COPD Biologics: Right Patient, Right Pathway, Right Time

Abstract

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease that is entering a new era in precision medicine. Advances in disease endotyping have challenged the traditional view of COPD as a uniformly neutrophilic disorder and revealed biologically distinct subgroups in whom targeted immunomodulation may be effective. Reproducible signatures of type 2 (T2) inflammation and epithelial-derived alarmin activation have emerged as actionable pathways, reshaping therapeutic development in COPD. This narrative review synthesises mechanistic insights and clinical trial evidence for biologic therapies targeting key T2 cytokines such as interleukin-5 (IL-5) IL-4/IL-13 and upstream epithelial alarmins, including interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP). We examine why earlier approaches targeting neutrophilic inflammation failed, and how biomarker-driven trial design has enabled success in selected populations. Across these programmes, therapeutic efficacy has depended not only on the pathway targeted but also on patient selection, disease stage and timing of intervention. We propose that the future of biologics in COPD lies in integrating biomarkers, treatable traits and longitudinal phenotyping to align the right patient with the right pathway at the right time, closing persistent treatment gaps in this common, overlooked and burdensome disease.

Key Summary Points

Chronic obstructive pulmonary disease (COPD) is heterogeneous, but biologic therapies are effective when targeted to specific endotypes.

The success or failure of clinical trials targeting the interleukin-5 (IL-5), IL-4/IL-13 and alarmin pathways shows that patient selection, disease stage and timing are critical determinants of biologic efficacy.

Selecting people who have COPD with frequent exacerbations and blood eosinophil counts ≥ 300 cells/µL has helped identify those most likely to respond to T2 targeting biologics.

Biologics targeting alarmins interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP) may have broader efficacy in COPD, but further phase 3 trials are needed to identify which patients will benefit.

Learning from clinical trials has helped us understand more about COPD pathophysiology. Moving forwards, real-world evidence is needed decide which patients will benefit most from pathway-directed treatment.

Introduction

Chronic obstructive pulmonary disease (COPD) affects 480 million people worldwide and is a leading cause of morbidity, mortality and healthcare utilisation [1]. While COPD is defined physiologically as airflow obstruction which is not fully reversible [2], this belies the complexity of the disease, which includes several clinical phenotypes including frequent exacerbations, chronic bronchitis and emphysema which can coexist with substantial diversity in underlying inflammatory and structural pathways which can evolve over the disease course. This heterogeneity has presented several challenges in driving forwards therapeutic developments for COPD.

Many early setbacks can now be viewed as a result of applying broadly immunosuppressive strategies to a disease in which inflammatory mechanisms may be context-dependent and often dysfunctional rather than excessive. As a result, traditional “one-size-fits-all” approaches may have concealed potential benefit in responder subgroups. Over the past decade, a subset of patients with COPD have been identified who exhibit reproducible features of type 2 (T2) inflammation which predict response to corticosteroids and, more recently, biologic therapies. In parallel, epithelial-derived alarmins such as interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP) have emerged as upstream regulators that integrate environmental injury, innate immunity and airway remodelling, offering additional therapeutic strategies beyond classical cytokine blockade. Crucially, the success and failure of biologics in COPD has revealed that therapeutic efficacy depends not only on the pathway targeted, but also on patient selection and disease endotyping.

In this narrative review, we examine the evolving landscape of biologics in COPD through the lens of precision medicine. We synthesise mechanistic and clinical trial evidence across T2 cytokines and epithelial alarmins, highlighting why certain targets may have succeeded while others have failed. We also summarise key data from biologic trials in asthma to highlight similarities and differences between the response to biologic treatment in these different airways’ diseases. Moving forwards, we cover how clinicians can identify the right patient, the right pathway and the right time for biologic intervention in COPD, and outline priorities for future therapeutic development.

COPD Pathogenesis

COPD has long been associated with airway inflammation which typically includes infiltration of neutrophils, goblet cell hypertrophy leading to mucus hypersecretion, airway smooth muscle hypertrophy and small airway fibrosis [3]. While breakdown of alveolar tissue leads to emphysema and reduced gas exchange. At a cellular level, airway epithelial cells and fibroblasts may display a pro-inflammatory phenotype due to cellular senescence [4–6]. Macrophage numbers are increased but exhibit a pro-inflammatory phenotype with reduced clearance of apoptotic cells and invading pathogens [7–9]. Neutrophils infiltrate the bronchial epithelium and appear primed, leading to ongoing tissue damage due to increased production of proteases and neutrophil extracellular traps [10–12]. However, these neutrophils are often dysfunctional in COPD with reduced chemotaxis, delayed apoptosis and impaired phagocytosis of invading pathogens resulting in chronic inflammation [13, 14].

Biologics Targeting Neutrophilic Inflammation in COPD

Because COPD was traditionally viewed as a neutrophilic airway disease, treatment with biologics targeting neutrophilic inflammation has been explored extensively. However, this approach was limited as many biological targets have the effect of reducing neutrophil number but also reduce neutrophil killing of invading pathogens. The has caused problems in a disease punctuated by exacerbations driven by infections, and airway neutrophils which are high abundance but often dysfunctional [12]. As a result, clinical trials targeting neutrophilic inflammation have often been unsuccessful. For example, a clinical trial of an oral CXCR2 antagonist MK-7123 improved forced expired volume in 1 s FEV1 compared with placebo but was discontinued owing to systemic neutropenia [15]. Meanwhile, a phase 2b trial of another oral CXCR2 antagonist Darixin in COPD found an increased risk of exacerbations and pneumonia in the Darixin-treated group, resulting in an unfavourable benefit–risk profile in COPD. Drugs targeting specific cytokines involved in neutrophil chemotaxis and neutrophil activation such as IL-8 [16], IL-1β [17, 18] and tumour necrosis factor (TNF) [19, 20] have also been unsuccessful owing to poor efficacy or increased risk of infection, as summarised in Table 1.

Table 1.

Summary of biologic trials in chronic obstructive pulmonary disease (COPD)

Target/pathway	Biologic	Key clinical trials	Main population	Key outcomes (simplified)
IL-4Rα (type 2 inflammation)	Dupilumab	BOREAS, NOTUS	COPD + eosinophils ≥ 300 cells/µL	Reduced exacerbations (~ 30–34%; RR 0.687, 95% CI 0.595–0.793; p < 0.0001) improvement in FEV1 (~ 80 mL)
IL-5	Mepolizumab	METREX, METREO, MATINEE	METREX: eosinophilic and non-eosinophilic COPD METREO: eosinophilic COPD (≥ 150 eosinophils) MATINEE: eosinophilic COPD (eosinophils ≥ 300)	METREX: no overall reduction in exacerbations (RR 0.98 CI 0.85–1.12, p > 0.99) but did in patients with an eosinophilic phenotype (RR 0.82, CI 0.68–0.98, p < 0.04); METREO: reduction in exacerbations not meeting statistical significance Mepolizumab 100 mg versus placebo: RR 0.80, CI 0.65–0.98, p = 0.07 MATINEE: 21% reduction in total exacerbations compared with placebo, and 35% reduction in COPD-related admissions or ER visits (RR 0.79, CI 0.66–0.94, p < 0.01)
IL-5Rα	Benralizumab	GALATHEA, TERRANOVA	Eosinophilic COPD	No significant reduction in exacerbations overall; poor efficacy signal (RR 0.85, CI 0.71–1.01, p = 0.06)
IL-33	Itepekimab	Phase 2a trial (NCT03546907) Phase III trials: AERIFY-1 and AERIFY-2	COPD	Phase 2a trial did not meet primary endpoint of reduction in moderate–severe exacerbations (RR 0.81, 95% CI 0.61–1.07, p = 0.13). Did note exacerbations and some lung function improvement signals (in subsets of former smokers) Phase III trials showed inconsistent results in exacerbation reduction
	Tozorakimab	Phase 2a FRONTIER-4 study (NCT04631016)	Broad COPD population	No significant change in FEV1 at week 12, and no significant reduction in risk of COPD composite exacerbation events (hazard ratio 0.79, 80% CI 0.57–1.11, p = 0.186). Some numerical improvements in lung function and exacerbation-related outcomes, particularly in patients with a history of frequent exacerbations
IL-33 receptor (ST2)	Astegolimab	Phase IIb ALIENTO (NCT05037929) Phase III ARANSA (NCT05595642)	COPD	Mixed results; some reduction in exacerbations in selected groups (not definitive) ALIENTO Astegolimab 2 weeks versus placebo (RR 0.85, 95% CI 0.72–1.00; p = 0.049) Astegolimab 4 weeks versus placebo (0.93, 0.79–1.10; p = 0.38) ARNASA Astegolimab 2 weeks versus placebo (RR 0.85, 0.72–1.01; p = 0.068) Astegolimab 4 weeks versus placebo RR 0.82 (0.70–0.98; p = 0.024)
TSLP (alarmin pathway)	Tezepelumab	COURSE phase IIb	Broad COPD population	No overall reduction in annualised exacerbation rate (RR 0.83, 90% CI 0.64–1.06; p = 0.10) but signal towards greater reduction in young patients, and those with eosinophils ≥ 150
TNF-α	Infliximab	Small COPD trials	Moderate–severe COPD	No benefit; development abandoned
CXCR2	Darixin (and others)	Phase 2 trials	Neutrophilic COPD	Unfavourable risk–benefit profile

Targeting Type 2 Inflammation in COPD

Type 2 Inflammation in COPD

Eosinophils are generated in the bone marrow from multipotent haemoatopoietic stem cells and are regulated by T-lymphocytes which produce IL-13, IL-5 and granulocyte–macrophage colony-stimulating factor (GM-CSF). Upon release into the circulation, eosinophils are activated by IL-5, IL-13 and eotaxins and are able to migrate to tissues by chemotaxis directed by IL4, IL-13 and eotaxins [21]. Eosinophils play a role in pathogen clearance through degranulation and release of eosinophilic extracelluar traps (EETosis) and may also regulate resolution of inflammation through efferocytosis [22, 23].

While T2 inflammation has been associated with asthma, between 20% and 40% of people with COPD may have a blood or sputum eosinophilia in the stable state [24–27]. Circulating blood eosinophils have emerged as an accessible biomarker of T2 inflammation, with a blood eosinophil count ≥ 300 cells/μL predicting response to inhaled corticosteroids [28, 29], although the relationship between stable blood eosinophils and exacerbation risk is less clear [30–32]. While it may be tempting to view eosinophilic COPD and asthma as the same entity, there are differences in the histopathology and T2 activation pathways in COPD compared with asthma. In bronchial biopsies from people with eosinophilic COPD, eosinophils show patchy distribution and spatial clustering with other T2 cells (e.g. basophils and ILC2s) [33]. In asthma, intra-epithelial eosinophils are linked to IL-5 expression and airway hyperresponsiveness, potentially via interactions with airway nerves [34]; these functional relationships are less clear in COPD. Gene expression studies have shown up-regulation of T2 inflammation in COPD with an increased expression of IL-13-dependent genes, chloride channel accessory (CLCA1), C–C motif chemokine ligand 26 (CCL26) and cystatin SN (CST1) in bronchial brushes and sputum from patients with COPD and increased blood eosinophils, with only one of these genes (CST1) overlapping with gene expression in people who have asthma, suggesting that there may be differences in the activation of T2 pathways between airways diseases [35].

IL-5 Biology

Interleukin-5 (IL-5) is a key regulator of eosinophils in the lung and systemic circulation and subsequently has been a focus for modulating T2 inflammation in airways disease. IL-5 is primarily released by type 2 T-helper cells (Th2) and innate lymphoid cells (ILCs) in response to epithelial alarmins IL-25, IL-33 and thymic stromal lymphopoietin (TSLP), which can be triggered by exposure to aeroallergens, pollutants and airway pathogens [36, 37]. However, IL-5 may also be triggered by alternative pathways in COPD, including inflammasome activation and pro-inflammatory cytokine release [38, 39]. IL-5 acts on the bone marrow to drive terminal eosinophil differentiation and release into the circulation [40]. Crucially, IL-5 is not chemotactic and does not direct eosinophils to a site of injury. However, IL-5 primes eosinophil activation, promoting eosinophil degranulation and release of extra-cellular traps which promote pathogen clearance but can induce tissue damage [41]. IL-5 may also promote eosinophil persistence by reducing eosinophil apoptosis, increasing expression of adhesion molecules and promoting tissue retention [42].

Therapeutics Targeting IL-5 in COPD

Mononclonal antibodies targeting IL-5 (mepolizumab and reslizumab) or the IL-5 receptor (IL-5Ra) (benralizumab) have been shown to reduce exacerbations and improve quality of life in asthma [43–45]. Early trials targeting IL-5 in COPD were initially disappointing [46]. However, the identification of eosinophilic subtypes was crucial to the conduct and eventual success of further trials targeting a T2 endotype. The METREX trial randomized 836 patients with frequent exacerbations on triple inhaled therapy to either receiving mepolizumab 100 mg sub-cutaneous (SC) injections or placebo for 52 weeks [46]. Both eosinophilic and non-eosinophilic patients with COPD were included but were stratified according to eosinophil count. Overall, mepolizumab did not show a significant benefit in reducing exacerbations in the whole population with a rate ratio (RR) of 0.98 (CI 0.85–1.12; p > 0.99), but did show a significant reduction in exacerbations in patients with COPD with an eosinophilic phenotype (RR 0.82; CI 0.68–0.98; p < 0.04). The METREO study randomized people with COPD, who had frequent exacerbations, already on triple therapy 1:1:1 to either mepolizumab 100 mg, mepolizumab 300 mg or placebo for 52 weeks but only included patients with a blood eosinophil count of ≥ 150 cells/µL at screening or ≥ 300 cells/µL in the previous year [46]. This study showed a numerical reduction in the number of exacerbations in both mepolizumab arms, with the greatest effect in the 100 mg mepolizumab group (RR 0.80; CI 0.65–0.98; p = 0.07), but neither group met statistical significance. However, this did lay the groundwork for the Mepolizumab as Add-on Treatment IN participants with COPD characterized by frequent Exacerbations and Eosinophil levels (MATINEE) trial which was a randomised controlled trial of 800 patients who were randomized to mepolizumab 100 mg SC every 4 weeks or placebo for 52–104 weeks [47]. Participants had to have a blood eosinophil count of ≥ 300 cells/µL at screening and a blood eosinophil count ≥ 150 cells/µL in the previous year. By selecting this eosinophilic population, this trial achieved significance with a 21% reduction in exacerbations compared with placebo (RR 0.79; CI 0.66–0.94; p < 0.01) and a 35% reduction in COPD- related hospital admissions or emergency room visits. However, there was no effect on FEV1 or daily symptoms.

In contrast, IL-5Rα blockade has so far not shown a significant difference in preventing exacerbations in the TERRANOVA and GALATHEA trials. Both trials included people who had COPD with an FEV1 between 20% and 65% predicted and a blood eosinophil count ≥ 220 per cubic millimetre. TERRANOVA randomised participants to 10 mg, 30 mg or 100 mg benralizumab or placebo every 4 weeks, while GALATHEA randomised participants to 30 mg, 100 mg of benralizumab or placebo every 4 weeks [48]. Overall, there was no reduction in the annualised rate of exacerbations in the benralizumab arms compared with placebo. Although, there was a trend to a reduction in the lower benralizumab arm of 10 mg compared with placebo (RR 0.85; CI 0.71–1.01; p = 0.06), this did not meet significance. There was also no clear dose response seen and no effect on quality of life or lung function. In contrast, an acute study of randomising patients with either COPD or asthma, with a blood eosinophil count of ≥ 300 cells/µL, to either benralizumab 100 mg, benralizumab 100 mg and prednisolone or prednisolone only at the time of an exacerbation, showed a significant reduction in treatment failure, i.e. the number of patients who needed to be re-treated or admitted to hospital (odds ratio 0.26; 95% CI 0.13–0.56; p = 0.0005) [49]. This novel study showed that biologics could be beneficial as an acute treatment, however this was a mixed population and further studies of people with COPD would give greater insight into the potential role of giving T2 biologics at exacerbation.

Why Was There a Difference in IL-5- and IL-5Rα-Targeting Biologics in COPD?

The differential efficacy of IL-5 ligand blockade compared with IL-5 receptor-α (IL-5Rα) depletion in COPD could represent differences in the populations studied, as mepolizumab showed the greatest effect in patients with a blood eosinophil count ≥ 300 cells/µL. However, it may reflect a fundamental difference in eosinophil biology between COPD and asthma. We have previously shown that some patients only become eosinophilic at exacerbation, suggesting that eosinophils may be an episodic risk modifier for exacerbations rather than a central disease driver in the stable state [24]. As IL-5 blockade attenuates eosinophil production and trafficking in a partial and reversible manner, this may reduce potentially damaging eosinophilic surges while preserving homeostatic or potentially protective eosinophil functions. In contrast, IL-5Rα-directed therapies cause near-complete eosinophil depletion across compartments, which may overshoot the relevant biology in COPD where eosinophils may play beneficial roles in pathogen clearance or homeostasis [23], limiting clinical benefit despite significant pharmacodynamic effects.

IL-4 and IL-13 Biology

Other key drivers of type 2 inflammation are IL-13 and IL-4, which are secreted by type 2 innate lymphoid cells. Both molecules can independently activate signal transducer and activator of transcription 6 (STAT6) signalling by engaging the interleukin-4 receptor alpha (IL-4Rα) subunit.

While IL-4 drives differentiation of naïve CD4⁺ T cells into Th2 cells, STAT6 activation by both IL-4 and IL-13 exerts multiple shared downstream effects in the lung. These include B-cell class-switching to produce IgE, macrophage M2 polarisation and the epithelial release of eotaxins that drive localised eosinophil recruitment. In the context of COPD, this persistent signalling leads to pathological structural changes, including goblet cell hyperplasia, mucus hypersecretion and airway smooth muscle hyperresponsiveness.

Therapeutic Targeting of IL-4 and IL-13 in COPD

Agents inhibiting solely IL-4 (pascolizumab) or IL-13 (tralokinumab) have been investigated for the management of asthma. While the former did not reach phase 3 clinical trials, tralokinumab did. However, it showed inconsistent effects in reducing exacerbations in those with severe asthma versus placebo [50].

Given the critical function of the shared IL-4Rα subunit in both IL-4 and IL-13 signalling, it represents an attractive target for disrupting type 2 inflammation. Early attempts to target IL-4Rα in airway disease failed to meet primary clinical endpoints [51]. This was largely attributed to trial design that enrolled all-comers with moderate-to-severe asthma. The lack of biomarker stratification diluted the efficacy signal across patients with non-type 2 inflammation.

Studies of subsequent IL-4Rα antibodies, such as dupilumab, a fully human IL-4Rα monoclonal antibody, stratified randomisation by blood eosinophil count. The phase 3 QUEST trial showed efficacy in reducing rates of severe exacerbation and improving FEV₁ in those with moderate to severe asthma versus matched placebo [52]. Notably, the greatest clinical response was seen in patients with higher baseline blood eosinophil levels. Furthermore, the VESTIGE study showed a reduction in mucus plugging in asthmatic patients treated with dupilumab compared with placebo [53]. This is of interest as a potential mechanistic action of benefit in COPD, where mucus plugging has been associated with increased risk of exacerbations [54], airflow obstruction [55] and mortality [56]. The composition of mucus plugs in COPD has yet to be defined. However, mucus plugging has been associated with both systemic and sputum eosinophilia in COPD. This may be due to eosinophil activation, leading to the release of eosinophil peroxidase [57] which promotes crosslinking of cysteine-rich mucin polymers, resulting in stiffer mucus gels that favour airway plugging in asthma and COPD [22, 57, 58]. Airway eosinophil ETosis (EEtosis) is also associated with charot-laden crystal formation and mucus plugs in asthma and warrants further investigation in COPD [41]. The evaluation of further imaging biomarkers in clinical trials including computed tomography (CT) quantification of mucus plugs, measures of airway wall thickness such as Pi10 and their relationship to clinical outcomes and treatment response represent an exciting opportunity to improve outcomes in COPD [25]. Clinical trials are currently ongoing to investigate the impact of dupilumab treatment on mucus plugging in COPD (NCT07053423).

Informed by prior studies in asthma and studies of mepolizumab in COPD, the landmark BOREAS and NOTUS trials of dupilumab in COPD employed endotype-driven enrolment criteria [59, 60]. These trials required patients to have a blood eosinophil count of ≥ 300 cells/µL, a documented history of exacerbations and be receiving maximal background therapy. In this highly selected COPD population, IL-4Rα blockade proved highly efficacious. A 30–34% reduction in the rate of moderate-to-severe exacerbations was observed with a pooled analysis of the BOREAS and NOTUS trials (RR 0.687; CI 0.595–0.793; p < 0.0001), as well as a 139–160 mL improvement in FEV₁ after 12 weeks [61]. Dupilumab was well-tolerated, with similar dropout rates observed between intervention and control arms over the study period.

Consequently, dupilumab received Food and Drug Administration (FDA) approval as the first biologic for patients with COPD in September 2024, followed by National Institute for Health and Care Excellence(NICE) approval in March 2026. NICE approval was in the same highly selected COPD cohort included in BOREAS and NOTUS, defined primarily by eosinophilia, exacerbation history and maximal inhaled therapy [62].

Real-world evidence has demonstrated the tolerability and efficacy of dupilumab in COPD and highlighted limitations restricting its wider adoption [63, 64]. Limitations include cost and the treatment regimen, as dupilumab is administered as a 2-weekly 300 mg subcutaneous injection. The improvement in lung function seen in the controlled clinical trial setting was not observed in a small cohort of 23 people with COPD treated with dupilumab [64]. Further real-world evidence generation is underway (AURORA, NCT07380711). This cohort study will follow up 350–500 participants over 36 months at 50 sites in France to assess safety and efficacy outside of a clinical trial setting.

Targeting Alarmins in COPD

IL-33 Biology and Signalling

Interleukin (IL)-33 is a member of the interleukin-1 (IL-1) superfamily of cytokines and is a key mediator of inflammatory responses following tissue damage or infection. It contributes to type 1, type 2 and regulatory immune responses and is involved in both allergic and non-allergic inflammation [65]. IL-33 is a dual-function cytokine that localises to the nucleus under homeostatic conditions but is released extracellularly as an alarmin by epithelial cells or endothelial cells in response to cell damage or injury [66]. Once released, IL-33 binds to the receptor ST2 (IL1RL1), in complex with the IL-1 receptor accessory protein (IL-1RAcP), activating downstream pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinases (MAPKs) [67]. ST2 exists in two main isoforms: a transmembrane form (ST2L), which mediates intracellular signalling [6], and a soluble form (sST2), which functions as a decoy receptor by sequestering IL-33 and regulating its activity [68].

IL-33 is tightly regulated by context-dependent inactivation. During apoptosis, IL-33 caspase-mediated cleavage suppresses its activity, with extracellular oxidation further restricting IL-33 activity, preventing exaggerated inflammation and promoting tissue repair [69]. In contrast, during necrosis, intact IL-33 is released and retains full biological activity, acting as an alarmin [66]. As a result, IL-33 signalling plays a dual role in promoting inflammatory mediator release and facilitating tissue repair, with its net effect determined by the local cellular context and regulatory mechanisms such as sST2 and oxidative inactivation [70].

IL-33 in COPD

The IL-33/ST2 axis has emerged as a potential contributor to the pathogenesis of COPD as IL-33 participates in airway remodelling, T1 and T2 inflammatory responses and the coordination of innate and adaptive immunity. In the lung, IL-33 is primarily expressed by airway epithelial basal cells, endothelial cells and fibroblasts, positioning it as a key epithelial-derived “alarmin” in response to tissue damage [71, 72].

IL-33 promotes type 2 inflammation via activation of ILC2s, driving IL-5 and IL-13 production, and enhances mast cell release of pro-inflammatory mediators. Circulating IL-33, ST2 and IL-1RAcP levels are elevated in people with COPD, alongside increased numbers of IL-33-expressing peripheral blood lymphocytes. Clinically, elevated IL-33 levels have been associated with worse outcomes in COPD including increased exacerbation risk, greater smoking exposure and reduced lung function.

Beyond inflammation, IL-33 contributes to airway remodelling and fibrosis through its ability to activate fibroblasts and promote extracellular matrix deposition [73, 74]. IL-33 also modulates host responses to viral infection, a major trigger for COPD exacerbations [75]. Viral infection triggers phosphorylation of interferon regulatory factors (IRF), leading to interferon production to control viral replication, with mouse models also suggesting a role for IRFs in IL-33 regulation [76]. IL-33 may therefore sit at the interface of infection and inflammation, amplifying immune responses but potentially contributing to disease exacerbation and progression.

Therapeutic Targeting of the IL-33/ST2 Axis in COPD

In COPD, monoclonal antibody therapies targeting IL-33 or its receptor ST2 have shown heterogeneous and, at times, conflicting results, highlighting both the therapeutic potential and the complexity of this pathway.

Itepekimab, a monoclonal antibody targeting IL-33, has been evaluated across multiple clinical trials. In the phase 2a study (NCT03546907), itepekimab did not meet its primary endpoint of reducing the annualised rate of moderate-to-severe COPD exacerbations (relative risk 0.81; CI 0.61–1.07; p = 0.13) [77]. However, prespecified subgroup analyses suggested clinically meaningful benefits in former smokers, including reductions in exacerbation rates and improvements in lung function. This signal informed the design of the phase III AERIFY-1 (NCT04701983) and AERIFY-2 (NCT04751487) trials, which specifically enrolled former smokers with inadequately controlled COPD receiving standard inhaled therapy. While AERIFY-1 demonstrated a statistically significant 27% reduction in moderate-to-severe exacerbations at 52 weeks versus placebo, AERIFY-2 failed to replicate this finding. This divergence underscores the challenges of reproducibility and suggests potential heterogeneity in treatment response even within enriched populations. The full trial data had not been released at the time of writing; however potential differences may be due to geographical location and viral exposure patterns. Whether there were any other differences in treatments and co-morbidities between the two trials is not yet known.

Astegolimab, a fully human anti-ST2 monoclonal antibody, blocks IL-33 signalling at the receptor level. In the phase IIb ALIENTO study (NCT05037929), astegolimab met its primary endpoint, achieving a modest but statistically significant 15% reduction in annualised exacerbation rate at 52 weeks versus placebo with a 2 week dosing schedule (RR 0.85; CI 0.72–1.00; p = 0.049) but no significant reduction in the 4-weekly dosing group (RR 0.93; CI 0.79–1.10; p = 0.38) [78]. Notably, this effect was observed irrespective of smoking status or blood eosinophil count, suggesting a broader potential target population than some other biologics. However, these findings were not confirmed in the phase III ARNASA trial (NCT05595642), in which a 14.5% reduction in exacerbation rate did not reach statistical significance with astegolimab every 2 weeks (RR 0.85; CI 0.72–1.01; p = 0.068) but a modest improvement with 4-weekly astegolimab (RR 0.82 CI 0.70–0.98; p = 0.024) [78]. As with itepekimab, these results highlight inconsistency targeting this pathway.

Tozorakimab is a next-generation anti-IL-33 monoclonal antibody with the ability to block both reduced and oxidised forms of IL-33, thereby inhibiting signalling through both ST2 and the receptor for advanced glycation end-products (RAGE)/epidermal growth factor receptor (EGFR) complex pathways. In the phase 2a FRONTIER-4 study (NCT04631016), conducted in patients with moderate-to-severe COPD and chronic bronchitis on dual or triple inhaled therapy, the primary endpoint, viz. change in pre-bronchodilator FEV₁ at week 12, was not met and tozorakimab did not significantly reduce the risk of COPD composite exacerbation events (hazard ratio 0.79, 80% CI 0.57–1.11, p = 0.186) [79]. However, exploratory analyses demonstrated numerical improvements in lung function and exacerbation-related outcomes, particularly in patients with a history of frequent exacerbations, supporting progression to phase 3. Two ongoing parallel, replicate phase III trials (TITANIA, NCT05158387; OBERON, NCT05166889) have recently met their primary endpoint of a reduction in exacerbations, while the PROSPERO and MIRANDA extension studies (NCT05742802) are expected to further clarify the long-term clinical utility of IL-33 blockade.

Taken together, these studies suggest that, while targeting the IL-33/ST2 axis is biologically compelling, clinical efficacy in COPD has been inconsistent. A recurring theme is the presence of subgroup-specific signals, particularly in former smokers or patients with frequent exacerbations, indicating that patient selection and endotype stratification may be critical to clarifying therapeutic benefit. Future success in this space will likely depend on improved biomarker-driven approaches and a better understanding of IL-33 biology across different COPD phenotypes.

TSLP Biology

Thymic stromal lymphopoietin (TSLP) is a pro-inflammatory alarmin which is primarily expressed by epithelial cells in response to infectious, environmental or allergic stimuli as well as being expressed by smooth muscle cells, mast cells and basophils [37]. TSLP binds to a heterodimeric receptor consisting of the TSLP receptor (TSLPR) and IL-7 receptor alpha chain (IL-7RA), activating the Janus Kinase 1 (JAK1)/JAK2 and STAT5 pathway [80]. TSLP regulates T2 inflammation by binding to dendritic cells triggering Th2 T cells to express IL-4, IL-5, IL-9 and IL-13 [81]. However, TSLP also acts directly on ILC2s and mast cells driving T2 inflammation as well as contributing to tissue fibrosis [82–84].

TSLP has been of particular interest in COPD and non-T2 asthma owing to the role of TSLP in activating non-T2 inflammation. TSLP is expressed by neutrophils and monocytes, while neutrophils also express the TSLPR. TSLP has been shown to reduce apoptosis of mononuclear cells and increase IL-8 secretion, while also enhancing bacterial killing of staphylococcus aureus by neutrophils [85] and promoting neutrophil extracellular trap (NET) formation in neutrophils from the blood of patients with psoriasis [86]. In human models of infection, TSLP correlates with disease severity in the airways of neonates with bronchiolitis and adults with bacterial sepsis [87–89]. However, these studies have not shown a causal relationship between TSLP and disease severity. In vitro, TSLP has been shown to be upregulated by viral mimics in nasal epithelial cells from patients with nasal polyps [90], while TSLPR-deficient mice show reduced lung inflammation and viral replication compared with wild-type mice [91]. In bronchial epithelial cells from patients with severe COPD, Guo-Parke et al. found reduced expression of TSLP in people with COPD compared with healthy controls, with no significant induction by rhinovirus infection [92]. However, this conflicts with earlier work by Calven et al., who showed increased release of TSLP from COPD bronchial epithelial cells [93]. Both studies used bronchial epithelial cells (BECs) from patients with an FEV1 < 20%, who were a population not included in current biologic trials.

Therapeutic Targeting of TSLP in COPD

Tezepelumab is a human monoclonal antibody (IgG2λ) that binds specifically to TSLP, preventing it from binding to its receptor [94]. In a phase 3 randomised controlled trial of tezepelumab in a severe uncontrolled asthma population, tezepelumab significantly reduced exacerbations compared with placebo (RR 0.44; CI 0.37–0.53; p < 0.001). When patients were stratified according to blood eosinophil count, tezepelumab reduced exacerbations in each sub-group. The greatest effect was seen in those with blood eosinophil count ≥ 300 (RR 0.30; CI 0.22–0.40; p < 0.001). However, there remained a significant reduction in exacerbations in participants with blood eosinophils < 300 (RR 0.59; 95% CI 0.46–0.75; p < 0.001) and participants with blood eosinophil count ≤ 150 cells/µL (RR 0.61; CI 0.42–0.88) [94]. Similar effects were seen in the phase 2B PATHWAY study, although this analysed subgroups of blood eosinophils ≥ 250 cells/µL and < 250 cells/µL [95].

In asthma, tezepelumab has also been shown to reduce airway mucus plugging [96], improve pre-bronchodilator FEV1 and improve quality of life [94, 97]. However, a combined analysis of the NAVIGATOR and PATHWAY study showed no effect of tezepelumab on lung function in patients with abnormal lung function (FEV1 < 80% predicted) if they had a diagnosis of asthma for > 20 years, blood eosinophil count < 300 cells/µL or a fraction of exhaled nitric oxide (FeNO) < 25 parts per billion (ppbn) [98], suggesting that TSLP modulation may be less effective in the absence of any T2 inflammation or established airway remodelling.

Owing to promising effects on T2 low asthma, the COURSE trial was conducted as a phase 2b randomised controlled trial of tezepelumab 420 mg every 4 weeks in patients with moderate to severe COPD. Participants were included if they had moderate to severe airflow obstruction, were treated with inhaled triple therapy and had two or more moderate or one severe exacerbation of COPD in the previous year. Unfortunately, this phase 2B study of 333 participants did not meet its primary endpoint with no overall reduction in annualised exacerbation rate with tezepelumab versus placebo (RR 0.83; CI 0.64–1.06; p = 0.10). In pre-specified post hoc analyses, there was a trend to a reduction in exacerbation rate in those with blood eosinophil counts ≥ 150 ppbn (RR 0.63, CI 0.43–0.93), however this did not reach significance. There was also a signal towards a greater reduction in younger patients between age 40 and 65 (RR 0.55, CI 0.33–0.92) and a stabilisation in lung function in those with a blood eosinophil count < 150 cells/µL, suggesting that TSLP targeting biologics may affect airway remodelling in patients with active or less established disease [99]. As a result, the phase III JOURNEY study of tezepelumab is currently recruiting people with COPD and blood eosinophil counts ≥ 150 cells/µL [100].

Other biologics targeting the TSLP pathway are currently in clinical trials, with Upstream Bio currently recruiting to a phase 2 trial of Verekitug, a TSLP receptor blocker (VENTURE) for COPD [100], following a reduction in blood eosinophil count and FeNO in a phase 1b trial of Verektiug in asthma [101]. Meanwhile, lunsekimig a bispecific nanobody molecule inhibiting both TSLP and IL-13 that has been shown to be well tolerated in healthy volunteers [102], and has been announced as meeting its primary endpoint in asthma and CRSwNP [103].

Which Patients Will Respond Best to Which Biologic?

As more biologics are approved for COPD, the next question will be how to identify which patient populations are most likely to benefit from which biologic (Fig. 1). Biologics targeting specific T2 pathways such as IL-5 (mepolizumab) and IL-4/Il-13 (dupilumab) have been shown to be most effective in patients with a blood eosinophil count ≥ 300 cells/μL. However, other effects such as the effect of each of these treatments on other characteristics such as mucus plugging may also help identify patients most likely to benefit from specific treatments. Pooled data from the BOREAS and NOTUS trials suggest that dupilumab treatment may improve lung function and symptoms of breathlessness, cough and sputum in the E:RS, while younger patients also appeared to get the greatest benefit from dupilumab treatment. In contrast, mepolizumab did not appear to have a significant effect on lung function, but it had a consistent effect on older patients and a significant reduction in hospital admissions. However, real-world data will be key to identifying which patients get the greatest clinical benefit outside of a trial population.

Fig. 1.

Biologic targets under investigation or approved for management of chronic obstructive pulmonary disease (COPD). Created in BioRender. (Sethi 2026) https://BioRender.com/kiltdmh. There are a range of T2 targeting biologics and biologics targeting epithelial alarmins under investigation for COPD. Alarmins interleukin-33 (IL-33) and thymic stromal lymphopeitin (TSLP) are released in response to epithelial injury, with itepekimab and tozorakimab binding to IL-33, while astegolimab binds to the IL-33 receptor ST2. TSLP binds to its receptor TSLPR, with tezepelumab blocking this pathway by binding to TSLP. Activation of Th2 lymphocytes leads to the release of T2 cytokines IL-4, IL5 and IL-13. IL-5 is a potent activator of eosinophils and drives eosinophil activation by binding to the receptor IL-5Rα, with mepolizumab and rezilizumab binding to IL-5, while benralizumab binds to the IL-5Rα receptor and dupilumab binds to IL-13 and the IL-4Rα receptor

While alarmin-targeting biologics seem to be effective in patients with blood eosinophils ≥ 300 cells/μL, they have also shown clinical benefits in reducing exacerbations in patients with a lower blood eosinophil count between 150 cells/μL and 300 cells/μL, suggesting that they may benefit this broader population and may be an effective treatment in patients who do not have a high blood eosinophil count. However, there remains a significant treatment gap for people with COPD who persistently have a blood eosinophil count ≤ 150 cells/μL. Further research is needed to identify which treatments will be most beneficial in this non-T2 population.

There remains a significant challenge in clinical practice regarding how to manage people who have COPD but have a concurrent diagnosis of asthma, asthma–COPD overlap syndrome or childhood asthma. The BOREAS and NOTUS trials excluded patients with any history of asthma, yet a substantial proportion of participants demonstrated features consistent with T2 activation, with approximately 40% having FeNO ≥ 20 ppb. This supports the concept that T2 inflammation may arise independently of an asthma diagnosis.

In contrast, the METREX and METREO studies allowed inclusion of patients with a prior diagnosis of asthma, likely resulting in a more heterogeneous population. This was addressed in the MATINEE study, which excluded any history of asthma and instead selected patients on blood eosinophilia, suggesting that the greatest benefit can be seen when using an endotype-driven approach.

Taken together, these data suggest that treatment decisions should be guided less by historical diagnostic labels and more by the presence of T2 biomarkers. In practice, this requires careful consideration of the basis and timing of any previous asthma diagnosis, alongside biomarker profiles. Further studies and real-world evidence are needed to determine how best to position biologic therapies in patients with COPD and overlapping asthma diagnoses.

Another outstanding question is the impact of biologic treatment on patients with co-morbidities as many of these patients are excluded from randomised controlled trials. While the impact of T2 targeted biologics should be a reduction in oral corticosteroid use, which should have a positive impact on co-morbidities such as osteoporosis or diabetes, the effect of T2 biologics on cardiovascular co-morbidities is unknown. The IL-33/ST2 axis is of increasing interest in cardiovascular disease as IL-33 appears to play a protective role in acute myocardial infarction but may contribute to myocardial fibrosis in chronic disease [104]. Other co-morbidities such as chronic rhinosinusitis and nasal polyps identify patients most likely to respond to T2-targeting biologics in asthma. Similarly, large real-world studies evaluating the effect on co-morbid disease may aid clinicians in biologic selection.

One significant limitation to the existing trial evidence is limited ethnic diversity in clinical trials. Many trials have been conducted in predominantly Western populations, and therefore further work is needed in other populations including Asia and sub-Saharan Africa which may be under-represented. People from Asia and sub-Saharan Africa may have different exposures such as air pollution which may contribute to disease development and disease phenotypes [105–107]. Blood eosinophil counts may also vary geographically, and further work is needed to assess the effect of T2-targeted treatment on a more diverse population.

Conclusions

The evolving landscape of biologics in COPD has brought to the fore the importance of precision medicine to treat a complex disease. The success of biologics targeting IL-4Ra/IL-13 and IL-5 in highly selected populations demonstrates that biologic efficacy in COPD is dependent upon careful patient selection informed by disease endotyping, rather than disease label alone. Blood eosinophil count has emerged as a pragmatic biomarker to identify patients with type 2 inflammation who are most likely to benefit from targeted intervention, yet it represents only a partial surrogate of the underlying biology. The heterogeneity observed across trials targeting IL-5, IL-4/IL-13 and epithelial alarmins reinforces the concept that both the timing and context of pathway activation are critical determinants of treatment response.

Future research must therefore focus on refining precision strategies through improved biomarker integration, longitudinal phenotyping and a need for further mechanistic insight. Incorporation of emerging CT-based metrics, mucus plugging and oscillometry as a measure of small airway disease may give further insight into the mechanism of action and impact of biologics on airway remodelling in COPD. There remains a gap in biologics targeting non-T2 inflammation in COPD. However, alternative approaches to treating neutrophilic inflammation, including targeting the microbiome and neutrophil serine proteases, have been successful in bronchiectasis and could be explored further in COPD [108, 109].

For clinicians, this represents a call to move beyond a one-size-fits-all approach and to actively incorporate treatable traits including blood eosinophils, exacerbations and structural airway disease into therapeutic decision-making. Our hope is that a renewed drive to optimise and identify patients who may be candidates for biologics will raise the bar to optimise treatment for everyone who has COPD. Emerging real-world data are likely to provide further insight into which sub-groups of patients are most likely to benefit from which biologic. Ultimately, aligning the right patient with the right pathway at the right time will require close collaboration between clinicians, researchers and health systems, but offers a game-changing opportunity to meaningfully improve outcomes for people living with COPD.

Author Contributions

The review was conceptualised and designed by Lydia J Finney. Lydia Finney, Francesca Conway and Dheeraj Sethi contributed to planning the manuscript, acquisition and interpretation of data. All authors drafted the initial version of the manuscript and approved the final version of the submitted manuscript.

Funding

No funding or sponsorship was received for this study or publication of this article.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

Declarations

Conflict of interest

Lydia. J. Finney Reports Honoraria for educational events or travel to meetings from GSK, AstraZeneca, Sanofi and Roche. Francesca Conway has no conflicts of interest to report. Dheeraj Sethi has no conflicts of interest to report.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.