[ COPD Chest Reviews ]

The Emerging Role of Alarmin-Targeting

Biologics in the Treatment of Patients With
COPD
Bartolome R. Celli, MD, FCCP; Antonio Anzueto, MD; Dave Singh, MD; Nicola A. Hanania, MD; Leonardo Fabbri, MD;
Fernando J. Martinez, MD; Xavier Soler, MD, PhD; Michel Djandji, MD; Juby A. Jacob-Nara, MD; Paul J. Rowe, MD;
Yamo Deniz, MD; and Amr Radwan, MB BChir

TOPIC IMPORTANCE: COPD is a complex, heterogeneous lung disease characterized by

persistent airflow limitation secondary to airways and parenchymal abnormalities, and res-
piratory symptoms, including dyspnea, fatigue, chronic cough, and sputum production.
Cigarette smoke exposure is a major contributor to COPD; however, inhalation of toxic
particles and other environmental and host factors can contribute to its genesis. Over time,
the clinical course is frequently punctuated by exacerbations that further accelerate lung
function decline and increase exacerbation risk. Despite current optimal therapy, many
patients remain symptomatic, have exacerbations, and have increased morbidity, mortality,
and health care costs. This review focuses on current knowledge of COPD pathophysiology,
the role of inflammatory mechanisms, and the potential use of biologics to modulate these
mechanisms.
REVIEW FINDINGS: The inflammatory response in COPD includes both type 1 and type 2
immune cells. Type 2 inflammation is suggested by eosinophilia in a significant proportion of
patients with COPD. Studies targeting IL-5 in patients with COPD have failed to demonstrate
significant reductions in exacerbations, suggesting that eosinophil modulation alone may be
insufficient to treat COPD. Based on a better understanding of the disease and role of
alarmins, with a broader role in the inflammatory cascade, it is likely that some biologics may
benefit certain COPD endotypes. Ongoing trials will provide information about which groups
can benefit from the blocking of specific pathways (eg, IL-5, IL-4/IL-13, IL-33, thymic
stromal lymphopoietin).
SUMMARY: Biologics targeting inflammatory pathways may be effective treatments for specific
patients with COPD. CHEST 2025; 167(5):1346-1355

KEY WORDS: alarmin; biologic; COPD; type 2 inflammation

ABBREVIATIONS: ICS = inhaled corticosteroid; LABA = long-acting Italy; the New York-Presbyterian/Weill Cornell Medical Center (F. J.
b2-agonist; LAMA = long-acting muscarinic antagonist; ST-2 = sup- M.), New York, NY; Regeneron Pharmaceuticals Inc (X. S., Y. D., and A.
pression of tumorigenicity 2; TSLP = thymic stromal lymphopoietin R.), Tarrytown, NY; Sanofi (M. D.), Cambridge, MA; and Sanofi (J. A. J.-
AFFILIATIONS: From the Pulmonary and Critical Care Division (B. R. N. and P. J. R.), Bridgewater, NJ.
C.), Brigham and Women’s Hospital and Harvard Medical School, CORRESPONDENCE TO: Bartolome R. Celli, MD, FCCP; email: bcelli@
Boston, MA; the Department of Medicine (A. A.), South Texas Veterans copdnet.org
Health Care System, San Antonio, TX; the Department of Medicine (A. Copyright Ó 2024 The Author(s). Published by Elsevier Inc under li-
A.), University of Texas Health San Antonio, San Antonio, TX; the cense from the American College of Chest Physicians. This is an open
Medicines Evaluation Unit (D. S.), University of Manchester, Man- access article under the CC BY-NC-ND license (http://
chester University NHS Foundation Trust, Manchester, England; the creativecommons.org/licenses/by-nc-nd/4.0/).
Department of Medicine (N. A. H.), Section on Pulmonary and Critical DOI: https://doi.org/10.1016/j.chest.2024.09.049
Care Medicine, Baylor College of Medicine, Houston, TX; the Depart-
ment of Translational Medicine (L. F.), University of Ferrara, Ferrara,

1346 Chest Reviews [ 167#5 CHEST MAY 2025 ]

COPD is the third leading cause of death worldwide, of patients remain symptomatic and/or continue
contributing significantly to global health and economic experiencing exacerbations.14,15 The heterogeneity and
burdens.1,2 COPD is characterized by chronic limited understanding of the pathophysiology of COPD
respiratory symptoms and structural abnormalities in makes it a difficult disease to treat. The need to identify
the airways and lungs that lead to airflow limitation. The responsive endotypes (defined by pathobiological
natural course of the disease is punctuated by mechanisms) is derived from a lack of treatment
exacerbations, often caused by bacterial or viral efficacy in many patients with COPD.16,17 Although we
infections and environmental changes. These have still limited understanding of the biological
exacerbations, characterized by an inflammatory burst,3 pathways and have identified only a few COPD
are associated with increased morbidity, worse quality of phenotypes and endotypes (eg, rapid decliner,
life, higher mortality, and increased health care costs.1,4,5 eosinophilic, exacerbator, airway predominant,
If the episodes lead to hospitalization, prognosis is emphysemic),18 novel biologic therapies may provide
poor.6 Key objectives in COPD treatment include an opportunity to control the severe disease course of
reducing symptoms and, importantly, COPD many of these patients.
exacerbations.
The aim of this review is to discuss our current
Inflammation is present and is generally considered to understanding of the inflammatory mechanisms thought
play a role in the genesis and perpetuation of COPD. to play a role in COPD, with particular attention to the
The most common pattern of inflammation in COPD is role of type 2 inflammatory pathways observed in many
characterized by increased numbers of neutrophils and of these patients, and the potential role of biologic
macrophages in the lungs, and increased Th1 and CD8þ therapies in COPD treatment.
T cells.7 Some patients with COPD have increased
peripheral eosinophils, and this endotype exhibits a Literature Search
better response to inhaled corticosteroids (ICSs).8,9
We conducted a literature search of MEDLINE
Biomarkers have enabled targeted antiinflammatory
(PubMed) up to April 2024. Search terms included the
strategies, revealing that ICSs are effective in patients
following: COPD, chronic obstructive pulmonary
with COPD with eosinophilic inflammation. However,
disease, and mechanism of action. Reference lists of
in contrast with those with severe asthma, the response
included studies were reviewed to identify additional
to anti-IL-5 biologic therapies in COPD has shown small
relevant studies.
benefits for the same intensity of eosinophilic
inflammation, casting doubt on the role of eosinophils as
drivers of COPD. Epithelial-derived alarmins (eg, IL-33, Evidence Review
IL-25, thymic stromal lymphopoietin [TSLP]) can Heterogeneity of Inflammation in COPD
trigger both type 1 and type 2 inflammation and have
The pathophysiology of COPD is complex, and the
been found to be overexpressed in patients with COPD
underlying mechanisms of disease and its progression
and confirmed in animal models and genetic studies,7
are incompletely understood.19,20 The underlying
which has prompted phase 2 and 3 clinical studies with
pattern of inflammation in COPD is often dominated by
monoclonal antibodies itepekimab, an anti-IL-33
neutrophils, CD8þ T cells, and alveolar macrophages
biologic, and tezepelumab, an anti-TSLP biologic.10,11
(Fig 1). A proportion of patients, ranging from 20% to
Current management of COPD includes crucial 40%, exhibit a sputum and peripheral eosinophilic
nonpharmacologic strategies (eg, smoking cessation, signature9,21 and have been identified as having a type 2
pulmonary rehabilitation, management of endotype with specific response to therapies (eg, inhaled
comorbidities) complemented by pharmacologic steroids). 9,22,23 Increased neutrophil count with
strategies including inhaled therapies and systemic inflammasome activation is the most common
agents. The mainstay of pharmacologic therapy is the inflammatory pattern observed in COPD. However, to
use of inhaled long-acting bronchodilators (long-acting date, there is little evidence that biologic therapies
b2-agonists [LABAs] and long-acting muscarinic targeting these pathways provide significant benefit.24
antagonists [LAMAs]), in some cases adding Although bacterial, fungal, and viral infections can cause
antiinflammatory treatment with ICSs.12,13 However, peripheral eosinopenia, eosinophil counts in sputum are
despite including additional therapies (eg, macrolides, increased during exacerbations in some patients with
phosphodiesterase-4 inhibitors), a substantial number COPD.9,25 The airway microbiome in patients with

chestjournal.org 1347
 Epithelial damage

Inflammation IL-33 Tissue destruction and Faulty Remodeling

Type 1/Type 17 Mixed Type 2 Endothelial cell Mucus
inflammation inflammation inflammation activation production, cilia
Myofibroblast
proliferation dysregulation
Neutrophils Mast cells Eosinophils Mucus

Basophils
Th17 MM
NK DC CXCLs, MIPs
Th17 NK
DC
Th1 ILC2
Th2 Extracellular matrix
Th1 ILC2 remodelling
MMPs, IL-1E , IL-6,
TNF- D TGF-E, IL-4,
IFN J , IL-7 IL-4, IL-5, IL-13
IL-5, IL-13, IL-8,
IL-12, CXCLs

Airflow
Emphysema
obstruction

IMPAIRED LUNG FUNCTION

EXACERBATION

Targeted by: Itepekimab, tozurakimab Dupilumab Mepolizumab, benralizumab

Figure 1 – IL-33 drives airway inflammation and remodeling in COPD. CXCL ¼ chemokine (C-X-C motif) ligand; DC ¼ dendritic cells; IFN ¼
interferon; ILC2 ¼ type 2 innate lymphoid cell; MF ¼ macrophages; MIP ¼ macrophage inflammatory protein; MMP ¼ matrix metalloprotease;
NK ¼ natural killer; TGF ¼ transforming growth factor; Th ¼ T helper; TNF ¼ tumor necrosis factor.

COPD may also influence the underlying inflammatory inflammatory gene expression is observed in sputum
phenotype, including macrophages, IL-17, and and bronchial brushings from patients with eosinophilic
interferon, which could potentially guide therapy.26,27 COPD, supporting evidence for underlying mechanisms
beyond those that are only eosinophil-driven.23,36
Eosinophilic inflammation is also seen in asthma28,29;
however, despite some clinical similitudes, these 2
diseases behave differently, and biologics (eg, anti-IL-5) Role of Alarmin Cytokines in COPD
that are highly effective in type 2 inflammation in The epithelial-derived alarmin cytokines IL-33 and TSLP
asthma have not shown significant effect in large COPD can influence both type 1 and type 2 inflammation; both
clinical trials.30,31 However, the observation that IL-33 and TSLP are genetically implicated in COPD.10,11
treatments targeting eosinophils may be incompletely IL-33 acts as an initiator and amplifier of T1 and T2
effective in treating patients with eosinophilic inflammatory pathways. Signaling of IL-33 through its
COPD30,31 suggests a potential role for other elements of receptor suppression of tumorigenicity 2 (ST-2) leads to
the type 2 inflammatory cascade.32 This circumstance cellular processes (eg, proliferation, cell survival) and
could be explained by studies showing that IL-4 and IL- inflammatory cytokine secretion.37,38 ST-2 is
13, key drivers of type 2 inflammation, contribute to constitutively expressed at high levels on tissue-resident
airway remodeling and lung parenchyma immune cells, particularly mast cells, type 2 innate
destruction,33,34 promoting activation and trafficking of lymphoid cells, and regulatory T cells.39 The specific
type 2 inflammatory cells including eosinophils to the response to IL-33 differs by cell type: Th2 cells secrete IL-
airways.35,36 Furthermore, a wide profile of type 2 4, IL-5, and IL-1337; macrophages skew to a type 2

1348 Chest Reviews [ 167#5 CHEST MAY 2025 ]

alternatively activated phenotype40,41; and eosinophils optimizing treatment outcomes. Unfortunately, a
degranulate and release reactive oxygen species.38,42 IL- proportion of patients with COPD, approximately 38%,
33 can also contribute to neutrophilic responses, affecting continue to use tobacco, highlighting the difficulty of
neutrophil migration and chemotaxis.43 quitting.60
The relevant role for IL-33 in COPD pathogenesis has Active tobacco use has been shown to have a detrimental
been demonstrated in animal models. Mice treated with influence on certain COPD therapies, with people with
exogenous IL-33 had airway inflammation, including active tobacco use being less responsive to ICS or
eosinophilic infiltration, epithelial cell hypertrophy, and macrolides.10,61-63 When ICSs were added to LAMAs/
mucus secretion in the airway epithelium.37 Elevated LABAs, it resulted in greater reductions in COPD
expression of IL-33 and ST-2 is observed in the lungs of exacerbations in patients who previously smoked
cigarette-smoke-exposed mice, and in this experimental compared with patients with active tobacco use.61,62
model, smoke-induced lung pathology could be Similarly, in a randomized trial, azithromycin led to a
ameliorated with anti-IL-33 antibodies.44,45 Importantly, significant reduction in time to first COPD exacerbation
elevated expression of IL-33 and ST-2 has been reported in patients who previously smoked, but not in patients
in patients with COPD.44,46 Additionally, genetic with active tobacco use.63
analyses have demonstrated associations between the IL-
Interestingly, differences in therapeutic effect between
33 pathway and COPD risk; loss of function in IL33 was
patients with active tobacco use and patients who
associated with reduced COPD risk, whereas gain of
previously smoked have been found in clinical trials
function in IL33 and IL1RL1 variants was associated
investigating biologics (eg, anti-IL-33, anti-IL-5). In a
with increased risk of COPD.10
phase 2 proof-of-concept study in 343 patients with
TSLP levels are elevated in the airways of patients with moderate to severe COPD, itepekimab, a human
COPD,47 and increased TSLP is associated with a risk of monoclonal antibody against IL-33, improved lung
airflow obstruction in response to smoking.11 Expression function and reduced exacerbations, but did not reach
of TSLP may also be upregulated in response to viral statistical significance in the overall population.10
infection, suggesting a role for TSLP in COPD However, in this clinical trial, such benefits were
exacerbations.48 Association of lung function and TSLP significant in patients who previously smoked, but not in
genotypes with specific COPD phenotypes may reflect patients with active tobacco use.10 It is possible that this
underlying differences in pathophysiology.11 effect is mediated by the wide-ranging proinflammatory
effects of cigarette smoke, or by a more specific
Smoking Status in COPD Disease and Treatment mechanism in which cigarette smoke alters transcription
Cigarette smoking is the most common cause of COPD of IL-33 pathway genes, either epigenetically or by
in high-income countries. COPD may also be caused by changing IL-33 protein activity, potentially via
other occupational exposures or inhalation of toxic oxidation-driven inactivation.64 In the phase 3
fumes, with different expression of the disease.49,50 Mepolizumab as Adjunctive Therapy in Patients with
However, the current body of knowledge regarding Chronic Obstructive Pulmonary Disease (COPD)
COPD has emerged from studying a group of patients Characterized by Eosinophilic Inflammation (METREX)
with active tobacco use and patients who previously and Mepolizumab as Adjunctive Therapy in Patients
smoked. Because active tobacco use in COPD is With Chronic Obstructive Pulmonary Disease (COPD)
associated with poorer outcomes, including lower Characterized by Eosinophilic Inflammation
response to therapies, this patient group has been (METREO) clinical trials, anti-IL-5 mepolizumab
proposed as a clinical phenotype by Carrión Valero demonstrated a numerically greater risk reduction in
et al.50-52 Although smoking cessation slows the rate of patients who do not smoke/patients who previously
lung function decline, patients who previously smoked smoked compared with patients with active tobacco use
may experience a persistent decline in lung function, (21% vs 13%); however, this result was not statistically
and also remain at risk for exacerbations.13,53-55 significant.65 In another proof-of-concept study of MK-
Important benefits of quitting also include improvement 7123, a CXCR2 antagonist targeting the IL-8 receptor,
in both mental and physical aspects of quality of life.56-59 MK-7123 improved lung function and decreased time to
Because smoking cessation has been shown to reduce first exacerbation also in patients with active tobacco
morbidity and mortality, it is a critical first step to use, but not in patients who previously smoked.66

chestjournal.org 1349
TABLE 1 ] Biologic Therapies Under Investigation for COPD
Drug Target Trials Results
Targeting type 2
inflammation
Mepolizumab IL-5 Ph3 METREX/METREO Complete30
 Reduced exacerbations only in those with
highest blood eosinophils
Ph3 MATINEE Ongoing
 https://clinicaltrials.gov/ct2/show/
NCT04133909
Benralizumab IL-5 receptor Ph2a Complete69
 No exacerbation reduction
Ph3 GALATHEA/TERRANOVA Complete31
 No exacerbation reduction
Ph3 RESOLUTE Ongoing
 https://clinicaltrials.gov/ct2/show/NCT04
053634
Dupilumab IL-4Ra (IL-4 Ph3 BOREAS Complete70
and IL-13)  Significant reduction in moderate to severe
acute COPD exacerbations over 52 wk
 Significant improvements in lung function
from baseline, health-related quality of
life, and respiratory symptoms
Ph3 NOTUS Ongoing
 https://clinicaltrials.gov/ct2/show/
NCT04456673
Targeting alarmins
Itepekimab IL-33 Ph2 Complete10
 Reduced exacerbations and improved
lung function in subgroup of patients with
previous tobacco use
Ph3 AERIFY-1 Ongoing
 https://clinicaltrials.gov/ct2/show/
NCT04701983
Ph3 AERIFY-2 Ongoing
 https://clinicaltrials.gov/ct2/show/
NCT04751487
Ph3 AERIFY-3 Ongoing
 https://clinicaltrials.gov/study/
NCT05326412
Ph3 AERIFY-4 Ongoing
 https://clinicaltrials.gov/study/NCT062
08306
Tozorakimab IL-33 Ph2 FRONTIER-4 Ongoing
(MEDI3506)  https://clinicaltrials.gov/ct2/show/
NCT04631016
Ph3 TITANIA Ongoing
 https://clinicaltrials.gov/study/
NCT05158387
Ph3 OBERON Ongoing
 https://clinicaltrials.gov/study/
NCT05166889
Astegolimab ST-2 Ph2a COPD-ST2OP Ongoing
 https://clinicaltrials.gov/ct2/show/
NCT03615040
Ph2b Ongoing
 https://clinicaltrials.gov/ct2/show/NCT05
037929

(Continued)

1350 Chest Reviews [ 167#5 CHEST MAY 2025 ]

TABLE 1 ] (Continued)
Drug Target Trials Results
Ph3 ARNASA Ongoing
 https://clinicaltrials.gov/study/NCT055
95642?a¼16
Tezepelumab TSLP Ph2a COURSE Complete
 Nonsignificant reduction in rate of
moderate/severe exacerbations
vs placebo
 Greater reductions with baseline
eosinophils $ 150 cells/mL
Ph2 UPSTREAM COPD Ongoing
 https://clinicaltrials.gov/study/NCT055
07242

AERIFY-1 ¼ Study to Assess the Efficacy, Safety, and Tolerability of SAR440340/REGN3500/Itepekimab in Chronic Obstructive Pulmonary Disease (COPD);
AERIFY-2 ¼ Study to Assess the Efficacy, Safety, and Tolerability of SAR440340/REGN3500/Itepekimab in Chronic Obstructive Pulmonary Disease (COPD);
AERIFY-3 ¼ Mechanistic Study of the Effect of Itepekimab on Airway Inflammation in Patients With COPD; AERIFY-4 ¼ A Study to Investigate Long-term
Safety and Tolerability of Itepekimab in Participants With COPD; ARNASA ¼ A Study to Evaluate Astegolimab in Participants With Chronic Obstructive
Pulmonary Disease; BOREAS ¼ Evaluation of the Effectiveness and Quality of Life With the Administration of the Fixed Combination of Budesonide For-
moterol in Greek Patients With Asthma During Routine Clinical Practice; COPD-ST2OP ¼ Anti-ST2 (MSTT1041A) in COPD; COURSE ¼ Efficacy and Safety of
Tezepelumab Versus Placebo in Adults With Moderate to Very Severe Chronic Obstructive Pulmonary Disease; FRONTIER-4 ¼ A Phase II, Randomized,
Double-blind, Placebo-controlled Study to Assess MEDI3506 in Participants With COPD and Chronic Bronchitis; GALATHEA ¼ Benralizumab Efficacy in
Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD) With Exacerbation History; MATINEE ¼ Mepolizumab as Add-on Treatment IN
Participants With COPD Characterized by Frequent Exacerbations and Eosinophil Level; METREO ¼ Mepolizumab as Adjunctive Therapy in Patients With
Chronic Obstructive Pulmonary Disease (COPD) Characterized by Eosinophilic Inflammation; METREX ¼ Mepolizumab as Adjunctive Therapy in Patients
With Chronic Obstructive Pulmonary Disease (COPD) Characterized by Eosinophilic Inflammation; NOTUS ¼ Pivotal Study to Assess the Efficacy, Safety and
Tolerability of Dupilumab in Patients With Moderate to Severe COPD With Type 2 Inflammation; OBERON ¼ Efficacy and Safety of Tozorakimab in
Symptomatic Chronic Obstructive Pulmonary Disease With a History of Exacerbations; Ph ¼ phase; RESOLUTE ¼ Efficacy and Safety of Benralizumab in
Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD) With a History of Frequent Exacerbations; TERRANOVA ¼ Efficacy and Safety of
Benralizumab in Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD) With Exacerbation History; TITANIA ¼ Efficacy and Safety of
Tozorakimab in Symptomatic Chronic Obstructive Pulmonary Disease With a History of Exacerbations; TSLP ¼ thymic stromal lymphopoietin; UPSTREAM
COPD ¼ Effects of Blocking TSLP on Airway Inflammation and the Epithelial Immune-response to Exacerbation Triggers in Patients With COPD.

Collectively, these studies further support the previous Future Directions

findings that smoking status in COPD influences COPD exacerbations, particularly those associated with
treatment response, and therefore, as is already hospitalizations, have a considerable impact on patients,
recommended, it should be part of the current patient including morbidity, mortality, and increased health
with COPD assessment and follow-up. care costs.3,71 A significant proportion of patients do not
achieve disease control with currently available therapies
Side Effects and Cost of Biologics
(Fig 2).14,15 However, COPD management can still be
Other than small differences in local injection site improved because many patients remain symptomatic
reactions, the relatively small number of clinical trials of and experience exacerbations despite optimized
biologics in patients with COPD published to date have therapies. Identifying COPD endotypes may improve
shown no signal of clinically important side effects the efficacy of targeted treatments.
compared with placebo. Systematic reviews of the
effectiveness and tolerability of several biologics also used Advances in understanding the pathophysiology of
in the treatment of asthma, where experience is much COPD have led to the development of therapies that
larger, have associated these agents with a slight increase potentially target the underlying pathophysiology of the
in potential side effects; however, the conclusions are disease (Table 1). Currently, there are several active
based on low-quality evidence.67,68 In asthma, the cost- clinical trials investigating the effects of biologics in
effectiveness ratio of using biologics is regarded as patients with COPD, which will likely soon yield
justified by reductions in severe exacerbations, important insights into the targeted treatment of COPD
hospitalizations, and need for oral corticosteroid use. (Table 1). Two phase 3 studies targeting IL-5 have been
These data are not yet available for COPD, but results of completed, and 2 more are underway.73,74 Targeting
the studies cited in Table 1 will help inform this important other type 2 inflammatory pathways (eg, IL-4/IL-13) is
aspect of therapy with biologics. appealing,75 and the recently completed phase 3

chestjournal.org 1351
 Most frequently available medications for COPD treatment

Inhaled administration Systemic administration

PDE3/PDE4 Beta adrenergic Xanthines Biologics

inhibitors Anticholinergics agents Theophylline PDE4i Dupilumabb
Antibiotics Antioxidants
Ensifentrine Short acting (SAMA) Short acting (SABA) Aminophylline Roflumilast Tezepelumabb
Ipratropium Albuterol Corticosteroids Doxofylline Mepoluzimabb
Long acting (LAMA) Pirbuterol (ICS) Benralizumabb
Tiotropium
Beclomethasone Itepekimabc
Long acting (LABA) Fluticasone c
Aclidiniuma Astegolimab
Salmeterola
Umeclidinium
Budesonide Antibacterials Tozurakimabc
Formoterola Cyclesonide
Glycopyrroniuma Chosen by
Vilanterol Antinflammatory
Glycopirrolate regional
Olodaterol Macrolides
experience and
Indacaterol
sensitivity

Combined SAMA/SABA Combined beta agonists/

Ipratropium/Albuterol (ICS)
Combined LAMA/LABA Salmeterol/Fluticasone
Tiotropium/Olodaterol propionatea
Umeclidinium/Vilanterol Formoterol/Budesonidea
a
Glycopyrronium/Indacaterol Vilanterol/Fluticasone Furoate
Aclidinium/Glycopyrroniuma Beclomethasone/Formoterola

Triple combination (LAMA/LABA/ICS)

Umeclidinium/Vilanterol/Fluticasone Furoate
a
Glycopyrronium/Formoterol/beclomethasone

Figure 2 – Frequently used medications for the treatment of COPD.72 There has been an important increase in the number of medications available to
treat patients with clinically evident (symptomatic) COPD. Inhaled medications are preferred throughout the course of the disease, whereas oral or
systemic medications are considered for patients who have ongoing symptoms despite optimal therapy with inhaled agents. Short-acting bronchodilators
are effective for 4 to 6 h. ICS ¼ inhaled corticosteroid; LABA ¼ long-acting b2-agonist; LAMA ¼ long-acting muscarinic antagonist; PDE3 ¼
phosphodiesterase 3; PDE4 ¼ phosphodiesterase 4; PDE4i ¼ phosphodiesterase-4 inhibitor; SABA ¼ short-acting b2-agonist; SAMA ¼ short-acting
muscarinic antagonist. aLong-acting bronchodilators, the recommended dosing of which is twice daily. bBiologics that are US Food and Drug
Administration approved for treating eosinophilic asthma but not COPD. cBiologics without approval for any indication.

BOREAS trial investigated dupilumab (which blocks IL- (COURSE) study with the anti-TSLP antibody
4 and IL-13) in patients with COPD with moderate or tezepelumab have been presented in abstract form
severe exacerbations while on ICSs þ LAMAs þ LABAs (Table 1). A phase 2b study of astegolimab, an inhibitor
(or LAMAs þ LABAs, if ICSs were contraindicated) and of the IL-33 receptor ST-2, is ongoing.77
baseline blood eosinophil counts $ 300 cells/mL.70
Dupilumab significantly reduced moderate to severe Summary
acute COPD exacerbations by 30% over 52 weeks and Our findings indicate that current therapies for the
significantly improved lung function from baseline, treatment of COPD are only partially effective in
health-related quality of life, and respiratory symptoms. reducing the burden of COPD, improving symptoms,
Because alarmins regulate both type 1 and type 2 improving exercise tolerance, and/or decreasing
inflammation, they have been proposed as a target in exacerbations. Thus, there is an unmet need for more
COPD. In a prespecified analysis of a phase 2 proof-of- effective therapies. Biologic therapies are not yet
concept study, itepekimab, an anti-IL-33 biologic, approved for patients with COPD, but many studies
reduced exacerbations and improved lung function in targeting different pathways are active. If approved,
patients who previously smoked,10 and 3 ongoing phase 3 biologics could prove to be precise treatment options
studies are being conducted to confirm its efficacy and for specific patients with COPD.
safety (Clinicaltrials.gov NCT04701983, NCT04751487,
NCT06208306). Tozorakimab (MEDI3506), another Funding/Support
anti-IL-33 antibody, is also being investigated for Medical writing/editorial assistance was provided by
COPD.76 Results of the phase 2a Efficacy and Safety of Joseph Worrall, PhD, of Excerpta Medica, and was
Tezepelumab Versus Placebo in Adults With Moderate to funded by Sanofi and Regeneron Pharmaceuticals Inc.,
Very Severe Chronic Obstructive Pulmonary Disease according to the Good Publication Practice guidelines.

1352 Chest Reviews [ 167#5 CHEST MAY 2025 ]

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