0.04) -1.30 (0.06) -1.52 (0.04) LS mean difference versus matching
-- -0.39 (-0.53, -0.25) -- -0.22 (-0.36, -0.08) placebo (95%
CI).dagger-dbl. P value versus matching placebo.dagger-dbl.
<0.001 0.002 Change from baseline in AM symptom score at Week 24
LS mean (SE) change -0.33 (0.03) -0.52 (0.02) -0.37 (0.03) -0.49
(0.02) LS mean difference versus matching -0.19 (-0.27 to -0.11)
-0.12 (-0.20 to -0.04) placebo (95% CI).sctn. P value versus
matching placebo.sctn. <0.001 0.004 Change from baseline in AM
symptom score at Week 52 LS mean (SE) change -0.40 (0.04) -0.55
(0.03) -0.43 (0.04) -0.58 (0.03) LS mean difference versus matching
-0.15 (-0.24 to -0.06) -0.16 (-0.24 to -0.07) placebo (95%
CI).sctn. P value versus matching placebo.sctn. <0.001 <0.001
Change from baseline in PM symptom score at Week 24 LS mean (SE)
change -0.33 (0.04) -0.53 (0.03) -0.36 (0.04) -0.51 (0.03) LS mean
difference versus matching -0.20 (-0.28 to -0.11) -0.15 (-0.24 to
-0.06) placebo (95% CI).sctn. P value versus matching placebo.sctn.
<0.001 <0.001 Change from baseline in PM symptom score at
Week 52 LS mean (SE) change -0.39 (0.04) -0.57 (0.03) -0.42 (0.04)
-0.57 (0.03) LS mean difference versus matching -0.18 (-0.28 to
-0.09) -0.14 (-0.24 to -0.05) placebo (95% CI).sctn. P value versus
matching placebo.sctn. <0.001 0.003 Change from baseline in AM
PEF (L/min) at Week 24 LS mean (SE) change 6.15 (3.49) 28.19 (2.51)
15.61 (3.47) 25.01 (2.50) LS mean difference versus matching 22.04
(13.70 to 30.38) 9.40 (1.11 to 17.68) placebo (95% CI) P value
versus matching placebo <0.001 0.03 Change from baseline in AM
PEF (l/min) at Week 52 LS mean (SE) change 2.35 (3.94) 28.97 (2.82)
12.69 (3.91) 26.00 (2.82) LS mean difference versus matching 26.62
(17.20 to 36.04) 13.31 (3.94 to 22.67) placebo (95% CI) P value
versus matching placebo <0.001 0.005 Change from baseline in PM
PEF (l/min) at Week 24 LS mean (SE) change -2.86 (3.52) 19.62
(2.53) 8.14 (3.51) 16.53 (2.52) LS mean difference versus matching
22.48 (14.08 to 30.89) 8.39 (0.03 to 16.74) placebo (95% CI) P
value versus matching placebo <0.001 0.049 Change from baseline
in PM PEF (l/min) at Week 52 LS mean (SE) change -6.01 (3.96) 17.50
(2.84) 4.44 (3.95) 15.34 (2.84) LS mean difference versus matching
23.51 (14.04 to 32.99) 10.90 (1.47 to 20.32) placebo (95% CI) P
value versus matching placebo <0.001 0.024 Placebo 1.14 ml and 2
ml q2w Dupilumab 200 mg and 300 mg combined (N = 638) q2w combined
(N = 1264) Annualized rate of severe exacerbation events requiring
hospitalization or ER visit Estimate (95% CI) 0.065 (0.047 to
0.090) 0.035 (0.025 to 0.048) Relative risk versus matching
placebo# 0.532 (0.347 to 0.816) P value versus matching placebo#
0.004 * ACQ-5 denotes the Asthma Control Questionnaire 5-item
version, AQLQ Asthma Quality of Life Questionnaire, CI confidence
interval, ER emergency room, LS least square, PEF peak expiratory
flow, q2w every 2 weeks, q4w every 4 weeks, and SE standard error.
.sup..dagger.Derived from MMRM model with change from baseline in
AQLQ global score up to Week 24 or 52 as the response variable, and
the four treatment groups, age, region (pooled country), baseline
eosinophil strata, baseline ICS dose level, visit, treatment
by-visit interaction, baseline AQLQ global score and
baseline-by-visit interaction as covariates. .dagger-dbl.Derived
from an MMRM model with change from baseline in ACQ-5 up to Week 24
or 52 as the response variable, and the four treatment groups, age,
region (pooled country), baseline eosinophil strata, baseline ICS
dose level, visit, treatment by-visit interaction, baseline ACQ-5,
and baseline-by-visit interaction as covariates. .sctn.Derived from
MMRM model with change from baseline in AM/PM symptom score
(periodical average) up to week 52 as the response variable, and
treatment, age, region (pooled country), baseline eosinophil
strata, baseline ICS dose level, visit, treatment-by-visit
interaction, baseline AM/PM symptom score, and baseline-by-visit
interaction as covariates. Derived from MMRM model with change from
baseline in AM/PM PEF values (periodical average) up to week 52 as
the response variable, and treatment, age, sex, baseline height,
region (pooled country), baseline eosinophil strata, baseline ICS
dose level, visit, treatment-by-visit interaction, baseline AM/PM
PEF value, and baseline-by-visit interaction as covariates.
#Derived using a negative binomial model with the total number of
events starting from randomization up to Visit 18 or last contact
date as the response variable; the two pooled treatment groups,
age, region (pooled country), baseline eosinophil strata, baseline
ICS dose level, and number of severe exacerbations in the year
prior to the study as covariates; and log-transformed standardized
observation duration as an offset variable.
TABLE-US-00013 TABLE 13 Summary of Change from Baseline in Type 2
Biomarker Levels. Randomized treatment group Dupilumab Dupilumab
Placebo 200 mg Placebo 300 mg q2w (N = 317) q2w (N = 631) (N = 321)
(N = 633) Fractional exhaled nitric oxide Mean baseline (SD) - ppb
34.5 (28.7) 34.4 (34.9) 38.4 (38.0) 34.0 (29.8) Median (min to max)
26.0 23.0 27.0 24.0 baseline - ppb (3 to 197) (3 to 387) (5 to 351)
(4 to 202) Change from baseline to Week 12 Mean change (SD) - ppb
-2.4 (21.1) -15.1 (31.4) -3.6 (29.6) -15.8 (25.2) Mean change (SD)
- % 8.641 (68.047) -21.954 (49.522) 5.794 (63.044) -27.254 (46.861)
Median (min to max) -1.0 -6.0 -1.0 -7.0 change - ppb (-81 to 78)
(-371 to 69) (-309 to 69) (-177 to 62) Median (min to max) -6.782
-29.289 -5.814 -34.615 change - % (-83.93 to 500.00) (-95.87 to
360.00) (-91.96 to 450.00) (-93.16 to 266.67) Change from baseline
to Week 24 Mean change (SD) - ppb -2.9 (21.3) -16.6 (32.8) -4.6
(30.2) -16.6 (25.9) Mean change (SD) - % 9.774 (70.868) -24.710
(49.373) 4.383 (72.603) -28.165 (50.465) Median (min to max) -1.0
-7.0 -2.0 -8.0 change - ppb (-96 to 122) (-373 to 42) (-306 to 96)
(-171 to 29) Median (min to max) -6.667 -33.333 -10.526 -38.462
change - % (-87.50 to 583.33) (-97.16 to 420.00) (-91.07 to 620.00)
(-92.26 to 580.00) Change from baseline to Week 52 Mean change (SD)
- ppb -2.1 (20.7) -16.5 (27.3) -5.2 (36.0) -16.5 (27.0) Mean change
(SD) - % 5.494 (58.379) -28.705 (47.319) 1.561 (61.831) -26.450
(57.383) Median (min to max) -1.0 -8.0 -2.0 -8.0 change - ppb (-76
to 103) (-188 to 46) (-307 to 218) (-177 to 54) Median (min to max)
-5.882 -37.931 -10.000 -37.500 change - % (-82.35 to 381.48)
(-96.41 to 383.33) (-91.37 to 380.00) (-93.44 to 600.00) Total IgE
(IU/ml) Mean baseline (SD) - IU/ml 394.2 (626.2) 460.6 (816.6)
448.5 (796.7) 415.0 (701.4) Median (min to max) 174.5 154.0 178.5
174.0 baseline - IU/ml (1 to 5000) (1 to 5000) (3 to 5000) (1 to
5000) Change from baseline to Week 12 Mean change (SD) - IU/ml 11.6
(306.6) -161.9 (327.3) -4.5 (174.1) -143.9 (304.3) Mean change (SD)
in IU/ml - % 24.088 (349.934) -18.998 (207.581) 3.062 (33.718)
-10.317 (488.825) Median (min to max) -1.0 -53.0 -1.0 -57.0 change
- IU/ml (-1044 to 4545) (-2612 to 687) (-791 to 1337) (-4974 to
1384) Median (min to max) -1.875 -35.356 -0.327 -36.364 change - %
(-55.18 to 6060.00) (-94.85 to 3816.67) (-53.95 to 266.67) (-99.48
to 11600.00) Change from baseline to Week 24 Mean change (SD) -
IU/ml 13.9 (304.3) -246.6 (462.5) 33.9 (372.8) -217.0 (369.1) Mean
change (SD) in IU/ml - % 28.049 (306.538) -44.719 (98.770) 28.770
(380.881) -47.871 (65.897) Median (min to max) -1.0 -85.0 -1.0
-88.0 change - IU/ml (-1654 to 3851) (-4007 to 571) (-931 to 3478)
(-4241 to 871) Median (min to max) -2.020 -53.280 -0.697 -53.913
change - % (-70.83 to 5134.67) (-98.97 to 1841.94) (-65.31 to
6485.71) (-99.18 to 1060.00) Change from baseline to Week 52 Mean
change (SD) - IU/ml 2.2 (433.3) -318.1 (582.3) -3.9 (323.2) -303.4
(521.7) Mean change (SD) in IU/ml - % 32.774 (436.822) -61.817
(67.319) 8.203 (64.731) -59.547 (160.018) Median (min to max) -3.0
-110.0 -3.0 -119.0 change - IU/ml (-1704 to 4925) (-4637 to 573)
(-1000 to 3246) (-4994 to 509) Median (min to max) -3.271 -69.427
-4.444 -70.258 change - % (-68.51 to 6566.67) (-96.91 to 1202.70)
(-80.12 to 652.94) (-99.88 to 3360.00) Blood eosinophils
(cells/.mu.l) Mean baseline (SD) - cells/.mu.l 370 (338) 349 (345)
391 (419) 351 (369) Median (min to max) 270 (0-2200) 250 (0-3610)
265 (0-3580) 250 (0-4330) baseline - cells/.mu.l Change from
baseline to Week 12 Mean change (SD) - cells/.mu.l -12.66 (269.52)
118.31 (539.03) -43.3 (350.43) 88.88 (532.6) Mean change (SD) - %
46.375 (172.116) 78.610 (403.288) 34.649 (181.064) 93.299 (576.646)
Median (min to max) 5 10 -10 0 change - cells/.mu.l (-1610 to 1630)
(-1790 to 5350) (-2220 to 1180) (-2970 to 6660) Median (min to max)
0.000 2.986 -3.704 0.000 change - % (-100.00 to 1400.00) (-97.67 to
6900.00) (-100.00 to 1700.00) (-100.00 to 10100.00) Change from
baseline to Week 24 Mean change (SD) - cells/.mu.l -23.556
(335.679) 86.52 (622.63) -32.049 (376.45) 49.657 (494.575) Mean
change (SD) - % 39.519 (156.576) 62.538 (250.177) 49.673 (252.040)
68.958 (367.619) Median (min to max) 0 0 0.000 0 change -
cells/.mu.l (-1290 to 2630) (-2170 to 10200) (-2970 to 1390) (-3080
to 5350) Median (min to max) 0.000 0.000 0.000 0.000 change - %
(-100.00 to 1200.00) (-100.00 to 2850.00) (-100.00 to 2300.00)
(-100.00 to 5800.00) Change from baseline to Week 52 Mean change
(SD) - cells/.mu.l -2.78 (313.82) 23.849 (399.395) -47.88 (344.83)
-2.26 (425.596) Mean change (SD) - % 115.548 (876.073) 28.472
(150.256) 33.603 (206.264) 43.764 (301.609) Median (min to max) 0
-20 -30 -25 change - cells/.mu.l (-1670 to 1540) (-1690 to 3170)
(-2330 to 1740) (-3670 to 3420) Median (min to max) 0.000 -9.091
-11.438 -14.583 change - % (-99.26 to 12800.00) (-100.00 to
1900.00) (-100.00 to 2400.00) (-100.00 to 4300.00) Thymus and
activation-regulated chemokine (TARC; pg/mL) Mean baseline (SD) -
pg/mL 377.8 (289.0) 393.8 (457.4) 398.0 (344.2) 364.7 (295.4)
Median baseline 296 314.5 300 295 (min to max) - pg/mL (33 to 1970)
(16 to 8600) (34 to 3210) (16 to 3170) Change from baseline to Week
12 Mean change (SD) - pg/mL -12.6 (199.2) -153.6 (392.3) 29.9
(472.7) -139.9 (226.8) Mean change (SD) - % 9.537 (57.893) -26.434
(40.121) 14.583 (77.359) -24.414 (86.001) Median change -1 -96.5
-7.1 -96.4 (min to max) - pg/mL (-1554 to 800) (-7560 to 835) (-617
to 7850) (-2011 to 1674) Median change -0.645 -32.883 -3.815
-34.559 (min to max) - % (-95.36 to 427.81) (-90.71 to 236.97)
(-77.37 to 827.81) (-91.79 to 1747.6) Change from baseline to Week
24 Mean change (SD) - pg/mL 0.6 (279.0) -160.5 (427.0) 118.0
(2206.6) -135.8 (215.8) Mean change (SD) - % 12.279 (75.287)
-26.666 (46.770) 16.714 (115.621) -26.925 (38.823) Median change
-10.0 -103.5 -0.0 -93.0 (min to max) - pg/mL (-1525 to 2820) (-7629
to 2327) (-910 to 37250) (-2005 to 590) Median change -3.175
-34.988 0.000 -34.251 (min to max) - % (-83.53 to 580.58) (-94.24
to 313.19) (-79.92 to 1354.55) (-92.12 to 211.47) Change from
baseline to Week 52 Mean change (SD) - pg/mL -11.4 (197.9) -161.4
(450.9) 138.3 (2169.6) -125.2 (219.5) Mean change (SD) - % 11.384
(69.774) -27.018 (42.836) 26.028 (148.647) -23.379 (50.305) Median
change -5.0 -101.0 8.0 -90.0 (min to max) - pg/mL (-1456 to 1090)
(-8187 to 885) (-669 to 33650) (-2196 to 590) Median change -2.419
-33.544 2.226 -34.483 (min to max) - % (-86.99 to 519.34) (-97.86
to 233.64) (-70.99 to 1725.64) (-91.24 to 586.71) Periostin (ng/mL)
Mean baseline (SD) - ng/mL 79.83 (36.60) 79.85 (39.12) 80.94
(40.73) 78.42 (37.94) Median baseline 72.1 70.6 71 69.7 (min to
max) - ng/mL (27.8 to 244.9) (20.5 to 368.2) (25.1 to 312.8) (19.2
to 298.5) Change from baseline to Week 12 Mean change (SD) - ng/mL
-1.22 (23.46) -16.52 (32.20) -1.27 (26.71) -15.54 (29.51) Mean
change (SD) - % 2.118 (27.112) -12.795 (29.683) 1.911 (28.007)
-13.554 (26.622) Median change -0.6 -8.40 -0.6 -10.65 (min to max)
- ng/mL (-119.7 to 106.6) (-266.4 to 66.4) (-103.5 to 127.6)
(-234.5 to 77.8) Median change -1.211 -13.483 -1.068 -15.350 (min
to max) - % (-48.88 to 121.94) (-75.76 to 296.59) (-92.47 to
141.78) (-78.56 to 105.03) Change from baseline to Week 52 Mean
change (SD) - ng/mL -4.79 (22.23) -18.83 (34.79) -5.24 (27.29)
-19.49 (30.37) Mean change (SD) - % -2.004 (25.992) -15.065
(31.303) -2.538 (29.531) -18.187 (24.427) Median change -3.90
-11.40 -4.20 -12.65 (min to max) - ng/mL (-108.4 to 75.7) (-260 to
70.4) (-110.3 to 189.5) (-202.4 to 38.2) Median change -5.410
-17.213 -6.988 -19.719 (min to max) - % (-70.89 to 134.18) (-77.16
to 343.41) (-70.84 to 236.28) (-72.28 to 75.11) Eotaxin-3 (pg/mL)
Mean baseline (SD) - pg/mL 52.172 (86.619) 78.202 (339.495) 50.892
(57.855) 69.516 (481.528) Median baseline 36.5 39.2 37.45 38.3 (min
to max) - pg/mL (1.95 to 1180) (1.95 to 6430) (1.95 to 723) .sup.
(1.95 to 12000) Change from baseline to Week 12 Mean change (SD) -
pg/mL -3.157 (27.405) -35.661 (137.286) -1.795 (30.136) -39.233
(355.197) Mean change (SD) - % 20.179 (145.501) -14.212 (137.332)
30.046 (260.896) -25.550 (107.262) Median change -0.2 -14.650 0
-14.000 (min to max) - pg/mL (-164 to 114.8) (-2110 to 245.3) (-233
to 119.6) (-8750 to 33) Median change -0.719 -39.587 0 -40.977 (min
to max) - % (-95.19 to 1571.73) (-98.78 to 1443.59) (-96.89 to
3858.97) (-98.73 to 1264.1) Change from baseline to Week 24 Mean
change (SD) - pg/mL -1.483 (34.127) -31.796 (153.247) -6.335
(35.606) -44.278 (448.676) Mean change (SD) - % 33.047 (191.426)
-17.149 (136.065) 15.413 (139.984) -24.072 (108.415) Median change
-0.700 -16.900 -2.500 -13.600 (min to max) - pg/mL (-235.00 to
270.00) (-2872.00 to 1650.00) (-315.20 to 200.60) (-10690.00 to
113.40) Median change -3.101 -42.700 -7.734 -40.326 (min to max) -
% (-96.88 to 1889.74) (-98.78 to 1458.97) (-96.88 to 1315.38)
(-98.61 to 1587.18) Change from baseline to Week 52 Mean change
(SD) - pg/mL -1.341 (52.531) 62.496 (2227.767) -1.178 (42.275)
-50.095 (533.671) Mean change (SD) - % 27.331 (132.523) -3.527
(210.111) 52.327 (304.987) -23.606 (113.851) Median change 0.000
-12.900 -0.850 -14.100 (min to max) - pg/mL (-528.00 to 337.30)
(-3178.00 to 48070.00) (-312.10 to 205.90) (-11374.00 to 222.50)
Median change 0.000 -35.157 -2.729 -39.962 (min to max) - % (-94.07
to 1094.87) (-99.58 to 3294.87) (-95.14 to 3156.41) (-97.19 to
1780.00) *min to max denotes minimum to maximum, ppb parts per
billion, q2w every two weeks, and SD standard deviation.
TABLE-US-00014 TABLE 14 Summary of Interaction Test For Efficacy.
Dupilumab 200 mg Dupilumab 300 mg q2w vs matching q2w vs matching
Overall placebo P Value placebo P Value P Value Annualized rate of
severe exacerbation during 52-week treatment period* Blood
Eosinophil <0.001 <0.001 <0.001 (cells/.mu.L) FeNO (ppb)
0.0076 <0.001 <0.001 Periostin (ng/mL) 0.1667 0.1347 0.1046
ECP (ng/mL) 0.0766 0.1302 0.079 Total IgE (IU/mL) 0.4161 0.2755
0.3036 TARC (pg/mL) 0.9688 0.5591 0.7689 Eotaxin-3 (pg/mL) 0.8099
0.1845 0.4494 Pre-bronchodilator FEV.sub.1 at Week 12.sup..dagger.
Blood Eosinophil 0.0361 <0.001 <0.001 (cells/.mu.L) FeNO
(ppb) <0.001 <0.001 <0.001 Periostin (ng/mL) 0.0154 0.0195
<0.001 ECP (ng/mL) 0.3076 0.0049 0.0102 Total IgE (IU/mL) 0.0270
0.0483 0.0245 TARC (pg/mL) 0.6540 0.3062 0.3759 Eotaxin-3 (pg/mL)
0.0421 0.0134 0.0151 *P-values of testing treatment-by-biomarker
interaction effects based on un-penalized negative binomial
regression spline models in the ITT population.
.sup..dagger.P-values of testing treatment-by-biomarker interaction
effects based on un-penalized regression spline models in the ITT
population.
DISCUSSION
[0327] Dupilumab significantly reduced annualized severe
exacerbation rates in the ITT population, with greater treatment
effects observed with increasing baseline levels of blood
eosinophils and FeNO. Dupilumab also significantly decreased the
rate of the most severe asthma exacerbations, those requiring
hospitalization or emergency room visits. Assessment of FEV.sub.1
and asthma control over time showed that efficacy of dupilumab was
rapid, with significant differences versus placebo evident as early
as the first evaluation at week 2 and maintained throughout the
52-week treatment period for both dose regimens. Significant and
clinically meaningful improvements in FEV.sub.1 of 0.32 to 0.34 L
were observed at week 12 irrespective of baseline blood eosinophil
count, with even larger increases of 0.43 to 0.47 L in patients
with baseline blood .gtoreq.300 eosinophils/.mu.L.
[0328] Furthermore, post-bronchodilator FEV.sub.1 slope analysis
indicated that compared with the loss of lung function observed in
placebo patients, no loss was observed in dupilumab-treated
patients suggesting a potential effect of dupilumab on airway
remodeling. The slope analysis showed that placebo patients lost on
average about 40 mL annually, which is consistent with data from
other asthma cohorts. Furthermore, as IL-4R.alpha. is expressed on
smooth muscle cells, it is possible that there is a direct
bronchodilator effect of the drug, in addition to the anti-Type 2
inflammatory effects.
[0329] The consistent and profound improvement seen with dupilumab
is likely attributable to its unique mechanism of action. With the
increasing recent focus of the asthma community on exacerbations,
driven by payer concerns of cost-effectiveness, emphasis has
shifted away from the significant morbidity and quality of life
issues associated with the substantial loss of lung function seen
in moderate-to-severe asthma patients. Despite current therapies,
these moderate-to-severe asthma patients are destined to continue
to lose further lung function and decline with time. Thus, the
possibility that a new treatment can provide substantial
restoration of clinically meaningful levels of lung function, and
perhaps even stave off future deterioration, could provide enormous
benefit to these patients.
[0330] The results of this study confirm that interleukin-4 and
interleukin-13 are key proximal drivers of Type 2 inflammation in
asthma. Dupilumab is the first biologic to significantly reduce
FeNO levels, in addition to other systemic Type 2 biomarkers such
as IgE, confirming its biological activity on airway inflammation.
Without intending to be bound by scientific theory, the unique
mechanism of action of dupilumab, with dual blockade of
interleukin-4 and interleukin-13 signaling, may explain why
dupilumab shows significant treatment effect in a broader patient
population and unprecedented effect on improvement in lung
function, suggesting a potential direct bronchodilator effect in
addition to its anti-inflammatory effect. It is noteworthy that
this study shows the most prominent association of benefit to
baseline levels of blood eosinophils compared to the other two
pivotal studies with dupilumab. Although there is no clear
explanation why the association was more prominent in this study,
blood eosinophils may be an insufficient measure of Type 2
inflammation, indicating that other biomarkers of type 2
inflammation such as FeNO may be important. Nevertheless, in
general across all three studies, dupilumab seems to address a
broader asthma population than those defined only by either
elevated blood eosinophils or IgE levels, which is required for
other approved biologics.
[0331] Dupilumab activity has been demonstrated against several
atopic/allergic conditions, which are often co-morbid in asthma
patients. In this study, over 80% of the patients suffered from a
co-morbid atopic or allergic condition, including atopic dermatitis
(about 10% of the population), nasal polyposis (about 20% of the
population), and allergic rhinitis (over 65% of the population).
The high rate of co-morbid atopic/allergic conditions suggests that
these patients suffer from systemic over-activity of the Type 2
inflammatory axis, and thus treatment of asthma with dupilumab
could simultaneously help alleviate these associated
conditions.
[0332] Dupilumab was generally well tolerated and had an acceptable
safety profile. With the exception of injection site reactions,
incidence of TEAEs was similar across treatment groups. Consistent
with the mechanism of action, and similar to what was observed in
atopic dermatitis trials, dupilumab-treated patients showed a
greater mean transient increase from baseline in blood eosinophil
counts compared with placebo. Per study protocol, all cases of
eosinophil counts .gtoreq.3,000 cells/.mu.L on treatment were to be
reported as AEs in this study. Most of the observed elevations in
eosinophil counts were laboratory findings without clinical
consequences or associated AEs. The increase in blood eosinophil
counts is consistent with the hypothesis that dupilumab blocks
interleukin-4 and interleukin-13 function in eosinophil survival,
activation and recruitment to tissues, but not regress from bone
marrow which is influenced by IL-5 As a result, initial treatment
with dupilumab may result in transient increase in circulating
blood eosinophil counts. No treatment-related conjunctivitis AEs
were observed between dupilumab and placebo groups, in contrast to
dupilumab atopic dermatitis studies.
[0333] In conclusion, in the largest study to date of dupilumab in
patients with uncontrolled moderate-to-severe asthma, it is here
demonstrated that dual blockade of interleukin-4 and interleukin-13
with dupilumab effectively treats a broad asthma population,
providing significant reduction in the rate of severe
exacerbations, rapid and sustained improvement in lung function and
asthma control, and symptom relief. The most robust results were
observed in patients with elevated Type 2 immune characteristics,
including eosinophil counts and FeNO. Dupilumab is the only
biologic to demonstrate efficacy in multiple studies of
moderate-to-severe asthma patients, independent of baseline Type 2
biomarker levels. Dupilumab was generally well tolerated and had an
acceptable safety profile. These data support the use of dupilumab
as effective add-on therapy for this population of asthma patients
with a high unmet need.
Example 3 QUEST Phase III Trial Study Dupilumab Reduces Severe
Exacerbation Rate and Improves Lung Function in Adolescent Patients
with Uncontrolled, Moderate-to-Severe Asthma
[0334] The prevalence of asthma in children and adolescents has
increased over the past 30 years (Asher (2014) Int. J. Tuberc. Lung
Dis.). In 2011, approximately 11.4% of adolescents (age 12-17
years) in the USA reported currently having asthma (Bloom (2011)
Vital and Health Statistics Series).
[0335] The rate of morbidity due to asthma is as high (or often
higher) in adolescents as in younger children, however, adolescents
are less likely to seek medical help (Couriel (2003) J. Paediatric
Resp. Rev.). Many adolescents underestimate the severity of their
asthma and overestimate their response to bronchodilators (Rhee
(2008) J. Asthma; Andersson (2013) Pediatrics). Asthma profoundly
influences adolescents' physical, psychological and social health
and adversely affects their health-related quality of life (Cui
(2016) J. Pediatrics).
[0336] This study assessed the efficacy and safety of dupilumab by
subgroups of adolescents (age 12-17 years) and adults (age
.gtoreq.18 years) with uncontrolled, moderate-to-severe asthma.
Endpoints assessed during the 52-week treatment period were the
annualized rate of severe exacerbations, and change from baseline
in pre-bronchodilator FEV.sub.1 (L). Baseline demographics and
clinical characteristics are shown at FIG. 12.
[0337] Inclusion criteria: Age .gtoreq.12 years with
physician-diagnosed uncontrolled asthma for .gtoreq.12 months
(Global Initiative for Asthma (GINA) 2014); On treatment with
medium-to-high dose ICS (inhaled corticosteroids) plus up to 2
additional controllers; Pre-bronchodilator FEV.sub.1 (forced
expiratory volume in 1 second).ltoreq.80% predicted normal (adults)
and .ltoreq.90% (adolescents) at screening and baseline;
Bronchodilator reversibility .gtoreq.12% and 200 mL; ACQ-5 (5-item
asthma control questionnaire) score .gtoreq.1.5 at screening and
baseline; .gtoreq.1 exacerbation during the previous year; No
minimum requirement for baseline blood eosinophil count or any
other type 2 biomarker.
[0338] Exclusion criteria: Chronic obstructive pulmonary disease or
other lung diseases that might impair lung function; Severe asthma
exacerbation within 1 month of the enrollment visit or during
screening period; Current smoker, smoker who stopped within 6
months before screening, or with a smoking history of .gtoreq.10
pack-years; Comorbid disease that might interfere with the
evaluation of the study drug.
[0339] Statistical Analysis: Efficacy analyses were performed on
the ITT population, defined as all randomized patients by allocated
treatment whether or not treatment was received.
[0340] The annualized rate of severe asthma exacerbations during
the 52-week treatment period was analyzed using a negative binomial
regression model. Change from baseline in FEV.sub.1 at various time
points during the 52-week treatment period was analyzed using a
mixed-effects model with repeated measures.
[0341] The primary endpoints, severe asthma exacerbation rates and
FEV.sub.1 were also analyzed in a subgroup of patients defined by
age (<18 years and .gtoreq.18 years). The safety population
included all patients who received .gtoreq.1 dose or part of a dose
of the investigational treatment, analyzed according to the
treatment received.
[0342] Dupilumab reduced severe exacerbations and improved
FEV.sub.1 in the overall ITT population (FIG. 13A and FIG. 13B),
reduced severe exacerbation rates in adolescents and adults (FIG.
14A and FIG. 14B), and improved FEV.sub.1 at weeks 12 (FIG. 15A)
and 52 (FIG. 15B), as well as throughout the 52-week treatment
period (FIG. 16A and FIG. 16B) in adolescents and adults.
[0343] Dupilumab improved percent predicted FEV.sub.1 during the
52-week treatment period in adolescents and adults (FIG. 18A and
FIG. 18B). FeNO levels (FIG. 19A and FIG. 19B), ACQ-5 scores (FIG.
20A and FIG. 20B), and AQLQ scores (FIG. 21A and FIG. 21B) were
assessed.
[0344] Adolescents comprised 107/1,902 enrolled patients (34 in
dupilumab groups, 21/18 in matched-placebo groups); 35.5% were
female, mean baseline FEV1 was 2.33 L, mean % predicted FEV1
70.45%, mean number of severe exacerbations in the previous year
1.91 Adolescents receiving placebo experienced fewer severe
exacerbations (0.36/0.33) than adults (0.89/1.00). In adolescents,
dupilumab 200 mg reduced annualized exacerbation rates by 46.4%
while dupilumab 300 mg had no treatment effect vs. placebo (without
intending to be bound by scientific theory, this was possibly due
to small sample size and unbalanced number of prior events (mean
1.53 vs 2.22, respectively)). Unadjusted exacerbation rates were
0.46 (dupilumab 300 mg) and 0.76 (placebo). Significant
improvements in change from baseline in FEV1 (L) vs placebo were
seen in adolescents (dupilumab 200 mg: least-squares mean 0.36 [95%
CI 0.12-0.61]300 mg: 0.27 [0.02-0.52]) (P<0.05) and were
numerically greater vs adults (200 and 300 mg: 0.12
[0.07-0.18]).
[0345] The adverse event profile was comparable between subgroups
(FIG. 17, FIG. 22, FIG. 23 and FIG. 24). The most common
treatment-emergent adverse events (TEAEs) occurring more frequently
in the dupilumab group combined were: Adolescents respiratory tract
infection viral (placebo, 2 [5.1%]); dupilumab, 7 [10.3%]); Adults
injection site erythema (placebo, 34 [5.7%]; dupilumab, 168
[14.1%]). Eosinophilia was only observed in the adult
population.
[0346] Dupilumab significantly reduced annualized rates of severe
exacerbation and improved lung function in adults with
uncontrolled, moderate-to-severe asthma. Improvement in FEV.sub.1
was rapid and sustained throughout the 52-week treatment period.
Dupilumab also significantly improved lung function in adolescents
with uncontrolled moderate-to-severe asthma, with numerical
reductions observed for severe exacerbations
[0347] As in adults, adolescents' improvement in FEV.sub.1 was
rapid and sustained throughout the 52-week treatment period. The
magnitude of improvement in FEV.sub.1 was greater in adolescents.
Dupilumab was generally well tolerated.
Example 4 QUEST Phase III Trial Study Dupilumab Improves
Health-Related Rhinoconjunctivitis Quality of Life, Improves Lung
Function and Reduces Severe Exacerbation Rate in Patients with
Moderate-to-Severe Asthma
[0348] Health-Related Quality of Life in Patients with Comorbid
Allergic Rhinitis
[0349] Allergic rhinitis (AR), a common type 2 comorbidity in
asthma patients, contributes to increased overall disease burden.
This analysis of the phase 3 LIBERTY ASTHMA QUEST study
(NCT02414854) in uncontrolled, moderate-to-severe asthma patients
assessed dupilumab's effect on the standardized rhinoconjunctivitis
quality of life questionnaire [RQLQ(S)+12] in patients with
self-reported comorbid AR.
[0350] Asthma patients, .gtoreq.12 years, uncontrolled with
medium-to-high-dose ICS plus .ltoreq.2 additional controllers
received add-on dupilumab 200/300 mg or matched placebo every 2
weeks (q2w) for 52 weeks. Patients with self-reported medical
history of AR (63.5%; n/N=1,207/1,902) completed the validated
RQLQ(S)+12 at weeks 12 and 52. A clinical AR diagnosis was not
recorded.
[0351] Overall RQLQ(S)+12 score (baseline mean [SD]
1.90[1.12]-2.01[1.16]) was significantly improved with dupilumab
200/300 mg q2w vs. placebo at week 52 (least squares mean
difference [95% CI]-0.42[-0.61,-0.24]/-0.39 [-0.56,-0.21];
P<0.0001). Dupilumab 200/300 mg significantly (P<0.001)
improved activities (0.44 [0.68, 0.21] 0.39 [0.61, 0.16]), sleep
(0.47 [0.69, 0.25] 0.38 [0.59, 0.17]), and eye symptoms (0.37
[0.58, 0.16] 0.39 [0.59, 0.19]) domain scores from baseline to week
52 vs placebo; and by week 12 for dupilumab 300 mg (0.23 [0.42,
0.04]0.26 [0.45, 0.07], 0.26 [0.45, 0.08] respectively; P<0.05).
Nasal symptoms domain scores significantly improved with dupilumab
200/300 mg vs. placebo by week 12 (0.36 [0.56, 0.16] 0.32 [0.51,
0.13]P<0.001) and week 52 (0.61 [0.84, 0.39] 0.55 [0.76,
0.33]P<0.0001). The most common adverse event, with higher
frequency in dupilumab vs. placebo, was injection-site reactions
(15% 18% vs. 5% 10%).
[0352] Dupilumab significantly improved
rhinoconjunctivitis-specific health-related quality of life in
patients with uncontrolled, moderate-to-severe asthma and comorbid
AR, and was generally well tolerated.
[0353] Population: patients with comorbid AR. Endpoints/Visit: LS
mean change from baseline during the 52-week treatment period for
RQLQ domains (nasal symptoms, eye symptoms, activities, sleep);
safety (ITT). Treatment arms: Dupilumab 200 mg and 300 mg q2w and
matched placebo.
Improved Lung Function and Reduced Severe Exacerbation in Patients
with or without Comorbid Allergic Rhinitis
[0354] A post hoc analysis of the phase 3 LIBERTY ASTHMA QUEST
study (NCT02414854) in asthma patients (.gtoreq.12 years,
uncontrolled with medium-to-high-dose ICS plus .ltoreq.2 additional
controllers) with a self-reported medical history of comorbid AR
(63.5%; n/N=1,207/1,902) or without comorbid AR assessed the effect
of add-on dupilumab 200 mg or 300 mg or matched placebo every 2
weeks (q2w) on the annualized rate of severe exacerbations and
forced expiratory volume in 1 second (FEV.sub.1). A clinical
diagnosis of AR was not recorded.
[0355] Baseline characteristics of patients with and without AR
were generally similar. The annualized rate of severe exacerbations
was reduced vs placebo with dupilumab 200 mg q2w (relative risk
with AR:0.606 [95% CI, 0.451-0.814]P=0.0009 without AR:0.406 [95%
CI, 0.273-0.605]; P<0.0001) with similar results for 300 mg q2w.
FEV.sub.1 was improved at week 12 with dupilumab 200 mg q2w (LS
mean difference vs. placebo with AR:0.14 L [95% CI,
0.07-0.21]P<0.0001 without AR:0.13 L [95% CI,
0.05-0.22]P=0.0023) and sustained to week 52 (both with and without
AR: P<0.0001), with similar results at week 52 for 300 mg q2w.
The most common adverse event in dupilumab-treated (vs. placebo)
groups was injection-site reactions (200 mg/300 mg vs.
matched-placebos: 15% 18% vs. 5% 10%).
[0356] Dupilumab significantly improved FEV.sub.1 and reduced
annual severe exacerbation rates in this difficult-to-control
asthma population with comorbid AR and also in patients without
concomitant AR.
[0357] Population: Patients with and without comorbid AR (AR
defined according to CSR). Endpoints: LS mean change from baseline
in FEV1 at weeks 12 and 52 severe exacerbations during the 52-week
treatment period. Safety: ITT.
Example 5 QUEST Phase III Trial Study Dupilumab Suppresses Type 2
Biomarkers in Asthma Patients with and without Comorbid Chronic
Rhinosinusitis with Nasal Polyposis (CRS+NP) or Chronic
Rhinosinusitis without Nasal Polyposis (CRS NP) in Patients with
Moderate-to-Severe Asthma
[0358] In the phase 3 LIBERTY ASTHMA QUEST study (NCT02414854),
dupilumab 200/300 mg every 2 weeks versus matched placebo
suppressed type 2 biomarkers in patients with uncontrolled,
moderate-to-severe asthma and improved health-related quality of
life, assessed by SNOT-22 in the difficult-to-treat subgroup with
comorbid chronic rhinosinusitis with nasal polyposis (CRS+NP) or
(CRSwNP) and comorbid chronic rhinosinusitis without nasal
polyposis (CRS NP). This post hoc analysis assessed dupilumab's
effect on type 2 biomarkers in this subgroup.
[0359] Baseline/change from baseline over time were assessed for
fractional exhaled nitric oxide (FeNO), total IgE, and eotaxin-3
CRS with or without NP was self-reported by 20.1% (n/N=382/1,897)
patients.
Baseline FeNO and eotaxin-3 values were numerically higher in
patients with CRS NP or CRS+NP than in those without. Biomarker
suppression was evident in all dupilumab-treated patients by week
12 At week 52 significant biomarker suppression was observed in
patients with and without CRS NP or CRS+NP, as shown by median
percentage changes from baseline (dupilumab 200/300 mg vs. matched
placebo), with CRS NP or CRS+NP: FeNO 46.2/37.7 vs. 5.5/6.4 IgE
74.8/76.8 vs. 0.0/2.0 eotaxin-3 47.7/50.9 vs. 1.5/5.4 (all
P<0.0001); without CRS NP or CRS+NP: FeNO 31.0/35.9 vs. 5.9/10.1
IgE 67.3/67.7 vs. 3.3/6.6 eotaxin-3 31.8/37.2 vs. 0.0/0.8 (all
P<0.0001). The most common adverse event, with higher frequency
in dupilumab vs placebo, was injection-site reactions (15% 18% vs.
5% 10%).
[0360] Dupilumab suppressed local and systemic type-2 biomarkers in
patients with and without CRS+/-NP.
[0361] Population: patients with and without comorbid CRS or NP.
Endpoints: percent change from baseline serum total IgE, plasma
eotaxin-3 and FeNO over the 52-week treatment period. Safety: ITT.
Treatment arms: dupilumab 200 and 300 mg q2w and matched
placebo.
Example 6 QUEST Phase III Trial Study Dupilumab Reduces Severe
Exacerbations and Improves Lung Function in Late-Onset,
Uncontrolled, Moderate-to-Severe Asthma Patients
[0362] In the phase 3 LIBERTY ASTHMA QUEST study (NCT02414854),
this post-hoc analysis assessed the efficacy of dupilumab in
patients with late onset of asthma (age >40 years) and baseline
post-bronchodilator FEV1/forced vital capacity [FVC] ratio <0.7
(which suggests fixed airway obstruction), or .gtoreq.0.7.
[0363] Annualized rate of severe exacerbations during the 52-week
treatment period was assessed using negative binomial regression
models. Change from baseline in pre- and post-bronchodilator FEV1
(L) and pre-bronchodilator FEV1/FVC ratio at weeks 12 and 52 were
analyzed using mixed-effect models with repeated measures.
[0364] Dupilumab 200 mg and 300 mg q2w vs. placebo significantly
reduced the annualized rate of severe exacerbations in patients
with late-onset asthma and fixed airway obstruction (68.8% and
75.7%, respectively, both P<0.0001) and in patients without
fixed airway obstruction (55.1% and 50.7%, respectively, both
P<0.05) (FIG. 27). At week 12 pre- and post-bronchodilator FEV1
and FEV1/FVC ratio improved in dupilumab-treated patients with
late-onset asthma and fixed airway obstruction (P<0.05 vs
placebo, either or both doses). Similar improvements were observed
at week 52 (dupilumab 200 mg q2w P<0.05 for pre- and
post-bronchodilator FEV1 dupilumab 300 mg q2w pre-bronchodilator
FEV1 P=0.09 post-bronchodilator FEV1 P=0.06). Late-onset asthma
patients without fixed airway obstruction, had more modest
improvements vs. placebo in pre-bronchodilator FEV1 at weeks 12 and
52 than did those with fixed airway obstruction (P.gtoreq.0.05).
The most frequent adverse event in dupilumab-treated groups vs.
matched-placebo was injection-site reactions (15%/18% vs.
5%/10%).
[0365] In patients with late-onset asthma with or without fixed
airway obstruction, dupilumab significantly reduced severe
exacerbation rates. Furthermore, lung function improvements were
observed at weeks 12 and 52 in patients with late-onset asthma and
fixed airway obstruction, who typically experience worse asthma
outcomes than do those without fixed airway obstruction.
[0366] Population: ITT population with age of onset asthma >40
years and post-BD FEV1/FVC<0.7 ITT population with age of onset
asthma >40 years and post-BD FEV1/FVC.gtoreq.0.7.
[0367] Endpoints/Visit (data for inclusion in abstract: severe
exacerbations during the 52-week treatment period; LS mean change
from baseline in pre-BD FEV1 (L) at weeks 12 and 52 LS mean change
from baseline in post BD FEV1 (L) at weeks 12 and 52 LS mean change
from baseline in FEV1/FVC ratio at weeks 12 and 52 safety.
[0368] Treatment arms: Dupilumab 200 mg q2w, dupilumab 300 mg q2w
and matched-placebo groups.
Sequence CWU 1
1
81124PRTArtificial SequenceDescription of Artificial Sequence
Synthetic HCVR polypeptide 1Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Glu Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Gly Ser
Gly Phe Thr Phe Arg Asp Tyr 20 25 30Ala Met Thr Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Ile Ser Gly Ser Gly
Gly Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Asp
Arg Leu Ser Ile Thr Ile Arg Pro Arg Tyr Tyr Gly Leu 100 105 110Asp
Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser 115
1202112PRTArtificial SequenceDescription of Artificial Sequence
Synthetic LCVR polypeptide 2Asp Ile Val Met Thr Gln Ser Pro Leu Ser
Leu Pro Val Thr Pro Gly1 5 10 15Glu Pro Ala Ser Ile Ser Cys Arg Ser
Ser Gln Ser Leu Leu Tyr Ser 20 25 30Ile Gly Tyr Asn Tyr Leu Asp Trp
Tyr Leu Gln Lys Ser Gly Gln Ser 35 40 45Pro Gln Leu Leu Ile Tyr Leu
Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu
Ala Glu Asp Val Gly Phe Tyr Tyr Cys Met Gln Ala 85 90 95Leu Gln Thr
Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105
11038PRTArtificial SequenceDescription of Artificial Sequence
Synthetic HCDR1 peptide 3Gly Phe Thr Phe Arg Asp Tyr Ala1
548PRTArtificial SequenceDescription of Artificial Sequence
Synthetic HCDR2 peptide 4Ile Ser Gly Ser Gly Gly Asn Thr1
5518PRTArtificial SequenceDescription of Artificial Sequence
Synthetic HCDR3 peptide 5Ala Lys Asp Arg Leu Ser Ile Thr Ile Arg
Pro Arg Tyr Tyr Gly Leu1 5 10 15Asp Val611PRTArtificial
SequenceDescription of Artificial Sequence Synthetic LCDR1 peptide
6Gln Ser Leu Leu Tyr Ser Ile Gly Tyr Asn Tyr1 5 1073PRTArtificial
SequenceDescription of Artificial Sequence Synthetic LCDR2 peptide
7Leu Gly Ser189PRTArtificial SequenceDescription of Artificial
Sequence Synthetic LCDR3 peptide 8Met Gln Ala Leu Gln Thr Pro Tyr
Thr1 5
* * * * *