Biologics in Chronic Obstructive Pulmonary Disease: Current Status and Future Prospects

Abstract

Significant progress has been made in managing chronic obstructive pulmonary disease (COPD), yet substantial unmet needs persist due to the disease's heterogeneity and the diverse underlying inflammatory mechanisms. Recent advances have broadened our understanding of COPD beyond a single pathophysiologic model, leading to the development of biologic therapies that target specific immune pathways. This review summarizes current evidence from clinical trials involving biologics in COPD. Early efforts to inhibit non-type 2 inflammation yielded limited results, highlighting the necessity for more refined, endotype-based approaches. Subsequent phase 3 trials have shown considerable clinical benefits in specific patient subsets: dupilumab, which blocks interleukin (IL)-4 and IL-13 signaling, and mepolizumab, which targets IL-5, consistently reduced exacerbation frequency among patients with high blood eosinophil counts (≥300 cells/μL). In contrast, other biologics—such as benralizumab, tezepelumab, and IL-33/suppression of tumorigenicity 2 pathway inhibitors like itepekimab, tozorakimab, and astegolimab—have demonstrated variable efficacy, often influenced by biomarker profiles and patient characteristics. These findings emphasize the importance of precise patient stratification based on inflammatory endotypes. While biologics mark a significant advancement for select COPD populations, further research is needed to clarify long-term outcomes, refine biomarker thresholds, and broaden treatment options for non-eosinophilic COPD.

Introduction

Chronic obstructive pulmonary disease (COPD) affects more than 380 million people worldwide, is the third leading cause of death, and significantly contributes to healthcare costs and the socioeconomic burden [1,2]. Despite its enormous burden, therapeutic options have largely remained limited for decades. Bronchodilators and inhaled corticosteroids (ICS) provide only symptomatic relief and modest reductions in exacerbation risk, without addressing the underlying disease mechanisms [3]. Moreover, clinical responses to these treatments vary significantly among patients, indicating that COPD is not a single disease but rather a heterogeneous syndrome with multiple distinct pathophysiological pathways [4,5].

1. Neutrophilic inflammation and the limitations of early biologic therapies

For decades, the neutrophilic inflammation model dominated the scientific understanding of COPD pathophysiology [6]. According to this framework, exposure to noxious agents like cigarette smoke activates innate immune responses in airway epithelial cells and alveolar macrophages. This process leads to the recruitment and activation of neutrophils and CD8+ T cells. These inflammatory cells are considered the primary mediators of the proteolytic destruction of alveolar walls, resulting in emphysema, as well as the fibrotic remodeling of small airways that characterize COPD.

Building on this understanding, investigators have sought to develop biologic therapies that target key mediators of neutrophilic inflammation [7]. Multiple clinical trials evaluated monoclonal antibodies targeting interleukin-8 (IL-8), a potent neutrophil chemoattractant; tumor necrosis factor-alpha (TNF-α), a central pro-inflammatory cytokine; IL-1, an early inflammatory mediator; and IL-17, which promotes neutrophil recruitment [7,8]. The rationale for each of these approaches was scientifically sound; however, the results were uniformly disappointing. An anti-IL-8 antibody trial showed improvement in dyspnea scores but did not demonstrate benefits in other outcomes [8]. Trials of anti-TNF-α, anti-IL-1, and anti-IL-17 antibodies similarly failed to demonstrate consistent therapeutic benefits across multiple studies [8]. Repeated failures of therapies targeting neutrophilic inflammation prompted a reassessment of COPD pathogenesis. These findings indicate that the pathophysiology of COPD cannot be fully explained by neutrophilic inflammation alone.

2. Emergence of the eosinophilic phenotype

As the limitations of neutrophil-targeted therapies became clear, attention shifted to other inflammatory pathways, prompting a re-evaluation of eosinophils. These cells, recognized as hallmarks of type 2 inflammation and typically associated with asthma, were previously regarded as less relevant to the COPD disease process [6].

However, emerging evidence suggested that they were more involved than originally assumed. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study, a large prospective cohort of patients with COPD, revealed that eosinophilic inflammation was more prevalent than previously recognized [9].

The study revealed that 37.4% of patients had consistently elevated blood eosinophil counts (BECs) of 2% or higher at every study visit, while another 49% experienced intermittent elevations. Additionally, cluster analyses of acute exacerbations of COPD indicated that eosinophil-predominant exacerbations represented more than 30% of all cases [10].

Critically, this eosinophilia was not just a secondary finding; it carried significant clinical implications. An analysis of the Chronic Obstructive Pulmonary Disease Genetic Epidemiology study (COPDGene) and the ECLIPSE study by Yun et al. [11] demonstrated that patients with a BEC of 300 cells/μL or higher experienced a 32% increase in annual exacerbation frequency and were 58% more likely to be frequent exacerbators (defined as two or more exacerbations per year) compared to those with lower counts. Moreover, the risk of exacerbations increased progressively with higher eosinophil levels, establishing a clear dose-response relationship.

Additionally, BECs have emerged as a strong predictive biomarker for treatment response, particularly to ICS. A post hoc analysis of a randomized, double-blind trial comparing vilanterol alone to the fluticasone furoate/vilanterol combination in patients with COPD showed that those receiving the combination therapy with a BEC ≥2% experienced significant benefits from the addition of ICS in terms of exacerbation prevention [12]. In contrast, patients with BECs below this threshold showed no significant benefit from the combination therapy of ICS and long-acting beta-agonists (LABA) compared to LABA monotherapy. The effect of ICS treatment increased progressively with higher eosinophil levels.

These findings enhance our understanding of COPD heterogeneity, establishing eosinophilic inflammation not only as a prognostic indicator of disease progression but also as a key determinant of treatment response. This recognition has redefined the eosinophilic COPD phenotype as a clinically actionable ‘treatable trait,’ guiding the use of targeted anti-inflammatory therapies and personalized management strategies.

3. Molecular distinctions between asthma and COPD

Although eosinophilic inflammation occurs in both COPD and asthma, recent molecular studies indicate that the underlying mechanisms differ significantly between the two diseases [13]. A transcriptomic analysis comparing bronchial samples from COPD and asthma cohorts showed minimal overlap in eosinophil-associated gene expression [13]. In asthma, 1,197 genes were significantly correlated with BECs, while only 12 genes showed similar associations in COPD. The only gene common to both conditions was CST1, a member of the cystatin family that plays a role in immune and inflammatory regulation.

These findings suggest that the regulation of eosinophilic inflammation differs between COPD and asthma, indicating distinct upstream pathways. This molecular divergence helps explain why biologic agents that are effective in treating asthma often demonstrate limited or inconsistent efficacy in COPD, highlighting the necessity for COPD-specific clinical validation of biologic therapies.

4. Scope and objectives of this review

With the increasing understanding of COPD biology and the development of new treatment approaches, research on biologic therapies for COPD has advanced rapidly in recent years. Several large clinical trials have been completed, some biologics have received regulatory approval, and real-world data are beginning to emerge. This review aims to summarize and critically assess the current evidence on biologic therapies for COPD and discuss their future potential (Table 1 and Figure 1).

Table 1.

Summary of key clinical trials of biologic therapies in COPD

Target	Agent	Trial (phase)	Study population (key inclusion criteria)	Primary endpoint (exacerbation rate)	Key secondary outcomes & Subgroup findings	Reference
IL-4Rα	Dupilumab	BOREAS (Ph3)	BEC ≥300 cells/μL	Met (–30% vs. placebo)	Improved FEV1 (mean difference, 83 mL) and SGRQ	[17]
		NOTUS (Ph3)	BEC ≥300 cells/μL	Met (–34% vs. placebo)	Confirmed efficacy in FEV1 (mean difference, 82 mL) and SGRQ	[16]
IL-5	Mepolizumab	METREX (Ph3)	All comers (stratified by BEC)	Not met (overall)	Met in subgroup with BEC ≥150 cells/μL (–18%)	[21]
		METREO (Ph3)	BEC ≥150 cells/μL	Not met	Dose-response relationship observed with higher BEC	[21]
		MATINEE (Ph3)	BEC ≥300 cells/μL	Met (–21% vs. placebo)	No significant improvement in lung function or SGRQ	[22]
IL-5Rα	Benralizumab	GALATHEA & TERRANOVA (Ph3)	BEC ≥220 cells/μL	Not met	Failed to consistently reduce exacerbations	[25]
		RESOLUTE (Ph3)	BEC ≥300 cells/μL	Not met	Confirmed lack of prophylactic efficacy even in high eosinophil subgroup	[27]
IL-33	Itepekimab	Phase 2a	Mod-severe COPD (no BEC cutoff)	Not met (overall)	Met in former smokers (–42% exacerbations, 90 mL FEV1)	[39]
ST2 (IL-33R)	Astegolimab	COPD-ST2OP (Ph2a)	Mod-severe COPD (no BEC cutoff)	Not met (overall)	Reduced exacerbations in low BEC (<300 cells/μL) subgroup (–37%)	[42]
		ALIENTO (Ph2b)	Mod-severe COPD	Met (–15.4% vs. placebo)	Trend towards benefit in non-eosinophilic subgroup, but not statistically significant	[44,45]
TSLP	Tezepelumab	COURSE (Ph2a)	Mod-severe COPD (no BEC cutoff)	Not met (overall)	Significant benefit in patients with BEC ≥150 cells/μL and FeNO ≥25 ppb	[36]

COPD: chronic obstructive pulmonary disease; IL: interleukin; Ph: phase; BEC: blood eosinophil count; FEV₁: forced expiratory volume in 1 second; SGRQ: St. George’s Respiratory Questionnaire; Mod-severe: moderate-to-severe; ST2: suppression of tumorigenicity 2; TSLP: thymic stromal lymphopoietin; FeNO: fractional exhaled nitric oxide.

Fig. 1.

Summary of clinical evidence for biologic therapies in chronic obstructive pulmonary disease. EOS: eosinophil; CB: chronic bronchitis; FEV₁: forced expiratory volume in 1 second; SGRQ: St. George’s Respiratory Questionnaire.

Targeting the IL-4/IL-13 Pathway: Dupilumab

IL-4 and IL-13 are essential drivers of type 2 inflammation, leading to eosinophil activation, excessive mucus production, airway remodeling, and immunoglobulin E synthesis [14,15]. Both cytokines utilize a shared signaling pathway via the IL-4Rα receptor, highlighting its significance as a therapeutic target. Dupilumab, a fully human monoclonal antibody, binds to IL-4Rα to inhibit the activities of both IL-4 and IL-13 (Figure 2) [16,17]. After demonstrating strong efficacy in treating asthma, atopic dermatitis, and chronic rhinosinusitis with nasal polyps, dupilumab has recently shown promising benefits for patients with eosinophilic COPD, marking a significant advancement in biologic therapy for this condition [5].

Fig. 2.

Schematic representation of type 2 inflammatory pathways and therapeutic targets of biologics in chronic obstructive pulmonary disease. Airway epithelium releases alarmins (thymic stromal lymphopoietin [TSLP], interleukin 33 [IL-33]) in response to stimuli such as cigarette smoke, viruses, and pollutants. Tezepelumab targets TSLP, while itepekimab and tozorakimab target IL-33. Astegolimab blocks the suppression of tumorigenicity 2 (ST2) receptor to inhibit IL-33 signaling. These alarmins activate innate lymphoid cells group 2 (ILC2s) and Th2 cells, leading to the release of type 2 cytokines (IL-4, IL-5, IL-13). Dupilumab blocks the shared IL-4Rα, inhibiting both IL-4 and IL-13 signaling. Mepolizumab targets IL-5, preventing eosinophil maturation and activation, whereas benralizumab binds to the IL-5Rα on eosinophils, inducing direct depletion via antibody-dependent cell-mediated cytotoxicity (ADCC). IgE: immunoglobulin E.

1. Evidence from phase 3 trials

The efficacy and safety of dupilumab in COPD were conclusively demonstrated in two large, replicate phase 3 randomized controlled trials (RCTs): BOREAS and NOTUS [16,17]. These studies employed identical designs to evaluate dupilumab’s effects in a high-risk COPD population with evidence of type 2 inflammation. These studies utilized identical designs to assess the effects of dupilumab in a high-risk COPD population exhibiting evidence of type 2 inflammation.

The methodology concentrated on a precisely defined patient group, comprising individuals aged 40 to 85 years with moderate-to-severe COPD who had been on stable triple inhaler therapy for at least 3 months. Key inclusion criteria included a BEC of ≥300 cells/μL, indicating type 2 inflammation, and a frequent exacerbator phenotype characterized by at least two moderate exacerbations or one severe exacerbation in the previous year. Patients were also required to have significant symptoms, evidenced by a modified Medical Research Council dyspnea score of ≥2 and chronic bronchitis symptoms. The primary endpoint was the annualized rate of moderate or severe acute exacerbations.

The results of both trials were remarkably consistent, demonstrating the robust therapeutic effects of dupilumab. In the BOREAS trial, the annualized exacerbation rate in the dupilumab group was 0.78, reflecting a 30% reduction compared to 1.10 in the placebo group (rate ratio [RR], 0.70; 95% confidence interval [CI], 0.58 to 0.86; p<0.001) [17]. Similarly, the NOTUS trial showed a 34% reduction in exacerbations, with rates of 0.86 and 1.30 in the dupilumab and placebo groups, respectively (RR, 0.66; 95% CI, 0.54 to 0.82; p<0.001) [16].

In addition to preventing exacerbations, dupilumab significantly improved lung function. In the BOREAS trial, the pre-bronchodilator forced expiratory volume in 1 second (FEV₁) at week 12 was 160 mL higher in the dupilumab group compared to the placebo group (p<0.001), and this effect was sustained through week 52. Similarly, the NOTUS trial observed a 139 mL improvement at week 12 (p<0.001), with a significant 115 mL difference maintained at week 52. Health-related quality of life also improved. In BOREAS, 52% of patients receiving dupilumab achieved a clinically meaningful improvement of ≥4 points on the St. George’s Respiratory Questionnaire (SGRQ) at week 52, compared to 43% in the placebo group (p=0.009). While the NOTUS trial did not achieve statistical significance for mean SGRQ change, it indicated a numerical trend toward improvement. Across both studies, the safety profile of dupilumab was consistent with its established use in other indications, showing adverse event rates similar to those of the placebo group and no new safety concerns.

2. Pooled analysis and real-world evidence

The strong evidence from the BOREAS and NOTUS trials has been further supported by a pre-specified pooled analysis and recently published real-world data. This pooled analysis, which included 1,874 patients, confirmed that dupilumab significantly reduced the annualized rate of moderate or severe exacerbations by 31.3% compared to placebo (RR, 0.687; 95% CI, 0.595 to 0.793; p<0.0001) [18]. It also demonstrated statistically significant improvements in lung function (FEV₁) and health-related quality of life, as measured by the SGRQ. Additionally, real-world clinical evidence is accumulating. A 7-year, multicenter, population-based cohort study in the United States highlighted the real-world benefits of dupilumab [19].

COPD patients treated with dupilumab experienced significantly lower rates of all-cause mortality, emergency department visits, and hospitalizations compared to those receiving LABA-based therapy. Notably, the risk of COPD exacerbations was reduced by approximately 41.5%. This finding suggests that dupilumab may positively impact critical outcomes such as survival. Based on this robust and consistent body of evidence, the U.S. Food and Drug Administration (FDA) approved Dupixent (dupilumab) on September 27, 2023, as an addon maintenance therapy for adults with uncontrolled COPD with an eosinophilic phenotype [20]. This milestone marked the first biologic therapy approved for COPD and the first new treatment approach for the disease in more than a decade.

Targeting the IL-5 Pathway

IL-5 is a key cytokine that plays a crucial role in the differentiation, proliferation, activation, and survival of eosinophils [14]. Accordingly, inhibition of IL-5 or its receptor is a direct strategy to suppress eosinophilic inflammation. Mepolizumab (an anti-IL-5 monoclonal antibody) and benralizumab (an anti-IL-5Rα monoclonal antibody) have shown significant clinical benefits in patients with severe eosinophilic asthma, resulting in their approval as targeted biologics for this condition [14]. Given these positive results in asthma, both agents have been assessed in patients with COPD to see if targeting the IL-5 pathway can reduce exacerbations and enhance clinical outcomes.

1. Mepolizumab (anti-IL-5 monoclonal antibody)

1) Early trials and the role of eosinophil stratification

The first large-scale evaluation of mepolizumab in COPD was conducted through two phase 3 RCTs, METREX and METREO. These trials aimed to assess the drug’s efficacy in reducing exacerbations in patients with eosinophilic inflammation [21]. Although these studies yielded inconsistent primary outcomes, they offered valuable insights into the significance of patient stratification based on eosinophilic inflammation.

Both trials enrolled patients with COPD and a history of frequent exacerbations, yet their blood eosinophil inclusion criteria varied. The METREX study included patients regardless of BEC and conducted a stratified analysis using a threshold of 150 cells/μL. In contrast, the METREO trial specifically enrolled patients with an eosinophilic phenotype, defined as a BEC of at least 150 cells/μL at screening or 300 cells/μL in the previous year.

In the METREX trial, mepolizumab 100 mg did not significantly reduce the annualized rate of moderate or severe exacerbations in the overall population. However, among patients with eosinophilic COPD (BEC ≥150 cells/μL), there was a statistically significant 18% reduction in exacerbation rates compared to placebo (RR, 0.82; p=0.04). Conversely, the METREO trial, despite focusing solely on eosinophilic patients, did not achieve statistical significance for its primary endpoint, as neither the 100 nor 300 mg doses demonstrated a meaningful reduction in exacerbations (100 mg arm, RR, 0.80; p=0.07). A pre-specified meta-analysis combining the two trials showed that the overall treatment effect did not achieve statistical significance across all eosinophil strata [21].

However, a clear trend was observed: the RR progressively decreased as baseline BEC increased, suggesting a potential therapeutic benefit of mepolizumab for patients with higher levels of eosinophilic inflammation.

2) Confirmatory evidence from the MANTINEE trial

The lessons from METREX and METREO informed the design of the MANTINEE trial, a large phase 3 study specifically aimed at confirming the therapeutic benefit of mepolizumab in an eosinophilic COPD population [22]. MANTINEE included patients with a BEC of at least 300 cells/μL who continued to experience exacerbations despite receiving optimal triple inhaler therapy. Mepolizumab significantly decreased the annualized rate of moderate or severe exacerbations by 21% compared to placebo (RR, 0.79; 95% CI, 0.66 to 0.94). Additionally, the time to first exacerbation was extended (hazard ratio [HR], 0.77; p=0.009). Severe exacerbations necessitating emergency department visits or hospitalization were reduced by 35% (RR, 0.65; 95% CI, 0.43 to 0.96). However, there were no significant differences between treatment groups in quality-of-life measures, including the SGRQ or COPD Assessment Test, nor in post-bronchodilator FEV₁. Following the positive outcomes of the MANTINEE trial, the U.S. FDA approved mepolizumab (Nucala) in 2025 as an add-on maintenance therapy for adults with uncontrolled COPD exhibiting an eosinophilic phenotype [23].

In contrast, a subsequent single-center phase 2b trial conducted at Glenfield Hospital (UK) evaluated mepolizumab in patients hospitalized for COPD exacerbations with a BEC of ≥300 cells/μL [24]. The treatment did not significantly reduce rehospitalization or mortality; however, a modest trend toward fewer moderate or severe exacerbations was observed. Given these conflicting results across trials, further studies are needed to clarify the therapeutic role of IL-5 blockade in COPD.

2. Benralizumab (anti-IL-5Rα monoclonal antibody)

Unlike mepolizumab, which neutralizes IL-5, benralizumab binds to the IL-5Rα on the surface of eosinophils [25]. This mechanism is more potent because it induces natural killer (NK) cells to directly and rapidly eliminate eosinophils through antibody-dependent cell-mediated cytotoxicity (ADCC). Despite this powerful mechanism, its use as a prophylactic treatment for COPD has yielded disappointing results [25], potential as a rescue treatment for exacerbations has recently emerged [26].

1) Evaluation in stable COPD: the GALATHEA and TERRANOVA trials

The preventive efficacy of benralizumab was assessed in the phase 3 GALATHEA and TERRANOVA trials, which involved patients with moderate-to-very-severe COPD and frequent exacerbations who were receiving dual or triple inhaled therapy. The primary analyses focused on participants with BECs of ≥220 cells/μL [25]. In both trials, benralizumab did not significantly reduce the annualized rate of moderate or severe exacerbations, nor did it yield consistent improvements in lung function or SGRQ scores.

To further evaluate the efficacy of benralizumab in a more targeted population, the phase 3 RESOLUTE trial (NCT04053634) was conducted with patients who had a history of frequent exacerbations and elevated blood eosinophils (≥300 cells/μL) [27]. However, recent reports indicate that this trial also failed to meet its primary endpoint of reducing the annualized rate of moderate or severe exacerbations, reinforcing the inconsistent efficacy of benralizumab as a prophylactic maintenance therapy in stable COPD.

2) Benralizumab as an exacerbation rescuer: the ABRA trial

In contrast to its ineffectiveness in prophylactic use, the ABRA trial investigated benralizumab as an acute ‘rescue therapy’ during eosinophilic exacerbations [26]. This phase 2 RCT included patients hospitalized for acute exacerbations of COPD or asthma with a BEC of ≥300 cells/μL. Participants were assigned to receive either prednisolone alone, benralizumab alone, or a combination of both.

The group receiving benralizumab showed a significantly lower rate of treatment failure at 90 days compared to the prednisolone-only group (odds ratio [OR], 0.26; 95% CI, 0.13 to 0.56). Additionally, improvements in symptoms by day 28 and longer periods without exacerbations were noted. These findings indicate that rapid eosinophil depletion during acute eosinophilic exacerbations may be beneficial, supporting the use of IL-5Rα blockade as a short-term rescue strategy.

While benralizumab has not shown clear efficacy in stable COPD, further research is needed to assess its preventive potential. Nonetheless, its positive outcomes as a rescue treatment during eosinophilic exacerbations are promising and suggest potential for future clinical applications.

3. Divergent outcomes between anti-IL-5 and anti-IL-5Rα therapies

Although both mepolizumab and benralizumab target the IL-5 pathway, they yield different clinical outcomes in COPD. Mepolizumab targets the IL-5 ligand, which reduces eosinophil maturation and recruitment, ultimately lowering eosinophil levels without completely eliminating them. This strategy has proven effective in reducing exacerbations, as demonstrated in the MANTINEE trial [22]. In contrast, benralizumab binds to the IL-5Rα on eosinophils, inducing apoptosis through ADCC. This results in rapid and nearly complete depletion of eosinophils in both blood and tissue [28]. Despite this significant reduction, benralizumab did not consistently decrease exacerbations in the GALATHEA, TERRANOVA, and RESOLUTE trials [25,27].

One hypothesis for this discrepancy is related to the physiological role of eosinophils in host defense. Eosinophils have antiviral and antibacterial properties that contribute to local immunity [29,30]. Given that COPD exacerbations are often triggered by viral or bacterial infections, the complete elimination of eosinophils may hinder airway pathogen clearance, potentially negating the anti-inflammatory benefits. However, the precise effects of eosinophil depletion on COPD exacerbation risk are not yet fully understood. Further research is needed to determine whether preserving physiological eosinophil levels provides a therapeutic advantage over their complete depletion in COPD management.

Targeting Upstream Alarmin Pathways

Alarmins are innate immune cytokines released by airway epithelial cells in response to various external stimuli, such as smoking, pollutants, viruses, and bacteria [31-33]. Key alarmins include thymic stromal lymphopoietin (TSLP), IL-33, and IL-25 [31]. They serve as initiators of a wide range of downstream immune responses, including type 2 inflammation. Consequently, blocking alarmins represents a more ‘upstream’ strategy compared to targeting IL-5 or IL-4/13, which could potentially yield broader effects. However, clinical data in COPD have revealed complex and inconsistent results in phase 2 trials.

1. Tezepelumab (anti-TSLP monoclonal antibody)

Tezepelumab, a monoclonal antibody that targets TSLP, has demonstrated proven efficacy in severe asthma [34,35]. Its role in COPD was first assessed in the phase 2a COURSE trial, which enrolled patients with moderate-to-severe disease who had experienced at least two exacerbations in the previous year despite receiving triple inhaler therapy [36]. The primary endpoint—the annualized rate of moderate or severe exacerbations—was not achieved in the overall population (RR, 0.83; 90% CI, 0.64 to 1.06), indicating no significant benefit for unselected patients.

Biomarker-based subgroup analyses revealed meaningful signals. In patients with both elevated eosinophils (≥150 cells/μL) and fractional exhaled nitric oxide (FeNO ≥25 ppb), the exacerbation rate was reduced by 83% (RR, 0.17; 95% CI, 0.06 to 0.49). High levels of type 2 inflammation markers were also associated with significant improvements in FEV₁ and SGRQ scores.

These results suggest that tezepelumab may benefit only COPD patients with clear evidence of type 2 inflammation, highlighting the importance of biomarker-guided selection instead of broad application in unselected populations. A further phase 3 trial is needed to confirm these findings and assess the clinical efficacy of tezepelumab in COPD.

2. The IL-33/ST2 pathway

IL-33, another significant alarmin released from airway epithelial cells, signals through its receptor, suppression of tumorigenicity 2 (ST2) [37]. This pathway presents an attractive therapeutic target because it is known to induce type 2 inflammation via group 2 innate lymphoid cells (ILC2s) and is also involved in non-type 2 inflammation through cells such as Th17 [37,38]. However, the clinical development of several biologics targeting this pathway has produced complex and inconsistent results in phase 2 studies involving patients with COPD.

1) Itepekimab (anti-IL-33 monoclonal antibody)

Itepekimab, a monoclonal antibody that targets IL-33, was initially assessed in a phase 2a trial involving patients with moderate-to-severe COPD [39]. The overall population did not demonstrate a significant reduction in exacerbation rates. However, a stratified analysis based on smoking status revealed an interesting finding: former smokers experienced approximately a 43% reduction in exacerbations, while no benefit was seen in current smokers. This lack of efficacy in current smokers may be attributed to the widespread pro-inflammatory effects of cigarette smoke or a specific effect on IL-33 pathway gene transcription or protein activity, such as oxidation-driven inactivation [39]. Moreover, current smoking has been linked to lower plasma IL-33 levels, potentially limiting the availability of the therapeutic target [39].

In light of these findings, two replicate phase 3 studies, AERIFY-1 and AERIFY-2, have been designed to assess the efficacy of itepekimab specifically in former smokers and are currently underway [40].

2) Tozorakimab (anti-IL-33 monoclonal antibody)

Tozorakimab, a monoclonal antibody targeting IL-33, was assessed in the phase 2a FRONTIER-4 trial involving patients with moderate-to-severe COPD [41]. The study did not achieve its primary endpoint of change in pre-bronchodilator FEV₁ at 12 weeks (least-squares mean difference of 24 mL; p=0.216). However, there was a significant improvement in post-bronchodilator FEV₁ (67 mL; p=0.044), along with favorable trends in lung function and exacerbation reduction observed in a high-risk subgroup with two or more prior exacerbations. Additionally, treatment with tozorakimab significantly reduced mucus plugging, indicating a potential positive effect on airway remodeling. Building on these results, the clinical efficacy of tozorakimab is currently being evaluated in two ongoing phase 3 trials, PROSPERO (NCT05742802) and OBERON (NCT05166889). These studies aim to assess the reduction of moderate or severe exacerbations in patients with moderate- to-very-severe COPD, regardless of blood eosinophil levels.

3) Astegolimab (anti-ST2 monoclonal antibody)

Astegolimab, a monoclonal antibody targeting the IL-33 receptor ST2, has shown mixed results in COPD [42]. In an initial phase 2a study, no overall reduction in exacerbation rates was observed. However, a post hoc analysis revealed a 37% lower exacerbation risk in patients with BECs below 300 cells/μL, suggesting a potential non-eosinophilic mechanism of action [42].

To further evaluate these findings, two large randomized, double-blind, placebo-controlled trials—ALIENTO (phase 2b, NCT05037929) and ARNASA (phase 3, NCT05595642)—were conducted involving patients with moderate-to-very-severe COPD who had a history of at least two moderate or severe exacerbations despite standard triple inhaler therapy [43]. Each trial enrolled approximately 1,290 patients and assessed two dosing regimens of astegolimab (administered every 2 weeks or every 4 weeks) versus placebo over a 52-week period. The primary endpoint was the annualized rate of moderate or severe exacerbations, with secondary endpoints including time to first exacerbation, change in post-bronchodilator FEV₁, and patient-reported outcomes. In the ALIENTO trial, astegolimab administered every 2 weeks achieved a 15.4% reduction in the annualized exacerbation rate at week 52 compared to placebo, thereby meeting its primary endpoint [44]. However, concerning the non-eosinophilic subtype—where efficacy was anticipated based on phase 2a data—subgroup analyses in ALIENTO did not demonstrate a statistically significant benefit in patients with low eosinophil counts, only showing a numerical trend [45]. In the larger ARNASA trial, the drug did not meet its primary endpoint, exhibiting only a non-significant 14.5% reduction in the exacerbation rate over 52 weeks.

Overall, these findings suggest that while the IL-33/ST2 pathway is a promising therapeutic target, the clinical benefits of astegolimab are modest and inconsistent. Further investigation in biomarker-defined populations is warranted to clarify its therapeutic role, particularly regarding its potential effects in non-eosinophilic COPD.

Clinical Implications

1. Comparative efficacy and safety: a meta-analytic perspective

A recent meta-analysis of major clinical trials evaluating biologic therapies for COPD, including dupilumab, mepolizumab, benralizumab, astegolimab, and itepekimab, has offered important insights into their relative efficacy and safety profiles [46]. Overall, biologic therapy significantly decreased the annualized rate of moderate- to-severe exacerbations compared to placebo, with a pooled risk ratio of 0.79. Among the individual agents, dupilumab showed the highest efficacy (RR, 0.68), followed by mepolizumab (RR, 0.81), while benralizumab had a modest reduction (RR, 0.88).

In pooled analyses, biologics also enhanced lung function, with a mean increase in FEV₁ of approximately 48 mL, and lowered SGRQ scores by an average of 2.24 points, indicating a meaningful improvement in health-related quality of life. Notably, biologics were well tolerated, exhibiting a lower incidence of treatment-emergent adverse events (OR, 0.80) and no increase in all-cause mortality compared to standard therapy.

Overall, these findings suggest that biologics targeting type 2 inflammation provide consistent, though variable, clinical benefits in COPD. Further head-tohead and biomarker-stratified studies are needed to clarify their relative efficacy and to identify the patient populations most likely to benefit.

2. Patient selection in the era of biologics: the central role of blood eosinophils

Recent clinical trials highlight the critical importance of patient selection. Among the currently available biomarkers, the BEC remains the most reliable and validated indicator for identifying COPD patients who are likely to benefit from biologic therapy targeting type 2 inflammation [16,17,22,36].

In most biological trials, treatment efficacy was greater in patients with higher BECs. The BOREAS and NOTUS studies of dupilumab, along with the MANTINEE study of mepolizumab, demonstrated significant efficacy using a threshold of BEC ≥300 cells/μL [16,17,22]. Similarly, in the COURSE trial of tezepelumab, treatment effects were most evident in patients with BEC ≥150 cells/μL, reinforcing the role of type 2 inflammation as a key therapeutic target [36].

Interestingly, astegolimab, an anti-ST2 antibody that targets the IL-33 receptor, demonstrated a contrasting trend [42]. In its phase 2a study, no benefit was observed in the overall population; however, a post hoc analysis revealed a 37% reduction in exacerbations among patients with low eosinophil counts (<300 cells/μL), suggesting a potential role for treatment in non-eosinophilic COPD.

Overall, these findings indicate that BEC ≥300 cells/μL is a validated threshold for identifying the COPD population most likely to benefit from type 2-targeted biologics. Conversely, lower eosinophil levels may predict responsiveness to alternative inflammatory pathways, such as IL-33/ST2. Further phase 3 studies are needed to confirm these findings and establish optimal thresholds for clinical use.

3. Remaining challenges and future directions

Despite the remarkable progress made with biologics in COPD, several key challenges persist. First, most therapeutic advances have concentrated on eosinophilic inflammation, leaving a significant unmet need for the 60%–80% of patients who do not have an eosinophilic phenotype [9]. Future studies should investigate alternative inflammatory mechanisms, including neutrophilic pathways, airway microbiome-related inflammation, and other non-type 2 endotypes. Second, the long-term safety and durability of efficacy beyond one to 2 years remain uncertain. It is essential to determine whether biologics can modify the natural progression of COPD rather than merely controlling inflammation and exacerbations. Third, there is a lack of direct comparative studies between biologics. Head-to-head trials, such as comparisons between dupilumab and mepolizumab, would be invaluable for guiding therapeutic selection in clinical practice. Fourth, recent data from the ABRA trial suggest a potential role for biologics as acute-phase or ‘rescue’ therapies [26]. Further studies are needed to evaluate whether other agents may offer similar benefits during acute exacerbations. Additionally, the high cost of biologics raises concerns about their long-term cost-effectiveness and accessibility. Comprehensive health economic analyses will be essential for determining their appropriate use and sustainability within healthcare systems.

Conclusion

Over the past decade, the management of COPD has evolved from a ‘one-size-fits-all’ approach to a precision medicine paradigm that takes into account the heterogeneity of the disease [5]. Central to this shift is the acknowledgment that the eosinophilic endotype is a distinct and treatable trait [9,11,12]. Early failures of biologics targeting non-type 2 inflammatory pathways highlighted the complexity of COPD pathophysiology and redirected focus toward type 2-driven inflammation [8]. The consistent effectiveness of dupilumab in the BOREAS and NOTUS trials, which target the IL-4/IL-13 pathway, demonstrated significant improvements in exacerbation frequency, lung function, and quality of life for patients with eosinophilic COPD [16,17]. Similarly, mepolizumab, an IL-5 inhibitor, showed considerable benefits in well-defined eosinophilic populations, as confirmed by the MANTINEE trial [22]. These findings collectively underscore the clinical utility of biologics for patients with high BECs.

In contrast, the variable outcomes associated with benralizumab and alarmin-targeted agents illustrate ongoing challenges [25,36,39,41,42]. The limited preventive efficacy of benralizumab, its potential role in managing acute exacerbations, and the biomarker-dependent responses observed with tezepelumab and other alarmin inhibitors highlight the necessity for improved patient stratification and a deeper understanding of underlying mechanisms.

In summary, biologic therapies have underscored the importance of patient stratification in COPD, as treatment responses differ across various inflammatory and clinical subtypes. Future research should concentrate on developing personalized treatment strategies and expanding therapeutic options for non-type 2 COPD.