Unmet Needs and New Opportunities in Chronic Obstructive Pulmonary Disease in Italy: A Narrative Review with Insights from the GULP Study

Abstract

The “DescribinG bUrden of COPD and occurrence of mortaLity in a cohort of Italian Patients” (GULP) study was conducted to investigate the potential of biological treatments for patients with severe chronic obstructive pulmonary disease (COPD). The purpose of this article was to perform a narrative review highlighting the role of type 2 inflammation in the mechanism of disease for COPD, summarizing the efficacy data of the Phase III RCTs that investigated biologics in COPD, and exploring the potential role for biological treatment in this setting with a particular focus on Italian patients with COPD. To this end, we conducted an exploratory analysis of GULP study data to identify patients at high risk of exacerbations, with high symoptom burden and classify them based upon the eosinophilic counts, to provide further insights into the potential use of biologics in this cohort. Out of the 1111 patients of the GULP cohort, we retrieved in total 286 (25.7%) GULP participants with ≥2 moderate or ≥1 severe exacerbation per year. Of them, despite maintenance therapy with dual bronchodilators or triple therapy, a high symptom burden (dyspnea, cough and chronic sputum production) was present in between 51.1 and 74.8%, while patients that presented with eosinophilic COPD accounted for the 7.2% of the patients at risk. This indicates that biological agents, specifically those that target the type 2 inflammatory response in COPD, should be considered in symptomatic patients with COPD and unstable disease, but that careful and pro-active phenotyping through clinical and biomarker evaluation is mandatory. Dupilumab is currently approved in Italy for eosinophilc exacerbating COPD patients, and through its favorable efficacy and safety profile, could represent a valid opportunity for these patients.

Introduction

More than 210 million people worldwide are estimated to have chronic obstructive pulmonary disease (COPD) and 3.3 million people die from COPD each year.¹ The prevalence is expected to increase by 23% by 2050 due to a growing and ageing population, and potentially the impact of air pollution.²

In addition to death, COPD also causes substantial morbidity,¹ and significantly impacts lifestyle, physical activity and mobility.³ As a result, the economic and social burden of COPD is marked.⁴ In Italy, the estimated direct medical cost of COPD is ~€7500.00 (~USD7800.00) per patient-year, and indirect costs exceed direct costs by an additional 61%.⁵

The key goals of therapy are to reduce symptoms, minimize the incidence of exacerbations and prevent further lung function decline.⁶ Exacerbations affect the course of COPD, increasing the disease-associated risk of mortality and morbidity, and contributing to the economic burden of disease.^7,8 Even patients with mild airflow impairment and symptoms may experience exacerbations, although the risk of exacerbation increases with disease severity.⁷ Not only do exacerbations increase the risk of death and hospitalization, but they accelerate lung function and health status decline.⁷ Therefore, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend selecting treatment based on both symptoms and exacerbation risk.⁶

Monoclonal antibodies have transformed the management of severe asthma with T2 phenotype, and in recent years they have also been investigated for patients with COPD who have eosinophilic inflammation and are at high risk of exacerbation.^9,10 Initial Phase 3 studies with biologicals targeting IL-5 (mepolizumab) or the IL-5 receptor (benralizumab) showed only a limited effect on the annualized rate of moderate or severe exacerbations in patients with COPD and an eosinophilic phenotype (blood eosinophil count [BEC] of ≥150 cells/µL or ≥300 cells/µL in the previous 12 months).^11,12 However, stricter inclusion criteria for BEC in the MATINEE trial (≥300 cells/µL at screening and ≥150 cells/µL in the previous 12 months) were associated with a significant reduction in exacerbation frequency in patients treated with mepolizumab compared with placebo.¹³

In contrast, two phase III RCTs that investigated dupilumab, a monoclonal antibody that blocks the IL-4/IL-13 signaling pathway via blockade of a shared receptor component for IL-4 and IL-13, showed significant reductions compared with placebo in exacerbation rates and improvements in lung function, as well as significant improvements in QoL and symptoms in patients with COPD and type 2 inflammation.^14,15 In the last years, several other biologics covering different inflammatory pathways have been studied for COPD, with conflicting results. In light of the heterogeneity of the clinical results and of the recent approval of dupilumab for COPD in the European and US markets, we designed a narrative review to respond to the following needs: (1) to overview the role of inflammation in the disease mechanism of COPD and the clinical evidence of biological treatment in this setting; and (2) to investigate the potential use of these agents among Italian patients with COPD. To address the second objective, we conducted an exploratory analysis using data from the “DescribinG bUrden of COPD and occurrence of mortaLity in a cohort of Italian Patients” (GULP) study.^16,17

Research Methods

A literature search has been performed using MEDLINE and EMBASE via Ovid SP. The following search string was applied: ((((((((((((biologic therapy[Title/Abstract]) OR (biologics[Title/Abstract])) OR (benralizumab[Title/Abstract])) OR (dupilumab[Title/Abstract])) OR (mepolizumab[Title/Abstract])) OR (astegolimab[Title/Abstract])) OR (itepekimab[Title/Abstract])) OR (depemokimab[Title/Abstract])) OR (tezepelumab[Title/Abstract])) OR (tozorakimab[Title/Abstract])) OR (TILREKIMIG[Title/Abstract]))) AND (COPD[Title/Abstract]). Only phase III randomized clinical trials were included. Published phase III RCTs protocols were also included. Clinicaltrials.gov was searched for ongoing trials investigating biologics in COPD. Abstracts were independently reviewed: for those studies fitting the inclusion criteria on the basis of the title and abstract, full-text was achieved. Reference lists were also examined for any additional relevant studies not identified through the former search. No time restriction for publication was applied and only papers in English language were retrieved. A flow chart diagram of the studies included in the narrative review is provided in Figure 1.

Figure 1.

Flow chart showing selection criteria and inclusion/exclusion of relevant manuscripts for the narrative review.

Inflammation in COPD

The pathophysiology of COPD is complex and involves a range of inflammatory cells and mediators, and both type 1 and type 2 immune responses.¹⁸ The type 1 immune response is driven primarily by cytotoxic T lymphocytes, macrophages, neutrophils and CD4+ T-helper cells type 1 (Th1), while the type 2 response is associated with allergic diseases such as asthma and involves Th2 cells, eosinophils and innate lymphoid cells (ILCs).¹⁸

So far, biologicals for COPD target type 2 inflammation, which is present in ~20–40% of patients with COPD.¹⁸ The type 2 inflammatory response is triggered by alarmins, inflammatory mediators secreted by the airway epithelium in response to pathogenic stimuli such as cigarette smoke or pollutants, viruses, bacteria, or oxidative stress (Figure 2).^18,19 These trigger eosinophils and ILCs to secrete IL-4, IL-5 and IL-13. IL-4 and IL-13 stimulate the activation and trafficking of type 2 inflammatory cells, such as eosinophils, to the lungs.¹⁸ The eosinophils resident in lung tissue play a largely homeostatic function, whereas those recruited by IL-4/IL-13 stimulation are involved in the inflammatory response.²⁰

Figure 2.

Type 2 inflammation in COPD pathogenesis, and inflammatory mediators targeted by selected biological drugs. Adapted from Figure 2 in Calhoun WJ, Chupp GL. Allergy Asthma Clin Immunol. 2022;18(1):42. doi: 10.1186/s13223-022-00676-0,¹⁹ which was published under a CC-BY 4.0 license (creativecommons.org/licenses/by/4.0). Created in BioRender. Italia Srl, S. (2026) https://BioRender.com/j3jly4m. Black arrows indicate a promoting/positive effect; flat‑headed red arrows indicate a blocking effect on the specific pathway.

Abbreviations: APC, antigen-presenting cell; COPD, chronic obstructive pulmonary disease; FcεR, Fcε receptor; IgE, immunoglobulin E; IL, interleukin; ILC2, innate lymphoid cell type 2; lL4-Rα, interleukin-4 receptor-alfa; lL5-Rα, interleukin-5 receptor-alfa; IFNγ, interferon-gamma; MMP-9, matrix metallopeptidase 9; MHC2, major histocompatibility complex 2; PGD2, prostaglandin D2; TCR, T cell receptor; TGFβ, tumor growth factor beta; TNFα, tumor necrosis factor alfa; T_H, T helper cell; T_reg, Regulatory T cell; TSLP, thymic stromal lymphopoietin.

In the lungs, eosinophils release granule proteins that potentiate the inflammatory response, affect epithelial activation and the expression of remodeling factors, and contribute to mucus plug formation.²¹ Elevated blood levels of eosinophils are a marker for lung eosinophil numbers and increased levels of Th2 inflammatory markers in the airways of patients with COPD,²⁰ and are associated with an increased risk of exacerbations.²²

Biologicals for COPD

Most of the phase 3 studies of biologicals in patients with COPD were conducted in patients with evidence of type 2 inflammation, based on BECs at screening or in the year prior to enrolment (Table 1).^11–15,23

Table 1.

Phase III Randomized Clinical Trials with Biologicals for Patients with Chronic Obstructive Pulmonary Disease

Study	Study Design	Definition of Eosinophilia	Treatment	N	Moderate or Severe Exacerbations per Year	Difference vs Placebo RR (95% CI)	P-value
IL-5 or IL-5 receptor inhibitors
METREX12	MC, R, DB, PC	BEC ≥150 cells/μL at screening or ≥300 cells/μL within previous year	Mepolizumab 100 mg vs placebo q4w	417 vs 419	1.49 vs 1.52	0.98 (0.85, 1.12)	>0.99
METREO12	MC, R, DB, PC	BEC ≥150 cells/μL at screening or ≥300 cells/μL within previous year	Mepolizumab 100 mg vs placebo q4w	223 vs 226	1.19 vs 1.49	0.80 (0.65, 0.98)	0.07
			Mepolizumab 300 mg vs placebo q4w	225 vs 226	1.27 vs 1.49	0.86 (0.70, 1.05)	0.14
MATINEE13	MC, R, DB, PC	BEC ≥300 cells/μL at screening	Mepolizumab 100 mg vs placebo q4w	403 vs 401	0.80 vs 1.01	0.79 (0.66, 0.94)	0.01
GALATHEA11	MC, R, DB, PC	Baseline BEC ≥220 cells/μL	Benralizumab 30 mg vs placebo q8w	382 vs 359	1.19 vs 1.24	0.96 (0.80, 1.15)	0.65
			Benralizumab 100 mg vs placebo q8w	379 vs 359	1.03 vs 1.24	0.83 (0.69, 1.00)	0.05
TERRANOVA11	MC, R, DB, PC	Baseline BEC ≥220 cells/μL	Benralizumab 10 mg vs placebo q8w	377 vs 388	0.99 vs 1.17	0.85 (0.71, 1.01)	0.06
			Benralizumab 30 mg vs placebo q8w	394 vs 388	1.21 vs 1.17	1.04 (0.88, 1.23)	0.66
			Benralizumab 100 mg vs placebo q8w	386 vs 388	1.09 vs 1.17	0.93 (0.78, 1.10)	0.40
ENDURA-124	MC, R, DB, PC	NR	Depemokimab (dose NR) vs placebo	NR	NR	NR	NR
ENDURA-225	MC, R, DB, PC	NR	Depemokimab (dose NR) vs placebo	NR	NR	NR	NR
VIGILANT26	MC, R, DB, PC	NR	Depemokimab (dose NR) vs placebo	NR	NR	NR	NR
IL-4/IL-13 inhibitors
BOREAS15	MC, R, DB, PC	BEC ≥300 cells/μL at screening	Dupilumab 300 mg vs placebo q2w	471 vs 468	0.78 vs 1.10	0.70 (0.58, 0.86)	<0.001
NOTUS14	MC, R, DB, PC	BEC ≥300 cells/μL at screening	Dupilumab 300 mg vs placebo q2w	470 vs 465	0.86 vs 1.30	0.66 (0.54, 0.82)	<0.001
AERIFY-127,28	MC, R, DB, PC	NR	Itepekimab 300 mg q2w vs placebo q2w vs Itepekimab 300 mg q4w	310 vs 310 vs 310	NR	NR	NR
AERIFY-227,29	MC, R, DB, PC	NR	Itepekimab 300 mg vs placebo q2w	140 vs 140	NR	NR	NR
TSLP inhibitors
EMBARK30	MC, R, DB, PC	NR	Monthly subcutaneous injection of one of two different doses of tezepelumab or placebo	NR	NR	NR	NR
JOURNEY31	MC, R, DB, PC	NR	Monthly subcutaneous injection of one of two different doses of tezepelumab or placebo	NR	NR	NR	NR
IL- 33 inhibitors
ALIENTO32	MC, R, DB, PC	NR	Astegolimab 476 mg q2w vs placebo q2w	433 vs 431	1.21 vs 1.40	0.85 (0.72–1.00)	0.049
			Astegolimab 476 mg q4w vs placebo q4w	437 vs 431	1.30 vs 1.40	0.93 (0.79–1.10)	0.38
ARNASA32	MC, R, DB, PC	NR	Astegolimab q2w vs placebo q2w Astegolimab q4w vs placebo q4w	459 vs 457 459 vs 457	1.00 vs 1.17 0.96 vs 1.17	0.85 (0.72–1.01) 0.82 (0.7–0.98)	0.068 0.024
LUNA33 (OBERON, TITANIA, MIRANDA, PROSPERO)	MC, R, DB, PC	NR	Different dosages of Tozorakimab vs placebo	NR	NR	NR	NR
IL-4, IL-3 and TSLP inhibitors
PF-0727531534	MC, R, DB, PC	NR	Multiple shots of PF-07275315 or placebo over months	NR	NR	NR	NR

Abbreviations: BEC, blood eosinophil count; CI, confidence interval; DB, double-blind; IL, interleukin; MC, multicenter; N, number of patients randomized to treatment; NR, not reported; PC, placebo-controlled; q2w, every 2 weeks; q4w, every 4 weeks; q8w, every 8 weeks; R, randomized; RR, rate ratio.

The METREX and METREO studies with mepolizumab did not exclude patients based on BEC, but stratified their enrolment by BEC, and evaluated outcomes in the overall population and in the subgroup with high BECs (≥300 cells/µL).^12,23 Accordingly, the MATINEE study, enrolled patients based upon a BEC threshold of ≥300/µL at screening and ≥150/µL within the previous year.¹³ The patients in the METREX, METREO and MATINEE studies were all on triple therapy consisting of an inhaled corticosteroid (ICS), long-acting muscarinic antagonist (LAMA) and long-acting beta2-agonist (LABA).^11–15,23

The METREX and METREO trials showed no difference in the annualized rate of moderate or severe exacerbations (primary endpoint) in the overall study population (METREX overall modified intention-to-treat [mITT] population: 1.49 with mepolizumab 100 mg vs 1.52 with placebo; rate ratio [RR] 0.98 [95% confidence interval [CI] 0.85, 1.12]; p>0.99; METREO mITT population: 1.19 with mepolizumab 100 mg and 1.27 with mepolizumab 300 mg vs 1.49 with placebo; RR 0.80 [95% CI 0.65, 0.98]; p=0.07, and 0.86 [0.70, 1.05]; p=0.14, respectively; Table 1). A limited but statistically significant reduction in moderate to severe exacerbations in patients treated with mepolizumab compared with placebo in the subgroup with high baseline BEC (1.40 vs 1.71; RR 0.82 [95% CI 0.68, 0.98]; p=0.04) was observed in the METREX study but not seen in the METREO study, with either the 100 mg or the 300 mg mepolizumab doses.¹² In contrast, the MATINEE study reported a significant reduction in the annualized rate of moderate or severe exacerbations (primary endpoint) with mepolizumab 100 mg versus placebo in COPD patients on triple therapy and at high risk of exacerbations (≥2 moderate or ≥1 severe exacerbation), and a baseline BEC of ≥300 cells/μL and ≥150 cells/µL in the previous 12 months (0.80 vs 1.01; RR 0.79 [95% CI 0.66, 0.94]; p=0.01).¹³ Despite the efficacy data on exacerbations favored mepolizumab over placebo, no between-group differences in HRQoL or lung function were observed in the MATINEE study.¹³

Astegolimab, an anti-ST2 IgG2 monoclonal antibody, has been evaluated in two pivotal 52-week, placebo-controlled trials — ALIENTO (Phase 2b, n=1301) and ARNASA (phase 3, n=1375) — which enrolled current or former smokers with frequent exacerbations irrespective of baseline blood eosinophil count (>85% of participants <300 cells/µL, ~50% <150 cells/µL; mean [SD] 180.9 [140.8] and 184.2 [179.2] cells/µL, respectively).³⁵ In ALIENTO, astegolimab 476 mg every 2 weeks reduced the adjusted annualized rate of moderate or severe exacerbations from 1.31 to 1.11 (rate ratio [RR] 0.85, 95% CI 0.72–1.00; p=0.049), whereas the every-4-week regimen did not (1.22; RR 0.93, 0.79–1.10; p=0.38). In ARNASA the corresponding estimates were 1.00 versus 1.17 (RR 0.85, 0.72–1.01; p=0.068) and 0.96 (RR 0.82, 0.70–0.98; p=0.024), the latter falling outside the fixed-sequence testing hierarchy.³⁶ Reductions in severe exacerbations (hospitalization >24 h or death) with the every-2-week dose were consistent across both trials — 0.18 versus 0.26 in ALIENTO (RR 0.71, 0.49–1.05; p=0.088) and 0.14 versus 0.20 in ARNASA (RR 0.67, 0.47–0.95; p=0.024), corresponding to 29% and 33% relative reductions — and were numerically larger in GOLD 2 patients (RR 0.67, 0.48–0.94 in ALIENTO; 0.73, 0.52–1.01 in ARNASA) and in patients previously hospitalized for COPD (RR 0.68, 0.48–0.97 in ALIENTO).³⁵ Lung function did not significantly improve in both trials: the adjusted mean difference versus placebo in post-bronchodilator FEV1 at week 52 was 16 mL (95% CI −17 to 48; p=0.34) in ALIENTO and 14 mL (−17 to 46; p=0.37) in ARNASA for the every-2-week regimen. In terms of symptoms and quality of life, the odds ratio for an improvement of ≥4-points of the St. George’s Respiratory Questionnaire for COPD patients (SGRQ-C) reached significance only in ARNASA (1.49, 1.14–1.96; p=0.0037).³⁵

The anti-IL-5Rα cytolytic antibody Benralizumab was tested in the replicate 56-week phase 3 trials GALATHEA and TERRANOVA in moderate-to-very-severe COPD with blood eosinophils ≥220 cells/µL (in the primary analysis population ~93% of patients were GOLD group D and 69.6% and 58.6% of patients were on triple therapy, respectively).¹¹ Neither trial met its primary endpoint. In GALATHEA the annualized exacerbation rates were 1.19 (95% CI: 1.04–1.36) with 30 mg and 1.03 (95% CI: 0.90–1.19) with 100 mg versus 1.24 (95% CI: 1.08–1.42) with placebo (RR 0.96, p=0.65; and 0.83, p=0.05); in TERRANOVA they were 0.99 (95% CI: 0.87–1.13), 1.21 (95% CI: 1.08–1.37) and 1.09 (95% CI: 0.96–1.23) for 10, 30 and 100 mg versus 1.17 (95% CI: 1.04–1.32) for placebo (RR 0.85, p=0.06; 1.04, p=0.66; 0.93, p=0.40), with no evident dose–response relationship. Severe exacerbation rate ratios were equally inconsistent (GALATHEA: 1.20 [95% CI: 0.80–1.80] for 30 mg, 0.57 [95% CI: 0.36–0.91] for 100 mg; TERRANOVA: 0.75 [95% CI: 0.51–1.11], 0.88 [95% CI: 0.61–1.27] and 0.68 [95% CI: 0.46–1.00]). Lung function appeared not to be affected by the active treatment, with between-group differences in change from baseline in pre-bronchodilator FEV1 at week 56 of 7 mL (−35 to 48) and 21 mL (−21 to 62) in GALATHEA and 15 mL (−29 to 59), −7 mL (−51 to 37) and 20 mL (−24 to 64) in TERRANOVA; SGRQ differences ranged from −0.602 to −2.136 points, not reaching the 4-point minimal clinically important difference.¹¹

The monoclonal antibody dupilumab, blocking the IL-4/IL-13 signaling pathway via blockade of a shared receptor component for IL-4 and IL-13, was studied in two large phase III RCTs, BOREAS and NOTUS, that compared dupilumab 300 mg with placebo and demonstrated a significant reduction in exacerbation rates in patients with COPD and chronic bronchitis at risk of exacerbations and concomitant T2 inflammation (Table 1).^14,15 In both studies, patients were on triple therapy (ICS/LABA/LAMA) or LABA/LAMA alone if ICS was contraindicated. The BEC criterion for study entry in both trials was ≥300 cells/μL at screening;^14,15 this BEC threshold has been validated as an indicator of increased risk of exacerbation.^36,37 However, BEC levels fluctuated at baseline,³⁸ decreasing to <300 cells/μL from screening to baseline in up to 40% of patients included in BOREAS and NOTUS. The reduction in the annualized rate of moderate or severe exacerbations with dupilumab versus placebo was 30% in the BOREAS study (RR 0.70 [95% CI 0.58, 0.86]; p<0.001)¹⁵ and 34% in the NOTUS study (RR 0.66 [95% CI 0.54, 0.82]; p<0.001).¹⁴ Patients in both studies also showed statistically and clinically significant improvements in lung function (forced expiratory volume in 1 second [FEV₁]) compared with placebo,^14,15 and patients in the BOREAS study also showed significant improvements in HRQoL and respiratory symptoms.¹⁵ These improvements in both studies were seen regardless of baseline BEC level (≥150 cells/μL and ≥300 cells/μL).³⁸

These data indicate that patients who have high BECs and continue to experience exacerbations despite triple inhaled therapy may benefit from biological therapy with dupilumab. Commentators have speculated that the more marked benefits of dupilumab compared with mepolizumab or benralizumab are due to a broader inhibition of type 2 inflammation achieved with the blockade of IL-4 and IL-13 compared with IL-5,³⁹ which suggests that eosinophils play different roles in COPD and asthma.

The advent of biologicals for COPD marks the start of a treatment approach tailored to addressing “treatable traits” (such as the presence of type 2 inflammation or other clinical phenotypes), and future drug treatments and biomarkers will allow further personalization of treatment.^39,40

There are currently limited data on the real-world effectiveness of biologicals in patients with COPD. A small study in Canada (n=17) indicated that treatment with IL-5 inhibitors was associated with a significant reduction in moderate or severe exacerbations compared with baseline, from 4.06 to 1.15 per patient-year (p<0.001).⁴¹

Real-world studies of biologicals including dupilumab, mepolizumab, benralizumab, omalizumab, reslizumab, or tezepelumab have been limited to patients with both asthma and COPD, but show improvements in FEV₁,^32,42 and reductions in eosinophil levels,^32,42 asthma exacerbations,^27,32 and the use of oral corticosteroids (OCS).^27,42

Safety and Adverse Event of Biologics in COPD

Across the pivotal COPD trials, all four biologics showed adverse-event profiles closely comparable to placebo, dominated by COPD itself and by respiratory infections. With dupilumab, any adverse event occurred in 77.4% versus 76.0% (BOREAS) and 66.7% versus 65.9% (NOTUS) of patients, serious events in 13.6% versus 15.5% and 13.0% versus 15.9%, and fatal events in 1.5% versus 1.7% and 2.6% versus 1.5%; nasopharyngitis, upper respiratory tract infection, headache and COVID-19 predominated, adjudicated major adverse cardiovascular events were not increased (0.9% vs 1.9%; 0.6% vs 1.5%), and persistent antidrug antibodies were detected in 3.0% versus 0.7%.^14,15 Mepolizumab was similarly tolerated: in MATINEE adverse events occurred in 74% versus 77%, serious events or death during treatment in 25% versus 28%, deaths in 3% of both groups and adjudicated cardiovascular events in 3% of both, with systemic reactions in 1% and no anaphylaxis;¹³ METREX and METREO reported comparable overall rates, systemic (1–2%) and injection-site (3–5%) reactions similar to placebo, and non-neutralising antidrug antibodies in 4–6%.¹² In GALATHEA and TERRANOVA, benralizumab produced no excess of adverse events (70.4–80.6%), serious events (22.6–32.1%), pneumonia (3.9–5.9%) or death (<4% in every arm), and antidrug antibodies (<14%) had no apparent effect on outcomes, despite near-complete depletion of blood and sputum eosinophils.¹¹ Astegolimab, evaluated in ALIENTO and ARNASA, was likewise well tolerated: adverse events affected 84.0% and 85.5% of participants overall, serious and grade ≥3 events were no more frequent than with placebo (24.4–28.0% vs 31.5% for serious events in ALIENTO), injection-site reactions occurred in 3.7–6.7%, and deaths were balanced across groups (3.1% and 3.2%; three considered treatment-related), with no signal of excess infection or major adverse cardiovascular events despite ST2/IL-33 blockade.³⁵

Ongoing Phase 2b/3 Programmes for Biologicals in COPD

Several biologics with distinct upstream targets are currently in confirmatory development for COPD. For itepekimab and tozorakimab the available publications report the study protocols of their pivotal programs. AERIFY-1 (n=960) and AERIFY-2 (n=930 former smokers plus a secondary cohort of 280 current smokers) are 52-week phase 3 trials that will test itepekimab 300 mg every 2 or 4 weeks in former smokers with moderate-to-severe COPD and chronic bronchitis, each powered at 90% to detect a 30% relative reduction in the annualized rate of moderate or severe exacerbations (assumed placebo rate 1.5/year, dispersion parameter 1.0, mean exposure 0.94 years), with change from baseline in pre-bronchodilator FEV1 at week 24 as the key secondary endpoint.^28,29,33 These assumptions derive from the phase 2 ACT15104 study, in which itepekimab improved pre-bronchodilator FEV1 by 90 mL versus placebo at week 24 in the pre-specified former-smoker subgroup (95% CI: 20–150 mL; nominal p=0.0076) while showing no effect in current smokers.^28,29,33 Tozorakimab, which neutralizes both reduced and oxidised IL-33, is being assessed in the four-trial LUNA programme — OBERON (n=1132), TITANIA (n=1172), MIRANDA (n=1454) and the extension study PROSPERO (~1272 former smokers) — the largest pivotal biologic programme in COPD to date, with the annualized rate of moderate-to-severe exacerbations in former smokers as primary endpoint and pre- and post-bronchodilator FEV1 among key secondary endpoints; 318 patients per arm in OBERON/TITANIA provide ~90% power for a 30% relative reduction (~87% power for 25% in the overall population), and MIRANDA (558 versus 372 former smokers) ~97% power for a 30% reduction.³⁰ The programme was advanced despite the phase 2 FRONTIER-4 study failing its primary endpoint of change from baseline in pre-bronchodilator FEV1 at week 12 in patients with moderate to severe airflow obstruction and chronic bronchitis, on the basis of responder analyses defined by exacerbation history and a numerical reduction in COPD composite exacerbation events (COPDCompEx) events irrespective of baseline eosinophil count.³⁰

Tezepelumab, an anti–thymic stromal lymphopoietin (TSLP) monoclonal antibody, is being evaluated in two identically designed Phase 3, randomised, double-blind, placebo-controlled, parallel-group, multicentre trials, EMBARK (NCT06883305) and JOURNEY (NCT06878261), each planning 990 participants aged 40–80 years with moderate to very severe COPD.^31,34 Eligibility requires ≥10 pack-years, post-bronchodilator FEV1/FVC <0.70 with FEV1 20–70% of predicted, a COPD Assessment Test score ≥15, blood eosinophils ≥150 cells/µL, at least two moderate or one severe exacerbation in the previous year, and stable dual or triple inhaled therapy; two subcutaneous tezepelumab dose regimens given every 4 weeks are compared with placebo over 52–76 weeks of treatment.^31,34 In both trials the primary endpoint is the annualised rate of investigator-reported moderate or severe COPD exacerbations versus placebo over the treatment period of up to 76 weeks.^31,34 PF-07275315 (tilrekimig), a trispecific antibody simultaneously neutralising IL-4, IL-13 and TSLP, is being tested in a single seamless phase 2b/3, randomised, double-blind, placebo-controlled study (NCT07363694; planned n = 1156) enrolling adults aged 35–80 years with COPD diagnosed for ≥12 months, FEV1 30–70% of predicted, ≥2 moderate or severe exacerbations in the previous year and ≥6 months of triple inhaled therapy; the Phase 2b component randomises two active doses against placebo over 24 weeks, with change from baseline in pre-bronchodilator FEV1 at week 24 as its primary measure, whereas the Phase 3 component extends treatment to 52 weeks.²⁴ Depemokimab, an anti–IL-5 antibody engineered for extended dosing intervals, is under investigation in two replicate phase 3 trials, ENDURA-1 (NCT06959095; n = 981) and ENDURA-2 (NCT06961214; n = 960), in patients aged 40–80 years with ≥10 pack-years, post-bronchodilator FEV1 >30% to ≤80% of predicted, elevated blood eosinophil counts and ≥2 moderate or one severe exacerbation despite ≥6 months of ICS/LABA/LAMA therapy; the primary endpoint is the annualised rate of moderate or severe exacerbations from baseline to week 104, with time to first exacerbation, severe-exacerbation and exacerbation-related emergency-visit or hospitalisation rates, and week-52 SGRQ and E-RS:COPD changes as secondary endpoints.^25,26 The companion VIGILANT trial (NCT07177339; n = 1196) applies the same agent earlier in the disease course—patients aged 40–75 years with a single moderate exacerbation in the preceding year on dual or triple therapy—with the annualised rate of moderate or severe exacerbations from baseline to week 156 as its primary endpoint.⁴³

COPD in Italy

The prevalence of COPD in Italy is ~3%, based on estimates from primary care.^44–46 BECs are highest in Italian COPD patients with recurrent wheezing as the predominant symptom, a group that represents about 13% of the COPD population in Italy, according to the Clinical Phenotypes in Actual Clinical Practice study.⁴⁷

According to data from the previous GULP study, 32% of COPD patients in Italy have ≥2 exacerbations per year.¹⁶ This is consistent with previous data from an observational study conducted across a number of European countries, which suggested that 30.5% of COPD patients in Italy have ≥2 exacerbations per year.⁴⁸

Even in patients with the mildest grade of COPD (according to GOLD classification), 45.5% of patients in the GULP study had ≥1 exacerbation over 2 years of follow-up, and 30.6% of these exacerbations were severe.¹⁷ Exacerbation frequency and the proportion of severe exacerbations tended to increase with worsening COPD, and the risk of death was significantly increased in patients with cardiovascular comorbidities (ischemic heart disease or chronic heart failure).¹⁷

Among inhaled therapies for COPD, the triple combination of an ICS, LAMA and LABA is associated with the most marked reduction in exacerbation frequency.⁴⁹ In the GULP study, ~43% of patients were receiving this combination.^16,17 A separate observational study suggested that 8.5% of the Italian COPD population would be candidates for biological therapy based on having a BEC of ≥300 cells/μL.⁴⁸

Insights from the GULP Study

Methods for the GULP Analysis

The GULP study was an observational, multicenter, retrospective cohort study based on a multicenter database. The design and methods of the GULP study have been described previously.¹⁶ The present descriptive analysis has the objective to put into context the potential role of biologic therapy in a well characterised cohort of Italian patients with COPD. To do so, we run an exploratory analysis of the clinical and functional characteristics and inhaled therapeutic regimens grouping patients based upon GOLD E category following the GOLD classification,⁶ ≥ 2 moderate exacerbation or 1 severe exacerbation. Categorial data were expressed as frequencies (proportions), while continuous data were reported as means (standard deviation) or medians (inter-quartile range) depending of the normality of the distribution assessed with the Kolmogorov–Smirnov test. Comparisons between proportions were assessed by means of the χ² test, while continuous variables were compared with the Student’s t-test, Mann–Whitney U or Kruskal–Wallis tests depending on their distribution, as appropriate. Missing data were not imputed. No correction for multiplicity was applied. The analysis used pooled and anonymized data. The GULP study was approved by the Local Ethics Committee (The Italian COPD Registry - protocol n. 20–27 Sept 2023) and all patients gave their written informed consent.

GULP Study Outcomes in Patients at High Risk of COPD Exacerbations

The GULP cohort originally included 1111 patients, 286 of whom had a history of ≥2 exacerbations (n=174, 60.8%) or ≥1 exacerbation requiring hospitalization (n=112, 39.2%) in the last year; of the 286 patients at high risk of exacerbations, 61 (21.3%) patients were on LABA/LAMA therapy and 151 (52.8%) were on ICS/LABA/LAMA therapy (Table 2). Of the 112 patients with ≥1 severe exacerbation, 16 (14.3%) were on LABA/LAMA and 68 (60.7%) were on ICS/LABA/LAMA, while of the 174 patients with ≥2 moderate exacerbations, 45 (25.9%) were on LABA/LAMA and 83 (47.7%) were on ICS/LABA/LAMA (Table 2).

Table 2.

Dyspnea and Eosinophil Counts in COPD Patients with ≥2 Moderate Exacerbations and/or ≥1 Severe Exacerbations (GOLD Category E 2025) Receiving LABA/LAMA Therapy or LABA/LAMA/ICS Triple Therapy in the GULP Study (N = 1111)

Treatment/Clinical Characteristics, n (%)				≥2 Moderate and/or ≥1 Severe Exacerbations n=286
LABA/LAMA				61 (21.3)‡
ICS/LABA/LAMA				151 (52.8)
≥1 severe exacerbation				112 (39.2)
	LABA/LAMA			16 (5.6)*
		mMRC ≥2		12 (4.2)
			BEC ≥300 cells/µL	3 (1.0)
	ICS/LABA/LAMA			68 (23.8)**
		mMRC ≥2		53 (18.5)
			BEC ≥300 cells/µL	6 (2.1)
≥2 moderate exacerbations				174 (60.8)
	LABA/LAMA			45 (15.7)†
		mMRC ≥2		39 (13.6)
			BEC ≥300 cells/µL	3 (1.0)
	ICS/LABA/LAMA			83 (29.0)††
		mMRC ≥2		65 (22.7)
			BEC ≥300 cells/µL	9 (3.1)

Notes: The denominator for all reported frequencies and prevalences is n = 286. ‡ patients not on LABA/LAMA or ICS/LABA/LAMA were distributed as follows: LAMA n = 5, LABA/ICS n = 69; *equal to 14.3% of patients with ≥1 severe exacerbation; **equal to 60.7% of patients with ≥1 severe exacerbation; † equal to 25.9% of patients with ≥2 moderate exacerbations; †† equal to 47.7% of patients with ≥2 moderate exacerbations.

Abbreviations: BEC, blood eosinophil counts; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroids; LABA, long-acting beta₂-agonist; LAMA, long-acting muscarinic antagonist; mMRC, modified Medical Research Council.

The proportion of patients with a modified Medical Research Council (mMRC) dyspnea scale score of ≥2 tended to be higher in patients receiving ICS/LABA/LAMA therapy than in those receiving LABA/LAMA therapy in both exacerbation categories (18.5% vs 4.2% in patients with ≥1 severe exacerbation; p=0.002, and 22.7% vs 13.6% in patients with ≥2 moderate exacerbations per year; p=0.438; data not reported). Similarly, the proportions of patients with high BECs (≥300 cells/µL) on ICS/LABA/LAMA was numerically higher compared with patients on LABA/LAMA. In total, 7.2% of symptomatic patients at high risk of exacerbation had a BECs ≥300 cells/µL (Table 2).

Anthropometric characteristics and smoking histories of patients at high risk of exacerbation with a mMRC ≥2 did not differ from the rest of the study cohort (Table 3). Compared with other COPD patients in the GULP study, they showed significantly higher prevalence of cerebrovascular disease, lymphoma, cancer, long-term oxygen therapy and need for home-based non-invasive ventilation. Lung function and eosinophil distribution were similar between the two groups (Table 3).

Table 3.

Anthropometric/Clinical Characteristics of Patients with COPD Compared with COPD GOLD Category E with mMRC ≥2

Characteristics	All Patients with Data (N=1006)a		P-value
	< 2 Moderate and/or < 1 Severe Exacerbations n=784	≥2 Moderate and/or ≥1 Severe Exacerbations and mMRC ≥2 n=222b
Age, median (range), years	77 (70–82)	77 (71–82)	0.632
BMI, median (range), kg/m2	26.6 (23.5–29.4)	26.6 (23.5–29.6)	0.968
Male, n (%)	576 (77.8)	164 (73.9)	0.932
Smoking history, n (%)
Never-smokers	40 (5.2)	5 (2.3)	0.068
Active/Former smokers	734 (94.8)	217 (97.7)
Active smokers	185 (23.9)	63 (28.4)	0.096
Former smokers	549 (70.9)	154 (69.4)
Comorbidities, n (%)
AIDS	1 (0.1)	0	0.653
Cerebrovascular disease	128 (16.3)	58 (26.1)	0.002
Chronic heart failure	114 (14.6)	40 (18.0)	0.207
Connective tissue disease	60 (7.7)	18 (8.1)	0.778
Dementia	8 (1.0)	6 (2.7)	0.096
Hemiplegia	6 (0.8)	4 (1.8)	0.241
Leukemia	8 (1.0)	2 (0.9)	1.000
Lymphoma	3 (0.4)	4 (1.8)	0.046
Ischemic heart disease	137 (17.5)	44 (19.8)	0.430
Peripheral vascular disease	169 (21.6)	47 (21.2)	0.927
Atrial fibrillation	66 (11.6)	23 (11.9)	1.000
Peptic ulcer	52 (6.6)	13 (5.9)	0.867
Diabetes type 2	102 (13.0)	35 (15.8)	0.318
Liver disease	54 (6.9)	21 (9.5)	0.196
Kidney failure	60 (7.7)	21 (9.5)	0.402
Cancer	61 (7.8)	13 (5.9)	0.015
Sleep apnea syndrome	65 (11.2)	26 (16.8)	0.073
Long-term oxygen therapy	186 (23.8)	91 (41.0)	<0.001
Home-based NIMV	72 (9.2)	41 (18.5)	<0.001
Lung function, median (range)
FEV1, % predicted	63.2 (46.7–77.9)	60.4 (41.3–76.1)	0.173
FVC, % predicted	90 (73.0–107.0)	88.5 (69.0–107.0)	0.204
FEV1/FVC, % predicted	74.5 (61.2–86.0)	71.8 (53.2–86.9)	0.131
Eosinophil count, median (range)
Eosinophil count, cells/µL	140 (100–250)	100 (85–270)	0.140
Eosinophils, %	1.86 (1.1–3.3)	1.49 (0.7–3.0)	0.071

Notes: ^aOf the original 1111 patients in the GULP study, all of the relevant variables (eosinophils, dyspnea, treatment regimens) were present in 1006 patients. ^b222 of the 286 patients with ≥2 moderate and/or ≥1 severe exacerbations with complete clinical data. Please note that, despite the sum of patients with frequent or severe exacerbations and mMRC≥2 reported in Table 1 is equal to 169, for inclusion in Table 2 no inhaled therapy criterion was followed (ie patients were included independently of the chronic inhaled therapy).

Abbreviations: AIDS, acquired immunodeficiency syndrome; BMI, body mass index; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; mMRC, modified Medical Research Council dyspnea scale; NIMV, non-invasive mechanical ventilation.

The majority (~75.0%) of symptomatic patients at high risk of exacerbation (GOLD E 2025) experienced chronic cough, and among those with sputum data, chronic sputum production (both purulent and non-purulent) affected approximately 51.0% of patients. Purulent sputum was present in about 15.0% of these patients (Table 4).

Table 4.

Proportion of Patients with Chronic Cough and Sputum Among Patients with ≥2 Moderate and/or ≥1 Severe Exacerbations and mMRC ≥2

	≥2 Moderate and/or ≥1 Severe Exacerbations and mMRC ≥2 n=222a
Cough, n (%)
No	54 (25.2)
Yes	160 (74.8)
Sputum, n (%)
Never/occasional	5 (50)
Chronic (non-purulent)	77 (35.8)
Chronic (purulent)	33 (15.3)

Note: ^a222/286 patients with available data.

Abbreviations: COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; mMRC, modified Medical Research Council dyspnea scale.

Discussion

This narrative review has shown that biological agents that target the key inflammatory pathways underlying the pathophysiology of COPD have a potentially important role in the treatment of patients with severe disease with high risk of future exacerbation and an eosinophilic profile. In a limited subset of Italian symptomatic patients with COPD at high risk of exacerbation, we demonstrated the persistence of a high symptom burden (including cough and sputum production) and impaired HRQoL despite receiving LABA/LAMA or ICS/LABA/LAMA therapy in accordance with GOLD guidelines.

Interestingly, it is generally accepted that a BEC of ≥300 cells/µL represents a distinct phenotype that is at risk for an accelerated decline in FEV₁ and a higher risk of exacerbations compared with patients with lower eosinophil counts, and is a reliable predictor of treatment response to ICS in moderate-to-severe COPD.⁵⁰ However, eosinophilic levels fluctuate with time and are not stable,⁵¹ suggesting that it is important to perform serial eosinophil evaluations over time or collect data on historical eosinophil levels, irrespective of COPD exacerbation or use of ICS. Eosinophilic status of 100 patients with COPD was measured during stable state at four consecutive annual clinic visits, who were classified at all visits as “low BEC” or “high BEC” according to a BEC cut-off of 300 cells/µL.⁵¹ Based on stable BECs, patients were categorized as “persistent eosinophilic” (BEC ≥300 cells/µL at ≥3 annual timepoints), “intermittent eosinophilic” (BEC ≥300 cells/µL at 1–2 annual timepoints), or “never eosinophilic” (BEC 300 cells/µL at all timepoints). “Eosinophilic exacerbators” were defined as patients with ≥1 exacerbation visit with BEC ≥300 cells/µL. At Visit 1, 65% of the cohort was low BEC (<300 cells/µL) and 35% was high BEC (≥300 cells/µL). Across each subsequent timepoint, the number of patients with high BEC fell progressively by 50%, 40% and 35%, respectively. At the end of the observation period, 18%, 29%, and 53% of the cohort were defined as having an eosinophilic status of “persistent”, “intermittent”, or “never”, respectively. Within each group, 89%, 51%, and 26% of patients, respectively, experienced ≥1 eosinophilic exacerbation. Notably, an analysis of eosinophil status based on one timepoint instead of all four timepoints during follow-up found that 21.4%, 7.1%, 28.5%, and 21.4% of the “persistent high” cohort would be classified as having low BEC at Visits 1, 2, 3, and 4, respectively. Thus, a one-off BEC measurement would have missed around one-third (28.5%) of patients who would otherwise be categorized as eosinophilic.

An important consideration emerging from the Baraldi study is the finding that each of the three eosinophilic categories contained a subgroup of eosinophilic exacerbators (experiencing at least 1 eosinophilic exacerbation), all of whom had significantly higher COPD Assessment Test (CAT) scores and a significantly greater risk of exacerbations compared with the non-eosinophilic exacerbation subgroup.⁵¹ The authors suggest that this subgroup of eosinophilic exacerbators represents a new group of patients with COPD who may potentially respond to biological agents targeting the Th2 axis, which suggests that it is very important to tailor pharmacotherapy to the individual patient.

Consistent results from the pooled analysis of the BOREAS and NOTUS studies have highlighted the benefits of adding dupilumab to ICS/LABA/LAMA therapy in patients with symptomatic COPD, BEC ≥300 cells/µL and a reported chronic productive cough for ≥3 months in the past year at enrolment (a patient population comparable to a portion of the GULP study highlighted in the present analysis).^17,52,53 The BOREAS and NOTUS pooled analysis showed that dupilumab significantly reduced the risk of moderate or severe exacerbation events and improved lung function compared with placebo.^52,53 Treatment with dupilumab induced a 31.0% reduction in moderate or severe exacerbations over 52 weeks, with an annualized exacerbation rate of 0.794 in the dupilumab group and 1.156 in the placebo group (RR 0.687 [95% CI 0.595, 0.793]; p<0.0001).⁵³ In addition, dupilumab significantly prolonged the time to first moderate or severe exacerbation compared with placebo (hazard ratio 0.770 [95% CI 0.666, 0.892; p=0.0005). As for lung function, dupilumab-treated patients observed a greater improvement from baseline at Week 12 in pre- and post-bronchodilator FEV₁ compared with the placebo group; this improvement was maintained at Week 52.

Outcomes from the BOREAS and NOTUS studies highlight additional benefits associated with dupilumab for patients with COPD and eosinophilic phenotype with a high burden of disease, which, according to the current analysis, might correspond to the 7.2% of the GULP cohort.¹⁷ Importantly, dupilumab was also associated with significant improvements from baseline compared with placebo at Week 52 in HRQoL and respiratory symptom severity, as assessed by scores on the St. George’s Respiratory Questionnaire (SGRQ; least squares mean [LSM] difference −3.4 [95% CI −5.0, −1.8]; p<0.0001) and the Evaluating Respiratory Symptoms in COPD (E-RS:COPD) scale (LSM difference −0.91 [95% CI −1.44, −0.39]; p=0.0006), respectively. These results emphasize the importance of comprehensively assessing subjective, patient-reported respiratory symptom burden, as well as objective clinical measurements, in patients with COPD and type 2 inflammation, particularly in those at high risk of COPD exacerbations.

The improvements in HRQoL associated with dupilumab in the BOREAS and NOTUS studies were numerically greater than those shown with other studies involving mepolizumab (METREX, METREO and MATINEE) and benralizumab (GALATHEA and TERRANOVA) in patients with moderate or severe COPD on LABA/LAMA or ICS/LABA/LAMA therapy.^11–13 Moreover, patients exposed to dupilumab showed significant improvements in lung function and HRQoL, findings that were variably observed and did not reach statistical significance compared with placebo in RCTs involving mepolizumab and benralizumab.^11–13 The greater degree and consistency of improvements observed with dupilumab across subjective assessments in the BOREAS and NOTUS studies support the notion that IL-4 and IL-13 represent important drivers of COPD pathobiology in patients with COPD and type 2 inflammation.

During the writing of the present narrative review, dupilumab represents the only biologic therapy approved for COPD patients with eosinophilic phenotype and exacerbating despite triple therapy (or a LABA/LAMA in cases in which ICS is contraindicated). Indeed, COPD imposes a large and rising economic burden: in the United States, COPD-attributable direct medical costs were estimated at US$31.3 billion in 2019 and are projected to approach US$60.5 billion by 2029.⁵⁴ Dupilumab was the first ever biologic licensed for eosinophilic COPD. The corresponding absolute benefit— approximately 0.32–0.44 exacerbations averted per patient-year observed in the NOTUS and BOREAS trials—must be weighed against acquisition costs that differ markedly across jurisdictions. In the United States, the wholesale acquisition cost is US$4193 per four-week supply (two 300 mg injections), equivalent to approximately US$54,500 per patient-year at list price.⁵⁵ European list prices are approximately one third of this figure: €16,036 per patient-year in Germany, against €1000–3500 for the inhaled comparator regimens,⁵⁶ and £16,444 per patient-year in the United Kingdom.⁵⁷ Assuming no additional offsets, these prices translate into an undiscounted cost per moderate-to-severe exacerbation averted of roughly US$124,000–170,000 in the United States and €36,000–50,000 in Germany, so that cost-effectiveness becomes contingent on durability of benefit, on hospitalisation offsets in high-risk phenotypes and on confidential discounts. Value of such pharmacological approaches in COPD therefore should depend on stringent biomarker-based targeting and careful patient characterization. In fact, as also reported in the last GOLD document,⁶ dupilumab and mepolizumab are recommended for patients at high risk of exacerbation, namely those that continue exacerbating with ≥2 moderate exacerbations of experience hospitalizations despite inhaled triple therapy and have a BEC history of ≥300 cells/µL.⁶ As emphasized by the GULP analysis we showed in the present review, the patients at risk of exacerbations and with a high disease burden that can benefit from the biologic therapy do not necessarily overlap with all the patients with a high exacerbation burden and therefore a particular attention to follow up visits, biomarker retrieval and pro-active patients re-evaluation should be always promoted especially in patients with uncontrolled disease and experiencing symptoms such as cough and sputum despite chronic inhaled therapy. Limitations from the original GULP study need to be taken into consideration when interpreting these findings. In fact, the GULP study was observational and retrospective; therefore, the therapeutic allocation, switch and optimization were left to the treating physician and could not be modified by the participation to the study. Moreover, our analysis did not examine COPD prognostic markers, such as body mass index, age, respiratory variables (FEV1, need and frequency of hospitalization for acute exacerbation, smoking status) and comorbidities.

Conclusions

This narrative review provides the rationale for the use of biological agents in the treatment of COPD with type 2 inflammation and severe uncontrolled disease. As illustrated in our exploratory analysis of data from the GULP study, there is an unmet need for more effective treatment options among patients, in a proportion of whom, despite dual bronchodilator therapy or triple therapy, experience a high risk of exacerbation and a high symptom burden. We consider these patients to have severe COPD independently of the severity of airflow obstruction. So far, biologicals targeting IL-5, IL-5 receptor or IL-33 have shown variable effects on exacerbation prevention and no significant effects on HRQoL, while dupilumab, a specific IL-4/IL-13 signaling pathway inhibitor, has shown significant and consistent improvements in exacerbation reduction, lung function, and QoL improvement compared with placebo. This is consistent with the hypothesis that IL-4 and IL-13 are important drivers of COPD pathobiology, and that dupilumab, may be an important potential treatment option for patients with severe COPD and type 2 inflammation.

Funding Statement

Medical writing (Catherine Rees who provided medical writing assistance on behalf of Springer Health+ and Iona MacDonald of Springer Health+ who assisted with the first and subsequent drafts) unconditionally supported by Sanofi. Sanofi had no role in the review design, data access, analysis, interpretation, drafting, approval and the decision to submit the manuscript.

Abbreviations

BEC, blood eosinophil count; CI, confidence interval; COPD, chronic obstructive pulmonary disease; DB, double-blind; GOLD, Global Initiative for Chronic Obstructive Lung Disease; GULP, DescribinG bUrden of COPD and occurrence of mortaLity in a cohort of Italian Patients; HRQoL, health-related quality of life; ICL, innate lymphoid cell; ICS, inhaled corticosteroid; IL, interleukin; LABA, long-acting beta₂-agonist; LAMA, long-acting muscarinic antagonist; mITT, modified intention-to-treat; RR, rate ratio; Th1, T-Helper cell type 1.

Data Sharing Statement

As reported for the GULP study, data will be available from the Corresponding Author upon reasonable request.

Ethics Approval and Informed Consent

The GULP study was approved by the Local Ethics Committee (The Italian COPD Registry - protocol n. 20–27 Sept 2023) and all patients gave their written informed consent.

Consent for Publication

Consent for publication was deemed not applicable.

Author Contributions

Paolo Solidoro and Pierachille Santus share the last authorship. All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agreed to be accountable for all aspects of the work.

Disclosure

DR has received lecture fees from AstraZeneca, Berlin-Chemie, GlaxoSmithKline, Menarini, Sanofi and Zambon; and consultancy fees from AstraZeneca, Insmed Incorporated and Sanofi. FB has received research support from Chiesi Farmaceutici S.p.A., GSK, and Vitalaire; and honoraria/consulting fees from AstraZeneca, Chiesi Farmaceutici S.p.A., GlaxoSmithKline, Menarini Group, Bruschettini, Sanofi Regeneron, and Zambon. MC: research grants from Chiesi and GSK; personal payments for lectures, presentations or educational events from CHIESI, ASTRAZENECA, GSK, SANOFI, MENARINI, ALK ABELLO; personal payments for participation on Advisory Board from CHIESI, ASTRAZENECA, GSK, ALK ABELLO, SANOFI; nothing to declare related to the present manuscript. AGC has no competing interests to declare. FDM has received research support from AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici S.p.A., GSK and Sanofi; and lecture honoraria from AstraZeneca, Chiesi Farmaceutici S.p.A., Eurodrugs Laboratories, GlaxoSmithKline, Menarini Group, MSD, Neopharmed Gentili S.p.A., and Sanofi. CM has received speaker fees for national and international congresses from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi Farmaceutici S.p.A., GSK, Lusofarmaco, Menarini, Roche, Sanofi, and Zambon. GP has received lecture fees and advisory board fees from AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici S.p.A., FIRMA, GlaxoSmithKline, Guidotti, Insmed, Lusofarmaco, Menarini, Neopharmed Gentili, Sanofi, and Zambon. PR has received grants and research support for her Institution from Arcede Pharma, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici S.p.A., Sanofi, Verona Pharma, and Zambon; and honoraria/consultation fees from AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici S.p.A., GlaxoSmithKline, Menarini Group, Novartis, Pfizer, Recipharm, Regeneron, Roche, and Sanofi. NS has received research support from AstraZeneca, Chiesi Farmaceutici S.p.A., and Sanofi; and lecture honoraria from AstraZeneca, Chiesi Farmaceutici S.p.A., GlaxoSmithKline, Menarini Group, Sanofi. PS has received speaker/advisory fees from AstraZeneca, Behring, Biotest (now Grifols), Chiesi Farmaceutici S.p.A., GSK, Lusofarmaco, Menarini, Novartis, and Takeda. P. Santus has received lecture fees at national and international meetings and consultancy fees from AstraZeneca, Berlin-Chemie, Dompè, Edmond Pharma, GlaxoSmithKline, Neopharmed, Roche, Sanofi, and Zambon; and research grants from AstraZeneca, Chiesi Farmaceutici S.p.A., Edmond Pharma, GlaxoSmithKline, and Laboratori Guidotti S.p.A.