U.S. patent application number 15/804104 was filed with the patent office on 2018-03-01 for methods of treatment of eosinophilic bronchitis with an anti-il-5 antibody.
The applicant listed for this patent is GLAXOSMITHKLINE LLC. Invention is credited to Fredrick E. HARGREAVE, Giampietro Ventresca.
Application Number | 20180057582 15/804104 |
Document ID | / |
Family ID | 41114741 |
Filed Date | 2018-03-01 |
United States Patent
Application |
20180057582 |
Kind Code |
A1 |
HARGREAVE; Fredrick E. ; et
al. |
March 1, 2018 |
METHODS OF TREATMENT OF EOSINOPHILIC BRONCHITIS WITH AN ANTI-IL-5
ANTIBODY
Abstract
The present invention relates generally to the methods for the
treatment and diagnosis of conditions mediated by IL-5 and excess
eosinophil production, and more specifically to mAbs, Fabs,
chimeric and humanized antibodies. More particularly, the present
invention relates generally to the treatment of eosinophilic
bronchitis with an anti-IL-5 antibody or fragment thereof.
Inventors: |
HARGREAVE; Fredrick E.;
(Hamilton, CA) ; Ventresca; Giampietro;
(Hertfordshire, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GLAXOSMITHKLINE LLC |
Wilmington |
DE |
US |
|
|
Family ID: |
41114741 |
Appl. No.: |
15/804104 |
Filed: |
November 6, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12935038 |
Sep 28, 2010 |
9834600 |
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PCT/US09/38509 |
Mar 27, 2009 |
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15804104 |
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61040363 |
Mar 28, 2008 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 7/10 20180101; A61P
7/00 20180101; A61P 21/00 20180101; A61P 1/00 20180101; A61P 11/00
20180101; A61P 9/00 20180101; A61P 11/06 20180101; A61P 1/14
20180101; A61P 37/08 20180101; A61K 39/3955 20130101; A61P 17/00
20180101; C07K 14/5409 20130101; A61P 1/04 20180101; A61P 11/02
20180101; C07K 16/244 20130101; A61P 33/00 20180101; A61P 43/00
20180101; A61P 33/10 20180101 |
International
Class: |
C07K 16/24 20060101
C07K016/24; A61K 39/395 20060101 A61K039/395 |
Claims
1. A method for treating eosinophilic bronchitis, comprising
administering to a human suffering from eosinophilic bronchitis a
composition comprising at least one anti-IL-5 antibody.
2. The method of claim 1, wherein said human has steroid-dependent
eosinophilic bronchitis.
3. The method of claim 2, wherein said steroid is prednisone and/or
prednisolone.
4. The method of claim 1, wherein said eosinophilic bronchitis is
severe.
5. The method of claim 1, wherein said at least one anti-IL-5
antibody is to human IL-5.
6. The method of claim 5, wherein said at least one anti-IL
antibody is neutralizing.
7. The method of claim 1, wherein said at least one anti-IL-5
antibody is humanized.
8. The method of claim 1, wherein said at least one anti-IL-5
antibody comprises a heavy chain comprising SEQ ID NO: 19.
9. The method of claim 1 wherein said at least one anti-IL-5
antibody comprises a light chain comprising SEQ ID NO: 21.
10. The method of claim 1 wherein said human is suffering from at
least one additional disorder associated with excess eosinophil
production selected from the group consisting of atopic asthma,
atopic dermatitis, allergic rhinitis, non-allergic rhinitis,
asthma, severe asthma, chronic cosinophilic pneumonia, allergic
bronchopulmonary aspergillosis, coeliac disease, Churg-Strauss
syndrome, eosinophilic myalgia syndrome, hypereosinophilic
syndrome, oedematous reactions including episodic angiodema,
helminth infections, eosinophilia associated with a parasitic
infection and/or the treatment of parasitic infection, onchocercal
dermatitis eosinophilic oesophagitis, eosinophilic gastritis,
eosinophilic gastroenteritis, eosinophilic enteritis, eosinophilic
colitis, nasal micropolyposis, nasal polyposis, aspirin intolerance
asthma, obstructive sleep apnoe, chronic asthma, Crohn's disease,
scleroderma and endomyocardial fibrosis.
11. The method of claim 1, wherein said composition comprising at
least one anti-IL-5 antibody is administered intravenously.
12. The method of claim 11, wherein said composition comprising at
least one anti-IL-5 antibody is administered at a dose of 750
mg.
13. The method of claim 11, wherein said intravenous dose is
administered intravenously over 30 minutes.
14. The method of claim 2, wherein said human is receiving
prednisone for said steroid-dependent eosinophilic bronchitis and
said prednisone is reduced by at least about 90% in said human
suffering from steroid-dependent eosinophilic bronchitis after
treatment with said composition comprising at least one anti-IL-5
antibody.
15. The method of claim 2, wherein the human suffering from
steroid-dependent eosinophilic bronchitis experiences a
statistically significant reduction in exacerbations of
eosinophilic bronchitis after receiving at least one doses of said
composition comprising at least one anti-IL-5 antibody.
16. The method of claim 1, wherein eosinophil level in said human
are reduced to within normal limits after at least one dose of said
composition comprising at leas one anti-IL-5 antibody.
17. The method of claim 16, wherein said eosinophil level remains
within normal limits for at least 8 weeks after the last dose of
said composition comprising anti-IL-5 antibody.
18. The method of claim 1, wherein said composition comprising at
least one anti-IL-5 antibody comprises a first anti-IL-5 antibody
and a second anti-IL-5 antibody.
19. The method of claim 1, wherein said composition comprising at
least one anti-IL-5 antibody is co-administered with a steroid.
20. The method of claim 2, wherein said composition comprising at
least one anti-IL-5 antibody statistically significantly reduces
the amount of steroid required by a patient to control
exacerbations of eosinophilic bronchitis compared with placebo.
21. The method of claim 16, wherein said eosinophil level is
reduced in said human in blood and/or sputum.
22. The method of claim 1, wherein the patient also suffers from
asthma.
23. The method of claim 22, wherein the asthma is severe.
Description
[0001] This application claims the benefit of US Provisional
Application No. 61/040,363 filed 28 Mar. 2008 which is incorporated
herein in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates generally to the methods for
the treatment and diagnosis of conditions mediated by IL-5 and
excess eosinophil production, and more specifically to the
treatment of eosinophilic bronchitis with an anti- IL-5
antibody.
BACKGROUND OF THE INVENTION
[0003] Eosinophils have been implicated in the pathogenesis of a
wide variety of inflammatory disease states including allergic
disorders associated with hypersensitivity reactions in the lung
tissue (Butterfield et al., In: Immunopharmacology of Eosinophils,
H. Smith and R. Cook, Eds., p.151-192, Academic Press, London
(1993)). A notable example is asthma, a disease characterized by
reversible obstruction of the airways leading to non-specific
bronchial hyperresponsiveness. This in turn is dependent upon the
generation of a chronic inflammatory reaction at the level of the
bronchial mucosa and a characteristic infiltration by macrophages,
lymphocytes and eosinophils. The eosinophil appears to play a
central role in initiating the mucosal damage typical of the
disease (Corrigan et al., Immunol. Today, 13:501-507 (1992)).
Increased numbers of activated eosinophils have been reported in
the circulation, bronchial secretions and lung parenchyma of
patients with chronic asthma, and the severity of the disease, as
measured by a variety of lung function tests, correlates with blood
eosinophil numbers (Griffen et al., J. Aller. Clin. Immunol.,
67:548-557 (1991)). Increased numbers of eosinophils, often in the
process of degranulation, have also been recovered in
bronchoalveolar lavage (BAL) fluids of patients undergoing late
asthmatic reactions, and reducing eosinophil numbers, usually as a
consequence of steroid therapy, is associated with improvements in
clinical symptoms (Bousquet et al., N. Eng. J. Med., 323:1033-1039
(1990)).
[0004] Interleukin 5 (IL-5) is a homodimeric glycoprotein produced
predominantly by activated CD4+T lymphocytes. In man, IL-5 is
largely responsible for controlling the growth and differentiation
of eosinophils. Elevated levels of IL-5 are detected in the
bronchoalveolar lavage washings of asthmatics (Motojima et al.,
Allergy, 48:98 (1993)). Mice which are transgenic for IL-5 show a
marked eosinophilia in peripheral blood and tissues in the absence
of antigenic stimulation (Dent et al., J. Exp. Med., 172:1425
(1990)) and anti-murine IL-5 monoclonal antibodies have been shown
to have an effect in reducing eosinophilia in the blood and tissues
of mice (Hitoshi et al., Int. Immunol., 3:135 (1991)) as well as
the eosinophilia associated with parasite infection and allergen
challenge in experimental animals (Coffman et al., Science,
245:308-310 (1989), Sher et al., Proc. Natl. Acad. Sci., 83:61-65
(1990), Chand et al., Eur. J. Pharmacol., 211:121-123 (1992)).
[0005] Eosinophilic airway inflammation, an eosinophilic
bronchitis, is the component of asthma known to predict response to
treatment with corticosteroids (Hargreave, F E, J Allergy Clin
Immunol, 102:S102-5 (1998)). It is identified by sputum
eosinophilia and can also occur in patients without asthma
(Hargreave, F E and Paramerwaran, K. Eur Respir J, 28:264-7
(2006)). In patients with asthma (Jayaram, et al. Eur Respir J.
27:483-94 (2006)) or chronic obstructive pulmonary disease (Siva,
et al. Eur Respir J, 29:906-13 (2007)), normalizing airway
eosinophils improves asthma control and prevents exacerbation.
[0006] Although corticosteroids are extremely effective in
suppressing eosinophil numbers and other inflammatory components of
asthma and eosinophilic bronchitis, there are concerns about their
side effects in both severe asthmatics and more recently in mild to
moderate asthmatics. The only other major anti-inflammatory drug
therapies--cromoglycates (cromolyn sodium and nedocromil)--are
considerably less effective than corticosteroids and their precise
mechanism of action remains unknown.
[0007] At present, there is no outstanding drug which can have a
prednisone-sparing effect in the treatment of eosinophilic
bronchitis. Thus, there is a need for the methods of the present
invention to reduce eosinophils in a human in need thereof.
SUMMARY OF THE INVENTION
[0008] In one embodiment of the present invention, methods are
provided for treating eosinophilic bronchitis, comprising
administering to said human suffering from eosinophilic bronchitis
a composition comprising at least one anti-IL-5 antibody.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1: Study Design
[0010] FIG. 2: Time until first exacerbation after
randomization.
[0011] FIG. 3: Eosinophils in Sputum (Panel A) and Blood (Panel
B).
DETAILED DESCRIPTION OF THE INVENTION
[0012] I. Definitions.
[0013] As used herein an "anti-IL-5 antibody" refers to any
antibody, antibody fragment or single chain antibody that binds to
IL-5 from any species. Antibody fragments include antibodies
lacking all or part of an immunoglobulin constant region, e.g., Fv,
Fab, or F(ab).sub.2 and the like. An anti-IL-5 antibody may be
murine, chimeric, humanized or fully human. The antibody may be
neutralizing. Several examples of anti-IL-5 antibodies are
described in U.S. Pat. Nos. 5,683,892, 5,693,323, 5,783,184,
5,851,525, 6,129,913, 5,096,071, 6,056,957, and 6,451,982 herein
incorporated by reference in their entirety. In addition, humanized
anti-IL-5 antibodies are described in various references and
include relizumab (SCH55700) and mepolizumab (SB240563)
(Greenfeder, et al., Respiratory Research, 2(2):71-79 (2001)).
Mepolizumab (SB-240563) is a fully humanized monoclonal antibody
(IgG.sub.1, kappa, mAb) which is specific for human interleukin-5
(IL-5). Other anti-IL-5 antibodies are described in U.S. Pat. Nos.
7,422,742 and 7,141,653 also incorporated herein by reference.
[0014] "Neutralizing" refers to an antibody that inhibits IL-5
activity by preventing the binding of human IL-5 to its specific
receptor or by inhibiting the signalling of IL-5 through its
receptor, should binding occur. A mAb is neutralizing if it is 90%
effective, 95% effective or 100% effective in inhibiting IL-5
activity as measured in the B13 cell bioassay. Antibody binding can
be measured by a number of assays known in the art including using
a BIAcore optical biosensor (Pharmacia Biosensor, Uppsala, Sweden)
and/or an ELISA assay.
[0015] The term "high affinity" refers to an antibody having a
binding affinity characterized by a K.sub.d equal to or less than
3.5.times.10.sup.-11 M for human IL-5 as determined by optical
biosensor anaylsis. The K.sub.d for IL-5 of a Fab fragment might be
estimated to be about 9.times.10.sup.-11 M as determined by optical
biosensor.
[0016] By "binding specificity for human IL-5" is meant that the
antibody has a higher affinity for human IL-5 compared with any
non-human IL-5 orthologue such as, but not limited to, murine IL-5.
For instance, an antibody with binding specificity for human IL-5
might have a K.sub.d equal to or less than 2.2.times.10.sup.-11M
for human IL-5 while having a K.sub.d of greater than
2.2.times.10.sup.-11M for non-human IL-5 orthologue.
[0017] The terms Fv, Fc, Fd, Fab, or F(ab).sub.2 are used with
their standard meanings (see, e.g., Harlow et al., Antibodies A
Laboratory Manual, Cold Spring Harbor Laboratory, (1988)).
[0018] As used herein, an "engineered antibody" describes a type of
altered antibody, i.e., a full-length synthetic antibody (e.g., a
chimeric or humanized antibody as opposed to an antibody fragment)
in which a portion of the light and/or heavy chain variable domains
of a selected acceptor antibody are replaced by analogous parts
from one or more donor antibodies which have specificity for the
selected epitope. For example, such molecules may include
antibodies characterized by a humanized heavy chain associated with
an unmodified light chain (or chimeric light chain), or vice versa.
Engineered antibodies may also be characterized by alteration of
the nucleic acid sequences encoding the acceptor antibody light
and/or heavy variable domain framework regions in order to retain
donor antibody binding specificity. These antibodies can comprise
replacement of one or more CDRs (preferably all) from the acceptor
antibody with CDRs from a donor antibody described herein.
[0019] A "chimeric antibody" refers to a type of engineered
antibody which contains naturally-occurring variable region (light
chain and heavy chains) derived from a donor antibody in
association with light and heavy chain constant regions derived
from an acceptor antibody.
[0020] A "humanized antibody" refers to a type of engineered
antibody having its CDRs derived from a non-human donor
immunoglobulin, the remaining immunoglobulin-derived parts of the
molecule being derived from one (or more) human immunoglobulin(s).
In addition, framework support residues may be altered to preserve
binding affinity (see, e.g., Queen et al., Proc. Natl Acad Sci USA,
86:10029-10032 (1989), Hodgson et al., Bio/Technology, 9:421
(1991)).
[0021] The term "donor antibody" refers to an antibody (monoclonal
or recombinant) which contributes the nucleic acid sequences of its
variable regions, CDRs, or other functional fragments or analogs
thereof to a first immunoglobulin partner, so as to provide the
altered immunoglobulin coding region and resulting expressed
altered antibody with the antigenic specificity and neutralizing
activity characteristic of the donor antibody. One donor antibody
suitable for use in this invention is a non-human neutralizing
monoclonal antibody (i.e., murine) designated as 2B6 (see U.S. Pat.
Nos. 5,683,892, 5,693,323, 5,783,184, 5,851,525, and 6,129,913
herein incorporated by reference in their entirety). The antibody
2B6 is defined as a high affinity, human-IL-5 specific (i.e., does
not recognize murine IL-5), neutralizing antibody of isotype
IgG.sub.1 having the variable light chain DNA and amino acid
sequences of SEQ ID NOs: 2 and 16, respectively, and the variable
heavy chain DNA and amino acid sequences of SEQ ID NOs: 1 and 15,
respectively, on a suitable murine IgG constant region.
[0022] The term "acceptor antibody" refers to an antibody
(monoclonal or recombinant) heterologous to the donor antibody,
which contributes all (or any portion, but preferably all) of the
nucleic acid sequences encoding its heavy and/or light chain
framework regions and/or its heavy and/or light chain constant
regions to the first immunoglobulin partner. Preferably a human
antibody is the acceptor antibody.
[0023] "CDRs" are defined as the complementarity determining region
amino acid sequences of an antibody which are the hypervariable
regions of immunoglobulin heavy and light chains. See, e.g., Kabat
et al., Sequences of Proteins of Immunological Interest, 4th Ed.,
U.S. Department of Health and Human Services, National Institutes
of Health (1987). There are three heavy chain and three light chain
CDRs (or CDR regions) in the variable portion of an immunoglobulin.
Thus, "CDRs" as used herein refers to all three heavy chain CDRs,
or all three light chain CDRs (or both all heavy and all light
chain CDRs, if appropriate).
[0024] CDRs provide the majority of contact residues for the
binding of the antibody to the antigen or epitope. CDRs of interest
in this invention are derived from donor antibody variable heavy
and light chain sequences, and include analogs of the naturally
occurring CDRs, which analogs also share or retain the same antigen
binding specificity and/or neutralizing ability as the donor
antibody from which they were derived.
[0025] By `sharing the antigen binding specificity or neutralizing
ability` is meant, for example, that although mAb 2B6 (see U.S.
Pat. Nos. 5,683,892, 5,693,323, 5,783,184, 5,851,525, and 6,129,913
herein incorporated y reference) may be characterized by a certain
level of antigen affinity, a CDR encoded by a nucleic acid sequence
of 2B6 in an appropriate structural environment may have a lower,
or higher affinity. It is expected that CDRs of 2B6 in such
environments will nevertheless recognize the same epitope(s) as
2B6. Exemplary heavy chain CDRs of 2B6 include SEQ ID NO: 7; SEQ ID
NO: 8; SEQ ID NO: 9; and exemplary light chain CDRs of 2B6 include
SEQ ID NO: 10; SEQ ID NO: 11; and SEQ ID NO: 12.
[0026] A "functional fragment" is a partial heavy or light chain
variable sequence (e.g., minor deletions at the amino or carboxy
terminus of the immunoglobulin variable region) which retains the
same antigen binding specificity and/or neutralizing ability as the
antibody from which the fragment was derived.
[0027] An "analog" is an amino acid sequence modified by at least
one amino acid, wherein said modification can be chemical or a
substitution or a rearrangement of a few amino acids (i.e., no more
than 10), which modification permits the amino acid sequence to
retain the biological characteristics, e.g., antigen specificity
and high affinity, of the unmodified sequence. For example,
(silent) mutations can be constructed, via substitutions, when
certain endonuclease restriction sites are created within or
surrounding CDR-encoding regions.
[0028] Analogs may also arise as allelic variations. An "allelic
variation or modification" is an alteration in the nucleic acid
sequence encoding the amino acid or peptide sequences of the
invention. Such variations or modifications may be due to
degeneracy in the genetic code or may be deliberately engineered to
provide desired characteristics. These variations or modifications
may or may not result in alterations in any encoded amino acid
sequence.
[0029] The term "effector agents" refers to non-protein carrier
molecules to which the altered antibodies, and/or natural or
synthetic light or heavy chains of the donor antibody or other
fragments of the donor antibody may be associated by conventional
means. Such non-protein carriers can include conventional carriers
used in the diagnostic field, e.g., polystyrene or other plastic
beads, polysaccharides, e.g., as used in the BIAcore [Pharmacia]
system, or other non-protein substances useful in the medical field
and safe for administration to humans and animals. Other effector
agents may include a macrocycle, for chelating a heavy metal atom,
or radioisotopes. Such effector agents may also be useful to
increase the half-life of the altered antibodies, e.g.,
polyethylene glycol.
[0030] "Polypeptide" refers to any peptide or protein comprising
two or more amino acids joined to each other by peptide bonds or
modified peptide bonds, i.e., peptide isosteres. "Polypeptide"
refers to both short chains, commonly referred to as peptides,
oligopeptides or oligomers, and to longer chains, generally
referred to as proteins. Polypeptides may contain amino acids other
than the 20 gene-encoded amino acids. "Polypeptides" include amino
acid sequences modified either by natural processes, such as
posttranslational processing, or by chemical modification
techniques that are well known in the art. Such modifications are
well described in basic texts and in more detailed monographs, as
well as in a voluminous research literature. Modifications can
occur anywhere in a polypeptide, including the peptide backbone,
the amino acid side-chains and the amino or carboxyl termini. It
will be appreciated that the same type of modification may be
present in the same or varying degrees at several sites in a given
polypeptide. Also, a given polypeptide may contain many types of
modifications. Polypeptides may be branched as a result of
ubiquitination, and they may be cyclic, with or without branching
Cyclic, branched and branched cyclic polypeptides may result from
posttranslation natural processes or may be made by synthetic
methods. Modifications include acetylation, acylation,
ADP-ribosylation, amidation, covalent attachment of flavin,
covalent attachment of a heme moiety, covalent attachment of a
nucleotide or nucleotide derivative, covalent attachment of a lipid
or lipid derivative, covalent attachment of phosphotidylinositol,
cross-linking, cyclization, disulfide bond formation,
demethylation, formation of covalent cross-links, formation of
cysteine, formation of pyroglutamate, formylation,
gamma-carboxylation, glycosylation, GPI anchor formation,
hydroxylation, iodination, methylation, myristoylation, oxidation,
proteolytic processing, phosphorylation, prenylation, racemization,
selenoylation, sulfation, transfer-RNA mediated addition of amino
acids to proteins such as arginylation, and ubiquitination. See,
for instance, PROTEINS--STRUCTURE AND MOLECULAR PROPERTIES, 2nd
Ed., T. E. Creighton, W. H. Freeman and Company, New York, 1993 and
Wold, F., Posttranslational Protein Modifications: Perspectives and
Prospects, pgs. 1-12 in POSTTRANSLATIONAL COVALENT MODIFICATION OF
PROTEINS, B. C. Johnson, Ed., Academic Press, New York, 1983;
Seifter, et al., "Analysis for protein modifications and nonprotein
cofactors", Meth. Enzymol. (1990) 182:626-646 and Rattan, et al.,
"Protein Synthesis: Posttranslational Modifications and Aging", Ann
N.Y. Acad Sci (1992) 663:48-62.
[0031] "Variant" as the term is used herein, is a polynucleotide or
polypeptide that differs from a reference polynucleotide or
polypeptide respectively, but retains essential properties. A
typical variant of a polynucleotide differs in nucleotide sequence
from another, reference polynucleotide. Changes in the nucleotide
sequence of the variant may or may not alter the amino acid
sequence of a polypeptide encoded by the reference polynucleotide.
Nucleotide changes may result in amino acid substitutions,
additions, deletions, fusions and truncations in the polypeptide
encoded by the reference sequence, as discussed below. A typical
variant of a polypeptide differs in amino acid sequence from
another, reference polypeptide. Generally, differences are limited
so that the sequences of the reference polypeptide and the variant
are closely similar overall and, in many regions, identical. A
variant and reference polypeptide may differ in amino acid sequence
by one or more substitutions, additions, deletions in any
combination. A substituted or inserted amino acid residue may or
may not be one encoded by the genetic code. A variant of a
polynucleotide or polypeptide may be a naturally occurring such as
an allelic variant, or it may be a variant that is not known to
occur naturally. Non-naturally occurring variants of
polynucleotides and polypeptides may be made by mutagenesis
techniques or by direct synthesis.
[0032] As used herein "eosinophilic bronchitis" refers to a
condition in which a mammal has quantitative sputum cell counts
(eosinophils greater than 2%) which is responsive to corticosteroid
treatment. It may occur alone or in association with asthma or in
some patients with chronic obstructive pulmonary disease (COPD).
Typically, in comparison to asthmatic patients, those with
eosinophilic bronchitis experience the symptom of cough alone and
have both normal lung function and airway responsiveness (Thomson
and Chaudhuri American Journal of Respiratory and Critical Care
Medicine 170:4-5 (2004), and Gibson, et al. Thorax 57:178-182
(2002)). In most patients the eosinophilic bronchitis responds to
treatment with inhaled steroids but in some it requires a minimum
dose of prednisone to keep it controlled. Eosinophilic bronchitis
and/or asthma can be considered severe in a patient when the
patient requires at least 35-40 mg/day of predisone to control the
symptoms of either condition.
[0033] As used herein "airway eosinophilia" refers to any disease
or disorder in which a patient has any amount of eosinophils in any
airway, including but not limited to, lung. Eosinophils may be
detected, for example, in or by biopsy, sputum, and/or lavage.
Diseases associated with airway eosinophilia include, but are not
limited to, eosinophilic asthma, eosinophilic COPD, eosinophilic
bronchitis, and airway eosinophilia associated with viral
infections, including, but not limited to, rhino virus. (Shinohara,
et al. Allergol Int. 2008 Dec 1;57(4); Wos, et al. Am J Respir Crit
Care Med. 2008; Handzel, et al. T cells.J Immunol. 1998 Feb
1;160(3):1279-84.PMID; Mercer, et al. Respir Res. 2005; 6:151; and
Saetta, et al. Clin Exp Allerg 1996;26:766-774).
[0034] As used herein "refractory asthma" refers to a condition
wherein a patient has one or both major criteria and two minor
criteria as set forth below:
TABLE-US-00001 Major Characteristics In order to achieve control to
a level of mild-moderate persistent asthma: 1. Treatment with
continuous or near continuous ( 50% of year) oral corticosteroids
2. Requirement for treatment with high-dose inhaled
corticosteroids: Drug Dose (.mu.g/d ) Dose (puffs/d) a.
Bcclomcthasonc dipropionatc >1,260 >40 puffs (42
.mu.g/inhalation >20 puffs (84 .mu.g/inhalation b. Budesonide
>1,200 >6 puffs c. Flunisolide >2,000 >8 puffs d.
Fluticasone propionate >880 >8 puffs (110 .mu.g), >4 puffs
(220 .mu.g) e. Triamcinolone acetonide >2,000 >20 puffs Minor
Characteristics 1. Requirement for daily treatment with a
controller medication in addition to inhaled corticosteroids, e.g.,
long-acting 3-agonist, theophylline, or leukotriene antagonist 2.
Asthma symptoms requiring short-acting .beta.-agonist use on a
daily or near daily basis 3. Persistent airway obstruction
(FEV.sub.1 < 80% predicted; diurnal PEF variability > 20%) 4.
One or more urgent care visits for asthma per year 5. Three or more
oral steroid "bursts" per year 6. Prompt deterioration with 25%
reduction in oral or inhaled corticosteroid dose 7. Near fatal
asthma event in the past *Requires that other conditions have been
excluded, exacerbating factors treated, and patient felt to be
generally adherent. Fahy, J. Am. J. Respir. Crit. Care Med., Volume
162, Number 6, December 2000, 2341-2351
[0035] As used herein "severe asthma" is meant to include patients
with refractory asthma. Patients with severe asthma may not
necessarily have airflow obstruction all of the time, and may or
may not have airway hyperresponsiveness but may suddenly
deteriorate on a background of relatively stable disease (on
treatment). "Severe asthma" is also understood in the art to be
defined by various clinical scales other than the ATS such as
guidelines set for by Global Strategy for Asthma Management and
Prevention, Global Initiative for Asthma (GINA) 2007 as well as
other guidelines known in the art.
[0036] As used herein, "reduce" or "reducing" eosinophils refers to
a decrease in the amount of eosinophils observed in the blood
and/or sputum of a patient after administration at least one
anti-IL-5 antibody.
[0037] As used herein "co-administration" or "co-administering" as
used herein refers to administration of two or more compounds to
the same patient. Co-administration of such compounds may be
simultaneous or at about the same time (e.g., within the same hour)
or it may be within several hours or days of one another. For
example, a first compound may be administered once weekly while a
second compound is co-administered daily.
[0038] As used herein "disorder associated with excess eosinophil
production" means any disorder or disease in which atypical
symptoms may manifest due to the production of eosinophils.
Disorders associated with excess eosinophil production include but
are not limited to, eosinophilic bronchitis, atopic asthma, atopic
dermatitis, allergic rhinitis, non-allergic rhinitis, asthma,
severe asthma, chronic eosinophilic pneumonia, allergic
bronchopulmonary aspergillosis, coeliac disease, Churg-Strauss
syndrome (periarteritis nodosa plus atopy), eosinophilic myalgia
syndrome, hypereosinophilic syndrome, oedematous reactions
including episodic angiodema, helminth infections, eosinophilia
associated with parasite infection and/or the treatment of
parasitic infection, onchocercal dermatitis and
Eosinophil-Associated Gastrointestinal Disorders, including but not
limited to, eosinophilic oesophagitis, eosinophilic gastritis,
eosinophilic gastroenteritis, eosinophilic enteritis and
eosinophilic colitis, nasal micropolyposis and polyposis, aspirin
intolerance, asthma and obstructive sleep apnoe. Eosinophil-derived
secretory products have also been associated with the promotion of
angiogenesis and connective tissue formation in tumours and the
fibrotic responses seen in conditions such as chronic asthma,
Crohn's disease, scleroderma and endomyocardial fibrosis (Munitz A,
Levi-Schaffer F. Allergy 2004; 59: 268-75, Adamko et al. Allergy
2005; 60: 13-22, Oldhoff, et al. Allergy 2005; 60: 693-6).
[0039] The therapeutic response induced by the methods of this
invention is produced by the binding on an anti-IL-5 antibody to
human IL-5 and thus subsequently blocking eosinophil stimulation.
Thus, the methods of the present invention are highly desirable for
those persons experiencing eosinophilic bronchitis.
[0040] Methods are provided herein for treating eosinophilic
bronchitis, comprising administering to said human suffering from
eosinophilic bronchitis a composition comprising at least one
anti-IL-5 antibody. In some aspects, said human suffering from
eosinophilic bronchitis has steroid-dependent eosinophilic
bronchitis. In some aspects, the steroid is prednisone and/or
prednisolone. The anti-IL antibody may be neutralizing. In another
aspect, the at least one anti-IL-5 antibody is humanized. The least
one anti-IL-5 antibody may comprise a heavy chain comprising SEQ ID
NO: 19. The at least one anti-IL-5 antibody may comprise a light
chain comprising SEQ ID NO: 21. In yet another aspect, the human is
suffering from at least one additional disorder associated with
excess eosinophil production selected from the group consisting of
atopic asthma, atopic dermatitis, allergic rhinitis, non-allergic
rhinitis, asthma, severe asthma, chronic eosinophilic pneumonia,
allergic bronchopulmonary aspergillosis, coeliac disease,
Churg-Strauss syndrome, eosinophilic myalgia syndrome,
hypereosinophilic syndrome, oedematous reactions including episodic
angiodema, helminth infections, eosinophilia associated with
parasitic infection and/or the treatment of parasitic infection,
onchocercal dermatitis eosinophilic oesophagitis, eosinophilic
gastritis, eosinophilic gastroenteritis, eosinophilic enteritis,
eosinophilic colitis, nasal micropolyposis, nasal polyposis,
aspirin intolerance asthma, obstructive sleep apnoe, chronic
asthma, Crohn's disease, scleroderma and endomyocardial
fibrosis.
[0041] In yet another aspect, the composition comprising at least
one anti-IL-5 antibody is administered intravenously. The
composition comprising at least one anti-IL-5 antibody may be
administered at a dose of 750 mg. The intravenous dose may be
administered intravenously over 30 minutes. In another aspect, the
composition comprising at least one anti-IL-5 antibody may be
administered intravenously over a time range of about 10 minutes to
about 4 hours or more specifically over a range of about 20 minutes
to about 60 minutes. In another aspect of the present invention the
composition comprising at least one anti-TL-5 antibody is
administered subcutaneously, which may be at a dose of 250 mg. A
subcutaneous dose may be administered one to three times or more to
a human.
[0042] In yet another aspect, the human is receiving prednisone
and/or prednisolone for said steroid-dependent eosinophilic
bronchitis and said prednisone is reduced by at least about 90% in
said human suffering from steroid-dependent eosinophilic bronchitis
after treatment with said composition comprising at least one
anti-IL-5 antibody. The human suffering from steroid-dependent
eosinophilic bronchitis experiences a statistically significant
reduction in exacerbations of eosinophilic bronchitis after
receiving at least said composition comprising at least one
anti-IL-5 antibody. The eosinophil level in said human are reduced
to within normal limits, which is understood in the art and can be
measured by a variety of methods including, but not limited to,
bronchial scrubbing. By way of example, within normal limits would
include, but would not me limited to, quantitative sputum cell
counts having eosinophils less than 2%. The eosinophil levels
remain within normal limits for at least 8 weeks after the last
dose of said composition comprising anti-IL-5 antibody. Eosinophil
levels may be reduced in blood and/or sputum.
[0043] In another aspect, methods are provided for treating a human
with eosinophilic bronchitis wherein said composition comprising at
least one anti-IL-5 antibody comprises a first anti-IL-5 antibody
and a second anti-IL-5 antibody. The composition comprising at
least one anti-IL-5 antibody may be co-administered with a
steroid.
[0044] The present invention also provides methods for reducing
eosinophils in a human in suffering from eosinophilic bronchitis,
comprising administering a composition comprising a first anti-IL-5
antibody and a second anti-IL-5 antibody. Methods are also provided
herein wherein at least one anti-IL-5 antibody is co-administered
with a steroid.
[0045] The current invention also provides use of at least one
anti-IL-5 antibody in the manufacture of a medicament for the
treatment of eosinophilic bronchitis. The present invention
provides use of an anti IL-5 antibody or fragment thereof for
treatment of eosinophilic bronchitis comprising administering to a
patient in need thereof a composition comprising at least one
anti-IL-5 antibody. Also provided herein are pharmaceutical
compositions capable of treating eosinophilic bronchitis or
alleviating the symptoms produced thereby and formulated for the
methods and uses described herein. The present invention provides
an anti-IL-5 antibody for use in the treatment of eosinophilic
bronchitis, for administration alone or in combination with a
steroid. The anti-IL-5 antibodies of the present invention also
provide anti-IL-antibodies for all of the methods and uses
described herein.
EXAMPLES
[0046] The following examples illustrate various aspects of this
invention. The results of Example 1 are published in Parameswaran,
et al. The New Engl J Med 360(10):985-993 (2009), which is
incorporated by reference herein in its entirety.
Example 1
[0047] The study was a randomized, placebo-controlled, parallel
group trial of up to 26 weeks. Patients were seen every two weeks
and were randomized to treatment at week 2. Humanized monoclonal
antibody to IL-5, mepolizumab, was given at a dose of 750 mg or
placebo over 30 minutes at weeks 2, 6, 10, 14, and 18. The dose of
prednisone was reduced at weeks 6, 10, 14, 18, and 22, except in
patients who had required prednisone in a daily dose of 10 mg or
more. The variables measured every two weeks were: Juniper Asthma
Control Questionnaire (ACQ), symptom Likert score, maximal
expiratory flow-volume curves to measure FEV.sub.1, and slow vital
capacity (VC) before and 15 minutes after salbutamol 200 .mu.g,
sputum quantitative cell counts and blood eosinophils. As a result
of prednisone reduction, the patients could have a clinical
exacerbation or develop bothersome steroid withdrawal symptoms.
Exacerbations were defined by an increase in salbutamol use of 4 or
more puffs/day or of nocturnal or waking respiratory symptoms on
two consecutive days, or by a fall in post-salbutamol
FEV.sub.1>15% from the randomization visit or by a 2-point
change in the Likert score for cough or as decided by the
investigator.
[0048] Spirometry was performed according to the American Thoracic
Society recommendations (American Thoracic Society, Standardization
of Spiromerty, 1994 update, Am J Respir Crit Care Med,
152:1107-1136 (1995)) and predicted values were obtained from
Crapo, et al. (Crapo, et al. Am Rev Respir Dis, 123:659-94 (1981)).
Asthma control was assessed using the validated Asthma Control
Questionnaire (Juniper, et al, Eur Respir J, 14:902-7 (1999)). In
addition, symptoms of cough, wheeze, chest tightness and shortness
of breath were evaluated for the seven days prior to each visit on
a 7-point Likert scale (7 no symptoms, 1 worse) (Guyatt, et al. J
Chronic Dis, 40:1129-33 (1987)). Sputum was induced and processed
as described by Pizzichini, et al. (Pizzichini, et al. Eur Respir
J, 9:1174-1180 (1996)). Airway responsiveness to methacholine was
measured using the tidal breathing method described by Cockcroft,
et al. (Cockcroft, et al. Clin Allergy, 7:235-43 (1977) after
withholding .beta.-agonists for 24 hours.
[0049] Exacerbations for this example were defined as either a
patient-initiated increase in their daily dose of albuterol of four
or more puffs to control symptoms of chest tightness or as any one
of the following: nocturnal or waking respiratory symptoms on two
consecutive days, a decrease of more than 15% in the FEV.sub.1 from
the label at randomization after the use of albuterol, or a 2-point
worsening in the Likert score for cough by the investigators at
their discretion on the basis of general clinical worsening, For
the latter exacerbation, sputum-cell counts were not known to the
treating physician at the time this decision was made and were not
considered in the definition of exacerbations.
[0050] Exacerbations, unless accompanied by sputum neutrophilia,
were treated with 30 mg of prednisone for 7 days. During this time,
the patient was withdrawn from the study and was seen again at 2
and 4 weeks. If the exacerbation was accompanied by neutrophilic
airway inflammation (total cell count, >15.times.10.sup.6 per
gram of sputum; neutrophils, >80%), it was treated with 500 mg
of amoxicillin-clavulanic acid twice daily for 10 days; patients
with neutrophilic exacerbations were not withdrawn from the study,
and they continued with the protocol for prednisone reduction.
[0051] The sample size was based on the primary outcome of the
proportion of patients who would have exacerbations in each
treatment arm. It was expected that all patients on the placebo
would exacerbate when the dose was reduce by 50%, while not more
that 4 patients on the active arm would exacerbate for a similar
dose reduction. The study had 90% power to detect this difference.
Between group comparisons of normally distributed data were
compared using unpaired-t test and no-normally data were compared
using Median test in an intention-to treat analysis. Proportional
data was analyzed using Fisher's exact test. Cumulative probability
and time to exacerbation between treatment groups were compared by
Cox's proportional hazards methods. All tests were 2-sided and
significance was accepted at 95% level and the analyses were done
using the Statistical Package for Social Sciences, version 13.0
(SPSS, Chicago, Ill.).
[0052] Patients meeting the following inclusion criteria were
enrolled in a study of anti-IL5 monoclonal antibody therapy for
eosinophilic bronchitis sputum eosinophilia in patients with asthma
chronically treated with systemic and high dose inhaled
corticosteroids: [0053] Adult patients, aged 18-70 years, who have
been followed as an outpatient and who have been found to require a
minimum dose of prednisone treatment (in addition to high-dose
inhaled steroid treatment) to prevent frequent exacerbations
associated with induced sputum eosinophilia. [0054] Patients who,
at screening and baseline visits, demonstrate sputum eosinophilia
and symptoms. The symptoms may effect activity and sleep but should
not, in the opinion of the treating physician, be severe enough to
be of concern. [0055] While FEV.sub.1 after withholding
bronchodilators appropriately, before and after inhaled salbutamol
(200 mg), and methacholine PC20 will be measured, these need not be
abnormal since the prednisone is required for the control of
eosinophilic bronchitis and any clinical consequences of this, and
because the bronchitis can occur without these features of asthma.
[0056] On the same doses of corticosteroids for a least one-month.
The study was divided into 3 sequential study periods as follows
and presented in FIG. 1: [0057] Period 1: Symptomatic eosinophilic
bronchitis (with or without asthma) on the same dose of prednisone
for 6-weeks or more. [0058] Period 2: Standardized prednisone
reduction (and inhaled steroid if prednisone is discontinued during
the study treatment) at intervals of 4-weeks until there is a
clinical and eosinophilic exacerbation or bothersome steroid
withdrawal effects. [0059] Period 3: Washout.
[0060] The patients were seen every 2 weeks. Intravenous injections
of an anti-IL-5 antibody (mepolizumab) 750 mg or placebo were given
at weeks 2, 6, 10, 14 and 18. Doses of prednisone were reduced in a
standard way. A summary of patient demographics and baseline
characteristics is presented in Table 1.
TABLE-US-00002 TABLE 1 Demographic and Clinical Characteristics of
Patients at Baseline* Mepolizumab Placebo Characteristics (n = 9)
(n = 11) Age (years) 56.4 .+-. 10.9 58.2 .+-. 7.1 Gender, Male (no.
of patients) 4 8 Height, cm 166.2 .+-. 14.5 168.6 .+-. 9.9 Weight,
kg 85.8 .+-. 16.7 89.5 .+-. 14.9 Duration of symptoms, y 13.3 .+-.
10.3 12.5 .+-. 9.59 FEV.sub.1 Previous minimum.dagger. Value
(liters) 1.4 .+-. 0.6 1.6 .+-. 0.5 % of predicted value 48 .+-. 17
52 .+-. 13 Previous maximum.dagger. Improvement with bronchodilator
(%) 28.4 .+-. 12.03 24.6 .+-. 10.6 Decrease during exacerbation (%)
42.0 .+-. 16.9 45.5 .+-. 13.7 Current postbronchodilation % of
predicted value 66.6 .+-. 18.3 74.3 .+-. 17.9 Ratio of FEV.sub.1 to
vital capacity (%) 63.8 .+-. 16.2 65.9 .+-. 13.1 Sputum cosinophils
Median 16.6 4.0 Range 1.6-54.3 0-35.3 Duration of daily use of
prednisone 9.3 .+-. 7.6 8.9 .+-. 8.5 (years) Prednisone (mg/day)
Median 10 10 Range 5-25 2.5-20 Inhaled Corticosteroids (.mu.g/day)
Median 1000 1000 Range 600-2000 1000-2000 Short-acting
.beta.-agonist 10 .+-. 6 9 .+-. 8 (no. of puffs/week) Long-acting
.beta.-agonist 9 9 (no. of patients) Leukotriene-receptor
antagonists 2 1 (no. of patients) Atopy (no. of patients) 3 4 Nasal
polyp (no. of patients) 3 5 Smoking history of >10 pack years 2
3 (no. of patients) *Plus-minus values are means .+-. SD. Values
are those recorded at the time of screening unless otherwise
stated. There were no significant differences between the two
groups for any of the variables except the number of sputum
eosinophils (P = 0.03). FEV.sub.1 denotes forced expiry volume in 1
second. .dagger.Previous lowest and highest values for FEV.sub.1
refer to the historic lowest and highest values recorded since the
patients were first seen in the clinic. .dagger-dbl.The dose of
inhaled corticosteroid is the equivalent of inhaled
fluticasone.
Results
[0061] Nineteen of the 20 patients completed the study. One subject
who received the active drug was withdrawn from the study after the
3.sup.rd infusion because of heart failure, but was included in the
analysis. Thus, the main analyses included 20 patients, and the
per-protocol analysis included only the 18 subjects who had airway
eosinophilia at baseline.
Primary Outcomes
[0062] Exacerbations
[0063] There were 12 asthma exacerbations in the placebo group.
Nine were associated with sputum eosinophilia and three were
associated with sputum neutrophilia, of which two were in a patient
who was eventually treated for an exacerbation associated with
sputum eosinophilia. Thus, 10 of the 11 patients in the placebo
group had exacerbations that led to treatment with prednisone or
antibiotics. In contrast, there were two events in the mepolizumab
arm (1 neutrophilic exacerbation and one withdrawal due to adverse
event) (p=0.008). Exacerbations were identified by a decline in
FEV.sub.1 and additional criteria in seven patients (one in the
active treatment group and six in the placebo group), by an
increase in .beta..sub.2-agonist rescue (three patients in the
placebo group), and by nocturnal symptoms (one patient in the
placebo group). A change in the Likert scale alone or physician
discretion was not used in any patient to identify an exacerbation
or initiate a change in prednisone dose. The median time to
exacerbation (irrespective of type of bronchitis) was 12 weeks in
the placebo group and 20 weeks in the mepolizumab group (p=0.003).
(FIG. 2).
[0064] There were also no exacerbations associated with
neutrophilic bronchitis in the mepolizumab group while there were 3
in the placebo group.
[0065] Reduction in Prednisone Dose
[0066] In the mepolizumab group, patients had a mean (.+-.SD)
reduction of prednisone by 83.8%.+-.33.4% of the maximum possible
reduction per protocol compared to 47.4%.+-.40.5% in the placebo
group (p<0.04). In absolute terms, the mean dose of prednisone
was reduced from 11.9 mg to 3.9 mg in the mepolizumab group and
from 10.7 to 6.4 mg in the placebo group (median reduction in the
two groups, from 10 to 5 mg) (P=0.11).
[0067] Pre-specified Subgroup Analyses
[0068] Data for 8 of the 10 patients in the placebo group who had
an exacerbation accompanied by sputum eosinophilia and were
censored at that time, while none of the patients who received
mepolizumab had an exacerbation associated with sputum eosinophilia
(P=0.02). There were three exacerbations in the placebo group
associated with sputum neutrophilia. In the mepolizumab group,
there were five episodes of increased numbers of sputum neutrophils
(in four patients) during routine visits, but the episodes were not
associated with a change in the measures that defined an
exacerbation and thus were not treated.
[0069] In the mepolizumab group, there was a mean (.+-.SD)
reduction in use of prednisone by 94.3%.+-.12.9% of the maximum
possible reduction per protocol compared with 47.5%.+-.42.2% in the
placebo group (p=0.01).
[0070] Pre-Specified Secondary Outcomes
[0071] A single infusion of mepolizumab was associated with a
reduction in the number of eosinophils to within normal limits in
sputum (P=0.005) and blood (P=0.004). The levels remained within
normal limits after reductions in the dose of prednisone for up to
8 weeks after the last infusion of mepolizumab (P=0.01). In
contrast, a reduction in the dose of prednisone in the placebo
group was associated with a significant increase in the number of
eosinophils in sputum and blood (FIG. 3 and Tables 2A). There was
no significant effect of mepolizumab on cell types other than
eosinophils in sputum or blood, except for a significant reduction
of lymphocytes in sputum 4 weeks after the fifth infusion
(P=0.001). Mepolizumab treatment was associated with a modest
improvement in FEV1 (mean 300 ml), a nonsignificant improvement in
asthma symptoms, and a significant improvement in scores on the
Juniper Asthma Control Questionnaire (P=0.01) (Table 2A and FIG.
3).
[0072] Secondary Outcomes
[0073] A single infusion of mepolizumab reduced sputum and blood
eosinophils to within normal limits, where they remained after
reductions of prednisone dose (p<0.05) and for up to 8 weeks
after the last infusion of mepolizumab. In contrast, sputum and
blood eosinophils increased significantly with prednisone reduction
in the placebo arm (Table 2B). Mepolizumab treatment was associated
with the improvement in FEV.sub.1, asthma symptoms and asthma
control questionnaire score as shown in Tables 2A.
[0074] A summary of variables before and after treatment for
patients treated with mepolizumab are presented in Table 2A. A
summary of variables before and after treatment for patients
treated with placebo are presented in Table 2B.
TABLE-US-00003 TABLE 2A Variables before and after treatment with
mepolizumab. Visit 4 Visit 12 Visit 14 Visit 1 4 weeks post 4 weeks
post 8 weeks post Variables Baseline First dose Last dose Last dose
Number of patients 9 9 7 7 Sputum eosinophils (%) Median 16.6
0.0.dagger. 1.3.dagger. 0.3.dagger. Range 1.6-54.3 0-4.0 0.0-11.3
0.0-4.6 Blood eosinophils .+-. per mm.sup.3 664.4 .+-. 492.5 49.5
.+-. 37.46.dagger. 64.5 .+-. 37.94.dagger. 76.3 .+-. 39.36.dagger.
FEV.sub.1 after bronchodilation Value .+-. Liters 2.0 .+-. 0.88 2.1
.+-. 0.99 2.4 .+-. 1.06.dagger-dbl. 2.3 .+-. 0.87 % of predicted
value 66.6 .+-. 18.25 69.7 .+-. 17.7 71.9 .+-. 17.3.dagger-dbl.
70.3 .+-. 13.2 Juniper Asthma Control Questionnaire.sup.a 1.9 .+-.
0.78 1.3 .+-. 0.91.dagger. 1.2 .+-. 0.81.dagger. 1.3 .+-.
0.91.dagger. Cough Score.sup.b 6.0 .+-. 0.82 5.2 .+-. 0.80.dagger.
5.3 .+-. 0.96.dagger. 5.5 .+-. 1.00 Symptoms Scorc.sup.c 29.4 .+-.
2.9 28.7 .+-. 4.9 31.6 .+-. 2.30 30.1 .+-. 4.02 Plus-minus values
are means .+-. SD. FEV.sub.1 denotes forced expiry volume in 1
second. .dagger.P < 0.05 for the comparison with baseline value.
.dagger-dbl.P < 0.05 for the comparison with the corresponding
change from baseline in the placebo group. .sup.aThe Juniper Asthma
Control Questionnaire score ranges from 0 to 6, with higher scores
indicating worse control. .sup.bThe cough score, which was measured
only in patients without current asthma at screening, ranges from 1
to 7, with lower scores indicating a greater severity of symptoms.
.sup.cThe symptoms score ranges from 7 to 35 with lower scores
indicating greater severity of symptoms. This score consists of a
composite rating of shortness of breath, chest tightness, wheezing,
cough, and sputum production each graded on a 7-point Likert
scale.
TABLE-US-00004 TABLE 2B Variables before and after treatment with
placebo Visit 4 Visit 12 Visit 14 Visit 1 4 weeks post 4 weeks post
8 weeks post 4 weeks post Variables Baseline First dose Last dose
Last dose Exacerbation Exacerbation Number of patients 11 10 2 2 9
9 Sputum eosinophils (%) Median 4.0 3.0 3.2 5.0 25.3 4.0 Range
0-35.3 0.0-16.3 1.3-5.0 1.0-9.0 5.0-63.7 1.3-52.5 Blood eosinophils
.+-. per mm.sup.3 352.1 .+-. 253.74 295.8 .+-. 207.39 657.0 .+-.
413.23 1224.0 .+-. 1383.03 655.5 .+-. 254.77 622.4 .+-. 498.4
FEV.sub.1 after bronchodilation Value .+-. Liters 2.2 .+-. 0.92 2.3
.+-. 0.94 2.3 .+-. 0.44 2.3 .+-. 0.39 2.0 .+-. 0.97 2.2 .+-. 0.8 %
of predicted value 74.3 .+-. 17.8 75.6 .+-. 17.0 78.4 .+-. 20.9
78.1 .+-. 19.2 60.9 .+-. 20.7 74.4 .+-. 14.4 Juniper Asthma Control
1.8 .+-. 0.92 1.6 .+-. 0.88 1.2 .+-. 0.52 1.2 .+-. 0.28 2.0 .+-.
1.04 1.6 .+-. 1.4 Questionnaire.sup.a Cough Score.sup.b 6.3 .+-.
0.96 5.2 .+-. 1.2 NA NA 5.8 .+-. 1.1 6.2 .+-. 1.0 Symptoms
Score.sup.c 29.8 .+-. 5.14 30.8 .+-. 2.9 33.2 .+-. 1.56 32.5 .+-.
3.54 27.2 .+-. 4.18 29.4 .+-. 7.3 Plus-minus values are means .+-.
SD. FEV.sub.1 denotes forced expiry volume in 1 second and NA not
applicable. .sup.aThe Juniper Asthma Control Questionnaire score
ranges from 0 to 6, with higher scores indicating worse control.
.sup.bThe cough score, which was measured only in patients without
current asthma at screening, ranges from 1 to 7, with lower scores
indicating a greater severity of symptoms. .sup.cThe symptoms score
ranges from 7 to 35 with lower scores indicating greater severity
of symptoms. This score consists of a composite rating of shortness
of breath, chest tightness, wheezing, cough, and sputum production
each graded on a 7-point Likert scale.
Safety
[0075] One patient in the mepolizumab group had progressive
shortness of breath after receiving three infusions of the drug and
was removed from the study. Investigators, who were unaware of
study-group assignments, determined that this patient had
preexisting coronary artery disease; the breathlessness was
attributable to heart failure due to ischemic cardiomyopathy. The
patient did not undergo endocardial biopsy or cardiac magnetic
resonance imaging to rule out eosinophilic cardiomyopathy. One
patient in the placebo group died suddenly at home, 6 months after
the completing the full study. On autopsy, the cause of death was
identified as sudden cardiac arrest possibly due to a ventricular
tachyarrhythmia and was not ascribed to worsening asthma. One
patient in the mepolizumab group reported having aches and
tiredness when the prednisone dose was reduced to 2.5 mg. One
patient in the placebo group had hypoadrenalism during the
prednisone reduction from 12.5 mg to 5 mg per day (as demonstrated
by a blunted cortisol response to a short corticotrophin
stimulation test). There were no other serious adverse events.
There were no significant abnormalities in blood chemical values
attributable to mepolizumab.
Discussion
[0076] These data show that in the rare patient with asthma who
continues to have sputum eosinophilia even when treated with oral
prednisone and high dose inhaled corticosteroids, that treatment
with a humanized monoclonal antibody against IL-5 allows a
reduction in prednisone dose without the development of asthma
exacerbations. These results are contrary to the negative results
of earlier studies with a similar antibody (Leckie, et al. Lancet
2000; 356: 2144-8; Kips, et al. Am J Respir Crit Care Med 2003;
167: 1655-9; and Flood-Page, et al. Am J Respir Crit Care Med 2007;
176: 1062-71) in patients with more common forms of asthma and in
concordance with those in hypereosinophilia syndrome (HES) (Klion,
et al. Blood 2004; 103: 2939-2941; Garrett, et al. J Allergy Clin
Immunol 2004; 113: 115-119; and Rothenberg, et al. N Engl J Med
2008; 358: 1215-28), and in two case report abstracts of asthma
with sputum eosinophilia (Korn, et al. Am J Respir Crit Care Med
2007; 175: A486) and HES with asthma (Hargreave, et al. Clin Exp
Allergy (abstract) 2004; 34: 1807).
[0077] In patients in the present study, with adult onset asthma,
sputum eosinophilia that persisted in the presence of oral and
inhaled corticosteroid treatment was reversed by the anti-IL-5
treatment and the patients improved clinically. In contrast, in the
earlier studies, sputum eosinophils were either not measured, or
there was little or no sputum eosinophilia at the onset of the
study (Kips, et al. Am J Respir Crit Care Med 2003; 167: 1655-9
and
[0078] Flood-Page, et al. Am J Respir Crit Care Med 2007; 176:
1062-71). None of the prior studies reported the effect of this
treatment on the small subset of patients with baseline airway
eosinophilia. It is thus possible that the lack of clinical benefit
in previous trials was because the majority of patients randomized
did not have the clinical phenotype we studied, persistent airway
eosinophilia despite corticosteroid treatment.
[0079] This study has significant limitations. First, there was an
imbalance in the starting percentage of sputum eosinophils between
the two treatments, with the mepolizumab group having a higher
sputum eosinophil count. It is possible that the patients who
respond to mepolizumab are those with the highest numbers of
eosinophils in sputum despite corticosteroid treatment. Second,
although the study demonstrated a significant prednisone-sparing
effect, there was no statistically significant difference in the
more clinically meaningful outcome of the final prednisone doses in
the two treatment groups. Third, the study relied on past objective
evidence of asthma as indicated by variable airflow limitation.
Since most patients had frequent exacerbations in the past and were
on a maintenance dose of long-acting bronchodilator or had moderate
airflow obstruction at baseline, the study did not re-test for
albuterol reversibility or methacholine airway hyperresponsiveness
in all patients at baseline. Fourth, the patients studied represent
only a small proportion of patients with asthma and persistent
sputum eosinophilia and our results likely do not apply to most
patients with asthma. Fifth, despite efforts, investigators may not
have remained completely blinded to treatment allocation because
they were in part aware of sputum cell counts. Sixth the study is
quite small and cannot be considered clinically directive.
[0080] In summary, intravenous mepolizumab reduces blood and sputum
eosinophils and is prednisone-sparing in patients with asthma who
had sputum eosinophils despite oral prednisone and high dose
inhaled steroid treatment. This small pilot study is potentially
clinically directive and highlights the importance of selecting
subjects with airway eosinophilia to study an anti-eosinophil drug
in asthma.
Sequence CWU 1
1
211334DNAMurine 1acctggcctg gtggcgccct cacagagcct gtccatcact
tgcactgtct ctgggttttc 60attaaccagc tatagtgtac actgggttcg ccagcctcca
ggaaagggtc tggagtggct 120gggagtaata tgggctagtg gaggcacaga
ttataattcg gctctcatgt ccagactgag 180catcagcaaa gacaactcca
agagccaagt tttcttaaaa ctgaacagtc tgcaaactga 240tgacacagcc
atgtactact gtgccagaga tcccccttct tccttactac ggcttgacta
300ctggggccaa ggcaccactc tcacagtctc ctca 3342315DNAMurine
2tcctccctga gtgtgtcagc aggagagaag gtcactatga gctgcaagtc cagtcagagt
60ctgttaaaca gtggaaatca aaagaactac ttggcctggt accagcagaa accagggcag
120cctcctaaac ttttgatcta cggggcatcc actagggaat ctggggtccc
tgatcgcttc 180acaggcagtg gatctggaac cgatttcact ctttccatca
gcagtgtgca ggctgaagac 240ctggcagttt attactgtca gaatgttcat
agttttccat tcacgttcgg ctcggggaca 300gagttggaaa taaaa
3153334DNAMurine 3acctggcctg gtggcgccct cacagagcct gtccatcact
tgcactgtct ctgggttttc 60attaaccagt tatagtgtac actgggttcg ccagcctcca
ggaaagggtc tggagtggct 120gggagtaata tgggctagtg gaggcacaga
ttataattcg gctctcatgt ccagactgag 180catcagcaaa gacaactcca
agagccaagt tttcttaaaa ctgaacagtc tgcgaactga 240tgacacagcc
atgtactact gtgccagaga tcccccttct tccttactac ggcttgacta
300ctggggccaa ggcaccactc tcacagtctc ctca 3344315DNAMurine
4tcctccctga gtgtgtcagc aggagagaag gtcactatga gctgcaagtc cagtcagagt
60ctattaaaca gtggaaatca aaagaactac ttggcctggt accaacagaa accagggcag
120cctcctaaac ttttgatcta cggggcatcc actagggaat ctggggtccc
tgatcgcttc 180acaggcagtg gatctggaac cgatttcact cttaccatca
gcagtgtgca ggctgaagac 240ctggcagttt attactgtca gaatgatcat
agttttccat tcacgttcgg ctcggggaca 300gagttggaaa taaaa
3155334DNAMurine 5acctggcctg gtggcgccct cacagagcct gtccatcact
tgcactgtct ctgggttttc 60attaaccagc tatagtgtac actgggttcg ccagcctcca
ggaaagggtc tggagtggct 120gggagtaatc tgggctagtg gaggcacaga
ttataattcg gctctcatgt ccagactgag 180catcagcaaa gacaactcca
agagccaagt tttcttaaaa ctgaacagtc tgcaaactga 240tgacgcagcc
atgtactact gtgccagaga tccccctttt tccttactac ggcttgactt
300ctggggccaa ggcaccactc tcacagtctc ctca 3346315DNAMurine
6tcctctctga gtgtgtcagc aggagagaag gtcactatga gctgcaagtc cagtcagagt
60ctgttaaaca gtggaaatca aaaaaactac ttggcctggt accagcagaa accagggcag
120cctcctaaac ttttgatcta cggggcatcc actagggaat ctggggtccc
tgatcgcttc 180acaggcagtg gatctggaac cgatttcact cttaccatca
gcagtgtgca ggctgaagac 240ctggcagttt attactgtca gaatgatcat
agttttccat tcacgttcgg ctcggggaca 300gagttggaaa taaaa 31575PRTMurine
7Ser Tyr Ser Val His1 5 816PRTMurine 8Val Ile Trp Ala Ser Gly Gly
Thr Asp Tyr Asn Ser Ala Leu Met Ser 1 5 10 15 911PRTMurine 9Asp Pro
Pro Ser Ser Leu Leu Arg Leu Asp Tyr 1 5 10 1017PRTMurine 10Lys Ser
Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu 1 5 10 15
Ala117PRTMurine 11Gly Ala Ser Thr Arg Glu Ser1 5 129PRTMurine 12Gln
Asn Val His Ser Phe Pro Phe Thr1 5 139PRTMurine 13Gln Asn Asp His
Ser Phe Pro Phe Thr1 5 1411PRTMurine 14Asp Pro Pro Phe Ser Leu Leu
Arg Leu Asp Phe 1 5 10 15119PRTArtificial SequenceMurine/Homo
sapiens 15Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro
Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser
Leu Thr Ser Tyr 20 25 30 Ser Val His Trp Val Arg Gln Pro Pro Gly
Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ala Ser Gly Gly
Thr Asp Tyr Asn Ser Ala Leu Met 50 55 60 Ser Arg Leu Ser Ile Ser
Lys Asp Asn Ser Lys Ser Gln Val Phe Leu65 70 75 80 Lys Leu Asn Ser
Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95 Arg Asp
Pro Pro Ser Ser Leu Leu Arg Leu Asp Tyr Trp Gly Gln Gly 100 105 110
Thr Thr Leu Thr Val Ser Ser 115 16113PRTArtificial
SequenceMurine/Homo sapiens 16Asp Ile Val Met Thr Gln Ser Pro Ser
Ser Leu Ser Val Ser Ala Gly 1 5 10 15 Glu Lys Val Thr Met Ser Cys
Lys Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30 Gly Asn Gln Lys Asn
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys
Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro
Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser65 70 75
80 Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95 Val His Ser Phe Pro Phe Thr Phe Gly Ser Gly Thr Glu Leu
Glu Ile 100 105 110 Lys1760DNAHomo sapiens 17atggtgttgc agacccaggt
cttcatttct ctgttgctct ggatctctgg tgcctacggg 6018357DNAArtificial
SequenceMurine/Homo sapiens - humanized 18caggttaccc tgcgtgaatc
cggtccggca ctagttaaac cgacccagac cctgacgtta 60acctgcaccg tctccggttt
ctccctgacg agctatagtg tacactgggt ccgtcagccg 120ccgggtaaag
gtctagaatg gctgggtgta atatgggcta gtggaggcac agattataat
180tcggctctca tgtcccgtct gtcgatatcc aaagacacct cccgtaacca
ggttgttctg 240accatgacta acatggaccc ggttgacacc gctacctact
actgcgctcg agatccccct 300tcttccttac tacggcttga ctactggggt
cgtggtaccc cagttaccgt gagctca 35719119PRTArtificial
SequenceMurine/Homo sapiens - humanized 19Gln Val Thr Leu Arg Glu
Ser Gly Pro Ala Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu
Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr 20 25 30 Ser Val
His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45
Gly Val Ile Trp Ala Ser Gly Gly Thr Asp Tyr Asn Ser Ala Leu Met 50
55 60 Ser Arg Leu Ser Ile Ser Lys Asp Thr Ser Arg Asn Gln Val Val
Leu65 70 75 80 Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr
Tyr Cys Ala 85 90 95 Arg Asp Pro Pro Ser Ser Leu Leu Arg Leu Asp
Tyr Trp Gly Arg Gly 100 105 110 Thr Pro Val Thr Val Ser Ser 115
20339DNAArtificial SequenceMurine/Homo sapiens - humanized
20gatatcgtga tgacccagtc tccagactcg ctagctgtgt ctctgggcga gagggccacc
60atcaactgca agagctctca gagtctgtta aacagtggaa atcaaaagaa ctacttggcc
120tggtatcagc agaaacccgg gcagcctcct aagttgctca tttacggggc
gtcgactagg 180gaatctgggg tacctgaccg attcagtggc agcgggtctg
ggacagattt cactctcacc 240atcagcagcc tgcaggctga agatgtggca
gtatactact gtcagaatgt tcatagtttt 300ccattcacgt tcggcggagg
gaccaagttg gagatcaaa 33921113PRTArtificial SequenceMurine/Homo
sapiens - humanized 21Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu
Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser
Ser Gln Ser Leu Leu Asn Ser 20 25 30 Gly Asn Gln Lys Asn Tyr Leu
Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu
Ile Tyr Gly Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75 80 Ile
Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn 85 90
95 Val His Ser Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110 Lys
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