U.S. patent application number 17/339858 was filed with the patent office on 2021-11-25 for methods for treating active eosinophilic esophagitis.
The applicant listed for this patent is REGENERON PHARMACEUTICALS, INC., SANOFI BIOTECHNOLOGY. Invention is credited to Jennifer D. Hamilton, Leda Mannent, Allen RADIN.
Application Number | 20210363237 17/339858 |
Document ID | / |
Family ID | 1000005756802 |
Filed Date | 2021-11-25 |
United States Patent
Application |
20210363237 |
Kind Code |
A1 |
RADIN; Allen ; et
al. |
November 25, 2021 |
METHODS FOR TREATING ACTIVE EOSINOPHILIC ESOPHAGITIS
Abstract
The present invention provides methods for treating, preventing
or reducing the severity of active eosinophilic esophagitis. In
certain embodiments, the present invention provides methods of
increasing esophageal distensibility. The methods of the present
invention comprise administering to a subject in need thereof a
therapeutic composition comprising an interleukin-4/interleukin-13
(IL-4/IL-13) pathway inhibitor such as an anti-IL-4R antibody.
Inventors: |
RADIN; Allen; (New York,
NY) ; Hamilton; Jennifer D.; (Ridgefield, CT)
; Mannent; Leda; (Paris, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
REGENERON PHARMACEUTICALS, INC.
SANOFI BIOTECHNOLOGY |
Tarrytown
Paris |
NY |
US
FR |
|
|
Family ID: |
1000005756802 |
Appl. No.: |
17/339858 |
Filed: |
June 4, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16054583 |
Aug 3, 2018 |
11053309 |
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17339858 |
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62541242 |
Aug 4, 2017 |
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62561593 |
Sep 21, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07K 16/468 20130101;
A61K 2039/577 20130101; C07K 2317/565 20130101; A61K 2039/54
20130101; A61K 39/3955 20130101; C07K 16/247 20130101; C07K 16/2866
20130101; A61K 2039/545 20130101; A61P 1/00 20180101; A61K 2039/505
20130101; C07K 2317/76 20130101; C07K 2317/21 20130101 |
International
Class: |
C07K 16/24 20060101
C07K016/24; A61K 39/395 20060101 A61K039/395; A61P 1/00 20060101
A61P001/00; C07K 16/46 20060101 C07K016/46 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 8, 2018 |
EP |
18305252.1 |
Claims
1. A method of reducing dysphagia comprising: administering a
therapeutically effective amount of a pharmaceutical composition
comprising an interleukin-4/interleukin-13 (IL-4/IL-13) pathway
inhibitor to a patient in need thereof, wherein the patient has
eosinophilic esophagitis (EoE), and wherein the patient exhibits at
least two episodes of dysphagia per week for at least four weeks
and/or has a Straumann Dysphagia Instrument (SDI) score .gtoreq.5;
wherein the IL-4/IL-13 pathway inhibitor is an antibody or
antigen-binding fragment thereof that binds IL-4 receptor alpha
(IL-4R.alpha.), wherein the antibody or antigen-binding fragment
thereof comprises three heavy chain complementarity determining
regions (HCDR1, HCDR2 and HCDR3) and three light chain
complementarity determining regions (LCDR1, LCDR2 and LCDR3),
wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:
3, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 4, the
HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, the LCDR1
comprises the amino acid sequence of SEQ ID NO: 6, the LCDR2
comprises the amino acid sequence of SEQ ID NO: 7, and the LCDR3
comprises the amino acid sequence of SEQ ID NO: 8, thereby reducing
dysphagia.
2. The method of claim 1, wherein the patient has had EoE for at
least three years.
3. The method of claim 1, wherein the patient is .gtoreq.18 years
of age.
4. The method of claim 1, wherein the patient has been treated
previously with proton pump inhibitors (PPIs).
5. The method of claim 1, wherein the patient has had at least one
prior esophageal dilation.
6. The method of claim 1, wherein the patient to be treated: (1)
has a history of at least one other disease or condition selected
from the group consisting of food allergy, allergic rhinitis,
non-food allergy, asthma, chronic sinusitis, hives, atopic
dermatitis, and allergic conjunctivitis; (2) has a baseline SDI
score >7; and/or (3) has a baseline Eosinophilic Esophagitis
Severity and Activity Index (EEsAI) score .gtoreq.50.
7. The method of claim 1, wherein administration of the IL-4/IL-13
pathway inhibitor results in improvement of at least one parameter
selected from the group consisting of: (a) reduction of at least
40% from baseline in the SDI score; (b) reduction of .gtoreq.3
points from baseline in the SDI score; and (c) reduction of more
than 30% from baseline in Eosinophilic Esophagitis Severity and
Activity Index (EEsAI) score.
8. The method of claim 1, wherein the IL-4/IL-13 pathway inhibitor
is administered at a dose of about 50 to about 600 mg.
9. The method of claim 1, wherein the IL-4/IL-13 pathway inhibitor
is administered at a dose of about 300 mg.
10. The method of claim 1, wherein the IL-4/IL-13 pathway inhibitor
is administered at an initial dose followed by one or more
secondary doses, wherein each secondary dose is administered 1 to 4
weeks after the immediately preceding dose.
11. The method of claim 10, wherein the initial dose comprises 50
mg-600 mg of the IL-4/IL-13 pathway inhibitor.
12. The method of claim 10, wherein each secondary dose comprises
25 mg-400 mg of the IL-4/IL-13 pathway inhibitor.
13. The method of claim 10, wherein the initial dose comprises 600
mg of the IL-4/IL-13 pathway inhibitor, and each secondary dose
comprises 300 mg of the IL-4/IL-13 pathway inhibitor.
14. The method of claim 13, wherein each secondary dose is
administered one week or two weeks after the immediately preceding
dose.
15. The method of claim 9, wherein the IL-4/IL-13 pathway inhibitor
is administered once every week or once every two weeks.
16-20. (canceled)
21. The method of claim 1, wherein the IL-4/IL-13 pathway inhibitor
is administered in combination with a second therapeutic agent or
therapy, wherein the second therapeutic agent or therapy is
selected from the group consisting of an IL-1beta inhibitor, an
IL-5 inhibitor, an IL-9 inhibitor, an IL-13 inhibitor, an IL-17
inhibitor, an IL-25 inhibitor, a TNFalpha inhibitor, an eotaxin-3
inhibitor, an IgE inhibitor, a prostaglandin D2 inhibitor, an
immunosuppressant, a topical corticosteroid, an oral
corticosteroid, a systemic corticosteroid, an inhaled
corticosteroid, a glucocorticoid, a proton pump inhibitor, a NSAID,
esophagus dilation, allergen removal, and/or diet management.
22. The method of claim 1, wherein the IL-4/IL-13 pathway inhibitor
is administered subcutaneously.
23-30. (canceled)
31. The method of claim 1, wherein the antibody or antigen-binding
fragment thereof comprises a heavy chain variable region (HCVR)
that comprises the amino acid sequence of SEQ ID NO: 1, and a light
chain variable region (LCVR) that comprises the amino acid sequence
of SEQ ID NO: 2.
32. The method of claim 1, wherein the antibody or antigen-binding
fragment thereof comprises a heavy chain comprising the amino acid
sequence of SEQ ID NO: 9 and a light chain comprising the amino
acid sequence of SEQ ID NO: 10.
33. The method of claim 1, wherein the IL-4/IL-13 pathway inhibitor
is dupilumab or a bioequivalent thereof.
34. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/054,583 filed Aug. 3, 2018, entitled,
"Methods for Treating Active Eosinophilic Esophagitis", which
claims the benefit under 35 U.S.C. .sctn. 119(e) of U.S.
provisional application Nos. 62/541,242 filed Aug. 4, 2017; and
62/561,593, filed Sep. 21, 2017, and also claims priority to EP
18305252.1, filed Mar. 8, 2018. The disclosure of the
aforementioned patent applications are herein incorporated by
reference in their entireties.
SEQUENCE LISTING
[0002] The present application includes a Sequence Listing in
electronic format as an ASCII txt file entitled
"40848-0093USC1-SEQLIST", which was created on Jun. 4, 2021 and has
a size of 11 kilobytes (11 KB).
FIELD OF THE INVENTION
[0003] The present invention relates to the use of
interleukin-4/interleukin-13 pathway inhibitors to treat or prevent
active eosinophilic esophagitis in a subject in need thereof.
BACKGROUND
[0004] Esophageal stricture (narrowing of the esophagus) results
from injury to the esophageal lining and leads to, inter alia,
difficulty in swallowing (dysphagia), regurgitation of food or
liquid, heartburn and unintended weight loss. Treatment of
esophageal stricture is very important as it reduces quality of
life due to dysphagia, weight loss, and nutritional imbalance.
Esophageal stricture may be caused due to chronic ulceration or
chronic inflammation, as a complication due to chemotherapy,
radiotherapy, esophageal cancer or endoscopic surgery, peptic
ulcers or gastroesophageal reflux. Esophageal stricture is also
caused by eosinophilic esophagitis.
[0005] Eosinophilic esophagitis (EoE) is an emerging, chronic,
immune-/antigen-mediated disease characterized by esophageal
dysfunction and eosinophil inflammation in the esophagus (Liacouras
et al 2011, The Journal of Allergy and Clinical Immunology. 128:
3-20 e6; quiz 1-2; Weinbrand-Goichberg et al 2013, Immunologic
Research. 56: 249-60; Zhang et al 2013, Digestive Diseases and
Sciences 58: 1497-506). Adult patients with EoE have substantially
impaired quality of life (QOL) due to dysphagia and the possible
risk of food impaction (DeBrosse et al 2011, The Journal of Allergy
and Clinical Immunology 128: 132-8; Falk et al 2014,
Gastroenterology Clinics of North America 43: 231-42; Straumann
2008, Gastrointestinal Endoscopy Clinics of North America 18:
99-118; Straumann et al 2003, Gastroenterology 125: 1660-9).
Patients with active disease or with moderate-to-severe EoE suffer
from esophageal stricture leading to difficulty in swallowing,
regurgitation of food or liquid and weight loss. Emergency
endoscopy for prolonged food impactions is associated with a risk
of severe esophageal injury. EoE is found to be associated with
food allergy in many patients. Some patients may also have
concomitant asthma or an atopic disease such as atopic dermatitis,
or allergic rhinitis. The symptomatic burden of EoE, including food
avoidance, eating modification behaviors, and social, emotional,
financial, work and school, and sleep impacts, is also important
and relevant to the EoE population and, if improved, may reflect a
treatment benefit for EoE patients.
[0006] Current therapeutic approaches include chronic dietary
elimination (including food allergen withdrawal), swallowed topical
formulation corticosteroids (not approved for the treatment of EoE
in the US), and esophageal dilation. Although swallowed topical
corticosteroids have been reported in clinical trials to induce
partial clinical responses and histologic remission, they are not
uniformly effective and can be associated with fungal infections as
well as disease recurrence after discontinuation. There are
currently no approved drug therapies for EoE. Thus, an unmet need
exists in the art for effective therapeutic approaches without
adverse side effects that prevent or treat eosinophilic
esophagitis. Esophageal stricture may be treated with proton pump
inhibitors, which inhibit gastric acid secretion. Esophageal
dilation by endoscopy is currently used to treat esophageal
stricture and increase esophageal distensibility. However, it is a
surgical procedure that is invasive and may lead to complications
such as perforation and bleeding. Accordingly, there is an unmet
need for safe and effective therapies that increase esophageal
distensibility and treat esophageal stricture (e.g., in
eosinophilic esophagitis).
BRIEF SUMMARY OF THE INVENTION
[0007] According to one aspect of the present invention, methods
are provided for increasing the distensibility of the esophagus.
The methods, according to this aspect, comprise: (a) selecting a
patient with moderate-to-severe eosinophilic esophagitis (EoE),
wherein the patient in need thereof has an attribute or is selected
on the basis of a criterion selected from the group consisting of:
(i) the patient has 15 eosinophils per high powered field (hpf) in
the esophagus prior to or at the time of the treatment
("baseline"); (ii) the patient exhibits at least one episode of
dysphagia per week; and (iii) the patient has a Straumann Dysphagia
Instrument (SDI) score 2; and (b) administering a therapeutically
effective amount of a pharmaceutical composition comprising an
interleukin-4/interleukin-13 (IL-4/IL-13) pathway inhibitor to the
patient in need thereof, thereby increasing esophageal
distensibility, as measured by a functional lumen imaging probe
(EndoFLIP.RTM., Crospon, Ireland). In one embodiment, the patient
has active EoE. In one embodiment, the patient is .gtoreq.18 years
of age. In one embodiment, the patient has been treated previously
with proton pump inhibitors (PPIs). In one embodiment, the patient
has had at least one prior esophageal dilation. In one embodiment,
the patient has a characteristic selected from the group consisting
of: (1) prior treatment with at least one of PP Is, esophageal
dilation, corticosteroids, allergen withdrawal and/or diet
modification; (2) the patient is unresponsive or resistant to prior
treatment with PPIs or esophageal dilation; (3) the patient has an
Eosinophilic Esophagitis Severity and Activity Index (EEsAI)
score.gtoreq.30, .gtoreq.40, or .gtoreq.50; (4) the patient suffers
from EoE for at least 3 years; (5) the patient, prior to or at the
time of administration of the IL-4/IL-13 pathway inhibitor, has or
is diagnosed with a disease or disorder selected from the group
consisting of food allergy, atopic dermatitis, asthma, allergic
rhinitis and allergic conjunctivitis; and (6) the patient has an
elevated level of a biomarker selected from the group consisting of
eotaxin-3, periostin, serum IgE (total and allergen-specific),
IL-13, IL-5, serum thymus and activation regulated chemokine
(TARC), thymic stromal lymphopoietin (TSLP), serum eosinophilic
cationic protein (ECP), and eosinophil-derived neurotoxin
(EDN).
[0008] According to another aspect of the present invention,
methods are provided for treating, preventing or ameliorating at
least one symptom or indication of active eosinophilic esophagitis
(EoE) in a subject. The methods, according to this aspect of the
invention, comprise selecting a patient with moderate-to-severe
EoE, and administering a therapeutically effective amount of a
pharmaceutical composition comprising an
interleukin-4/interleukin-13 (IL-4/IL-13) pathway inhibitor to the
patient in need thereof. In certain embodiments, the patient in
need thereof is selected on the basis of an attribute or criterion
selected from the group consisting of: (1) the patient has 15
eosinophils per high powered field (hpf) in the esophagus prior to
or at the time of the treatment ("baseline"); (2) prior treatment
with at least one of high dose proton pump inhibitors (PPIs),
esophageal dilation, corticosteroids, allergen withdrawal and/or
diet modification; (3) the patient exhibits at least one episode of
dysphagia per week; (4) the patient is unresponsive or resistant to
prior treatment with high dose PPIs or esophageal dilation; (5) the
patient has a Straumann Dysphagia Instrument (SDI) score 5; (6) the
patient has an Eosinophilic Esophagitis Severity and Activity Index
(EEsAI) score.gtoreq.30, .gtoreq.40, or .gtoreq.50; (7) the patient
suffers from EoE for at least 3 years; (8) the patient, prior to or
at the time of administration of the IL-4/IL-13 pathway inhibitor,
has or is diagnosed with a disease or disorder selected from the
group consisting of food allergy, atopic dermatitis, asthma,
allergic rhinitis and allergic conjunctivitis; and (9) the patient
has an elevated level of a biomarker selected from the group
consisting of eotaxin-3, periostin, serum IgE (total and
allergen-specific), IL-13, IL-5, serum thymus and activation
regulated chemokine (TARC), thymic stromal lymphopoietin (TSLP),
serum eosinophilic cationic protein (ECP), and eosinophil-derived
neurotoxin (EDN).
[0009] In embodiments of the invention that specify the selection
of "at least one . . . selected from the group consisting of" or
simply "selected from the group consisting of", the use of the
conjunction "and/or" between the final two items of the list
following such language indicates that the items in the sequence
are alternatives to one another, and that one (or more) of these
items is/are selected. It does not mean that each of the items is
necessarily selected. For example, for a method of increasing
esophageal distensibility, wherein the patient has at least one
characteristic selected from the group consisting of: [0010] (1)
prior treatment with at least one of PPIs, esophageal dilation,
corticosteroids, allergen withdrawal, and/or diet modification;
[0011] (2) the patient is unresponsive or resistant to prior
treatment with PPIs or esophageal dilation; [0012] (3) the patient
has an Eosinophilic Esophagitis Severity and Activity Index (EEsAI)
score .gtoreq.30, .gtoreq.40, or .gtoreq.50; [0013] (4) the patient
has suffered from EoE for at least 3 years; [0014] (5) the patient,
prior to or at the time of administration of the IL-4/IL-13 pathway
inhibitor, has or is diagnosed with a disease or disorder selected
from the group consisting of food allergy, atopic dermatitis,
asthma, allergic rhinitis, and/or allergic conjunctivitis; and/or
[0015] (6) the patient has an elevated level of at least one
biomarker selected from the group consisting of eotaxin-3,
periostin, serum IgE (total and allergen-specific), IL-13, IL-5,
serum thymus and activation regulated chemokine (TARC), thymic
stromal lymphopoietin (TSLP), serum eosinophilic cationic protein
(ECP), and/or eosinophil-derived neurotoxin (EDN), what is meant is
that the patient has at least characteristic (1) or characteristic
(2) or characteristic (3) or characteristic (4) or characteristic
(5) or characteristic (6). The patient can also, based on such
language, have more than one of the six characteristics (for
example, (1) and (2), or (4) and (5), or (1), (2), and (6), and so
on). It is not, however, meant that the patient must have at least
characteristic (1) and characteristic (2) and characteristic (3)
and characteristic (4) and characteristic (5) and characteristic
(6).
[0016] According to another aspect of the present invention,
methods are provided for reducing dysphagia, the methods comprising
selecting a patient with moderate-to-severe EoE wherein the patient
(i) exhibits episodes of dysphagia per week; (ii) has been treated
previously with high-dose proton pump inhibitors (PPIs); and/or
(iii) has had at least one prior esophageal dilation; and (b)
administering a therapeutically effective amount of a
pharmaceutical composition comprising an IL-4/IL-13 pathway
inhibitor to the patient in need thereof.
[0017] According to another aspect of the present invention,
methods are provided for improving a parameter, the methods
comprising selecting a patient with moderate-to-severe EoE; and
administering a therapeutically effective amount of a
pharmaceutical composition comprising an IL-4/IL-13 pathway
inhibitor, wherein the administration leads to an improvement in a
parameter selected from the group consisting of: (a) reduction of
at least 40% from baseline in dysphagia frequency and severity, as
measured by Straumann Dysphagia Instrument (SDI) score; (b)
reduction of 3 points from baseline in the SDI score; (c) reduction
of more than 85% from baseline in peak intraepithelial eosinophil
count in proximal, mid and/or distal regions of the esophagus; (d)
increase of at least 10% from baseline in esophageal
distensibility, as measured by impedance planimetry; (e) decrease
of more than 50% from baseline in severity and extent of disease,
as measured by EoE Histology Scoring System (HSS) score; and (f)
reduction of more than 30% from baseline in dysphagia, as measured
by Eosinophilic Esophagitis Severity and Activity Index (EEsAI)
score.
[0018] According to another aspect of the present invention,
methods are provided for reducing the eosinophilic infiltration of
esophagus in a patient in need thereof. In certain embodiments,
methods are provided for reducing inflammation in the esophagus.
The methods comprise administering a therapeutically effective
amount of a pharmaceutical composition comprising an IL-4/IL-13
pathway inhibitor. In certain embodiments, the eosinophilic
infiltration of the esophagus is represented by greater than or
equal to about 15 eosinophils per high powered field in the
esophagus of the subject in need thereof. In certain embodiments,
the number of eosinophils is reduced .gtoreq.85%, following
administration of the IL-4/IL-13 pathway inhibitor. In certain
embodiments, the inflammation (e.g., mucosal inflammation) is
identified by endoscopy and features such as esophageal edema,
rings, exudates, furrows and strictures (EREFS). In certain
embodiments, administration of the IL-4/IL-13 pathway inhibitor
leads to reduction in the EREFS score to less than 8, less than 7,
less than 6, less than 5, less than 4, less than 3, or less than 2
(disclosed elsewhere herein).
[0019] According to another aspect of the present invention,
methods are provided for reducing the level of an EoE-associated
biomarker in a subject. In certain embodiments, the EoE-associated
biomarker is selected from the group consisting of, e.g.,
circulating or esophagus eosinophils, eotaxin-3, periostin, serum
IgE (total and allergen-specific), IL-13, IL-5, serum thymus and
activation regulated chemokine (TARC; CCL17), thymic stromal
lymphopoietin (TSLP), serum eosinophilic cationic protein (ECP),
and eosinophil-derived neurotoxin (EDN). The methods comprise
administering a therapeutically effective amount of a
pharmaceutical composition comprising an IL-4/IL-13 pathway
inhibitor.
[0020] In certain embodiments, the IL-4/IL-13 pathway inhibitor is
administered in combination with a second therapeutic agent or
therapy.
[0021] In certain embodiments, the subject in need thereof has a
concurrent disease or disorder selected from the group consisting
of food allergy, atopic dermatitis, asthma, allergic rhinitis,
allergic conjunctivitis and inherited connective tissue
disorders.
[0022] Exemplary IL-4/IL-13 pathway inhibitors that can be used in
the context of the methods of the present invention include, but
are not limited to, an anti-IL-4 antibody, an anti-IL-13 antibody,
a bispecific anti-IL-4/IL-13 antibody and an IL-4 receptor (IL-4R)
inhibitor. In one embodiment, the IL-4/IL-13 pathway inhibitor is
an IL-4R inhibitor (such as an anti-IL-4R antibody).
[0023] Exemplary IL-4R inhibitors that can be used in the context
of the methods of the present invention include, e.g., small
molecule chemical inhibitors of IL-4R or its ligands (IL-4 and/or
IL-13), or biological agents that target IL-4R or its ligands.
According to certain embodiments, the IL-4R inhibitor is an
antibody or antigen-binding protein that binds the IL-4R.alpha.
chain and blocks signaling by IL-4, IL-13, or both IL-4 and IL-13.
In certain embodiments, the anti-IL-4R antibody or antigen-binding
protein comprises the heavy chain complementarity determining
regions (HCDRs) of a heavy chain variable region (HCVR) comprising
the amino acid sequence of SEQ ID NO: 1 and the light chain CDRs of
a light chain variable region (LCVR) comprising the amino acid
sequence of SEQ ID NO: 2. One such type of antigen-binding protein
that can be used in the context of the methods of the present
invention is an anti-IL-4R.alpha. antibody such as dupilumab.
[0024] In certain embodiments, the present invention provides use
of an IL-4/IL-13 pathway inhibitor in the manufacture of a
medicament to treat or inhibit or prevent active eosinophilic
esophagitis in a subject, including humans.
[0025] In certain embodiments, the present invention provides use
of an antibody or antigen-binding fragment thereof that binds to
IL-4R in the manufacture of a medicament to treat or inhibit or
prevent active eosinophilic esophagitis in a subject, including
humans.
[0026] In certain embodiments, the present invention provides use
of an IL-4/IL-13 pathway inhibitor in the manufacture of a
medicament to increase esophageal distensibility in a subject,
including humans. In one embodiment, the subject has active EoE. In
one embodiment, the subject has moderate-to-severe EoE.
[0027] In certain embodiments, the present invention provides use
of an antibody or antigen-binding fragment thereof that binds to
IL-4R in the manufacture of a medicament to increase esophageal
distensibility in a subject, including humans. In one embodiment,
the subject has active EoE. In one embodiment, the subject has
moderate-to-severe EoE
[0028] Other embodiments of the present invention will become
apparent from a review of the ensuing detailed description.
BRIEF DESCRIPTION OF THE FIGURES
[0029] FIG. 1 lists the components comprising the weekly
Eosinophilic Esophagitis Severity and Activity Index (EEsAI)
score.
[0030] FIG. 2 shows mean change from baseline in Straumann
Dysphagia Instrument (SDI) scores during the 12-week treatment
period in patients administered once-a-week (qw) 300 mg dupilumab
vs placebo.
[0031] FIG. 3 shows mean percent change from baseline in dysphagia
frequency and severity components of the Straumann Dysphagia
Instrument (SDI) score at week 10 and week 12 upon administration
of once-a-week (qw) 300 mg dupilumab vs placebo.
[0032] FIG. 4 shows the mean percent change from baseline in EEsAI
score during the 12-week treatment period in patients administered
once-a-week (qw) 300 mg dupilumab vs placebo.
[0033] FIG. 5 shows mean percent change from baseline in total EoE
Edema Rings Exudates Furrows and Strictures (EREFS) score as well
as in the subcomponents of the EREFS score at week 12 in patients
administered once-a-week (qw) 300 mg dupilumab vs placebo.
[0034] FIG. 6 shows mean change from baseline in total EoE
Histology Scoring System (HSS) score for the grade (severity)
subcomponent at week 12 in patients administered once-a-week (qw)
300 mg dupilumab vs placebo.
[0035] FIG. 7 shows mean change from baseline in total EoE HSS
score for the stage (extent) subcomponent at week 12 in patients
administered once-a-week (qw) 300 mg dupilumab vs placebo.
[0036] FIG. 8 is made up of FIGS. 8A, 8B, 8C, and 8D. FIG. 8A shows
mean change from baseline in EoE HSS grade scores for basal zone
hyperplasia; FIG. 8B shows mean change from baseline in EoE HSS
grade scores for eosinophil surface layering; FIG. 8C shows mean
change from baseline in EoE HSS grade scores for eosinophil
inflammation; and FIG. 8D shows mean change from baseline in EoE
HSS grade scores for eosinophil abscess in proximal, mid and distal
regions of the esophagus sampled at week 12 from patients
administered once-a-week (qw) 300 mg dupilumab vs placebo.
[0037] FIG. 9 is made up of FIGS. 9A, 9B, 9C, and 9D. FIG. 9A shows
mean change from baseline in EoE HSS stage scores for basal zone
hyperplasia; FIG. 9B shows mean change from baseline in EoE HSS
stage scores for eosinophil abscess;
[0038] FIG. 9C shows mean change from baseline in EoE HSS stage
scores for eosinophil inflammation; and FIG. 9D shows mean change
from baseline in EoE HSS stage scores for eosinophil surface
layering in proximal, mid and distal regions of the esophagus
sampled at week 12 from patients administered once-a-week (qw) 300
mg dupilumab vs placebo.
[0039] FIG. 10 is made up of FIGS. 10A, 10B, and 10C. FIG. 10A
shows mean change from baseline in EoE HSS grade scores for dilated
intercellular spaces; FIG. 10B shows mean change from baseline in
EoE HSS grade scores for surface alteration and
[0040] FIG. 10C shows mean change from baseline in EoE HSS grade
scores for apoptotic epithelial cells in proximal, mid and distal
regions of the esophagus sampled at week 12 from patients
administered once-a-week (qw) 300 mg dupilumab vs placebo.
[0041] FIG. 11 is made up of FIGS. 11A, 11B, and 11C. FIG. 11A
shows mean change from baseline in EoE HSS stage scores for dilated
intercellular spaces; FIG. 11B shows mean change from baseline in
EoE HSS stage scores for surface alteration and FIG. 11C shows mean
change from baseline in EoE HSS stage scores for apoptotic
epithelial cells in proximal, mid and distal regions of the
esophagus sampled at week 12 from patients administered once-a-week
(qw) 300 mg dupilumab vs placebo.
[0042] FIG. 12 shows percent change from baseline in distensibility
plateau at week 12 in patients administered once-a-week (qw) 300 mg
dupilumab vs placebo
DETAILED DESCRIPTION
[0043] Before the present 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, since the
scope of the present invention will be limited only by the appended
claims.
[0044] 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. 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.).
[0045] Although any methods and materials similar or equivalent to
those described herein can be used in the practice of the present
invention, the preferred methods and materials are now described.
All publications mentioned herein are incorporated herein by
reference to describe in their entirety.
[0046] Methods for Treating, Preventing or Ameliorating
Eosinophilic Esophagitis
[0047] The present invention includes methods for treating,
preventing, or ameliorating at least one symptom or indication of
active eosinophilic esophagitis (EoE) in a subject. The methods
according to this aspect of the invention comprise administering a
therapeutically effective amount of a pharmaceutical composition
comprising an IL-4/IL-13 pathway inhibitor to the subject in need
thereof. 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 eosinophilic inflammation in the
esophagus. In certain embodiments, the present methods are useful
for treating or ameliorating at least one symptom or indication of
EoE including, but not limited to, eosinophilic infiltration of the
esophagus, thickening of the esophageal wall, inflammation in the
esophagus, appearance of trachea-like rings or ridges in the
esophagus, chest and abdominal pain, food refusal, vomiting,
dysphagia and food impaction.
[0048] "Eosinophilic Esophagitis" (EoE), as used herein, means an
inflammatory disease characterized by abnormal eosinophilic
inflammation within the esophagus and esophageal dysfunction. The
primary symptoms of EoE include, but are not limited to, chest and
abdominal pain, dysphagia, heartburn, food refusal, vomiting and
food impaction. The clinicopathology of EoE is characterized by
presence of ridges or trachea-like rings in the esophageal wall and
eosinophilic infiltration in the esophageal mucosa. EoE is
diagnosed by endoscopy of the esophagus followed by microscopic and
biochemical analysis of the esophageal mucosal lining. EoE may be
classified as allergic or non-allergic depending upon the status of
the subject. The present invention includes methods to treat both
allergic and non-allergic forms of EoE.
[0049] As used herein, the term "active EoE" refers to the EoE
disease in a patient wherein the patient has eosinophils/high
powered field (hpf) in an esophageal biopsy even after 8 weeks of
treatment with proton pump inhibitors (PPIs). The term also refers
to the EoE disease in patients that exhibit frequent dysphagia,
e.g., the patient has 2, 3, 4, 5, or more episodes of dysphagia per
week. The term "active EoE" includes mild EoE as well as
moderate-to-severe EoE. The term "moderate-to-severe" refers to EoE
disease in patients that in addition to eosinophilia (e.g.,
.gtoreq.15 eosinophils/hpf in the esophageal mucosa) and frequent
episodes of dysphagia, have SDI score .gtoreq.2 and/or EEsAI score
.gtoreq.30 have duration of EoE for at least 2 years, and/or are
non-responsive or resistant to prior therapy (including PPIs or
esophageal dilation).
[0050] As used herein, the expression "a subject in need thereof"
means a human or non-human mammal that exhibits one or more
symptoms or indications of eosinophilic esophagitis, and/or who has
been diagnosed with eosinophilic esophagitis (EoE). Throughout the
present disclosure, the term "subject" is used interchangeably with
the term "patient". The term "a subject in need thereof" may also
include, e.g., patients who, prior to treatment, exhibit (or have
exhibited) one or more indications of EoE such as, e.g., esophageal
overexpression of pro-inflammatory mediators such as mast cells,
eosinophilic infiltration of the esophagus, thickening of the
esophageal wall, dysphagia, food impaction and chest and abdominal
pain and/or an elevated level of a EoE-associated biomarker. The
term specifically includes subjects who show the presence of
.gtoreq.15 eosinophils per high power field in the esophagus. In
certain embodiments, the term also includes subjects with elevated
peripheral eosinophil counts (e.g., .gtoreq.100, .gtoreq.200, or
.gtoreq.300 cells/.mu.l) or elevated serum IgE (>150 kU/L).
[0051] In certain embodiments, the present methods may be used to
treat patients who exhibit pathology and symptoms that are observed
in subjects with chronic esophagitis including in gastroesophageal
reflux disease (GERD). In certain embodiments, the term "a subject
in need thereof" includes subjects that are non-responsive to or
resistant to anti-GERD therapy. For example, the present methods
may be used to treat subjects that are resistant to proton pump
inhibitors (PPI).
[0052] In the context of the present invention, "a subject in need
thereof" may include a subset of population that is more
susceptible to EoE or may show an elevated level of an
EoE-associated biomarker. For example, "a subject in need thereof"
may include a subject suffering from an atopic disease or disorder
such as food allergy, atopic dermatitis, asthma, allergic rhinitis
and allergic conjunctivitis. In certain embodiments, the term "a
subject in need thereof" includes a patient who, prior to or at the
time of administration of the IL-4/IL-13 pathway inhibitor, has or
is diagnosed with a disease or disorder selected from the group
consisting of food allergy, atopic dermatitis, asthma, allergic
rhinitis and allergic conjunctivitis. In certain embodiments, the
term "a subject in need thereof" may include patients with
inherited connective tissue disorders. Such a subject population
may show an elevated level of an EoE-associated biomarker such as,
e.g., IgE, eotaxin-3, periostin, IL-5, or IL-13.
[0053] In certain embodiments, "a subject in need thereof" includes
a patient susceptible to an allergen. For example, "a subject in
need thereof" includes a patient who may exhibit one of the
following characteristics: (a) is prone to allergic reactions or
responses when exposed to one or more allergens; (b) has previously
exhibited an allergic response or reaction to one or more
allergens; (c) has a known history of allergies; and/or (d)
exhibits a sign or symptom of an allergic response or anaphylaxis.
In certain embodiments, the patient is allergic to an allergen
associated with EoE or that renders the subject susceptible and/or
prone to developing EoE.
[0054] The term "allergen," as used herein, includes any substance,
chemical, particle or composition that is capable of stimulating an
allergic response in a susceptible individual. Allergens may be
contained within or derived from a food item such as, e.g., dairy
products (e.g., cow's milk), egg, wheat, soy, corn, rye, fish,
shellfish, peanuts and tree nuts. Alternatively, an allergen may be
contained within or derived from a non-food item such as, e.g.,
dust (e.g., containing dust mite), pollen, insect venom (e.g.,
venom of bees, wasps, mosquitoes, etc.), mold, animal dander,
latex, medication, drugs, ragweed, grass and birch.
[0055] In certain embodiments, the term "a subject in need thereof"
includes a subset of population that exhibits an allergic reaction
to a food allergen. For example, "a subject in need thereof" may
include a subject who has an allergy to an allergen contained in a
food item including, but not limited to, a dairy product, egg,
wheat, soy, corn, rye, fish, shellfish, peanut, a tree nut, beef,
chicken, oat, barley, pork, green beans, and fruits such as apple
and pineapple.
[0056] In certain embodiments, the term includes a subject allergic
to a non-food allergen such as allergens derived from dust, mold,
insects, plants including pollen, and pets such as cats and dogs.
Examples of non-food allergens (also known as environmental
allergens or aeroallergens) include, but are not limited to, house
dust mite allergens, pollen allergens, animal dander allergens,
insect venom, grass allergens, and latex.
[0057] As used herein, the phrases "allergic response," "allergic
reaction," "allergic symptom," and the like, include one or more
signs or symptoms selected from the group consisting of urticaria
(e.g., hives), angioedema, rhinitis, asthma, vomiting, sneezing,
runny nose, sinus inflammation, watery eyes, wheezing,
bronchospasm, reduced peak expiratory flow (PEF), gastrointestinal
distress, flushing, swollen lips, swollen tongue, reduced blood
pressure, anaphylaxis, and organ dysfunction/failure. An "allergic
response," "allergic reaction," "allergic symptom," etc., also
includes immunological responses and reactions such as, e.g.,
increased IgE production, increased allergen-specific
immunoglobulin production and/or eosinophilia.
[0058] In some embodiments, the methods herein are for the
treatment of adults, adolescents or children. An adult is
.gtoreq.18 years of age, an adolescent is .gtoreq.12 and .ltoreq.18
years of age and children are .ltoreq.12 years of age. In some
embodiments, the methods herein may be used to treat EoE in
children who are .ltoreq.3 years old. In one embodiment, an
inhibitor of the IL-4/IL-13 pathway is used to treat moderate-to
severe EoE in subjects that are not adequately controlled with
standard-of-care treatment (e.g., oral corticosteroids, dilation,
etc.) The subject can be an adult, an adolescent or a child.
[0059] The present invention also includes methods to increase
esophageal distensibility. The methods according to this aspect of
the invention comprise administering to the patient in need thereof
one or more doses of a pharmaceutical composition comprising an
IL-4/IL-13 pathway inhibitor, thereby increasing the distensibility
of the esophagus in the patient.
[0060] The present invention also includes methods for reducing
eosinophilic infiltration. The methods according to this aspect of
the invention comprise administering to the patient in need thereof
one or more doses of a pharmaceutical composition comprising an
IL-4/IL-13 pathway inhibitor to reduce or eliminate the number of
eosinophils, e.g., in the esophageal mucosa.
[0061] As used herein, "eosinophilic infiltration" refers to the
presence of eosinophils in an organ or tissue including blood,
esophagus, stomach, duodenum, and ileum of a subject. In the
context of the invention, the term "eosinophilic infiltration"
refers to presence of eosinophils in the mucosal lining of a region
of the gastro-intestinal tract including, but not limited to,
esophagus and stomach. Eosinophilic infiltration is analyzed, for
example, in an esophageal tissue biopsy of a subject suffering from
EoE. According to particular embodiments, "eosinophilic
infiltration" refers to the presence of 15 eosinophils per high
power field in the esophagus. The term "high power field" refers to
a standard total magnification of 400.times. by a microscope used
to view eosinophils in a tissue, e.g., from the esophagus of a
subject. In certain embodiments, "eosinophilic infiltration"
includes infiltration into a tissue by leucocytes, for example,
lymphocytes, neutrophils and mast cells. The leucocyte infiltration
into, e.g., esophageal tissue can be detected by cell surface
markers such as eosinophil-specific markers (e.g.,
CD11c.sup.Low/Neg, SiglecF.sup.+, F4/80.sup.+, EMR1.sup.+, Siglec
8.sup.+, and MBP2.sup.+), macrophage-specific markers (e.g., CD11
b.sup.+, F4/80.sup.+, CD14.sup.+, EMR1.sup.+, and CD68.sup.+),
neutrophil-specific markers (e.g., CD11b.sup.+, Ly6G.sup.+,
Ly6C.sup.+, CD11b.sup.+, and CD66b.sup.+), and T-cell-specific
markers (e.g., CD3.sup.+ CD4.sup.+ CD8.sup.+).
[0062] As used herein, a reduction in esophagus eosinophils means
that the number of eosinophils and other leucocytes measured in the
esophagus of a subject with EoE and who has been treated with an
IL-4/IL-13 pathway inhibitor, is at least 5%, 10%, 20%, 50%, 70%,
80%, or 90% lower than the esophagus eosinophils measured in the
same or an equivalent subject that has not been treated with the
IL-4/IL-13 pathway inhibitor. In certain embodiments, reducing
eosinophilic infiltration means detecting less than 15 eosinophils
per high power field, more preferably less than 10 eosinophils,
less than 9 eosinophils, less than 8 eosinophils, less than 7
eosinophils, less than 6 eosinophils, or less than 5 eosinophils
per high power field in a biopsy of the esophageal mucosa. In
certain embodiments, a reduction in esophagus eosinophils means
that no eosinophils are detected in the esophageal mucosa of a
subject.
[0063] The present invention includes methods for treating,
preventing or reducing the severity of eosinophilic esophagitis
comprising administering a therapeutically effective amount of a
pharmaceutical composition comprising an IL-4/IL-13 pathway
inhibitor to a subject in need thereof, wherein the pharmaceutical
composition is administered to the subject in multiple doses, e.g.,
as part of a specific therapeutic dosing regimen. For example, the
therapeutic dosing regimen may comprise administering multiple
doses of the pharmaceutical composition to the subject at a
frequency of about once a day, once every two days, once every
three days, once every four days, once every five days, once every
six days, once a week, once every two weeks, once every three
weeks, once every four weeks, once a month, once every two months,
once every three months, once every four months, or less
frequently.
[0064] The methods of the present invention, according to certain
embodiments, comprise administering to a subject a therapeutically
effective amount of a pharmaceutical composition comprising an
IL-4/IL-13 pathway inhibitor in combination with a second
therapeutic agent. The second therapeutic agent may be an agent
selected from the group consisting of, e.g., an IL-1 beta
inhibitor, an IL-5 inhibitor, an IL-9 inhibitor, an IL-13
inhibitor, an IL-17 inhibitor, an IL-25 inhibitor, a TNFalpha
inhibitor, an eotaxin-3 inhibitor, an IgE inhibitor, a
prostaglandin D2 inhibitor, an immunosuppressant, a topical
corticosteroid, an oral corticosteroid (e.g., budesonide), a
systemic corticosteroid, an inhaled corticosteroid, a
glucocorticoid, a proton pump inhibitor, a decongestant, an
antihistamine, and a non-steroidal anti-inflammatory drug (NSAID).
In certain embodiments, the IL-4/IL-13 pathway inhibitor of the
invention may be administered in combination with therapy including
esophagus dilation, allergen removal and diet management. As used
herein, the phrase 'in combination with" means that the
pharmaceutical composition comprising an IL-4/IL-13 pathway
inhibitor is administered to the subject at the same time as, just
before, or just after administration of the second therapeutic
agent. In certain embodiments, the second therapeutic agent is
administered as a co-formulation with the IL-4/IL-13 pathway
inhibitor. In a related embodiment, the present invention includes
methods comprising administering a therapeutically effective amount
of a pharmaceutical composition comprising an IL-4/IL-13 pathway
inhibitor to a subject who is on a background anti-allergy
therapeutic regimen. The background anti-allergy therapeutic
regimen may comprise a course of administration of, e.g., steroids,
antihistamines, decongestants, anti-IgE agents, etc. The IL-4/IL-13
pathway inhibitor (e.g., an anti-IL-4R antibody) may be added on
top of the background anti-allergy therapeutic regimen. In some
embodiments, the IL-4/IL-13 pathway inhibitor is added as part of a
"background step-down" scheme, wherein the background anti-allergy
therapy is gradually withdrawn from the subject over time (e.g., in
a stepwise fashion) while the IL-4/IL-13 pathway inhibitor is
administered the subject at a constant dose, or at an increasing
dose, or at a decreasing dose, over time. In certain embodiments,
the IL-4/IL-13 pathway inhibitor is administered as a
monotherapy.
Eosinophilic Esophagitis-Associated Biomarkers
[0065] The present invention also includes methods involving the
use, quantification, and analysis of EoE-associated biomarkers. As
used herein, the term "EoE-associated biomarker" means any
biological response, cell type, parameter, protein, polypeptide,
enzyme, enzyme activity, metabolite, nucleic acid, carbohydrate, or
other biomolecule which is present or detectable in an EoE patient
at a level or amount that is different from (e.g., greater than or
less than) the level or amount of the marker present or detectable
in a non-EoE patient. Exemplary EoE-associated biomarkers include,
but are not limited to, e.g., esophagus eosinophils, eotaxin-3
(CCL26), periostin, serum IgE (total and allergen-specific), serum
IgG (total and allergen-specific), IL-13, IL-5, serum thymus and
activation regulated chemokine (TARC; CCL17), thymic stromal
lymphopoietin (TSLP), serum eosinophilic cationic protein (ECP),
calpain 14, filaggrin (FLG), signal transducer and activator of
transcription 6 (STATE), interleukin 4 receptor (IL-4R), and
eosinophil-derived neurotoxin (EDN). The term "EoE-associated
biomarker" also includes a gene or gene probe known in the art that
is differentially expressed in a subject with EoE as compared to a
subject without EoE. For example, genes which are significantly
up-regulated in a subject with EoE include, but are not limited to,
T-helper 2 (Th2)-associated chemokines such as CCL8, CCL23 and
CCL26, periostin, cadherin-like-26, and TNF.alpha.-induced protein
6 (Blanchard et al 2006, J. Clin. Invest. 116: 536-547).
Alternatively, "EoE-associated biomarker" also includes genes that
are down regulated due to EoE such as terminal differentiation
proteins (e.g., filaggrin) (Blanchard et al 2006, J. Clin. Invest.
116: 536-547). Certain embodiments of the invention relate to use
of these biomarkers for monitoring disease reversal with the
administration of the IL-4/IL-13 pathway inhibitor. Methods for
detecting and/or quantifying such EoE-associated biomarkers are
known in the art; kits for measuring such EoE-associated biomarkers
are available from various commercial sources; and various
commercial diagnostic laboratories offer services which provide
measurements of such biomarkers as well.
[0066] According to certain aspects of the invention, methods for
treating EoE are provided which comprise: (a) selecting a subject
who exhibits a level of at least one EoE-associated biomarker prior
to or at the time of treatment which signifies the disease state;
and (b) administering to the subject a pharmaceutical composition
comprising a therapeutically effective amount of an IL-4/IL-13
pathway inhibitor. In certain embodiments of this aspect of the
invention, the subject is selected on the basis of an elevated
level of IgE or eotaxin-3.
[0067] According to other aspects of the invention, methods for
treating EoE are provided which comprise administering to a subject
a pharmaceutical composition comprising a therapeutically effective
amount of an IL-4/IL-13 pathway inhibitor, wherein administration
of the pharmaceutical composition to the subject results in a
decrease in at least one EoE-associated biomarker (e.g., esophagus
eosinophils, eotaxin-3, IgE, etc.) at a time after administration
of the pharmaceutical composition, as compared to the level of the
biomarker in the subject prior to the administration.
[0068] As will be appreciated by a person of ordinary skill in the
art, an increase or decrease in an EoE-associated biomarker can be
determined by comparing (i) the level of the biomarker measured in
a subject at a defined time point after administration of the
pharmaceutical composition comprising an IL-4/IL-13 pathway
inhibitor to (ii) the level of the biomarker measured in the
patient prior to the administration of the pharmaceutical
composition comprising an IL-4/IL-13 pathway inhibitor (i.e., the
"baseline measurement"). The defined time point at which the
biomarker is measured can be, e.g., at about 4 hours, 8 hours, 12
hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8
days, 9 days, 10 days, 15 days, 20 days, 35 days, 40 days, 50 days,
55 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, or
more after administration of the of the pharmaceutical composition
comprising an IL-4/IL-13 pathway inhibitor.
[0069] According to certain embodiments of the present invention, a
subject may exhibit a decrease in the level of one or more of IgE
and/or eotaxin-3 following administration of a pharmaceutical
composition comprising an IL-4/IL-13 pathway inhibitor (e.g., an
anti-IL-4R antibody). For example, at about day 1, day 4, day 8,
day 15, day 22, day 25, day 29, day 36, day 43, day 50, day 57, day
64, day 71 or day 85, following administration of a first, second,
third or fourth dose of a pharmaceutical composition comprising
about 75 mg to about 600 mg of an anti-IL-4R antibody (e.g.,
dupilumab), the subject, according to the present invention, may
exhibit a decrease in eotaxin-3 of about 1%, 2%, 5%, 10%, 15%, 20%,
25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,
90%, 95% or more from baseline (wherein "baseline" is defined as
the level of eotaxin-3 in the subject just prior to the first
administration). Similarly, at about day 1, day 4, day 8, day 15,
day 22, day 25, day 29, day 36, day 43, day 50, day 57, day 64, day
71 or day 85, following administration of a first, second, third or
fourth dose of a pharmaceutical composition comprising about 75 mg
to about 600 mg of an anti-IL-4R antibody (e.g., dupilumab), the
subject, according to the present invention, may exhibit a decrease
in IgE of about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,
50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more from
baseline (wherein "baseline" is defined as the level of IgE in the
subject just prior to the first administration).
[0070] The present invention also includes methods for determining
whether a subject is a suitable subject for whom administration of
a pharmaceutical composition comprising an IL-4/IL-13 pathway
antagonist would be beneficial. For example, if an individual,
prior to receiving a pharmaceutical composition comprising an
IL-4/IL-13 pathway antagonist, exhibits a level of an
EoE-associated biomarker that signifies the disease state, the
individual is therefore identified as a suitable patient for whom
administration of a pharmaceutical composition of the invention (a
composition comprising an anti-IL-4R antibody) would be beneficial.
In related embodiments, the present invention includes methods for
treating suitable subjects, wherein a suitable subject may be more
susceptible to EoE, for example, due to food allergy, or an atopic
disease. For example, the present invention includes methods
comprising administering an IL-4/IL-13 pathway antagonist to
subjects who have food allergy, atopic dermatitis, asthma, allergic
rhinitis or allergic conjunctivitis. In another example, the
present invention includes methods comprising administering an
IL-4/IL-13 pathway antagonist to subjects who have,
Mendelian-inherited connective tissue disorders, e.g., Marfan
syndrome, Loeys-Dietz syndrome, hypermobile Ehlers Danlos syndrome
(EDS) or joint hypermobility syndrome (JHS). Such subject
populations may have an elevated level of an EoE-associated
biomarker.
[0071] According to certain exemplary embodiments, an individual
may be identified as a good candidate for anti-IL-4/IL-13 therapy
if the individual exhibits one or more of the following: (i) an
eotaxin-3 level greater than about 30 pg/ml, greater than about 40
pg/ml, greater than about 50 pg/ml, greater than about 100 pg/ml,
greater than about 1500 pg/ml, greater than about 200 pg/ml,
greater than about 250 pg/ml, greater than about 300 pg/ml, greater
than about 350 pg/ml, greater than about 400 pg/ml, greater than
about 450 pg/ml, or greater than about 500 pg/ml; or (ii) a serum
IgE level greater than about 114 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; or (iii) 15 eosinophils per
high power field in the esophagus of the subject. Additional
criteria, such as other clinical indicators of EoE (e.g.,
dysphagia, thickening of the esophageal wall, and food allergy
indicative of EoE), may be used in combination with any of the
foregoing EoE-associated biomarkers to identify an individual as a
suitable candidate for anti-IL-4/IL-13 therapy as described
elsewhere herein.
Eosinophilic Esophagitis-Related Parameters
[0072] The present invention includes methods for improving one or
more eosinophilic esophagitis (EoE)-related parameters in a subject
in need thereof, wherein the methods comprise administering a
pharmaceutical composition comprising an IL-4/IL-13 pathway
inhibitor to the subject.
[0073] Examples of "EoE-related parameters" include: (a) Straumann
Dysphagia Instrument (SDI); (b) Eosinophilic Esophagitis Activity
Index (EEsAI); (c) Eosinophilic Esophagitis Edema Rings Exudates
Furrows and Strictures (EoE-EREFS); (d) Eosinophilic Esophagitis
Histological Scoring System (EoE-HSS) (e) Esophageal
intraepithelial eosinophils; and (f) Esophageal distensibility. An
"improvement in an EoE-related parameter" means a decrease from
baseline of one or more of SDI, EEsAI, EoE-EREFS, EoE-HSS, or
esophageal intraepithelial eosinophils. An improvement in
esophageal distensibility means an increase from the baseline. As
used herein, the term "baseline," with regard to an EoE-related
parameter, means the numerical value of the EoE-related parameter
for a subject prior to or at the time of administration of a
pharmaceutical composition of the present invention.
[0074] To determine whether an EoE-related parameter has
"improved," the parameter is quantified at baseline and at one or
more time-points after administration of the pharmaceutical
composition of the present invention. For example, an EoE-related
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, day 15, day
22, day 25, day 29, day 36, day 43, day 50, day 57, day 64, day 71,
day 85; or at the end of week 1, week 2, 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 a pharmaceutical composition of the present
invention. 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" (e.g., a decrease) in the
EoE-related parameter.
[0075] Straumann Dysphagia Instrument (SDI). The SDI is a
non-validated patient reported outcome (PRO) that has been used in
clinical studies to determine the frequency and intensity of
dysphagia (Straumann 2010). The SDI has a 1-week recall period.
Frequency of dysphagia events is graded on a 5-point scale: 0=none,
1=once per week, 2=several times per week, 3=once per day, and
4=several times per day, and intensity of dysphagia events is
graded on a 6-point scale: 0=swallowing unrestricted, 1=slight
sensation of resistance, 2=slight retching with delayed passage,
3=short period of obstruction necessitating intervention (e.g.,
drinking, breathing), 4=longer-lasting period obstruction only
removable by vomiting, and 5=long-lasting complete obstruction
requiring endoscopic intervention. The total SDI score ranges from
0 to 9. According to certain embodiments of the present invention,
administration of an IL-4/IL-13 pathway inhibitor to a patient
results in a decrease in SDI score of 3 points from the baseline.
For example, the present invention includes therapeutic methods
that result in a decrease from baseline in SDI score of decrease of
1, 2, 3, 4, 5, 6 or more points from baseline in SDI. In certain
exemplary embodiments, administration of an IL-4/IL-13 pathway
inhibitor to a patient results in a decrease at least about 10%,
15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more at day 4, 8, 15,
22, 25, 29, 36, 43, 50, 57, 64, 71, 85 or later following
administration of the IL-4/IL-13 pathway inhibitor (e.g., following
subcutaneous administration of about 300 mg of an anti-IL-4R
antibody or antigen-binding fragment thereof). In certain exemplary
embodiments of the present invention, administration of an
IL-4/IL-13 pathway inhibitor to a subject results in a decrease
from baseline in SDI of at least 40%.
[0076] Eosinophilic Esophagitis Activity Index (EEsAI).
[0077] The EEsAI is a non-validated, multimodular index in
development at University Hospital Inselspital (Berne, Switzerland)
(Schoepfer 2014), a part of the international EEsAI study group.
The EEsAI PRO module (questionnaire) used in this study includes
items related to the intensity and frequency of dysphagia, the
influence of specific food groups on dysphagia symptoms, and other
symptoms independent of eating or drinking (i.e., heartburn, acid
regurgitation, and chest pain). The total EEsAI PRO score ranges
from 0 to 100 (FIG. 1), wherein higher scores indicate worse
symptoms. The score consists of 5 parts: frequency of trouble
swallowing, duration of trouble swallowing, pain when swallowing,
visual dysphagia question, and avoidance, modification and slow
eating (AMS). According to certain embodiments of the present
invention, administration of an IL-4/IL-13 pathway inhibitor to a
patient results in a decrease in EEsAI score. For example, the
present invention includes therapeutic methods which result in a
decrease from baseline in EEsAI score of at least about 5%, 10%,
15%, 20%, 25%, 30%, 35%, or more at day 4, 8, 15, 22, 25, 29, 36,
43, 50, 57, 64, 71, 85 or later following administration of the
IL-4/IL-13 pathway inhibitor (e.g., following subcutaneous
administration of about 300 mg of an anti-IL-4R antibody or
antigen-binding fragment thereof). In certain exemplary embodiments
of the present invention, administration of an IL-4/IL-13 pathway
inhibitor to a subject results in a decrease from baseline in EEsAI
score of at least 30% after administration.
[0078] Eosinophilic Esophagitis Edema Rings Exudates Furrows and
Strictures (EoE-EREFS).
[0079] The EoE-EREFS (edema, rings, exudates, furrows, strictures)
is used to measure the endoscopically identified EoE esophageal
mucosal inflammatory and remodeling features. This instrument
includes a total of 17 items related to the presence and severity
of esophageal features. The specific esophageal features include:
rings (concentric rings around esophagus--absent, mild, moderate,
severe, not applicable); strictures (narrowing of the
esophagus--yes, no, not applicable); diameter of the stricture (if
applicable); exudates (refer to white plaques--absent, mild,
severe), furrows (vertical lines down the esophagus--absent,
present); edema (loss of vascular markings of the mucosa--absent,
present); cr pe paper esophagus (absent, present); overall general
appearance incorporating all endoscopically identified EoE findings
(i.e., fixed rings, strictures, whitish exudates, furrowing, edema,
and cr pe paper mucosa). In addition, mucosal changes associated
with gastroesophageal reflux disease are recorded using the Los
Angeles classification system for erosions (No Erosions or LA
Classification A, B, C, D). The EoE esophageal characteristics are
analyzed based on the EoE-EREFS, a validated scoring system for
inflammatory and remodeling features of disease using both overall
scores and scores for each individual characteristic (Hirano 2014).
According to certain embodiments of the present invention,
administration of an IL-4/IL-13 pathway inhibitor to a patient
results in a decrease in EoE-EREFS score. For example, the present
invention includes therapeutic methods which result in a decrease
from baseline in EREFS score of at least about 10%, 15%, 20%, 25%,
30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more at day 4,
8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85 or later following
administration of the IL-4/IL-13 pathway inhibitor (e.g., following
subcutaneous administration of about 300 mg of an anti-IL-4R
antibody or antigen-binding fragment thereof).
[0080] Eosinophilic Esophagitis Histological Scoring System
(EoE-HSS).
[0081] The EoE-HSS generate separate severity (grade) and extent
(stage) disease scores. The score is used to measure 8 histologic
features (parameters) of EoE from 3 different regions (proximal,
mid and distal) of the esophagus (Collins et al 2017). The 8
parameters include: eosinophil density, basal zone hyperplasia,
eosinophil abscesses, eosinophil surface layering, dilated
intercellular spaces, surface epithelial alteration, dyskeratotic
cells, and lamina propria fibrosis. A scale of 0-3 is used for each
parameter, both grade and stage (0 being least inflamed, normal).
According to certain embodiments of the present invention,
administration of an IL-4/IL-13 pathway inhibitor to a patient
results in a decrease in EoE-HSS score. For example, the present
invention includes therapeutic methods which result in a decrease
from baseline in EoE-HSS of at least about 10%, 15%, 20%, 25%, 30%,
35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more at day 4, 8,
15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85 or later following
administration of the IL-4/IL-13 pathway inhibitor (e.g., following
subcutaneous administration of about 300 mg of an anti-IL-4R
antibody or antigen-binding fragment thereof). In certain exemplary
embodiments of the present invention, administration of an
IL-4/IL-13 pathway inhibitor to a subject results in a decrease
from baseline in EoE-HSS score of at least 50%.
[0082] Esophageal Intraepithelial Eosinophils.
[0083] It refers to eosinophils per high powered field (hpf) in
esophageal biopsies. Peak intraepithelial eosinophils refers to
eosinophils per high powered field in at least 2 of 3 esophageal
regions sampled. According to certain embodiments of the present
invention, administration of an IL-4/IL-13 pathway inhibitor to a
patient results in a decrease in peak intraepithelial eosinophils.
For example, the present invention includes therapeutic methods
which result in a decrease from baseline in intraepithelial
eosinophils of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%,
45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or more at day 4, 8,
15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85 or later following
administration of the IL-4/IL-13 pathway inhibitor (e.g., following
subcutaneous administration of about 300 mg of an anti-IL-4R
antibody or antigen-binding fragment thereof). In certain exemplary
embodiments of the present invention, administration of an
IL-4/IL-13 pathway inhibitor to a subject results in a decrease
from baseline in intraepithelial eosinophils of at least 85%.
[0084] Esophageal Distensibility.
[0085] Esophageal distensibility is assessed by using the
endoluminal functional lumen imaging probe (EndoFLIP, Crospon,
Ireland) to measure the diameter of the esophageal lumen and
pressure. The EndoFLIP device is a catheter based procedure that
measures the cross sectional area at multiple sites along the
esophagus with simultaneous intraluminal pressure recordings during
volumetric distension of the esophagus. The analyses of cross
sectional area versus pressure relationships of the esophagus allow
for determination of esophageal compliance as well as the
distensibility plateau (DP). The DP has been shown to be
significantly reduced in patients with EoE compared to healthy
controls (Kwiatek 2011). According to certain embodiments of the
present invention, administration of an IL-4/IL-13 pathway
inhibitor to a patient results in an increase in esophageal
distensibility. For example, the present invention includes
therapeutic methods which result in an increase from baseline in
esophageal distensibility of at least about 5%, 10%, 15%, 20%, 25%
or more at the end of week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
or later following administration of the IL-4/IL-13 pathway
inhibitor (e.g., following subcutaneous administration of about 300
mg of an anti-IL-4R antibody or antigen-binding fragment thereof).
In certain exemplary embodiments of the present invention,
administration of an IL-4/IL-13 pathway inhibitor to a subject
results in an increase from baseline in esophageal distensibility
of at least 10%, as measured by impedance planimetry.
[0086] Adult Eosinophilic Esophagitis Quality of Life (EoE-QoL-A)
Questionnaire.
[0087] The EoE-QOL-A questionnaire is a validated disease-specific
measure of health-related quality of life in EoE patients (Taft
2011). The instrument used in this study, the EoE-QOL-A v.3.0,
includes 30 items related to established domains such as social
functioning, emotional functioning, and disease impact of daily
life experiences. The EoE-QOL-A has a 1-week recall period. The
items are graded on a 5-point scale: `Not at All,` `Slightly,`
`Moderately,` `Quite a bit,` and `Extremely`. According to certain
embodiments, administration of an IL-4/IL-13 pathway inhibitor to a
patient results in an increase in quality of life parameters in the
patient.
IL-4/IL-13 Pathway Inhibitors
[0088] The methods of the present invention comprise administering
to a subject in need thereof a therapeutic composition comprising
an IL-4/IL-13 pathway inhibitor.
[0089] As used herein, an "IL-4/IL-13 pathway inhibitor" (also
referred to herein as an "IL-4/IL-13 pathway antagonist," an
"IL-4/IL-13 pathway blocker," etc.) is any agent that inhibits or
attenuates at least one of: (i) the binding of IL-4 and/or IL-13 to
their respective receptors; (ii) signaling and/or activity of IL-4
and/or IL-13; and/or (iii) the downstream signaling/activity that
results from binding of IL-4 and/or IL-13 to their respective
receptors. Exemplary IL-4/IL-13 pathway inhibitors include, but are
not limited to, anti-IL-4 antibodies (e.g., the antibodies
disclosed in U.S. Pat. No. 7,740,843, and U.S. Patent Application
Publications 20100297110, 20160207995), anti-IL-13 antibodies
(e.g., the antibodies disclosed in U.S. Pat. Nos. 7,501,121,
7,674,459, 7,807,788, 7,910,708, 7,915,388, 7,935,343, 8,088,618,
8,691,233, 9,605,065, U.S. Patent Application Publications
20060073148, 20080044420, and EP2627673B1), bispecific antibodies
that bind to IL-4 and IL-13 (e.g., the antibodies disclosed in U.S.
Pat. No. 8,388,965, U.S. Patent Application Publications
20110008345, 20130251718, 20160207995), and IL-4 receptor (IL-4R)
inhibitors (described below).
[0090] As used herein, an "IL-4R inhibitor" (also referred to
herein as an "IL-4/IL-13 pathway inhibitor," an "IL-4R.alpha.
antagonist," an "IL-4R blocker," an "IL-4R.alpha. blocker," etc.)
is any agent that binds to or interacts with IL-4R.alpha. or an
IL-4R ligand, and inhibits or attenuates the normal biological
signaling function a type 1 and/or a type 2 IL-4 receptor. Human
IL-4R.alpha. has the amino acid sequence of SEQ ID NO: 11. A type 1
IL-4 receptor is a dimeric receptor comprising an IL-4R.alpha.
chain and a .gamma.c chain. A type 2 IL-4 receptor is a dimeric
receptor comprising an IL-4R.alpha. chain and an IL-13R.alpha.1
chain. Type 1 IL-4 receptors interact with and are stimulated by
IL-4, while type 2 IL-4 receptors interact with and are stimulated
by both IL-4 and IL-13. Thus, the IL-4R inhibitors that can be used
in the methods of the present invention may function by blocking
IL-4-mediated signaling, IL-13-mediated signaling, or both IL-4-
and IL-13-mediated signaling. The IL-4R inhibitors of the present
invention may thus prevent the interaction of IL-4 and/or IL-13
with a type 1 or type 2 receptor.
[0091] Non-limiting examples of categories of IL-4R inhibitors
include IL-4 muteins (e.g., pitrakinra), small molecule IL-4R
inhibitors, anti-IL-4R aptamers, peptide-based IL-4R inhibitors
(e.g., "peptibody" molecules), "receptor-bodies" (e.g., engineered
molecules comprising the ligand-binding domain of an IL-4R
component), and antibodies or antigen-binding fragments of
antibodies that specifically bind human IL-4R.alpha.. As used
herein, IL-4R inhibitors also include antigen-binding proteins that
specifically bind IL-4 and/or IL-13.
Anti-IL-4R.alpha. Antibodies and Antigen-Binding Fragments
Thereof
[0092] According to certain exemplary embodiments of the present
invention, the IL-4/IL-13 pathway inhibitor is an anti-IL-4R.alpha.
antibody or antigen-binding fragment thereof. The term "antibody,"
as used herein, includes 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). In a typical antibody, 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 of the invention, 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.
[0093] The term "antibody," as used herein, 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 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.
[0094] 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," as used
herein.
[0095] 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.
[0096] 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 of the present
invention 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 which result in a flexible or semi-flexible
linkage between adjacent variable and/or constant domains in a
single polypeptide molecule. Moreover, an antigen-binding fragment
of an antibody of the present invention 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)).
[0097] The term "antibody," as used herein, also includes
multispecific (e.g., bispecific) antibodies. A multispecific
antibody or 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 antibody or antigen-binding fragment of an antibody of the
present invention using routine techniques available in the art.
For example, the present invention includes methods comprising the
use of bispecific antibodies wherein one arm of an immunoglobulin
is specific for IL-4R.alpha. or a fragment thereof, and the other
arm of the immunoglobulin is specific for a second therapeutic
target or is conjugated to a therapeutic moiety. Exemplary
bispecific formats that can be used in the context of the present
invention include, without limitation, e.g., scFv-based or diabody
bispecific formats, IgG-scFv fusions, dual variable domain
(DVD)-Ig, Quadroma, knobs-into-holes, common light chain (e.g.,
common light chain with knobs-into-holes, etc.), CrossMab,
CrossFab, (SEED) body, leucine zipper, Duobody, IgG1/IgG2, dual
acting Fab (DAF)-IgG, and Mabe.sup.2 bispecific formats (see, e.g.,
Klein et al. 2012, mAbs 4:6, 1-11, and references cited therein,
for a review of the foregoing formats). Bispecific antibodies can
also be constructed using peptide/nucleic acid conjugation, e.g.,
wherein unnatural amino acids with orthogonal chemical reactivity
are used to generate site-specific antibody-oligonucleotide
conjugates which then self-assemble into multimeric complexes with
defined composition, valency and geometry. (See, e.g., Kazane et
al., J. Am. Chem. Soc. [Epub: Dec. 4, 2012]).
[0098] The antibodies used in the methods of the present invention
may be human antibodies. The term "human antibody," as used herein,
is intended to include antibodies having variable and constant
regions derived from human germline immunoglobulin sequences. The
human antibodies of 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," as used herein, is not intended to 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.
[0099] The antibodies used in the methods of the present invention
may be recombinant human antibodies. The term "recombinant human
antibody," as used herein, is intended to include 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.
[0100] According to certain embodiments, the antibodies used in the
methods of the present invention specifically bind IL-4R.alpha..
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.alpha., as used in the
context of the present invention, includes antibodies that bind
IL-4R.alpha. or portion thereof with a K.sub.D of 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.alpha. may, however, have cross-reactivity to other antigens,
such as IL-4R.alpha. molecules from other (non-human) species.
[0101] According to certain exemplary embodiments of the present
invention, the IL-4/IL-13 pathway inhibitor is an anti-IL-4R.alpha.
antibody, or antigen-binding fragment thereof comprising a heavy
chain variable region (HCVR), light chain variable region (LCVR),
and/or complementarity determining regions (CDRs) comprising any of
the amino acid sequences of the anti-IL-4R antibodies as set forth
in U.S. Pat. No. 7,608,693. In certain exemplary embodiments, the
anti-IL-4R.alpha. antibody or antigen-binding fragment thereof that
can be used in the context of the methods of the present invention
comprises the heavy chain complementarity determining regions
(HCDRs) of a heavy chain variable region (HCVR) comprising the
amino acid sequence of SEQ ID NO: 1 and the light chain
complementarity determining regions (LCDRs) of a light chain
variable region (LCVR) comprising the amino acid sequence of SEQ ID
NO: 2. According to certain embodiments, the anti-IL-4R.alpha.
antibody or antigen-binding fragment thereof comprises three HCDRs
(HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3),
wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:
3; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; the
HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; the LCDR1
comprises the amino acid sequence of SEQ ID NO: 6; the LCDR2
comprises the amino acid sequence of SEQ ID NO: 7; and the LCDR3
comprises the amino acid sequence of SEQ ID NO: 8. In yet other
embodiments, the anti-IL-4R antibody or antigen-binding fragment
thereof comprises an HCVR comprising SEQ ID NO: 1 and an LCVR
comprising SEQ ID NO: 2. In certain embodiments, the methods of the
present invention comprise the use of an anti-IL-4R antibody,
wherein the antibody comprises a heavy chain comprising the amino
acid sequence of SEQ ID NO: 9. In some embodiments, the anti-IL-4R
antibody comprises a light chain comprising the amino acid sequence
of SEQ ID NO: 10. An exemplary antibody comprising a heavy chain
comprising the amino acid sequence of SEQ ID NO: 9 and a light
chain comprising the amino acid sequence of SEQ ID NO: 10 is the
fully human anti-IL-4R antibody known as dupilumab. According to
certain exemplary embodiments, the methods of the present invention
comprise the use of dupilumab, or a bioequivalent thereof. The term
"bioequivalent", as used herein, refers to anti-IL-4R antibodies or
IL-4R-binding proteins or fragments thereof that are pharmaceutical
equivalents or pharmaceutical alternatives whose rate and/or extent
of absorption do not show a significant difference with that of
dupilumab when administered at the same molar dose under similar
experimental conditions, either single dose or multiple dose. In
the context of the invention, the term refers to antigen-binding
proteins that bind to IL-4R which do not have clinically meaningful
differences with dupilumab in their safety, purity and/or
potency.
[0102] Other anti-IL-4R.alpha. antibodies that can be used in the
context of the methods of the present invention include, e.g., the
antibody referred to and known in the art as AMG317 (Corren et al.,
2010, Am J Respir Crit Care Med., 181(8):788-796), or MEDI 9314, or
any of the anti-IL-4R.alpha. antibodies as set forth in U.S. Pat.
Nos. 7,186,809, 7,605,237, 7,638,606, 8,092,804, 8,679,487, or U.S.
Pat. No. 8,877,189.
[0103] The anti-IL-4R.alpha. antibodies used in the context of the
methods of the present invention may have pH-dependent binding
characteristics. For example, an anti-IL-4R.alpha. antibody for use
in the methods of the present invention may exhibit reduced binding
to IL-4R.alpha. at acidic pH as compared to neutral pH.
Alternatively, an anti-IL-4R.alpha. antibody of the invention may
exhibit enhanced binding to its antigen at acidic pH as compared to
neutral pH. The expression "acidic pH" includes pH values less than
about 6.2, e.g., about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65,
5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05,
5.0, or less. As used herein, the expression "neutral pH" means a
pH of about 7.0 to about 7.4. The expression "neutral pH" includes
pH values of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35, and
7.4.
[0104] In certain instances, "reduced binding to IL-4R.alpha. at
acidic pH as compared to neutral pH" is expressed in terms of a
ratio of the K.sub.D value of the antibody binding to IL-4R.alpha.
at acidic pH to the K.sub.D value of the antibody binding to
IL-4R.alpha. at neutral pH (or vice versa). For example, an
antibody or antigen-binding fragment thereof may be regarded as
exhibiting "reduced binding to IL-4R.alpha. at acidic pH as
compared to neutral pH" for purposes of the present invention if
the antibody or antigen-binding fragment thereof exhibits an
acidic/neutral K.sub.D ratio of about 3.0 or greater. In certain
exemplary embodiments, the acidic/neutral K.sub.D ratio for an
antibody or antigen-binding fragment of the present invention can
be about 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0,
8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5,
14.0, 14.5, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0,
or greater.
[0105] Antibodies with pH-dependent binding characteristics may be
obtained, e.g., by screening a population of antibodies for reduced
(or enhanced) binding to a particular antigen at acidic pH as
compared to neutral pH. Additionally, modifications of the
antigen-binding domain at the amino acid level may yield antibodies
with pH-dependent characteristics. For example, by substituting one
or more amino acids of an antigen-binding domain (e.g., within a
CDR) with a histidine residue, an antibody with reduced
antigen-binding at acidic pH relative to neutral pH may be
obtained. As used herein, the expression "acidic pH" means a pH of
6.0 or less.
Pharmaceutical Compositions
[0106] The present invention includes methods that comprise
administering an IL-4/IL-13 pathway inhibitor to a subject wherein
the IL-4/IL-13 pathway inhibitor is contained within a
pharmaceutical composition. The pharmaceutical compositions of the
invention may be 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.
[0107] Various delivery systems are known and can be used to
administer the pharmaceutical composition of 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, 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.
[0108] A pharmaceutical composition of the present invention can be
delivered subcutaneously or intravenously with a standard needle
and syringe. In addition, with respect to subcutaneous delivery, a
pen delivery device readily has applications in delivering a
pharmaceutical composition of the present 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.
[0109] In certain situations, the pharmaceutical composition can be
delivered in a controlled release system. In one embodiment, a pump
may be used. 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.
[0110] 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 preferably filled in an appropriate
ampoule.
[0111] 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.
[0112] Exemplary pharmaceutical compositions comprising an
anti-IL-4R antibody that can be used in the context of the present
invention are disclosed, e.g., in U.S. Pat. No. 8,945,559.
Administration Regimens
[0113] The present invention includes methods comprising
administering to a subject an IL-4/IL-13 pathway inhibitor at a
dosing frequency of about four times a week, twice a week, once a
week, once every two weeks, once every three weeks, once every four
weeks, once every five weeks, once every six weeks, once every
eight weeks, once every twelve weeks, or less frequently so long as
a therapeutic response is achieved. In certain embodiments
involving the administration of an IL-4/IL-13 pathway inhibitor
(e.g., an anti-IL-4R antibody), once a week dosing at an amount of
about 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 300 mg, is employed.
In certain embodiments involving the administration of an
anti-IL-4R antibody, once in 2 weeks dosing at an amount of about
25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 300 mg, is employed.
[0114] According to certain embodiments of the present invention,
multiple doses of an IL-4/IL-13 pathway inhibitor may be
administered to a subject over a defined time course. The methods
according to this aspect of the invention comprise sequentially
administering to a subject multiple doses of an IL-4/IL-13 pathway
inhibitor. As used herein, "sequentially administering" means that
each dose of IL-4/IL-13 pathway inhibitor 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 present invention includes methods that comprise
sequentially administering to the patient a single initial dose of
an IL-4/IL-13 pathway inhibitor, followed by one or more secondary
doses of the IL-4/IL-13 pathway inhibitor, and optionally followed
by one or more tertiary doses of the IL-4/IL-13 pathway
inhibitor.
[0115] The terms "initial dose," "secondary doses," and "tertiary
doses," refer to the temporal sequence of administration of the
IL-4/IL-13 pathway inhibitor. 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-4/IL-13 pathway inhibitor, but
generally may differ from one another in terms of frequency of
administration. In certain embodiments, however, the amount of
IL-4/IL-13 pathway inhibitor 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, the initial dose comprises a first amount of the
antibody or antigen-binding fragment thereof and the one or more
secondary doses each comprise a second amount of the antibody or
antigen-binding fragment thereof. In some embodiments, the first
amount of antibody or fragment thereof (initial dose) is
1.5.times., 2.times., 2.5.times., 3.times., 3.5.times., 4.times.,
or 5.times. the second amount of the antibody or antigen-binding
fragment thereof (secondary dose). In certain embodiments, one or
more (e.g., 1, 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"). For example, an IL-4/IL-13 pathway
inhibitor may be administered to a patient in need thereof at a
loading dose of about 300 mg to about 600 mg followed by one or
more maintenance doses of about 25 mg to about 400 mg. In one
embodiment, the initial dose and the one or more secondary doses
each include 10 mg to 600 mg of the IL-4/IL-13 pathway inhibitor,
e.g., 100 mg to 400 mg of the IL-4/IL-13 pathway inhibitor, e.g.,
10 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg
or 500 mg of the IL-4/IL-13 pathway inhibitor. In one embodiment,
the initial dose is 2.times. the secondary dose.
[0116] In one exemplary embodiment of the present invention, each
secondary and/or tertiary dose is administered 1 to 14 (e.g., 1,
11/2, 2, 21/2, 3, 31/2, 4, 41/2, 5, 51/2, 6, 61/2, 7, 71/2, 8,
81/2, 9, 91/2, 10, 101/2, 11, 111/2, 12, 121/2, 13, 131/2, 14,
141/2, or more) weeks after the immediately preceding dose. The
phrase "the immediately preceding dose," as used herein, means, in
a sequence of multiple administrations, the dose of IL-4/IL-13
pathway inhibitor that is administered to a patient prior to the
administration of the very next dose in the sequence with no
intervening doses.
[0117] The methods according to this aspect of the invention may
comprise administering to a patient any number of secondary and/or
tertiary doses of an IL-4/IL-13 pathway inhibitor. 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.
[0118] 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 6 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 regimen.
[0119] The methods of the present invention, according to certain
embodiments, comprise administering to the subject a corticosteroid
(CS) in combination with an IL-4/IL-13 pathway inhibitor (e.g., an
anti-IL-4R antibody). As used herein, the expression "in
combination with" means that the CS is administered before, after,
or concurrent with the IL-4/IL-13 pathway inhibitor. The term "in
combination with" also includes sequential or concomitant
administration of IL-4/IL-13 pathway inhibitor and CS.
[0120] For example, when administered "before" the IL-4/IL-13
pathway inhibitor, the CS may be administered more than 72 hours,
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 IL-4/IL-13 pathway inhibitor. When
administered "after" the IL-4/IL-13 pathway inhibitor, the CS 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, about 72 hours, or
more than 72 hours after the administration of the IL-4/IL-13
pathway inhibitor. Administration "concurrent" with the IL-4/IL-13
pathway inhibitor means that the CS 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 IL-4/IL-13
pathway inhibitor, or administered to the subject as a single
combined dosage formulation comprising both the CS and the
IL-4/IL-13 pathway inhibitor.
[0121] Dosage
[0122] The amount of IL-4/IL-13 pathway inhibitor (e.g.,
anti-IL-4R.alpha. antibody) administered to a subject according to
the methods of the present invention is, generally, a
therapeutically effective amount. As used herein, the phrase
"therapeutically effective amount" means an amount of IL-4/IL-13
pathway inhibitor that results in one or more of: (a) a reduction
in the severity or duration of a symptom of eosinophilic
esophagitis; (b) a reduction in the number of eosinophils in
esophagus; (c) increase in esophagus distensibility; (d) reduction
in episodes of dysphagia; (e) prevention or alleviation of an
allergic reaction; and (f) a reduction in the use or need for
conventional allergy therapy (e.g., reduced or eliminated use of
antihistamines, decongestants, nasal or inhaled steroids, anti-IgE
treatment, epinephrine, etc.).
[0123] In the case of an anti-IL-4R.alpha. antibody, a
therapeutically effective amount can be from about 0.05 mg to about
600 mg, e.g., about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5
mg, about 2.0 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, or about 600 mg,
of the anti-IL-4R antibody. In certain embodiments, 300 mg of an
anti-IL-4R antibody is administered.
[0124] The amount of IL-4/IL-13 pathway inhibitor 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-4/IL-13 pathway inhibitor (e.g., anti-IL-4R.alpha.
antibody) may be administered to a patient at a dose of about
0.0001 to about 100 mg/kg of patient body weight.
SELECTED EMBODIMENTS
[0125] In Embodiment 1, the present invention includes a method of
reducing dysphagia comprising: (a) selecting a patient with at
least one of the following characteristics: (i) the patient
exhibits episodes of dysphagia per week; (ii) the patient has been
treated previously with high-dose proton pump inhibitors (PPIs);
and (iii) the patient has had at least one prior esophageal
dilation; and (b) administering a therapeutically effective amount
of a pharmaceutical composition comprising an
interleukin-4/interleukin-13 (IL-4/IL-13) pathway inhibitor to the
patient in need thereof.
[0126] In Embodiment 2, the present invention includes a method of
increasing esophageal distensibility comprising: (a) selecting a
patient with at least one of the following characteristics: (i) the
patient exhibits episodes of dysphagia per week; (ii) the patient
has been treated previously with high-dose PPIs; and (iii) the
patient has had at least one prior esophageal dilation; and (b)
administering a therapeutically effective amount of a
pharmaceutical composition comprising an IL-4/IL-13 pathway
inhibitor to the patient in need thereof.
[0127] In Embodiment 3, the present invention includes the method
of Embodiment 1 or 2, wherein the patient has moderate-to-severe
EoE.
[0128] In Embodiment 4, the present invention includes a method of
treating, preventing or ameliorating at least one symptom or
indication of active eosinophilic esophagitis (EoE) comprising
administering a therapeutically effective amount of a
pharmaceutical composition comprising an IL-4/IL-13 pathway
inhibitor to a patient in need thereof.
[0129] In Embodiment 5, the present invention includes the method
of any one of Embodiments 1 to 4, wherein the patient has one or
more characteristics selected from the group consisting of: (1) the
patient has 15 eosinophils per high powered field (hpf) in the
esophagus prior to or at the time of the treatment ("baseline");
(2) prior treatment with at least one of high dose PP Is,
esophageal dilation, corticosteroids, allergen withdrawal and/or
diet modification; (3) the patient exhibits episodes of dysphagia
per week; (4) the patient is unresponsive or resistant to prior
treatment with high dose PPIs or esophageal dilation; (5) the
patient has a Straumann Dysphagia Instrument (SDI) score 2; (6) the
patient has an Eosinophilic Esophagitis Severity and Activity Index
(EEsAI) score or 50; (7) the patient suffers from EoE for at least
3 years; (8) the patient, prior to or at the time of administration
of the IL-4/IL-13 pathway inhibitor, has or is diagnosed with a
disease or disorder selected from the group consisting of food
allergy, atopic dermatitis, asthma, allergic rhinitis and allergic
conjunctivitis; and (9) the patient has an elevated level of a
biomarker selected from the group consisting of eotaxin-3,
periostin, serum IgE (total and allergen-specific), IL-13, IL-5,
serum thymus and activation regulated chemokine (TARC), thymic
stromal lymphopoietin (TSLP), serum eosinophilic cationic protein
(ECP), and eosinophil-derived neurotoxin (EDN).
[0130] In Embodiment 6, the present invention includes the method
of any one of Embodiments 1 to 5, wherein administration of the
IL-4/IL-13 pathway inhibitor results in improvement of an
EoE-related parameter selected from the group consisting of: (a)
reduction of at least 40% from baseline in dysphagia frequency and
severity, as measured by Straumann Dysphagia Instrument (SDI)
score; (b) reduction of 3 points from baseline in the SDI score;
(c) reduction of more than 85% from baseline in peak
intraepithelial eosinophil count in proximal, mid and/or distal
regions of the esophagus; (d) increase of at least 10% from
baseline in esophageal distensibility, as measured by impedance
planimetry; (e) decrease of more than 50% from baseline in severity
and extent of disease, as measured by EoE Histology Scoring System
(HSS) score; and (f) reduction of more than 30% from baseline in
dysphagia, as measured by Eosinophilic Esophagitis Severity and
Activity Index (EEsAI) score.
[0131] In Embodiment 7, the present invention includes the method
of any one of Embodiments 1 to 6, wherein the IL-4/IL-13 pathway
inhibitor is an antibody or antigen-binding fragment thereof that
specifically binds IL-4 receptor (IL-4R).
[0132] In Embodiment 8, the present invention includes the method
of any one of Embodiments 1 to 7, wherein the IL-4/IL-13 pathway
inhibitor is administered at a dose of about 50-600 mg.
[0133] In Embodiment 9, the present invention includes the method
of any one of Embodiments 1 to 8, wherein the IL-4/IL-13 pathway
inhibitor is administered at a dose of about 300 mg.
[0134] In Embodiment 10, the present invention includes the method
of any one of Embodiments 1 to 7, wherein the IL-4/IL-13 pathway
inhibitor is administered at an initial dose followed by one or
more secondary doses, wherein each secondary dose is administered 1
to 4 weeks after the immediately preceding dose.
[0135] In Embodiment 11, the present invention includes the method
of Embodiment 10, wherein the initial dose comprises 50-600 mg of
the IL-4/IL-13 pathway inhibitor.
[0136] In Embodiment 12, the present invention includes the method
of Embodiment 10 or 11, wherein each secondary dose comprises
25-400 mg of the IL-4/IL-13 pathway inhibitor.
[0137] In Embodiment 13, the present invention includes the method
of any one of Embodiments 10 to 12, wherein the initial dose
comprises 600 mg of the IL-4/IL-13 pathway inhibitor and each
secondary dose comprises 300 mg of the IL-4/IL-13 pathway
inhibitor.
[0138] In Embodiment 14, the present invention includes the method
of Embodiment 13, wherein each secondary dose is administered one
week after the immediately preceding dose.
[0139] In Embodiment 15, the present invention includes the method
of Embodiment 13, wherein each secondary dose is administered 2
weeks after the immediately preceding dose.
[0140] In Embodiment 16, the present invention includes the method
of any one of Embodiments 4 to 15, wherein the symptom or
indication of EoE is selected from the group consisting of
eosinophilic infiltration of the esophagus, thickening of the
esophageal wall, food refusal, vomiting, abdominal pain, heartburn,
regurgitation, dysphagia and food impaction.
[0141] In Embodiment 17, the present invention includes the method
of any one of Embodiments 1 to 16, wherein the patient exhibits an
allergic reaction to a food allergen contained in a food item
selected from the group consisting of a dairy product, egg, wheat,
soy, corn, fish, shellfish, peanut, a tree nut, beef, chicken, oat,
barley, pork, green beans, apple and pineapple.
[0142] In Embodiment 18, the present invention includes the method
of any one of Embodiments 1 to 17, wherein the patient exhibits an
allergic reaction to a non-food allergen derived from one of dust,
pollen, mold, plant, cat, dog or insect.
[0143] In Embodiment 19, the present invention includes the method
of any one of Embodiments 1 to 18, wherein the administration of
the IL-4/IL-13 pathway inhibitor results in reducing the level of
an EoE-associated biomarker in the subject.
[0144] In Embodiment 20, the present invention includes the method
of Embodiment 19, wherein the EoE-associated biomarker is selected
from the group consisting of eotaxin-3, periostin, serum IgE (total
and allergen-specific), IL-13, IL-5, serum TARC, TSLP, serum ECP,
and EDN.
[0145] In Embodiment 21, the present invention includes the method
of any one of Embodiments 1 to 20, wherein the IL-4/IL-13 pathway
inhibitor is administered in combination with a second therapeutic
agent or therapy, wherein the second therapeutic agent or therapy
is selected from the group consisting of an IL-1beta inhibitor, an
IL-5 inhibitor, an IL-9 inhibitor, an IL-13 inhibitor, an IL-17
inhibitor, an IL-25 inhibitor, a TNFalpha inhibitor, an eotaxin-3
inhibitor, an IgE inhibitor, a prostaglandin D2 inhibitor, an
immunosuppressant, a topical corticosteroid, an oral
corticosteroid, a systemic corticosteroid, an inhaled
corticosteroid, a glucocorticoid, a proton pump inhibitor, a NSAID,
esophagus dilation, allergen removal and diet management.
[0146] In Embodiment 22, the present invention includes the method
of any one of Embodiments 1 to 21, wherein the IL-4/IL-13 pathway
inhibitor is selected from the group consisting of an anti-IL-4
antibody, an anti-IL-13 antibody, an anti-IL-4/IL-13 bispecific
antibody, an IL-4 receptor (IL-4R) inhibitor, and an anti-IL-4R
antibody.
[0147] In Embodiment 23, the present invention includes the method
of Embodiment 22, wherein the IL-4/IL-13 pathway inhibitor is an
IL-4R inhibitor.
[0148] In Embodiment 24, the present invention includes the method
of Embodiment 22, wherein the IL-4/IL-13 pathway inhibitor is an
anti-IL-4 antibody.
[0149] In Embodiment 25, the present invention includes the method
of Embodiment 22, wherein the IL-4/IL-13 pathway inhibitor is an
anti-IL-13 antibody.
[0150] In Embodiment 26, the present invention includes the method
of Embodiment 22, wherein the IL-4/IL-13 pathway inhibitor is a
bispecific antibody that specifically binds to IL-4 and IL-13.
[0151] In Embodiment 27, the present invention includes the method
of any one of Embodiments 1 to 23, wherein the IL-4/IL-13 pathway
inhibitor is an antibody or antigen-binding fragment thereof that
binds IL-4R.alpha. and prevents the interaction of IL-4 and/or
IL-13 with a type 1 or type 2 IL-4 receptor.
[0152] In Embodiment 28, the present invention includes the method
of Embodiment 27, wherein the antibody or antigen-binding fragment
thereof prevents the interaction of IL-4 with both type 1 and type
2 IL-4 receptors.
[0153] In Embodiment 29, the present invention includes the method
of Embodiment 28, wherein the antibody or antigen-binding fragment
thereof comprises the heavy chain complementarity determining
regions (HCDRs) of a heavy chain variable region (HCVR) comprising
the amino acid sequence of SEQ ID NO: 1 and the light chain
complementarity determining regions (LCDRs) of a light chain
variable region (LCVR) comprising the amino acid sequence of SEQ ID
NO: 2.
[0154] In Embodiment 30, the present invention includes the method
of Embodiment 28, wherein the antibody or antigen-binding fragment
thereof comprises three HCDRs (HCDR1, HCDR2 and HCDR3) and three
LCDRs (LCDR1, LCDR2 and LCDR3), wherein the HCDR1 comprises the
amino acid sequence of SEQ ID NO: 3; the HCDR2 comprises the amino
acid sequence of SEQ ID NO: 4; the HCDR3 comprises the amino acid
sequence of SEQ ID NO: 5; the LCDR1 comprises the amino acid
sequence of SEQ ID NO: 6; the LCDR2 comprises the amino acid
sequence of SEQ ID NO: 7; and the LCDR3 comprises the amino acid
sequence of SEQ ID NO: 8.
[0155] In Embodiment 31, the present invention includes the method
of Embodiment 30, wherein the HCVR comprises the amino acid
sequence of SEQ ID NO: 1 and the LCVR comprises the amino acid
sequence of SEQ ID NO: 2.
[0156] In Embodiment 32, the present invention includes the method
of any one of Embodiments 29 to 31, wherein the antibody or
antigen-binding fragment thereof comprises a heavy chain comprising
the amino acid sequence of SEQ ID NO: 9 and a light chain
comprising the amino acid sequence of SEQ ID NO: 10.
[0157] In Embodiment 33, the present invention includes the method
of any one of Embodiments 1 to 31, wherein the IL-4/IL-13 pathway
inhibitor is dupilumab or a bioequivalent thereof.
[0158] In Embodiment 34, the present invention includes the method
of Embodiment 23, wherein the IL-4R inhibitor is AMG317 or
MEDI9314.
EXAMPLES
[0159] 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 of
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.
Example 1: Clinical Trial of Subcutaneously Administered Dupilumab
in Adult Patients with Active, Moderate-to-Severe Eosinophilic
Esophagitis (EoE)
[0160] This study is a 32-week, double-blind, randomized,
placebo-controlled study to investigate the efficacy, safety,
tolerability and immunogenicity of dupilumab in adult patients with
active EoE. Dupilumab is a fully human anti-IL-4R antibody
comprising a heavy chain comprising the amino acid sequence of SEQ
ID NO: 9 and a light chain comprising the amino acid sequence of
SEQ ID NO: 10; an HCVR/LCVR amino acid sequence pair comprising SEQ
ID NOs: 1/2; and heavy and light chain CDR sequences comprising SEQ
ID NOs: 3-8.
Study Objectives
[0161] The primary objective of the study was to assess the
clinical efficacy of repeat subcutaneous (SC) doses of dupilumab,
compared with placebo, to relieve symptoms in adult patients with
active, moderate to severe EoE.
[0162] The secondary objectives of the study were: (1) to assess
the safety, tolerability, and immunogenicity of SC doses of
dupilumab in adult patients with active, moderate to severe EoE;
(2) to assess the effect of dupilumab on esophageal eosinophilic
infiltration; and (3) to evaluate the pharmacokinetics (PK) of
dupilumab in adult patients with EoE.
[0163] The exploratory objective of the study was to assess the
effect of dupilumab on other esophageal biopsy pathologic features
associated with EoE.
Study Design
[0164] This was a multicenter, double-blind, randomized,
placebo-controlled study investigating the efficacy, safety,
tolerability, PK, and immunogenicity of dupilumab in adult patients
with EoE.
[0165] After providing informed consent, patient eligibility was
assessed at the screening visit (to occur between day -35 and day
-1). Patients who met eligibility criteria underwent day 1 baseline
assessments. Patients were randomized in a 1:1 ratio to receive
dupilumab or placebo during the 12-week double-blind treatment
phase. After the 12-week double-blind treatment phase, patients
were followed off study drug for an additional 16 weeks.
[0166] Patients received concomitant medications (except for
prohibited medications [see below]) as needed, while continuing
study treatment. Efficacy, safety, and laboratory assessments, and
samples for dupilumab concentration and potential anti-drug
antibody (ADA) response to dupilumab, as well as research samples
were performed or collected at specified time points throughout the
study.
Study Population
[0167] The target population included adult (18 to 65 years old)
male or female patients with active EoE.
[0168] Inclusion Criteria: A patient had to meet the following
criteria to be eligible for inclusion in the study: [0169] (1) Male
or female, 18 to 65 years old; [0170] (2) Documented diagnosis of
EoE by endoscopy prior to or at screening. Note: Must include a
demonstration of intraepithelial eosinophilic infiltration (peak
cell count eosinophils/high power field [eos/hpf] [400.times.])
from esophageal biopsy specimens from endoscopy performed no more
than 2 weeks after at least 8 weeks of treatment with high dose (or
twice-daily dosing) proton pump inhibitors (PP Is); [0171] (3)
History (by patient report) of on average at least 2 episodes of
dysphagia (with intake of solids off anti-inflammatory therapy) per
week in the 4 weeks prior to screening and on average at least 2
episodes of documented dysphagia per week in the weeks between
screening and baseline; dysphagia is defined as trouble swallowing
solid food, or having solid food stick, by patient report; [0172]
(4) Must remain on a stabilized diet for at least 6 weeks prior to
screening and during the course of the study; stable diet is
defined as no initiation of single or multiple elimination diets or
reintroduction of previously eliminated food groups; [0173] (5) SDI
PRO score .gtoreq.5 at screening and baseline; [0174] (6)
Documented history of or presence of 1 or more of any of the
following: allergic disease (e.g., allergic asthma, allergic
rhinitis, AD, or food allergies), peripheral eosinophil counts
.gtoreq.0.25 GILL, serum total Immunoglobulin E (IgE).gtoreq.100
kU/L; [0175] (7) Willing and able to comply with all clinic visits
and study-related procedures; able to understand and complete
study-related questionnaires; provide signed informed consent; and
[0176] (8) Endoscopy with photographs performed at screening, with
a demonstration of intraepithelial eosinophilic infiltration (peak
cell count 5 eos/hpf) in at least 2 of the 3 biopsied esophageal
regions (proximal, mid, or distal).
[0177] Exclusion Criteria:
[0178] A patient who met any of the following criteria was
ineligible to participate in this study: (1) Prior participation in
a dupilumab (anti-IL-4R) clinical trial; (2) Other causes of
esophageal eosinophilia or the following diseases:
hypereosinophilic syndromes, Churg-Strauss vasculitis, and
eosinophilic gastroenteritis; (3) History of achalasia, active
Helicobacter pylori infection, Crohn's disease, ulcerative colitis,
celiac disease, and prior esophageal surgery prior to screening;
(4) Any esophageal stricture unable to be passed with a standard,
diagnostic, adult (9 to 10 mm) upper endoscope or any critical
esophageal stricture that requires dilation at screening; (5)
History of bleeding disorders or esophageal varices; (6) Use of
chronic aspirin, nonsteroidal agents, or anti-coagulants within 2
weeks prior to screening. Patients should not stop these agents
solely to become eligible for entry into this study; (7) Treatment
with an investigational drug within 2 months or within 5 half-lives
(if known), whichever is longer, prior to screening; (8) Use of
systemic corticosteroids within 3 months or swallowed topical
corticosteroids within 6 weeks prior to screening; (9) Use of
inhaled or nasal corticosteroids within 3 months prior to screening
and during the study, except stable dose for at least 3 months
prior to screening biopsy, which cannot be changed during the
study; (10) Treatment with oral immunotherapy (OIT) within 6 months
prior to screening; (11) Allergen immunotherapy (sublingual
immunotherapy [SLIT] and/or subcutaneous immunotherapy [SCIT],
unless on stable dose for at least 1 year prior to screening; (12)
The following treatments within 3 months before the screening
visit, or any condition that, in the opinion of the investigator,
is likely to require such treatment(s) during the 3 months of study
treatment: Systemic immunosuppressive/immunomodulating drugs (e.g.,
omalizumab, cyclosporine, mycophenolate-mofetil, interferon-gamma
[IFN-.gamma.], Janus kinase inhibitors, azathioprine, methotrexate,
leukotriene inhibitors [except stable dose for at least 3 months
prior to screening], etc.); (13) Diagnosed with active parasitic
infection; suspected parasitic infection, unless clinical and (if
necessary) laboratory assessments have ruled out active infection
before randomization; (14) Chronic or acute infection requiring
treatment with systemic antibiotics, antivirals, or antifungals
within 1 month prior to screening; (15) Use of oral
antibiotics/anti-infectives within 2 weeks prior to screening; (16)
Known or suspected immunosuppression, including history of invasive
opportunistic infections (e.g., tuberculosis, non-tuberculous
mycobacterial infections, histoplasmosis, listeriosis,
coccidioidomycosis, pneumocystis, aspergillosis) despite infection
resolution, or otherwise recurrent infections of abnormal
frequency, or prolonged infections suggesting an immune-compromised
status, as judged by the investigator; (17) Known history of human
immunodeficiency virus (HIV) infection; (18) Positive or
indeterminate hepatitis B surface antigen (HBsAg) or hepatitis C
antibody at screening; (19) Elevated transaminases (alanine
aminotransferase [ALT] and/or aspartate aminotransferase [AST])
more than 3 times the upper limit of normal (>3.times.upper
limit of normal [ULN]) at screening; (20) History of malignancy
within 5 years prior to screening, except completely treated in
situ carcinoma of the cervix and completely treated and resolved
non-metastatic squamous or basal cell carcinoma of the skin; (21)
History of patient-reported alcohol or drug abuse within 6 months
prior to screening; (22) Any other medical or psychological
condition including relevant laboratory abnormalities at screening
that, in the opinion of the investigator, suggest a new and/or
insufficiently understood disease, may present an unreasonable risk
to the study patient as a result of his/her participation in this
clinical trial, may make patient's participation unreliable, or may
interfere with study assessments. The specific justification for
patients excluded under this criterion will be noted in study
documents (chart notes, case report form [CRF], etc.); (23) Severe
concomitant illness(es) that, in the investigator's judgment, would
adversely affect the patient's participation in the study; (24)
Planned or anticipated use of any prohibited medications and
procedures (see below) during study treatment; (25) Treatment with
a live (attenuated) vaccine within 3 months prior to screening;
(26) Patient or his/her immediate family is a member of the
investigational team; (27) Pregnant or breastfeeding women, or
women planning to become pregnant or breastfeed during the study;
(28) Women unwilling to use adequate birth control, if of
reproductive potential* and sexually active.
Study Treatments
[0179] Investigational drug: Dupilumab SC, a loading dose of 600 mg
on day 1 followed by weekly doses of 300 mg from week 1 to week
11
[0180] Placebo: Placebo (same formulation as dupilumab without the
active substance, anti-IL-4R monoclonal antibody) SC, a volume
matching the dupilumab loading dose on day 1 followed by weekly
doses matching the volume of dupilumab weekly dose from week 1 to
week 11.
[0181] Patients received SC dupilumab 300 mg or matching placebo qw
during the 12-week double-blind treatment phase. Patients received
2 injections (300-mg initial dose, followed by a 300-mg loading
dose) on day 1, followed by weekly injections.
Permitted (Concomitant) Medications
[0182] Treatment with concomitant medications was permitted during
the study. This included treatment with contraceptives, stable dose
of proton pump inhibitors (PPIs) (patients who were using PPIs at
screening did not discontinue or change the dosing regimen prior to
end of treatment [EOT] visit); stable dose (for at least 3 months
prior to screening) of systemic leukotriene inhibitors, topical,
nasal, and/or inhaled corticosteroids; oral antihistamines for any
duration; and oral antibiotics for up to 2 weeks.
Restricted Medications and Procedures
[0183] Restricted medications during duration of study included:
(1) Medications used for the treatment of EoE (these were
considered rescue medications): Swallowed topical corticosteroids,
Systemic corticosteroids, Start or dose change of systemic
leukotriene inhibitors, topical, nasal, and/or inhaled
corticosteroids, and Systemic treatment for EoE with an
immunosuppressive/immunomodulating substance (including, but not
limited to, omalizumab, cyclosporine, mycophenolate-mofetil,
azathioprine, methotrexate, IFN-.gamma., or other biologics); (2)
Allergen immunotherapy (SCIT and SLIT were allowed if dose was
stable for 1 year or more; however, OIT was prohibited); (3)
Patients who were not using PPI in the 8 weeks prior to screening
were prohibited from starting PPI therapy prior to EOT visit; (4)
Treatment with a live (attenuated) vaccine (Chickenpox (varicella),
FluMist-Influenza, Intranasal influenza, Measles (rubella),
Measles-mumps-rubella combination, Measles-mumps-rubella-varicella
combination, Mumps, Oral polio (Sabin), Oral typhoid, Rubella,
Smallpox (vaccinia), Yellow fever, Bacille Calmette-Guerin,
Varicella zoster (shingles), Rotavirus); and (5) Treatment with an
investigational drug (other than dupilumab)
[0184] The following concomitant procedures were prohibited during
study treatment (through week 12): (1) Major elective surgical
procedures; (2) Esophageal dilation (considered rescue procedure);
and (3) Diet change (patients were to remain on stable diet for at
least 6 weeks prior to screening and during the course of the
study; stable diet was defined as no initiation of single or
multiple elimination diets or reintroduction of previously
eliminated food groups).
Study Endpoints
[0185] The primary efficacy endpoint was: Change in the Straumann
Dysphagia Instrument (SDI) patient-reported outcome (PRO) score
from baseline to week 10.
[0186] The secondary endpoints were: Percent change in weekly
Eosinophilic Esophagitis Activity Index (EEsAI) PRO score from
baseline to week 10; Change in weekly EEsAI PRO score from baseline
to week 10; Percent change in weekly EEsAI PRO score from baseline
to week 12; Change in weekly EEsAI PRO score from baseline to week
12; Percent change in the SDI PRO score from baseline to week 10;
Percent change in the SDI PRO score from baseline to week 12;
Change in the SDI PRO score from baseline to week 12; Change in
Adult Eosinophilic Esophagitis Quality of Life (EoE-QOL-A)
(questionnaire) PRO score from baseline to week 12; Percentage of
patients with SDI PRO response at week 10; where response is
defined as a decrease of at least 3 points on the SDI compared to
baseline; Percentage of patients who achieve .gtoreq.40%
improvement in EEsAI score from baseline to week 10; Percent change
in overall peak esophageal intraepithelial eos/hpf (400.times.)
from baseline to week 12; Change in Eosinophilic
Esophagitis-Endoscopic Reference Score (EoE-EREFs) (endoscopy
visual anatomical score) from baseline to week 12; Percentage of
patients with use of rescue medication or procedure (e.g.,
esophageal dilation) through week 12; and Incidence of
treatment-emergent adverse events (TEAEs)
[0187] The exploratory efficacy endpoints were: Change in mean
esophageal intraepithelial eosinophil counts (eos/hpf) [calculated
using peak count from each esophageal site] from baseline to week
12; Proportion of patients who achieve esophageal intraepithelial
eosinophil count <1 eos/hpf at week 12; Change in Collins
Histology Score from baseline to week 12; and Change in esophageal
distensibility plateau as measured by functional lumen imaging from
baseline to week 12.
Procedures and Assessments
[0188] Screening/Baseline Procedures:
[0189] The following procedures were performed only at the
screening and/or baseline visit for the sole purpose of determining
study eligibility or characterizing the baseline population: serum
FSH (for confirmation of menopausal status), serum total IgE,
HBsAg, and hepatitis C antibody.
[0190] Efficacy Procedures:
[0191] Efficacy was assessed during the study at specified clinic
visits using patient-reported outcomes (PROs), including Straumann
Dysphagia Instrument (SDI), Eosinophilic Esophagitis Activity Index
(EEsAI), and the Eosinophilic Esophagitis Quality of Life
(EoE-QOL-A) questionnaire, as well as esophageal biopsies and
photographs (endoscopy procedure). Measurement of inflammatory and
remodeling esophageal features based on the Eosinophilic
Esophagitis Edema rings Exudates Furrows and Strictures (EoE-EREFS)
score was included as part of the endoscopy procedure. The
endolumenal functional lumen imaging probe (EndoFLIP) procedure to
measure esophageal distensibility was performed during the
endoscopy procedures. The EoE Histological Scoring System (HSS) was
used to measure 8 histologic features of EoE.
Straumann Dysphagia Instrument--Patient-Reported Outcome
[0192] The SDI is a non-validated PRO that has been used in
clinical studies to determine the frequency and intensity of
dysphagia (Straumann 2010). The SDI has a 1-week recall period.
Frequency of dysphagia events is graded on a 5-point scale: 0=none,
1=once per week, 2=several times per week, 3=once per day, and
4=several times per day, and intensity of dysphagia events is
graded on a 6-point scale: 0=swallowing unrestricted, 1=slight
sensation of resistance, 2=slight retching with delayed passage,
3=short period of obstruction necessitating intervention (e.g.,
drinking, breathing), 4=longer-lasting period obstruction only
removable by vomiting, and 5=long-lasting complete obstruction
requiring endoscopic intervention. The total SDI score ranges from
0 to 9. In the Straumann study, a clinical response (improvement)
was defined as a decrease in SDI score of at least 3 points from
baseline.
[0193] This assessment was completed by the patient electronically
weekly in a questionnaire from the beginning of screening through
end of study or early termination. Items utilized to quantitate the
SDI were included in the EEsAI/SDI.
Eosinophilic Esophagitis Activity Index--Patient-Reported
Outcome
[0194] The EEsAI is a non-validated, multimodular index in
development at University Hospital Inselspital (Berne, Switzerland)
(Schoepfer 2014), a part of the international EEsAI study group.
The EEsAI PRO module (questionnaire) used in this study includes
items related to the intensity and frequency of dysphagia, the
influence of specific food groups on dysphagia symptoms, and other
symptoms independent of eating or drinking (i.e., heartburn, acid
regurgitation, and chest pain). The total EEsAI PRO score ranges
from 0 to 100 (FIG. 1), wherein higher scores indicate worse
symptoms. The score consists of 5 parts: frequency of trouble
swallowing, duration of trouble swallowing, pain when swallowing,
visual dysphagia question, and avoidance, modification and slow
eating (AMS). The EEsAI PRO utilizes 24-hour and 1-week recall
periods.
[0195] This assessment was completed by the patient electronically
daily and weekly in a questionnaire from the beginning of screening
through end of study or early termination.
Adult Eosinophilic Esophagitis Quality of Life
Questionnaire--Patient-Reported Outcome
[0196] The EoE-QOL-A questionnaire is a validated disease-specific
measure of health-related quality of life in EoE patients (Taft
2011). The instrument used in this study, the EoE-QOL-A v.3.0,
includes 30 items related to established domains such as social
functioning, emotional functioning, and disease impact of daily
life experiences. The EoE-QOL-A has a 1-week recall period. The
items are graded on a 5-point scale: `Not at All,` `Slightly,`
`Moderately,` `Quite a bit,` and `Extremely`.
[0197] This assessment was recorded by the patient in a
questionnaire at baseline and then monthly through end of study or
early termination.
Endoscopy with Esophageal Biopsies and Photographs
[0198] Esophageal biopsies were obtained by endoscopy at the
screening and week 12 visits. The screening endoscopy was performed
during the screening period to allow results to be available prior
to day -1 for assessment of eligibility. A total of 9 mucosal pinch
biopsies were collected at each time point from 3 esophageal
regions: 3 proximal, 3 mid, and 3 distal. Two samples from each
region were used for the histology (needed for study inclusion
criteria, as well as secondary endpoint). To participate in the
study, patients had to have a peak intraepithelial eosinophil count
.gtoreq.15 eos/hpf (400.times.) in at least 2 of the 3 esophageal
regions sampled. Change in peak esophageal eos/hpf (400.times.)
from baseline to week 12 was a secondary endpoint; this was
determined by counting eosinophils in the most inflamed areas of
each esophageal region sampled at each time point and calculating
the change in the peak count at each site obtained at baseline
compared to the count obtained at week 12. As an exploratory
objective, the change in the mean of all 3 peak counts, i.e., the
peak count at each of the 3 esophageal regions for each patient at
each time point (screening and week 12) was calculated. Tissue
blocks remaining after the histological assessment were banked for
exploratory research.
[0199] The EoE-EREFS (edema, rings, exudates, furrows, strictures)
was used to measure the endoscopically identified EoE esophageal
mucosal inflammatory and remodeling features. This instrument
includes a total of 17 items related to the presence and severity
of esophageal features. The specific esophageal features include:
rings (concentric rings around esophagus--absent, mild, moderate,
severe, not applicable); strictures (narrowing of the
esophagus--yes, no, not applicable); diameter of the stricture (if
applicable); exudates (refer to white plaques--absent, mild,
severe), furrows (vertical lines down the esophagus--absent,
present); edema (loss of vascular markings of the mucosa--absent,
present); cr pe paper esophagus (absent, present); overall general
appearance incorporating all endoscopically identified EoE findings
(i.e., fixed rings, strictures, whitish exudates, furrowing, edema,
and cr pe paper mucosa). In addition, mucosal changes associated
with gastroesophageal reflux disease were also recorded using the
Los Angeles classification system for erosions (No Erosions or LA
Classification A, B, C, D). The EoE esophageal characteristics were
analyzed based on the EoE-EREFS, a validated scoring system for
inflammatory and remodeling features of disease using both overall
scores and scores for each individual characteristic (Hirano 2014).
The modified EREFS score in this study was based on a total score
range of 0-8; wherein higher scores indicate greater impairment.
Each score comprised: Edema: 0-1; Rings: 0-3; Exudates: 0-2;
Furrows: 0-1; and Strictures: 0-1 to give a total possible score of
8.
[0200] The assessment of esophageal distensibility utilizing the
endolumenal functional lumen imaging probe (EndoFLIP, Crospon,
Ireland) was also performed to measure the diameter of the
esophageal lumen and pressure (e.g., esophageal rigidity), with
measurements taken as part of the endoscopy procedure performed at
screening and week 12. The EndoFLIP device is a catheter based
procedure that measures the cross sectional area at multiple sites
along the esophagus with simultaneous intraluminal pressure
recordings during volumetric distension of the esophagus. The
analyses of cross sectional area versus pressure relationships of
the esophagus allow for determination of esophageal compliance as
well as the distensibility plateau (DP). The DP has been shown to
be significantly reduced in patients with EoE compared to healthy
controls (Kwiatek 2011). Moreover, the esophageal distensibility
has been associated with outcomes of both food impaction and need
for esophageal dilation (Nicodeme 2013).
[0201] The EoE-HSS generated separate severity (grade) and extent
(stage) disease scores. The score was used to measure 8 histologic
features (parameters) of EoE from 3 different regions (proximal,
mid and distal) of the esophagus (Collins, et al. 2017). The 8
parameters include: eosinophil density, basal zone hyperplasia,
eosinophil abscesses, eosinophil surface layering, dilated
intercellular spaces, surface epithelial alteration, dyskeratotic
cells, and lamina propria fibrosis. A scale of 0-3 was used for
each parameter, both grade and stage (0 being least inflamed,
normal). Total score range for each region for this study was 0-21
(excluding lamina propria parameter). The lamina propria assessment
was excluded given that 50% of pinch biopsies would not be deep
enough for lamina propria assessment. Total score per patient was
calculated as (0-21 score.times.3 regions=total possible score of
63 per time point). Two scores were generated per patient per time
point, one each for grade (severity) and stage (extent).
[0202] Photographs were taken by the site as part of the endoscopic
procedure and biopsy collection.
[0203] Safety Procedures:
[0204] An AE is any untoward medical occurrence in a patient
administered a study drug, which may or may not have a causal
relationship with the study drug. Therefore, an AE is any
unfavorable and unintended sign (including abnormal laboratory
finding), symptom, or disease that is temporally associated with
the use of a study drug, whether or not considered related to the
study drug. An AE also includes any worsening (i.e., any clinically
significant change in frequency and/or intensity) of a pre-existing
condition that is temporally associated with the use of the study
drug.
[0205] A serious adverse event (SAE) is any untoward medical
occurrence that at any dose results in death, is life-threatening,
requires in-patient hospitalization, results in persistent or
significant disability/incapacity, is a congenital anomaly/birth
defect and/or is an important medical event (e.g., such as an event
may jeopardize the patient or may require intervention to prevent 1
of the other serious outcomes listed above.
[0206] Safety and tolerability was assessed by physical
examinations, vital signs, electrocardiograms (ECGs), clinical
laboratory tests, and clinical evaluations. Patients were asked to
monitor all AEs experienced from the time of informed consent until
their last study visit.
[0207] Pharmacokinetic and Antibody Procedures:
[0208] Serum samples were collected for assay of dupilumab level
and PK parameters were calculated using the dupilumab concentration
data. Serum samples were collected for assay of ADA, and
exploratory analyses.
Results
[0209] Baseline Characteristics:
[0210] Patients were randomized in a 1:1 ratio to receive a
subcutaneous (SC) 600 mg dupilumab or SC placebo loading dose
followed by weekly SC 300 mg dupilumab or SC placebo during the
12-week double-blind treatment phase. The randomization was
stratified by baseline Straumann Dysphagia Instrument (SDI) PRO
score (.gtoreq.5 and .ltoreq.7 versus >7). Baseline demographic
and disease characteristics were generally balanced between the two
groups (Tables 1-2), except for mean total IgE (dupilumab 217.8
kU/L; placebo 468.2 kU/L).
TABLE-US-00001 TABLE 1 Summary of Baseline Demographic
Characteristics 300 mg dupilumab Placebo qw (N = 24) (N = 23) Age,
mean (SD), 36.1 (12.75) 33.1 (8.70( years Age Group, n (%)
.gtoreq.18 to <40 years 15 (62.5%) 16 (69.6%) .gtoreq.40 to
<65 years 9 (37.5%) 7 (30.4%) .gtoreq.65 years 0 0 Male sex, n
(%) 10 (41.7%) 13 (56.5%) Race: White, n (%) 21 (87.5%) 23 (100%)
BMI (mean kg/m.sup.2) 30.0 27.7
TABLE-US-00002 TABLE 2 Summary of Baseline Disease Characteristics
Placebo 300 mg dupilumab qw (N = 24) (N = 23) Age at EoE onset, n
(%) 0 to 18 years 4 (16.7%) 7 (13.0%) 19 to 24 years 5 (20.8%) 10
(21.7%) 25 to 50 years 13 (54.2%) 28 (65.2%) >50 years 2 (8.3%)
0 Duration of EoE years 5.0 3.6 Blood Eosinophils (SD) GI/L 0.43
(0.3) 0.31 (0.2) Mean total IgE (SD) kU/L 486.2 (900.7) 217.8
(288.8) Mean SDI score (SD), (0-9) 6.4 (1.0) 6.4 (1.0) Weekly EEsAI
score (0-100) 62.2 62.0 Mean overall peak 101.1 (57.1) 102.1 (53.5)
eosinophils/hpf (SD) EoE Histology Scoring System 27.4 27.9 (0-63)
# of dysphagia/week between 12.4 13.7 screening and baseline EREF
endoscopy score (0-9) 4.3 3.9 Prior treatment with high dose 24
(100%) 23 (100%) PPIs, n (%) Prior topical corticosteroid 20 (83.3)
18 (78.3) use, n (%) Prior dilation, n (%) 10 (41.7) 11 (47.8)
Number of prior esophageal 3.9 (3.3) 5.7 (8.0) dilations (SD) Any
comorbid disease, n (%) 19 (79.2) 20 (87.0)
[0211] Both groups showed a high level of atopic disease (Table
3).
TABLE-US-00003 TABLE 3 Summary of EoE/Allergic Disease Personal
History 300 mg dupilumab Placebo qw (N = 24) (N = 23) Patients with
at least one 24 (100%) 23 (100%) Personal History Food allergy 17
(70.8%) 14 (60.9%) Allergic rhinitis 15 (62.5%) 16 (69.6%) Other
allergies 12 (50.0%) 14 (60.9%) (medications, animals, plants,
mold, dust mites, etc.) Asthma 9 (37.5%) 11 (47.8%) Chronic
sinusitis 8 (33.3%) 2 (8.7%) Hives 6 (25.0%) 7 (30.4%) Atopic
Dermatitis 5 (20.8%) 3 (13.0%) Allergic conjunctivitis 3 (12.5%) 3
(13.0%)
[0212] Efficacy Results:
[0213] Table 4 summarizes the primary and secondary endpoint
results. Dupilumab significantly improved subjective measures of
EoE as reflected by dysphagia, as well as objective histologic and
endoscopic measures of disease in EoE, compared with placebo. No
patients received rescue medication/procedure during the 12-week
double-blind treatment period.
TABLE-US-00004 TABLE 4 Results-Primary and Secondary Endpoints* 300
mg LS mean dupilumab difference vs Placebo.sup.1 qw.sup.1 placebo
(95% P- Endpoint (N = 24) (N = 23) CI) value** Primary Efficacy
Endpoint Change of the SDI score from baseline N = 14 N = 17 to
week 10 (range 0-9) -1.3 (0.6) -3.0 (0.5) -1.7 (-3.22, 0.0304
-0.16) Secondary Efficacy Endpoint % Change of weekly EEsAI score
from N = 13 n-17 baseline to week 10 (range 0-100) -11.3 (9.9)
-34.6 (9.1) -23.2 (-49.68, 0.0850 3.21) Change of weekly EEsAI
score from N = 13 N = 17 baseline to week 10 (range 0-100) -9.0
(5.6) -22.9 (5.0) -13.9 (-28.54, 0.0635 0.78) % Change of weekly
EEsAI score from N = 8 N = 15 baseline to week 12 (range 0-100)
-3.3 (12.7) -37.0 (11.2) -33.6 (-68.83, 0.0608 1.54) Change of
weekly EEsAI score from N = 8 N = 15 baseline to week 12 (range
0-100) -5.0 (7.1) -26.1 (5.9) -21.1 (-40.42, 0.0318 -1.86) % Change
of the SDI score from N = 14 N = 17 baseline to week 10 (range 0-9)
-18.6 (9.0) -45.0 98.4) -26.5 (-50.52, 0.0312 -2.39) Change of the
SDI score from baseline N = 9 N = 16 to week 12 (range 0-9) -2.2
(0.7) -2.9 (0.6) -0.8 (-2.48, 0.3830 0.96) % Change of the SDI
score from N = 9 N = 16 baseline to week 12 (range 0-9) -31.8 -42.8
(8.6) -11.0 (-37.46, 0.4147 (10.7) 15.47) Change of EoE-QOL-A PRO
total score N = 21 N = 23 from baseline to week 12 (range 1-5) 0.47
0.80 (0.14) 0.33 (-0.05, 0.0910 (0.14) 0.72) Proportion of patients
with decrease of N = 14 N = 17 at least 3 points on the SDI from 3
(12.5%) 9 (39.1%) 26.6 (-3.04, 0.049 baseline to week 10 51.05)
Proportion of patients that achieve .gtoreq.40% N = 13 N = 17
improvement in EEsAI PRO score from 2 (8.3%) 6 (26.1%) 17.8
(-11.54, 0.1365 baseline to week 10 -43.55) % Change of overall
peak esophageal N = 22 N = 22 intraepithelial eosinophils/high
power 15.1 -91.8 (12.3) -107 (-141.4, <0.0001 field (eos/hpf)
(400X) from baseline to (12.5) -72.46) week 12 Change of EoE-EREFS
total score N = 22 N = 22 (endoscopy visual anatomical score) -0.3
(0.33) -1.9 (0.32) -1.6 (-2.50, 0.0006 from baseline to week 12
(range 0-9) -0.68) .sup.1n represents # of patients with both
baseline and post-baseline actual observed values *For continuous
variables, multiple imputation/ANCOVA was used, LS (SE) was
presented; for binary variables, patients with missing data were
treated as non-responders and Fisher exact test was used for
comparison, number and % of responder was presented. **For the
secondary endpoints, all p-values were nominal
[0214] Dupilumab improved Straumann Dysphagia Instrument (SDI)
score compared to placebo (-3 vs. -1.3, P=0.0304; 45.05% vs.
18.59%, P=0.0312) at week 10 (Table 4, FIG. 2). 39% of
dupilumab-treated patients achieved reduction in SDI compared to
12.5% in the placebo group at week 10. At both week 10 and week 12,
dupilumab improved both frequency and severity components of
dysphagia of the SDI score (FIG. 3).
[0215] Dupilumab numerically reduced EEsAI score (-34.6% vs.
-11.3%, P=0.085) vs placebo through week 10 (Table 4, FIG. 4).
[0216] Dupilumab significantly reduced peak eosinophil count
(eos/hpf) from baseline to week 12, compared to placebo [-94.1
(-91.8%) vs -7.4 (+15.1%), P<0.0001] (Tables 4 and 6). A
reduction in eosinophil tissue infiltration was observed in all
patients in the dupilumab group (Table 5). The dupilumab effect was
similar on the proximal, mid and distal regions of the
esophagus.
TABLE-US-00005 TABLE 5 Responder Analysis Peak Eos Proportion of
patients with (eos/hpf) at week response at week 12, n (%) 12 300
mg dupilumab Placebo P value <1 3 (13) 0 (0) 0.1092 <6 14
(60.9) 0 (0) <0.0001 <15 18 (78.3) 0 (0) <0.0001
[0217] Dupilumab significantly reduced EREFS relative to placebo at
week 12 (LS mean change p=0.0006, LS mean % change p=0.0004) (Table
4). Dupilumab significantly reduced the total EREFS score, as well
as the exudates and furrows subcomponents with trends observed for
the edema, rings and strictures subcomponents (FIG. 5).
[0218] Dupilumab significantly reduced both the total grade and
stage scores of the EoE-HSS from baseline to week 12, compared to
placebo (P<0.001 vs placebo) (Table 6; FIGS. 6 and 7). Dupilumab
significantly reduced both grade (severity) and stage (extent)
scores for basal zone hyperplasia (BZH), eosinophil inflammation
(EI), eosinophil surface layering (SL) and eosinophil abscess (EA)
in proximal, mid and distal regions (FIGS. 8 and 9). Also,
dupilumab reduced grade and stage scores for dilated intracellular
spaces and surface alteration in all regions and distal apoptotic
epithelial cells (FIGS. 10 and 11).
[0219] Dupilumab significantly improved esophageal distensibility
at week 12 compared to placebo (Table 6). An increase (improvement)
in distensibility plateau was observed in more patients treated
with dupilumab than placebo (FIG. 12).
[0220] Table 6 summarizes the effect of dupilumab on subjective
patient-reported outcomes on dysphagia and on clinician-assessed
objective measures.
TABLE-US-00006 TABLE 6 Efficacy of dupilumab on subjective and
objective EoE measures Dupilumab 300 PBO mg qw LS mean difference
vs (N = 24) (N = 23) PBO (95% CI) SDI score BL score, mean (.+-.SD)
6.4 (1.01) 6.4 (1.04) Week 10 n = 14 n = 17 LS mean change from BL
(.+-.SE) -1.3 (0.6) -3.0 (0.5) -1.7 (-3.2, -0.2)* EEsAl score BL
score, mean (.+-.SD) 62.2 62.0 (18.36) (16.45) Week 10 n = 13 n =
17 LS mean % change from BL (.+-.SE) -11.3 -34.6 (9.1) -23.2
(-49.7, 3.2).sup.# (9.9) Peak esophageal intraepithelial (eos/hpf)
BL score, mean (.+-.SD) 101.1 102.1 (53.5) (57.1) Week 12 n = 22 n
= 22 LS mean change from BL (.+-.SE) -7.4 (9.61) -94.1 (9.52) LS
mean % change from BL (.+-.SE) 15.1 -91.8 (12.3) -106.9 (-141.4,
(12.5) -72.5)*** Pts with response <6 eos/hpf, n 0.0 14 (60.9)
(%) Pts with response <15 eos/hpf, n 0.0 18 (78.3) (%) EoE-EREFS
score BL score, mean (.+-.SD) 4.3 (1.46) 3.9 (1.87) Week 12 n = 22
n = 23 LS mean change from BL (.+-.SE) -0.3 (0.3) -1.9 (0.3) -1.6
(-2.5, -0.7)*** EoE-HSS BL score, mean (.+-.SD) 27.4 27.9 (6.05)
(6.46) Total-grade (severity) score Week 12 n = 20 n = 21 All LS
mean % change from BL 3.9 (6.6) -64.2 (6.4) -68.1 (-85.8, -50.3)***
(.+-.SE) Distal LS mean % change from BL 2.7 (5.3) -57.0 (5.3)
-59.7 (-74.3, -45.1)*** (.+-.SE) Mid LS mean % change from BL -8.1
(7.0) -70.8 (6.8) -62.7 (-81.7, -43.7)*** (.+-.SE) Proximal LS mean
% change 66.1 -50.2 (24.5) -116.3 (-188.0, from BL (.+-.SE) (27.4)
-44.5)*** Total-stage (extent) score Week 12 n = 20 n = 21 All LS
mean % change from BL -3.5 (5.0) -58.1 (4.7) -54.6 (-68.1,
-41.0)*** (.+-.SE) Distal LS mean % change from BL 5.1 (6.3) -50.6
(6.3) -55.6 (-73.2, -38.1)*** (.+-.SE) Mid LS mean % change from BL
-18.4 -62.0 (5.5) -43.5 (-59.1, -28.0)*** (.+-.SE) (5.7) Proximal
LS mean % change from 43.1 -46.9 (19.2) -90.0 (-146.5, BL (.+-.SE)
(21.6) -33.5)*** Distensibility plateau (mm) BL, mean (.+-.SD)
17.60 18.66 (3.799) (2.879) Week 12 n = 12 n = 12 LS mean % change
from BL (.+-.SE) -6.2 (2.7) 11.8 (2.7) 18.0 (10.9, 25.2)*** *P <
0.05, ***P < 0.001, .sup.#= P = 0.085 vs PBO. SDI is a 9-item
measure of dysphagia; score range 0-9 with higher scores indicating
worse symptoms. EEsAI is a 5-item measure of dysphagia; score range
0-100 with higher scores indicating worse symptoms. The EoE
Histology scoring system (EoEHSS) measures eosinophil density,
basal zone hyperplasia, eosinophil abscesses, eosinophil surface
layering, surface epithelial alteration, dyskeratotic epithelial
cells and dilated intercellular spaces. Lamina propria was excluded
from the analysis, as ~50% of pinch biopsies were not deep enough
for assessment. Esophageal distensibility plateau is measured using
the Functional Lumen Imaging Probe (EndoFLIP, .RTM. Crospon), a
probe using impedance planimetry. The continuous efficacy endpoints
were analyzed in the full analysis set (FAS) using multiple
imputation (MI), followed by an analysis of covariance (ANCOVA)
model with treatment group as fixed effect, and baseline SDI and
the relevant baseline value as covariates. LS, least-squares; qw,
every week
[0221] Safety Results:
[0222] Dupilumab was well tolerated in EoE patients. The most
common treatment-emergent adverse events (TEAEs) were
injection-site erythema (dupilumab 34.8%, placebo 8.3%) and
nasopharyngitis (dupilumab 17.4%, placebo 4.2%).
CONCLUSION
[0223] Compared to placebo, dupilumab demonstrated a statistically
significant reduction in the primary endpoint, change from baseline
in Straumann Dysphagia Instrument (SDI) at week 10, the LS mean
difference in change from baseline at week 10 between dupilumab and
placebo groups was -1.7 (p=0.0304). Improvements in other
subjective dysphagia measures including EEsAI (at week 10) and
EOE-QOL (at week 12) were also noted. Finally, there were marked,
statistical improvements in both histologic and visual endoscopic
objective assessments of disease activity, including the percent
change from baseline in peak eosinophils and absolute change from
baseline in Eosinophilic Esophagitis Edema, Rings, Exudates,
Furrows and Stricture (EoE-EREFS) score at week 12. Dupilumab
treatment was generally safe and well tolerated. The most common
TEAEs were mild ISRs and viral upper respiratory tract infections
and nasopharyngitis.
[0224] The present invention is not to be limited in scope by the
specific embodiments described herein. Indeed, various
modifications of the invention in addition to those described
herein will become apparent to those skilled in the art from the
foregoing description and the accompanying figures. Such
modifications are intended to fall within the scope of the appended
claims.
Sequence CWU 1
1
111124PRTArtificial SequenceHCVR 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 SequenceLCVR 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 SequenceHCDR1 3Gly Phe Thr Phe Arg Asp Tyr Ala1
548PRTArtificial SequenceHCDR2 4Ile Ser Gly Ser Gly Gly Asn Thr1
5518PRTArtificial SequenceHCDR3 5Ala Lys Asp Arg Leu Ser Ile Thr
Ile Arg Pro Arg Tyr Tyr Gly Leu1 5 10 15Asp Val611PRTArtificial
SequenceLCDR1 6Gln Ser Leu Leu Tyr Ser Ile Gly Tyr Asn Tyr1 5
1073PRTArtificial SequenceLCDR2 7Leu Gly Ser189PRTArtificial
SequenceLCDR3 8Met Gln Ala Leu Gln Thr Pro Tyr Thr1
59451PRTArtificial SequenceHC 9Glu 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 Ser Ala Ser Thr
115 120 125Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser
Thr Ser 130 135 140Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
Tyr Phe Pro Glu145 150 155 160Pro Val Thr Val Ser Trp Asn Ser Gly
Ala Leu Thr Ser Gly Val His 165 170 175Thr Phe Pro Ala Val Leu Gln
Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190Val Val Thr Val Pro
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys 195 200 205Asn Val Asp
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 210 215 220Ser
Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu225 230
235 240Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
Leu 245 250 255Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
Asp Val Ser 260 265 270Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
Val Asp Gly Val Glu 275 280 285Val His Asn Ala Lys Thr Lys Pro Arg
Glu Glu Gln Phe Asn Ser Thr 290 295 300Tyr Arg Val Val Ser Val Leu
Thr Val Leu His Gln Asp Trp Leu Asn305 310 315 320Gly Lys Glu Tyr
Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser 325 330 335Ile Glu
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 340 345
350Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
355 360 365Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
Ala Val 370 375 380Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
Lys Thr Thr Pro385 390 395 400Pro Val Leu Asp Ser Asp Gly Ser Phe
Phe Leu Tyr Ser Arg Leu Thr 405 410 415Val Asp Lys Ser Arg Trp Gln
Glu Gly Asn Val Phe Ser Cys Ser Val 420 425 430Met His Glu Ala Leu
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 435 440 445Ser Leu Gly
45010219PRTArtificial SequenceLC 10Asp 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
110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn
Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp
Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr
Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr
Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr
Lys Ser Phe Asn Arg Gly Glu Cys 210 21511207PRTArtificial
SequencehIL-4Ralpha 11Met Lys Val Leu Gln Glu Pro Thr Cys Val Ser
Asp Tyr Met Ser Ile1 5 10 15Ser Thr Cys Glu Trp Lys Met Asn Gly Pro
Thr Asn Cys Ser Thr Glu 20 25 30Leu Arg Leu Leu Tyr Gln Leu Val Phe
Leu Leu Ser Glu Ala His Thr 35 40 45Cys Ile Pro Glu Asn Asn Gly Gly
Ala Gly Cys Val Cys His Leu Leu 50 55 60Met Asp Asp Val Val Ser Ala
Asp Asn Tyr Thr Leu Asp Leu Trp Ala65 70 75 80Gly Gln Gln Leu Leu
Trp Lys Gly Ser Phe Lys Pro Ser Glu His Val 85 90 95Lys Pro Arg Ala
Pro Gly Asn Leu Thr Val His Thr Asn Val Ser Asp 100 105 110Thr Leu
Leu Leu Thr Trp Ser Asn Pro Tyr Pro Pro Asp Asn Tyr Leu 115 120
125Tyr Asn His Leu Thr Tyr Ala Val Asn Ile Trp Ser Glu Asn Asp Pro
130 135 140Ala Asp Phe Arg Ile Tyr Asn Val Thr Tyr Leu Glu Pro Ser
Leu Arg145 150 155 160Ile Ala Ala Ser Thr Leu Lys Ser Gly Ile Ser
Tyr Arg Ala Arg Val 165 170 175Arg Ala Trp Ala Gln Cys Tyr Asn Thr
Thr Trp Ser Glu Trp Ser Pro 180 185 190Ser Thr Lys Trp His Asn Ser
Tyr Arg Glu Pro Phe Glu Gln His 195 200 205
* * * * *