COPD: Journal of Chronic Obstructive Pulmonary Disease

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Biologic Drugs: A New Target Therapy in COPD?

Ahmed Yousuf & Christopher E Brightling

To cite this article: Ahmed Yousuf & Christopher E Brightling (2018): Biologic Drugs: A New
Target Therapy in COPD?, COPD: Journal of Chronic Obstructive Pulmonary Disease, DOI:
10.1080/15412555.2018.1437897

To link to this article: https://doi.org/10.1080/15412555.2018.1437897

Published online: 23 Apr 2018.

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COPD: JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
, VOL. , NO. , –
https://doi.org/./..

Biologic Drugs: A New Target Therapy in COPD?

Ahmed Yousuf and Christopher E Brightling
NIHR Leicester Biomedical Research Centre, Institute for Lung Health, Department of Infection, Immunity & Inflammation, University of Leicester,
Leicester, United Kingdom

ABSTRACT ARTICLE HISTORY

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease associated with significant mor- Received  January 
bidity and mortality. Current diagnostic criteria based on the presence of fixed airflow obstruction and Accepted  February 
symptoms do not integrate the complex pathological changes occurring within the lung and they do not KEYWORDS
define different airway inflammatory patterns. The current management of COPD is based on ‘one size fits COPD; biologics; eosinophil;
all’ approach and does not take the importance of heterogeneity in COPD population into account. The anti-IL; benralizumab;
available treatments aim to alleviate symptoms and reduce exacerbation frequency but do not alter the mepolizumab; anti-TNFα;
course of the disease. Recent advances in molecular biology have furthered our understanding of inflam- anti-IL; anti-ILβ, IL, IL;
matory pathways in pathogenesis of COPD and have led to development of targeted therapies (biologics TSLP
and small molecules) based on predefined biomarkers. Herein we shall review the trials of biologics in COPD
and potential future drug developments in the field.

Introduction
Chronic obstructive pulmonary disease (COPD) is defined by
airflow obstruction that is not fully reversible and that is usu-
ally progressive (1). Cigarette smoke is the main causative agent,
although other exposures (e.g. air pollution, occupational and
biomass fuel) are increasingly being recognised as important
(2–4). COPD is characterized by persistent symptoms punc-
tuated by episodes of worsening symptoms beyond day-to-day
variability known as exacerbations.
COPD is common and causes significant morbidity and
mortality. There are approximately 400 million cases of COPD
worldwide (5) and it is predicted to become the 3rd lead-
ing cause of mortality worldwide by 2030 (4). In the United
Kingdom it is responsible for approximately 30,000 deaths
per year and for >£800 million per year in direct health care
costs (6).
COPD is a heterogeneous condition with respect to clinical
presentation, underlying pathophysiology, disease progres-
sion and response to therapy (7). Current therapies alleviate
symptoms and reduce exacerbations, but have little or no effect
upon disease progression and follow a broadly ‘one size fits all’
approach to the disease. Greater understanding of the inflam-
matory mechanisms in COPD has led to advances in targeted
biologic therapies for specific cytokines or their receptors. The
success of such approaches is predicated on selection of a patient
group in which the intervention will be both safe and effective
and that the therapy will be affordable. We shall consider herein
the heterogeneity of the underlying airway inflammation and
remodeling and the success and failures of biological therapy to
date in COPD.
Pathophysiology
COPD is a heterogeneous disease, which is a consequence
of complex host-environment interactions over time as sum-
marized in Figure 1. Smoking together with other pollutants,
pathogens and in some cases allergens insult the lung promoting
airway inflammation and damage in a susceptible host (7,8).
This chronic airway inflammation and remodeling leads to
small airway obliteration and emphysema, which in turn cause
airflow obstruction and clinical expression of the disease.
Airway inflammation
The presence of airway inflammation in both stable COPD
and exacerbation episodes is well recognised, with severity of
airflow obstruction correlating with airway inflammation (8).
The inflammatory profile in COPD is typically associated with
increased CD8+ T-cells and neutrophils (9,10). In some cases
the neutrophilic response is a consequence of chronic airway
infection particularly a predominance of proteobacteria such as
Hemophilus Influenzae (11). In a subgroup of 15–40% COPD
patients there is eosinophilic inflammation (12). Eosinophils
have been found in sputum, Broncho-Alveolar Lavage (BAL)
fluid and tissue (12). An increase in the number of eosinophils
has been found during exacerbations (13). In asthma this is
predominately due to allergic mediated type-2 immunity with
a possible contribution independent from allergy mediated
by type-2 innate lymphoid cells (14). In COPD the cause of
eosinophilic inflammation is uncertain. The possible trig-
gers and cytokine networks involved in neutrophilic versus
eosinophilic COPD are described in Figure 2.

CONTACT Professor Christopher E Brightling ceb@le.ac.uk Institute for Lung Health, University Hospitals of Leicester, Leicester, LE QP, UK.
Color versions of one or more of the figures in this article can be found online at www.tandfonline.com/icop.
©  Taylor & Francis Group, LLC
2 A. YOUSUF AND C. E. BRIGHTLING
Figure . COPD is a heterogeneous complex disease as a consequence of complex
host-environment interactions across spatial scales within the host over time.
Airway remodeling
Airway remodeling refers to structural changes that occur in
small and large airways. Remodeling changes that occur in
COPD include disruption and loss of cilia, squamous metapla-
sia of the respiratory epithelium, goblet cell hyperplasia and
mucous gland enlargement, bronchiolar smooth muscle hyper-
plasia and hypertrophy, airway wall fibrosis and inflammatory
cell infiltration (15,16). Small airways are the major site of airway
obstruction in COPD. The airways obstruction in COPD is due
to a combination of remodeling and accumulation of inflamma-
tory exudates within the airway lumen (17,18). There is some
evidence that a reduction in number and luminal area of distal
airways is the cause of increased peripheral airway resistance in
COPD (19).
Cigarette smoke is a key trigger for tissue damage and is also
implicated in the abnormal lung repair processes seen in COPD
(20). Amongst the multiple effects of cigarette smoking, smok-
ing causes increased epithelial permeability (21) and can activate
epidermal growth factor (EGF) receptors. Increased EGF and
EGF receptor (EGFR) expression is seen in bronchial epithelium
in COPD and has been implicated in the remodeling processes
(22–25). Activation of EGFR can lead to mucin synthesis and
goblet cell hyperplasia, and EGF is also a stimulator of airway
smooth muscle proliferation (26). It has been shown that there
is a negative correlation between smooth muscle in the small air-
ways and Forced Expiratory Volume in 1 second (FEV1) (27,28).
Epithelial changes observed in COPD include small air-
way squamous metaplasia, which increases with increasing
Figure . Cytokine networks in COPD, in those with eosinophilic disease or non-eosinophilic predominately neutrophilic disease. Biologics that have shown promise and
are in phase  are shown in blue boxes, those that are in early phase trials in green boxes and those that have been unsuccessful are in orange boxes.
COPD severity (29). These squamous cells express increased
Interleukin 1 beta (IL-1β) which induces a fibrotic response
in adjacent airway fibroblasts and is implicated in activation
of transforming growth factor (TGF)-β. TGF-β is a potent
fibrogenic factor that is increased in the small airway epithe-
lial cells in COPD. This activation of TGF-β correlates with
disease severity and small airway thickening in COPD (30,31).
The EGF and TGF-β released from small airways may be
involved in fibroblast activation and proliferation. Increased
bronchial deposition of extracellular matrix proteins includ-
ing collagens, fibronectin and laminin is observed with depo-
sition increased on the epithelial basement membrane at sites
of damage. The negative correlation between bronchial extra-
cellular matrix deposition and FEV1 supports the view that
bronchial deposition of extracellular matrix is related to airway
remodeling (32).
Lung damage
In emphysema activated neutrophils release neutrophil elastase,
a proteinase that can destroy elastin (33). In healthy individuals,
elastase is neutralized by alpha-1-antitrypsin, a proteinase
inhibitor that protects lung tissue from neutrophil elastase
damage. Alpha-1-antitrypsin deficiency leads to an imbalance
between proteinases and anti-proteinases, which in turn leads
to uncontrolled elastin destruction resulting in parenchymal
lung destruction (34).
Macrophages and neutrophils are found in greater numbers
in COPD airways (35), and they release elastolytic proteinases
(e.g. matrix-metalloproteinases, cathepsins and collagenases)
when activated, which lead to degradation of the extra-cellular
matrix.
Current pharmacological therapies in stable COPD
The two main approaches for current drugs in management of
stable COPD are bronchodilators (e.g. β 2 agonists, antimus-
carinics, and methylxanthines) and anti-inflammatories (e.g.
corticosteroids). Current recommendations base treatment
decisions on COPD control determined by symptoms scores
e.g. Modified Medical Research Council (mMRC), COPD
Assessment Tool (CAT) and Clinical COPD Questionnaire
(CCQ) and future risk of disease progression and exacerba-
tions predicted by current lung function and exacerbation
 COPD: JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE 3

lung function, health status and walking distance (36–38).

Management directing corticosteroid therapy in stable disease
to minimize eosinophilic inflammation has led to reduced
hospitalization as observed also in asthma (39). Interestingly
the blood eosinophil count is consistently correlated with the
sputum eosinophil count and an increased blood eosinophil
count is associated with greater improvements to inhaled cor-
ticosteroids in stable disease and oral corticosteroids in acute
exacerbations (40,41). Thus, it is likely in the near future that
this measure will become part of standard-of-care in directing
corticosteroid therapy in COPD.

Biologics in COPD
Figure . Summary of drug treatment based on GOLD disease classification. (SABA With the neutrophil and pro-inflammatory cytokines implicated
= short acting beta agonist, LAMA = long acting muscarinic antagonist, LABA = in the pathogenies of COPD the first biologics in COPD have
long acting beta agonist, ICS = inhaled corticosteroid.)
targeted this element of the inflammatory response. The efficacy
has been disappointing and inhibiting these cytokines has led to
frequency (1). Phenotype-specific approaches to management adverse events which has diminished enthusiasm for biologics
of COPD are used in clinical practice as per Global Initiative for in COPD (42–44). In contrast, targeting eosinophilic inflamma-
Chronic Obstructive Lung Disease (GOLD) recommendations tion in those with evidence of this phenotype has demonstrated
as shown in Figure 3, but do not include measures of underlying efficacy without an increase in adverse events (45,46). These data
pathobiology. are more promising and have begun to pave a way forward for
As described above, eosinophilic inflammation is present in biologics in COPD. The Phase 2 and 3 studies of biologics in
a subset of COPD patients and an elevated sputum eosinophil COPD that have completed and reported their findings are as
count is associated with a greater response to inhaled and oral shown in Table 1 and how they map onto the cytokine networks
corticosteroids in stable disease in terms of improvement in is as shown in Figure 2.
Table . Completed and reported phase  and  trials of biologics in COPD (Anti-IL = anti-interleukin , Anti-TNF-α = anti- tumour necrosis factor alpha, Anti-IL = Anti-
interleukin , IL = Interleukin , CRQ = Chronic respiratory questionnaire, TDI = Transitional Dyspnoea Index, SGRQ-C = St. George’s Respiratory Questionnaire for COPD).

Drug, Dose & Duration Population Primary outcome Secondary outcome

Anti- Pro-inflammatory, neutrophilic, non-T2 inflammation

Anti-IL
 mg loading dose,  mg/month for
 months,  month follow-up ()
Anti-TNFα (Etanercept)
 mg,  days ()
Anti-TNFα (Infliximab)
mg/kg,  weeks ()
Anti-TNFα (Infliximab)
 mg/kg or  mg/kg,  weeks ()
Anti-IL (MEDI )
 mg every  weeks,  weeks ()
Anti- eosinophilic, T2 inflammation
Benralizumab/ IL-
 mg every  weeks ( doses) then every
 weeks ( doses),  week ()
Mepolizumab/ IL
 mg/month,  months ()
Mepolizumab/ IL-
 mg or  mg every  weeks,  weeks
()
Mepolizumab/ IL-
 mg or  mg every  weeks,  weeks
()
Mod-severe COPD (n = )
> years, MRC ࣙ
> pack year smoking history
ࣙ years old (n = )
Enrolled at exacerbation onset
Mild-mod COPD (n = )
Current smokers
Mod-severe COPD (n = )
> years, CRQ<
Mod-very severe COPD (n = )
– years, ࣙ exacerbations in past year
Mod-severe COPD (n = )
– years, ࣙ exacerbation in past year
Sputum eosinophils ࣙ%
Mod-severe COPD (n = )
Sputum eosinophils >%
ࣙ exacerbation in previous year
Mod-very severe COPD, (n = )
> years, ࣙ moderate or ࣙ severe
exacerbation in previous year
Mod-very severe COPD, (n = ),
> years, ࣙ moderate or ࣙ severe
exacerbation in previous year, blood
eosinophils >/µL
↓ Severity of dyspnoea as
measured by TDI
↔ FEV over  days from
exacerbation onset
↔ Sputum inflammatory cells
↔ CRQ
↔ Moderate-to-severe
exacerbations
↔ Moderate-to-severe
exacerbations
↓ Sputum eosinophils
↓ Exacerbations in pre-specified
eosinophilic group
↓ Exacerbations
↔ Health status, lung function, -min
walk test, rescue use of albuterol
↔ -day treatment failure, dyspnoea,
health status
↔ FEV , SGRQ
↔ FEV , -min walk test, TDI
↑ Malignancy, pneumonia
↔ SGRQ-C
↑ FEV in intervention group
↔ health status
↓ Blood and sputum eosinophils
↓ Blood eosinophil
↔ FEV , CAT, CRQ, exacerbations
↓ Time to first exacerbation
↔ FEV , SGRQ, CAT
↓ Time to first exacerbation
↔ FEV , SGRQ, CAT
4 A. YOUSUF AND C. E. BRIGHTLING

Anti- Pro-inflammatory, neutrophilic, non-T2 inflammation necrosis, apoptosis and oxidative stress. Biologics targeting
TNF-α have been very successful and indeed transformed treat-
Anti-IL and anti-CXCR
ment of several chronic inflammatory conditions including
The chemokine C-X-C Ligand 8 (CXCL8) (IL-8) is produced by
rheumatoid arthritis and inflammatory bowel disease (48).
a variety of cells, including monocytes, macrophages and neu-
In an observational study by Suissa and colleagues, etan-
trophils. It mainly attracts and activates neutrophils during an
ercept but not infliximab reduced COPD hospitalisation in a
inflammatory response (44). It binds to CXC chemokine recep-
group of patients who had rheumatoid arthritis and COPD (49).
tor 1 (CXCR1) and CXCR2 members of the G-protein coupled
The relative risk of COPD hospitalisation with the use of etan-
receptor family. CXCR2 is present on the surface of neutrophils
ercept was 0.47 and with infliximab 1.14. In this study, only 16
and is involved in their recruitment to the lung (44).
out of 1205 patient were on etanercept and 21 were on inflix-
Mahler and colleagues undertook a 3-month pilot study of
imab. Patients were identified from insurance claim data base,
an IL-8 monoclonal antibody in 109 subjects with COPD (47).
and therefore, it is not certain all the patients had lung function
Neutralization of IL-8 led to small but significant improve-
confirmed COPD. Notwithstanding this limitation, this pro-
ments in dyspnea measured using the transitional dyspnea index
vides some further support to study biologics against TNF-α in
(TDI). The study was not powered to detect differences in exac-
COPD.
erbation rate between the groups. This biologic was not pro-
Van der Vaart and colleagues undertook the first study of
gressed but gave encouragement to test inhibition of CXCR2
infliximab for 8 weeks in 22 subjects with COPD (50). There
with small molecule inhibitors. The major concern with this
was no increase in adverse events in those receiving infliximab
target is whether it might cause clinically important neutrope-
but also no benefits in lung function nor health status were
nia and subsequent predisposition of infection. Kirsten and
observed. This led to a larger study of infliximab in 234 sub-
colleagues undertook a 4-week study in 87 COPD subjects to
jects with COPD. In this study, there was no improvement in
investigate the safety and tolerability of a CXCR2 antagonist
health status, lung function, symptoms nor exacerbation fre-
(AZD5069) (44). The main adverse events reported were neu-
quency in those receiving infliximab versus placebo. Impor-
tropenia (<1× 109 /L) in intervention arm (3 patients in 50-
tantly there were more adverse events in those receiving inflix-
mg arm and 1 patient in 80-mg arm), and COPD exacerba-
imab with an increase in incidences of cancer (12 versus 3; 6
tions (1 in 50-mg arm and 1 in 80-mg arm). However, there was
lung cancers, 2 head and neck cancers, 1 breast cancer, 1 renal
no increase in infection in those receiving anti-CXCR2 versus
cell cancer, 1 Hodgkin’s lymphoma, 1 liver or pancreatic cancer
placebo. Rennard and colleagues undertook a 6-month dose-
versus 2 prostate cancer, 1 cervical cancer) and pneumonia (10
ranging proof-of-concept study of the CXCR2 antagonist MK-
versus 1). This difference in cancer risk during the study did not
7123 in 616 subjects with moderate-to-severe COPD (43). They
persist in the long-term follow-up of patients after the treatment
found a small significant improvement in FEV1 in those receiv-
cessation. However, the poor efficacy for anti-TNF-α in stable
ing the highest dose of anti-CXCR2 (50 mg daily) versus placebo.
disease and the increased cancer and infection risk has stopped
The benefit was observed in those that were current smokers
progress of this biologic as maintenance therapy.
with an improvement above placebo of 160 mL. There was also
Even though the poor safety of anti-TNF-α precludes its use
a reduction in the likelihood (hazards ratio 0.5) of exacerbation
in stable COPD, Aaron and colleagues undertook an acute study
in current smokers compared to placebo. Importantly, there was
of etanercept at the onset of an exacerbation versus prednisolone
no statistically significant difference in FEV1 or exacerbations
in 81 subjects with COPD. They found no increase in adverse
between ex-smokers in the intervention arm and placebo. The
events but neither did they find benefit in favor of etanercept.
study was terminated early at 12 months because not enough
No further studies of anti-TNF-α in COPD are ongoing.
patients continued with the study to the scheduled 18 months.
There was no difference in rate of infection between the two
groups at 6 months, however, in patients who continued with
Anti-interleukin  (anti- IL)
treatment beyond 6 months, the frequency of total infection and
IL-1 has been described as the master cytokine of inflamma-
respiratory infections was higher in intervention arm compared
tion and affects most cells and organs (51). In COPD IL-1 is
to placebo, 47% versus 35% and 40% versus 28% respectively.
increased in sputum, serum and BAL at stable state and exac-
Thus, the efficacy of CXCR2 inhibition was small and the poten-
erbation. IL-1 is primarily produced by macrophages, mono-
tial of increased adverse events has meant this target has not pro-
cytes and fibroblasts. IL-1A and IL-1B genes encode IL-1 α
gressed in COPD.
and IL-1 β, respectively (52). Both exert their effect by bind-
ing to IL-1 receptor 1 (IL-1R1), which is expressed in almost
Tumor necrosis factor –alpha (TNF-α) all cells. Unlike most other pro-inflammatory cytokines, IL-1
TNF-α is a potent pro-inflammatory mediator and plays a major exerts its effects at receptor and nucleus level. It stimulates local
role in driving inflammation in COPD exacerbations (43). The and systemic inflammation by facilitating the recruitment of
level of TNF-α in sputum rises significantly during an exacer- inflammatory cells. IL-1 antagonists have been used in treating
bation (42). It is mainly produced by monocytes and lympho- rheumatological conditions with mixed results and is associated
cytes. It is secreted in response to various stimuli. It exerts its with improved outcomes following myocardial infarction (52).
effect via TNF-α receptor 1 and TNF-α receptor 2 by activation Blocking the effects of IL-1 α and IL-1 β is thus a potential treat-
of nuclear factor-kappa B (NF-kB), which in turn leads to up ment strategy for COPD patients.
regulation of inflammatory genes. It stimulates leucocyte accu- Calverley and colleagues undertook a 1-year study of anti-
mulation and differentiation at the site of infection, as well as IL-1R1 in 324 subjects with COPD (53). The intervention arm

received a 600 mg loading of anti-IL-1 intravenously on day 1
followed by 300 mg subcutaneous every 4 weeks for a total of
14 doses. There was no reduction in exacerbation frequency
nor improvements in lung function and health status in those
receiving anti-IL-1R1 versus placebo. There were no differences
in adverse events between the groups. In another study, 147
patients with moderate to very severe COPD were randomized
to receive canakinumab, an IL1-1R1 antagonist or placebo for
1 year. No statistical analysis was provided at the completion
of the study, but changes in lung function that are reported
were very similar between those receiving canalinumab versus
placebo (54). There were no deaths reported in the study and
adverse events were similar between groups. No anti-IL-1 stud-
ies are currently ongoing.
Therefore, targeting neutrophilic inflammation via anti-IL-8
and anti-CXCR2 has led to small clinical benefit with evidence
of reduced blood neutrophil counts and possibly increased risk
of infection. Targeting TNF-α and IL-1 has not been associ-
ated with efficacy and inhibiting TNF-α has led to substantial
and clinically important adverse events. These findings have
stopped progress of biological therapy against pro-inflammatory
cytokines and neutrophilic inflammation in COPD.
Anti- eosinophilic, T2 inflammation
Biologics targeting T2-mediated inflammation has been suc-
cessful in severe asthma and led to newly licensed therapies
targeting IL-5 and its receptor (46,55–58). As described above
although eosinophilic inflammation is common in asthma it is
less frequent in COPD and not associated with increased atopy.
Thus, the mechanisms of the cause of eosinophilic inflamma-
tion in COPD is poorly understood but does offer a potential
therapeutic target.
Anti-IL- and anti-IL-R
IL-5 is released by CD4+ T-helper cell type 2 (Th2) lym-
phocytes, innate lymphoid cells and eosinophils. Its receptor
Interleukin 5 receptor (IL-5R) is expressed by eosinophils and
basophil. IL-5 stimulates maturation and release of eosinophils
from bone marrow and is an obligate survival factor for tis-
sue eosinophils (59). In asthma, biologics neutralizing IL-
5 (mepolizumab and reslizumab) substantially reduce blood
and sputum eosinophil counts and attenuate bronchial submu-
cosal eosinophils by about 50% (60). The afucosylated mono-
clonal antibody against the IL-5R, benralizumab, also induces
antibody-mediated cell cytotoxicity and thus has a greater effect
on reducing eosinophil number in the bronchial submucosa
(61).
Brightling and colleagues undertook a study of anti-IL-5R
(benralizumab) in 101 patients with moderate to severe COPD
(45). Subjects were randomized in a 1:1 ratio to either receive
benralizumab or placebo 4 weekly for the first 3 doses and
then 8 weekly for the remaining 5 doses. The primary outcome,
annual rate of acute exacerbations, was not met. The annual
rate of acute COPD exacerbations in placebo group was 0.92
and in intervention group was 0.95. The FEV1 was significantly
increased in those receiving benralizumab versus placebo but no
COPD: JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE 5
difference was observed in health status. In a post hoc analysis
those who had evidence of eosinophilic inflammation at screen-
ing, either a sputum eosinophil count >2% or a blood eosinophil
count >250 cells/μL, had a greater improvement in lung func-
tion, heath status and a numerical reduction in exacerbations.
These findings perhaps suggesting greater efficacy in a more
eosinophilic subgroup. There were no differences in adverse
events between those receiving benralizumab versus placebo.
Dasgupta and colleagues undertook a small pilot study
of mepolizumab in 18 COPD subjects (62). They found
that the sputum eosinophil count decreased in those receiv-
ing mepolizumab versus placebo, but there were no clinical
improvements in terms of lung function or health status. Pavord
and colleagues undertook two recent phase III trials (METREX
and METREO) in moderate to very severe COPD (46). Sub-
jects were randomized to receive 100 mg mepolizumab or
placebo in 1:1 ratio (METREX, n = 836), 100 mg mepolizumab,
300 mg mepolizumab or placebo in 1:1:1 ratio (METREO, n
= 674) every 4 weeks for 52 weeks. Subject stratification into
eosinophilic or non-eosinophilic phenotypes were based on
blood eosinophil count of ࣙ150/µL on screening or ࣙ300/µL in
previous year and blood eosinophil count of <150/µL on screen-
ing or <300/µL in previous year, respectively. In METREX they
included eosinophilic and non-eosinophilic patients, whereas in
METREO they only included eosinophilic patients. In METREX
the mean annual rate of moderate or severe exacerbations in the
mepolizumab group was 1.40 per year compared to 1.71 per year
in the placebo group (rate ratio, 0.82). In METREO, the mean
annual rate of moderate or severe exacerbations was 1.19 per
year in the 100-mg mepolizumab group and 1.27 per year in the
300-mg mepolizumab group, compared to 1.49 per year in the
placebo group (rate ratio [100 mg vs. placebo], 0.80; adjusted
P = 0.07; rate ratio [300 mg vs. placebo], 0.86; adjusted P =
0.04). In a pre-planned post hoc analysis, those with eosinophilic
phenotype who were treated with 100 mg mepolizumab had an
annual rate of moderate to severe exacerbation that was 18–20%
lower than placebo group. Higher dose of mepolizumab did not
confer any additional benefit. The time to the first moderate or
severe exacerbation was significantly longer with mepolizumab
than with placebo in the modified intention-to-treat population
with an eosinophilic phenotype (192 days versus 141 days; haz-
ard ratio, 0.75; adjusted P = 0.04). In keeping with the smaller
pilot study there were no improvements in lung function and
health status in those receiving mepolizumab versus placebo and
no differences in adverse events.
Mepolizumab is the first biologic to demonstrate a reduction
in COPD exacerbations. The findings from the mepolizumab
and benralizumab studies were consistent in showing that the
magnitude of benefit was related to the intensity of eosinophilic
inflammation (46). Importantly in both studies there was a
poorer outcome in those with low blood eosinophil counts
who received the biologic versus placebo. This is in contrast
to asthma where there is a failure of benefit in those with low
eosinophil counts but no difference compared with placebo.
Whether anti-IL-5 or anti-IL-5R approaches increase risk of
exacerbations in COPD subjects with low eosinophil counts
needs to be further explored and the possible mechanisms
elucidated.
6 A. YOUSUF AND C. E. BRIGHTLING
Anti-IL-
IL-13 is an archetypal Th2 cytokine produced by T-cells,
mast cells and eosinophils and acts upon inflammatory
cells and structural cells such as the bronchial epithe-
lium and airway smooth muscle (63). Anti-IL-13 signals
through interleukin 13 receptor type 1 (IL-13RI) and II
with IL-13RI sharing the interleukin 4 (IL-4) receptor alpha
chain subunit with the IL-4R interleukin 4 receptor (IL-
4R). Biologics have been tested in asthma that either neu-
tralize IL-13 or inhibit IL-4Rα and thus inhibit both IL-4
and −13. The former, lebrikizumab and tralokinumab, have
consistently shown benefits compared to placebo with improved
lung function but effects upon exacerbations have been incon-
sistent and too small to warrant further development (64,65). In
contrast, anti-IL-4Rα has had more promising results in phase 3
in asthma (66). Of these three biologics, only lebrikizumab has
been tested in COPD. The full results have not been reported
but the headline result in a press release reported that in COPD
exacerbations were not reduced in those receiving lebrikizumab
versus placebo.
Future biologics in COPD
In view of the poor response to biologics targeting neutrophilic
inflammation and pro-inflammatory cytokines versus the
promising results in targeting eosinophilic inflammation atten-
tion in COPD is to initially explore other cytokines implicated
in T2-mediated immunity and or eosinophilic inflammation.
Thymic stromal lymphopoietin (TSLP) is an IL-7 interleukin
7 (IL-7) like cytokine, which signals via IL-7 receptor alpha (IL-
7Rα) and thymic stromal lymphopoietin receptor (TSLPR) (67).
It stimulates thymocytes and B cell lymphopoiesis (68). TSLP
is produced by airway epithelial cells and stromal cells dur-
ing inflammation (69). TSLP orchestrates response to epithe-
lial injury by acting on CD4, CD8 T cells, B cells, mast cells,
basophils, eosinophils and innate lymphoid cells (70). There
has been a great deal of interest in role of TSLP in pathogen-
esis of asthma and COPD due to its ability to activate pro-
inflammatory cells. Studies have shown increased expression of
TSLP in airways disease (71,72). Tezepelumab a monoclonal
antibody that binds to TSLP and prevents it from attaching to
TSLP receptor reduced asthma exacerbations, improved lung
function and asthma control (73). It attenuated the peripheral
blood eosinophil count although response was also observed
in those without an elevated blood eosinophil count. Whether
targeting TSLP has benefit in an unselected COPD population
or in an eosinophilic subgroup is unknown and warrants fur-
ther investigation. This reduction in exacerbation frequency was
irrespective of eosinophil count. There has not been a similar
study on the effect of anti-TSLP in COPD.
There is also increasing interest in IL-33 as a target particu-
larly in asthma. IL-33 is an alarmin released from the epithe-
lium following damage (74). IL-33 is an IL-1 family alarmin
cytokine constitutively expressed at epithelial barrier surfaces
where it is rapidly released from cells during tissue injury. IL-
33 signals through a receptor complex of IL-1 receptor-like 1
(IL1RL1) (known as ST2) and IL-1 receptor accessory protein
(IL1RAcP) to initiate Myeloid differentiation primary response
88 (MyD88)-dependent inflammatory pathways (75). IL-33 has
been implicated in eosinophil recruitment to the airways and
maturation in the bone marrow largely via its effects upon innate
lymphoid cells (76). IL-33 increased following experimental
cold in asthma and thus might play a role in the consequent
inflammatory response and possible susceptibility to secondary
bacterial infection in obstructive lung disease (77). The role of
the IL-33/ST2 axis in COPD is uncertain. A correlation between
blood eosinophil, smoking status and IL-33 in COPD has been
reported and IL-33 levels in peripheral blood and airways of
COPD patients are increased (78). Both eosinophilic inflamma-
tion and viral infection drive COPD exacerbations and therefore
targeting the IL-33/ST2 axis might reduce COPD exacerbations.
Clinical trials of anti-IL33 or anti-ST2 biologics in COPD are
awaited.
Biologics might offer alternative strategies to target the expo-
some as well as the inflammatory response in the host. For exam-
ple, biologics can be developed to target bacteria; inhibit viru-
lence factors or block adhesion of viruses to cells and thus could
be adjuncts to antimicrobial strategies.
Conclusion
The heterogeneity of COPD is beginning to be dissected and
our understanding of the interaction between the host, chronic
infection and other exposures is becoming clearer. This has
provided insights but also underscored the complexity of
these relationships overtime. Biological therapy in COPD has
presented some surprises with respect to the lack of efficacy
for treatments targeting neutrophilic inflammation and pro-
inflammatory cytokines but has shown how blockade of these
cytokines can lead to profound increases in adverse events.
This is contrasted with the promising responses to biologics
targeting eosinophilic inflammation although responses are
more blunted than observed in asthma. These differences
are possibly due to different underlying mechanisms driving
the eosinophilic inflammation between asthma and COPD but
are pointing towards the possibility of biological therapy for
a subgroup with persistent eosinophilic inflammation. This
will perhaps present other opportunities for biologics targeting
more upstream molecules such as TSLP and IL-33. Biologics
might also offer alternative strategies to targeting acute and
chronic infection, which is problem in many subjects with
COPD. Biologics have not yet entered the clinic for COPD but
the likelihood is that the wait will be not much longer and then
we shall need to better understand which biological therapy has
value in which COPD patient to improve what outcome.
Declaration of interest
None.
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