Download PDF
1 / 2 Pages
Arch
Bronconeumol.
2017;
53(5)
:233–234
www.archbronconeumol.org
Editorial
Emerging
Therapies
in
Severe
Eosinophilic
Asthma
Nuevas
terapias
para
el
asma
eosinofílica
grave
Pee
Hwee
Pang
a
,
Christopher
E.
Brightling
b
,
a
Department
of
Respiratory
and
Critical
Care
Medicine,
Tan
Tock
Seng
Hospital,
Singapore
b
Institute
for
Lung
Health,
NIHR
Respiratory
Biomedical
Research
Unit,
Department
of
Infection,
Immunity
&
Inflammation,
University
of
Leicester
and
University
Hospitals
of
Leicester
NHS
Trust,
Leicester,
UK
Asthma
is
a
complex,
heterogeneous
disease
characterized
by
chronic
airway
inflammation,
episodic
respiratory
symptoms,
and
associated
with
variable
expiratory
airflow
limitation.
The
preva-
lence
of
asthma
is
increasing,
and
is
estimated
to
affect
358
million
people
worldwide
in
the
recent
Global
Burden
of
Disease
report.
1
5%–10%
are
said
to
have
severe
asthma,
defined
as
asthma
that
requires
treatment
with
high
dose
inhaled
corticosteroids
and
a
second
controller
for
the
previous
year,
and/or
systemic
cortico-
steroids
for
50%
of
the
previous
year
to
prevent
it
from
becoming
uncontrolled
or
that
remains
uncontrolled
despite
this
therapy.
2
This
subset
of
patients
has
poorer
lung
function,
quality
of
life,
and
recurrent
exacerbations;
is
at
increased
risk
of
significant
morbid-
ity
and
mortality,
and
exerts
a
substantial
burden
on
healthcare
resources.
Understanding
the
heterogeneity
of
the
airway
inflammation
in
severe
asthma
is
of
particular
importance
to
predict
future
risk
of
exacerbations
and
response
to
therapy.
The
presence
of
eosinophilic
airway
inflammation
is
associated
with
poorer
asthma
control
and
increased
risk
of
exacerbations,
3
and
is
a
good
predictor
of
a
favorable
response
to
corticosteroids.
4
Beyond
corticoste-
roids,
monoclonal
antibodies
targeting
Type
2
(T2)
immunity
and
consequent
eosinophilic
inflammation
in
severe
asthma
has
been
developed.
The
first
monoclonal
antibody
for
asthma
was
omalizumab,
a
humanized
monoclonal
antibody
against
IgE
used
since
2003
in
adults,
adolescents
and
children
over
6
years
of
age
with
moderate
to
severe
persistent
allergic
asthma
inadequately
con-
trolled
with
standard
therapy.
It
improved
asthma
symptoms
and
health-related
quality
of
life.
It
also
reduced
exacerbations
and
daily
inhaled
corticosteroid
dose.
5
Response
to
omalizumab
was
better
in
asthmatics
with
increased
biomarkers
of
T2
immunity
and
eosinophilic
inflammation
including
serum
periostin,
blood
eosinophil
count
and
fraction
of
exhaled
nitric
oxide.
6
Anti-interleukin-5
(IL-5)
monoclonal
antibodies
are
the
sec-
ond
class
of
biological
therapy
for
severe
eosinophilic
asthma.
IL-5
cytokine
plays
an
important
role
in
the
maturation
and
Corresponding
author.
E-mail
address:
ceb17@le.ac.uk
(C.E.
Brightling).
activation
of
eosinophils.
Mepolizumab
is
a
humanized
mono-
clonal
antibody
that
binds
to
IL-5,
preventing
it
from
binding
to
IL-5
receptors.
The
first
large
phase
IIb/III
trial
(DREAM
study)
showed
that
mepolizumab
at
a
range
of
doses
significantly
reduced
severe
exacerbation
rate
in
subjects
with
recurrent
exacerbations
and
evidence
of
eosinophilic
inflammation.
7
The
results
were
also
replicated
in
another
phase
III
trial
using
a
lower
intra-
venous
Mepolizumab
dose
of
75
mg
and
a
subcutaneous
dose
of
100
mg.
8
Mepolizumab
has
also
been
shown
to
have
steroid-
sparing
effects
by
significantly
reducing
daily
systemic
corticos-
teroid
use
compared
to
placebo,
while
maintaining
its
exacerbation
reduction
effect.
9
The
efficacy
of
mepolizumab
appeared
to
be
more
pronounced
in
subjects
with
higher
baseline
blood
eosinophil
levels
and
more
frequent
exacerbations,
with
no
benefit
in
exacerbation
reduction
in
those
with
a
blood
eosinophil
count
<150
cells/

L.
On
the
strength
of
these
positive
trial
results,
it
has
since
been
licensed
for
use
in
severe
eosinophilic
asthma.
Reslizumab,
another
monoclonal
antibody
targeting
IL-5,
was
also
recently
licensed
for
use
in
severe
eosinophilic
(
400
blood
eosinophils/

L)
asthma
following
phase
III
trials
demonstrating
significant
improvement
in
forced
expiratory
volume
in
1
sec-
ond
(FEV1),
asthma
control
scores,
asthma-related
quality
of
life
and
frequency
of
asthma
exacerbations.
10,11
However,
when
used
across
a
broad
range
of
blood
eosinophil
counts,
reslizumab
had
no
effect
on
lung
function
and
asthma
control.
12
Benralizumab
differs
from
mepolizumab
and
reslizumab
as
it
acts
on
the
alpha
chain
of
the
IL-5
receptor
causing
eosinophil
apoptosis.
Two
recent
phase
III
trials
in
subjects
with
inadequately
controlled
asthma,
frequent
exacerbations
and
elevated
blood
eosinophil
count
showed
sig-
nificant
reduction
of
annual
asthma
exacerbation
rate
compared
to
placebo.
13,14
It
also
significantly
improved
FEV1,
Asthma
Con-
trol
Questionnaire
(ACQ)
and
Asthma
Quality
of
Life
Questionnaire
(AQLQ)
scores
in
those
receiving
the
treatment
every
8
weeks.
Inhibiting
other
T2-cytokines
such
as
IL-13
neutralization
(Lebrikizumab
and
Tralokinumab)
or
the
alpha
chain
of
the
IL-4
receptor
which
attenuates
both
IL-4
and
IL-13
signaling
(Dupilumab)
are
attractive
targets.
None
of
these
strategies
have
demonstrated
an
effect
on
reducing
eosinophilic
inflammation,
but
benefits
for
these
approaches
are
greater
in
those
with
upregulated
T2-immunity
and
eosinophilic
inflammation.
Recent
http://dx.doi.org/10.1016/j.arbres.2017.01.012
0300-2896/©
2017
SEPAR.
Published
by
Elsevier
Espa
̃
na,
S.L.U.
All
rights
reserved.
http://dx.doi.org/10.1016/j.arbr.2017.01.017
1579-2129
234
P.H.
Pang,
C.E.
Brightling
/
Arch
Bronconeumol.
2017;
53(5)
:233–234
phase
III
studies
for
Lebrikizumab
failed
to
demonstrate
consis-
tent
benefit
for
reduction
in
asthma
exacerbations
15
and
phase
III
studies
for
Tralokinumab
are
ongoing
(NCT02194699
and
NCT02161757).
Findings
from
a
phase
IIb
study
of
Dupilumab
were
more
encouraging,
showing
reductions
in
exacerbation
fre-
quency
and
improvements
in
symptoms
in
all
comers
with
greatest
response
in
those
with
eosinophilic
inflammation.
16
In
addition
to
biological
therapy,
small
molecule
inhibitors
have
shown
promising
results
in
severe
asthma.
Prostaglandin
D
2
(PGD
2
)
is
a
prostanoid
mainly
produced
by
mast
cells,
which
binds
and
acti-
vates
G
protein-coupled
receptors:
D
prostanoid
1,
thromboxane
A
2
receptor
and
D
prostanoid
2
(DP
2
).
DP
2
is
also
known
as
chemoat-
tractant
receptor-homologous
molecule
on
T
helper
Type
2
cells
(CRTh
2
),
selectively
expressed
on
Th2
cells,
eosinophils,
basophils,
Type
2
innate
lymphoid
cells
(ILC2s),
epithelial
cells
and
airway
smooth
muscle.
In
a
recent
single-center
randomized
placebo-
controlled
study
of
patients
with
moderate-to-severe
asthma
and
sputum
eosinophilia
(
2%),
fevipiprant
(a
potent
and
highly
selec-
tive
DP
2
antagonist)
showed
significant
reduction
in
eosinophilic
inflammation
in
both
sputum
and
bronchial
submucosa
compared
with
placebo.
17
There
was
significant
effect
on
AQLQ
score,
post
bronchodilator
FEV1
and
functional
residual
capacity
in
all
patients,
and
the
ACQ-7
score
in
a
pre-defined
subgroup
of
patients
who
had
uncontrolled
asthma.
The
effect
on
asthma
exacerbations
is
now
being
evaluated
in
phase
III
clinical
trials.
Thus,
the
armamentarium
for
the
treatment
of
severe
eosinophilic
asthma
is
expanding.
Future
research
is
needed
to
give
further
insight
into
which
patients
are
most
likely
to
have
the
greatest
response
to
which
treatment,
and
to
better
define
both
response
and
failure
to
respond
to
these
new
therapies.
This
might
require
head-to-head
pragmatic
real
life
trials
of
licensed
therapies.
Notwithstanding
this
limitation,
the
prospect
of
new
and
effective
treatments
is
now
within
our
grasp.
Conflict
of
Interest
PHP
declares
to
have
no
conflict
of
interest
directly
or
indirectly
related
to
the
manuscript
contents.
CEB
has
received
consultancy
fees
and
or
grants
paid
to
his
Institution
from
AZ/Medimmune,
GSK,
Roche/Genentech,
BI,
Chiesi,
Teva,
Sanofi/Regeneron,
Vectura,
Theravance,
Novartis,
Gilead
and
Pfizer.
References
1.
GBD
2015
Disease
and
Injury
Incidence
and
Prevalence
Collaborators.
Global,
regional,
and
national
incidence,
prevalence,
and
years
lived
with
disability
for
310
diseases
and
injuries,
1990-2015:
A
systematic
analysis
for
the
global
burden
of
disease
study
2015.
Lancet.
2016;388:1545–602.
2.
Chung
KF,
Wenzel
SE,
Brozek
JL,
Bush
A,
Castro
M,
Sterk
PJ,
et
al.
International
ERS/ATS
guidelines
on
definition,
evaluation
and
treatment
of
severe
asthma.
Eur
Respir
J.
2014;43:343–73.
3.
Jatakanon
A,
Lim
S,
Barnes
PJ.
Changes
in
sputum
eosinophils
predict
loss
of
asthma
control.
Am
J
Respir
Crit
Care
Med.
2000;161:64–72.
4.
Green
RH,
Brightling
CE,
McKenna
S,
Hargadon
B,
Parker
D,
Bradding
P,
et
al.
Asthma
exacerbations
and
sputum
eosinophil
counts:
a
randomised
controlled
trial.
Lancet.
2002;360:1715–21.
5.
Normansell
R,
Walker
S,
Milan
SJ,
Walters
EH,
Nair
P.
Omalizumab
for
asthma
in
adults
and
children.
Cochrane
Database
Syst
Rev.
2014:CD003559,
doi(1):CD003559.
6.
Humbert
M,
Busse
W,
Hanania
NA,
Lowe
PJ,
Canvin
J,
Erpenbeck
VJ,
et
al.
Oma-
lizumab
in
asthma:
an
update
on
recent
developments.
J
Allergy
Clin
Immunol
Pract.
2014;2,
525,36.e1.
7.
Pavord
ID,
Korn
S,
Howarth
P,
Bleecker
ER,
Buhl
R,
Keene
ON,
et
al.
Mepolizumab
for
severe
eosinophilic
asthma
(DREAM):
a
multicentre,
double-blind,
placebo-
controlled
trial.
Lancet.
2012;380:651–9.
8.
Ortega
HG,
Liu
MC,
Pavord
ID,
Brusselle
GG,
FitzGerald
JM,
Chetta
A,
et
al.
Mepolizumab
treatment
in
patients
with
severe
eosinophilic
asthma.
N
Engl
J
Med.
2014;371:1198–207.
9.
Bel
EH,
Wenzel
SE,
Thompson
PJ,
Prazma
CM,
Keene
ON,
Yancey
SW,
et
al.
Oral
glucocorticoid-sparing
effect
of
mepolizumab
in
eosinophilic
asthma.
N
Engl
J
Med.
2014;371:1189–97.
10.
Castro
M,
Zangrilli
J,
Wechsler
ME,
Bateman
ED,
Brusselle
GG,
Bardin
P,
et
al.
Reslizumab
for
inadequately
controlled
asthma
with
elevated
blood
eosinophil
counts:
results
from
two
multicentre,
parallel,
double-blind,
ran-
domised,
placebo-controlled,
phase
3
trials.
Lancet
Respir
Med.
2015;3:
355–66.
11.
Bjermer
L,
Lemiere
C,
Maspero
J,
Weiss
S,
Zangrilli
J,
Germinaro
M.
Reslizumab
for
inadequately
controlled
asthma
with
elevated
blood
eosinophil
levels:
a
randomized
phase
3
study.
Chest.
2016;150:789–98.
12.
Corren
J,
Weinstein
S,
Janka
L,
Zangrilli
J,
Garin
M.
Phase
3
study
of
reslizumab
in
patients
with
poorly
controlled
asthma:
effects
across
a
broad
range
of
eosinophil
counts.
Chest.
2016;150:799–810.
13.
Bleecker
ER,
FitzGerald
JM,
Chanez
P,
Papi
A,
Weinstein
SF,
Barker
P,
et
al.
Efficacy
and
safety
of
benralizumab
for
patients
with
severe
asthma
uncon-
trolled
with
high-dosage
inhaled
corticosteroids
and
long-acting
beta2-agonists
(SIROCCO):
a
randomised,
multicentre,
placebo-controlled
phase
3
trial.
Lancet.
2016;388:2115–27.
14.
FitzGerald
JM,
Bleecker
ER,
Nair
P,
Korn
S,
Ohta
K,
Lommatzsch
M,
et
al.
Benral-
izumab,
an
anti-interleukin-5
receptor
alpha
monoclonal
antibody,
as
add-on
treatment
for
patients
with
severe,
uncontrolled,
eosinophilic
asthma
(CAL-
IMA):
a
randomised,
double-blind,
placebo-controlled
phase
3
trial.
Lancet.
2016;388:2128–41.
15.
Hanania
NA,
Korenblat
P,
Chapman
KR,
Bateman
ED,
Kopecky
P,
Paggiaro
P,
et
al.
Efficacy
and
safety
of
lebrikizumab
in
patients
with
uncontrolled
asthma
(LAVOLTA
I
and
LAVOLTA
II):
replicate,
phase
3,
randomised,
double-blind,
placebo-controlled
trials.
Lancet
Respir
Med.
2016;4:781–96.
16.
Wenzel
S,
Castro
M,
Corren
J,
Maspero
J,
Wang
L,
Zhang
B,
et
al.
Dupilumab
efficacy
and
safety
in
adults
with
uncontrolled
persistent
asthma
despite
use
of
medium-to-high-dose
inhaled
corticosteroids
plus
a
long-acting
beta2
agonist:
a
randomised
double-blind
placebo-controlled
pivotal
phase
2b
dose-ranging
trial.
Lancet.
2016;388:31–44.
17.
Gonem
S,
Berair
R,
Singapuri
A,
Hartley
R,
Laurencin
MF,
Bacher
G,
et
al.
Fevip-
iprant,
a
prostaglandin
D2
receptor
2
antagonist,
in
patients
with
persistent
eosinophilic
asthma:
a
single-centre,
randomised,
double-blind,
parallel-group,
placebo-controlled
trial.
Lancet
Respir
Med.
2016:699–707.

Other users also viewed these articles

Papel de los biomarcadores en el asma grave no controlada en la actualidad Ebymar Arismendi; César Picado Vallés;
Arch Bronconeumol. 2020;56:347-8
Validation of a Pathological Score for the Assessment of Bronchial Biopsies in Severe Uncontrolled Asthma: Beyond Blood Eosinophils Borja G. Cosio; Hanaa Shafiek; Amanda Iglesias; Mar Mosteiro; Ana Gonzalez-Piñeiro; Marta Rodríguez; Mónica García-Cosío; Eladio Busto; Javier Martin; Luis Mejías; Amparo Benito; Laura López Vilaro; Cristina Gómez;
Arch Bronconeumol. 2023;59:502-9
Global Initiative for Asthma Strategy 2021. Executive Summary and Rationale for Key Changes Helen K. Reddel; Leonard B. Bacharier; Eric D. Bateman; Christopher E. Brightling; Guy G. Brusselle; Roland Buhl; Alvaro A. Cruz; Liesbeth Duijts; Jeffrey M. Drazen; J. Mark FitzGerald; Louise J. Fleming; Hiromasa Inoue; Fanny W. Ko; Jerry A. Krishnan; Mark L. Levy; Jiangtao Lin; Kevin Mortimer; Paulo M. Pitrez; Aziz Sheikh; Arzu A. Yorgancioglu; Louis-Philippe Boulet;
Arch Bronconeumol. 2022;58:35-51